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a-mannosidosis	a-mannosidosis	[ "α-Mannosidosis", "a-Mannosidosis", "Lysosomal alpha-mannosidase", "MAN2B1", "Alpha-Mannosidosis" ]	Alpha-Mannosidosis	Can Ficicioglu, Karolina M Stepien	Summary The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. At least three clinical types have been suggested in untreated individuals: mild (clinically recognized after age ten years, with myopathy, slow progression, and absence of skeletal abnormalities); moderate (clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities); and severe (obvious progression leading to early death from primary central nervous system involvement or infection). Core features of untreated individuals generally include early childhood-onset non-progressive hearing loss, frequent infections due to immunodeficiency, rheumatologic symptoms (especially systemic lupus erythematosus), developmental delay / intellectual disability, low tone, ataxia, spastic paraplegia, psychiatric findings, bone disease (ranging from asymptomatic osteopenia to focal lytic or sclerotic lesions and osteonecrosis), gastrointestinal dysfunction (including diarrhea, swallowing issues / aspiration, and enlarged liver and spleen), poor growth, eye issues (including tapetoretinal degeneration and optic nerve atrophy), cardiac complications in adults, and pulmonary issues (including parenchymal lung disease). However, with the advent of enzyme replacement therapy, the natural history of this condition may change. Long-term velmanase alfa (VA) treatment outcomes are still being elucidated, but may include improvement in hearing, immunologic profile, and quality of life (improved clinical outcomes for muscle strength). Similarly, affected individuals who underwent hematopoietic stem cell transplantation (HSCT) experienced improvement in development (with preservation of previously learned skills), ability to participate in activities of daily living, stabilization or improvement in skeletal abnormalities, and improvement in hearing ability, although expressive speech and hearing deficiencies remained the most significant clinical problems after HSCT. The diagnosis of alpha-mannosidosis is established in a proband by identification of deficiency of lysosomal enzyme acid alpha-mannosidase (typically 5%-10% of normal activity) in leukocytes or other nucleated cells AND/OR by the identification of biallelic pathogenic variants in Alpha-mannosidosis 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 is possible if the pathogenic variants in the family are known. Prenatal testing for a pregnancy at increased risk is possible by assay of acid alpha-mannosidase enzymatic activity or molecular genetic testing once the pathogenic variants have been identified in the family.	Mild form (type 1): typically recognized after age ten years, with myopathy, slow progression, and no skeletal abnormalities Moderate form (type 2): typically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities Severe form (type 3): Obvious progression leading to early death from primary central nervous system involvement or infection For synonyms and outdated names, see For other genetic causes of these phenotypes, see • Mild form (type 1): typically recognized after age ten years, with myopathy, slow progression, and no skeletal abnormalities • Moderate form (type 2): typically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities • Severe form (type 3): Obvious progression leading to early death from primary central nervous system involvement or infection ## Diagnosis A proposed diagnostic algorithm for alpha-mannosidosis has been published, but clinical findings alone are not enough to establish the diagnosis because they overlap with clinical findings in other storage disorders [ Alpha-mannosidosis Macrocephaly with coarsening facial features. The facial features may progress to include: Prominent forehead Highly arched eyebrows Depressed nasal bridge Widely spaced teeth Macroglossia Prognathism Hearing loss (sensorineural or mixed) Frequent infections Developmental delay / intellectual disability Ataxia Dysostosis multiplex Focal lytic or sclerotic lesions Osteonecrosis Osteopenia Note: Histopathologic evaluation of peripheral blood lymphocytes is not required to make the diagnosis and absence of this finding does not preclude the diagnosis. The diagnosis of alpha-mannosidosis In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity. This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH. 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 alpha-mannosidosis, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of alpha-mannosidosis is not 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 Alpha-Mannosidosis 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 More than 130 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 few affected individuals were found to have a deletion of one or more exons [ • Macrocephaly with coarsening facial features. The facial features may progress to include: • Prominent forehead • Highly arched eyebrows • Depressed nasal bridge • Widely spaced teeth • Macroglossia • Prognathism • Prominent forehead • Highly arched eyebrows • Depressed nasal bridge • Widely spaced teeth • Macroglossia • Prognathism • Hearing loss (sensorineural or mixed) • Frequent infections • Developmental delay / intellectual disability • Ataxia • Prominent forehead • Highly arched eyebrows • Depressed nasal bridge • Widely spaced teeth • Macroglossia • Prognathism • Dysostosis multiplex • Focal lytic or sclerotic lesions • Osteonecrosis • Osteopenia • In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity. • This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH. • For an introduction to multigene panels click ## Suggestive Findings Alpha-mannosidosis Macrocephaly with coarsening facial features. The facial features may progress to include: Prominent forehead Highly arched eyebrows Depressed nasal bridge Widely spaced teeth Macroglossia Prognathism Hearing loss (sensorineural or mixed) Frequent infections Developmental delay / intellectual disability Ataxia Dysostosis multiplex Focal lytic or sclerotic lesions Osteonecrosis Osteopenia Note: Histopathologic evaluation of peripheral blood lymphocytes is not required to make the diagnosis and absence of this finding does not preclude the diagnosis. • Macrocephaly with coarsening facial features. The facial features may progress to include: • Prominent forehead • Highly arched eyebrows • Depressed nasal bridge • Widely spaced teeth • Macroglossia • Prognathism • Prominent forehead • Highly arched eyebrows • Depressed nasal bridge • Widely spaced teeth • Macroglossia • Prognathism • Hearing loss (sensorineural or mixed) • Frequent infections • Developmental delay / intellectual disability • Ataxia • Prominent forehead • Highly arched eyebrows • Depressed nasal bridge • Widely spaced teeth • Macroglossia • Prognathism • Dysostosis multiplex • Focal lytic or sclerotic lesions • Osteonecrosis • Osteopenia ## Establishing the Diagnosis The diagnosis of alpha-mannosidosis In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity. This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH. 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 alpha-mannosidosis, molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of alpha-mannosidosis is not 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 Alpha-Mannosidosis 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 More than 130 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 few affected individuals were found to have a deletion of one or more exons [ • In affected individuals, alpha-mannosidase enzyme activity in peripheral blood leukocytes is 5%-10% of normal activity. • This "residual" enzyme activity appears to represent mannosidase from other organelles or compartments (e.g., Golgi apparatus or cytosol), since they also show some activity at low pH. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of alpha-mannosidosis, 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 alpha-mannosidosis is not 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 Alpha-Mannosidosis 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 More than 130 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 few affected individuals were found to have a deletion of one or more exons [ ## Clinical Characteristics The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. Designating clinical types can be useful in prognosis and management. At least three clinical types (mild, moderate, and severe) have been suggested [ However, with the advent of ERT, the natural history of this condition may change. Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [ With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [ All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. The prognosis for individuals receiving VA treatment is not yet known. Post-transplant mannosidase activity was within normal limits in all eight affected individuals tested [ Developmental improvement in all affected individuals, though none have reached typical development levels for age; Preservation of previously learned skills in all affected individuals; Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently; Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [ Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved. HSCT has shown beneficial effects on the central nervous system pathology in individuals with alpha-mannosidosis, as follows [ Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals The morbidity and mortality rate associated with HSCT must be balanced against the benefits and is comparable to other non-malignant disases (88% survival rate). The benefits are greater in younger affected individuals before disease-related complications have developed. The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and, more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial [ The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described and can be seen in affected individuals post-HSCT as an immune-mediated mechanism [ Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [ Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections. Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80. The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests. Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty. In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [ In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one sib but not the other [ Follow-up observations have also suggested progressive impairment of motor function with age (see also A longitudinal study of a brother and sister indicated no progression over a period of 25 years [ Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy." Muscular hypotonia is common. Communicating hydrocephalus can occur at any age. Spastic paraplegia has also been described [ In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [ Genu valgum is common and contributes to the gait disturbance. Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [ Conventional radiographs may reveal: Thickened calvaria; Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; Hypoplasia of the inferior portions of the ilia; Mild expansion of the short tubular bones of the hands. Cranial MRI, including sagittal T Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations]. D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary. The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines. Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean. Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm. In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals. Narrow shoulders and convex chest were characteristic of the individuals in the study populations. Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population. A number of other ocular findings have also been reported in affected individuals, including hyperopia, myopia, strabismus, lenticular changes, superficial corneal opacities, and blurred discs. Fortunately, many ophthalmologic findings can be remedied (see Parenchymal lung disease was evident in three of five individuals with alpha-mannosidosis on CT [ In a literature review, No genotype-phenotype correlations are known. Alpha-mannosidosis may also be referred to as lysosomal alpha-d-mannosidase deficiency. General estimates for the prevalence of alpha-mannosidosis vary. The most recent study estimated the prevalence to be 1:1,000,000 [ A study from Australia reported a prevalence of 1:500,000 [ Studies from Norway reported six individuals in a population of 4.5 million [ A prevalence of 1:300,000 was reported in the Czech Republic [ The disease is not specific to individuals of any specific ancestry; individuals from all parts of the world have been described [ • Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [ • With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). • Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. • With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). • Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. • In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [ • All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; • It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. • All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; • It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. • The prognosis for individuals receiving VA treatment is not yet known. • With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). • Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. • All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; • It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. • Developmental improvement in all affected individuals, though none have reached typical development levels for age; • Preservation of previously learned skills in all affected individuals; • Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently; • Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [ • Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved. • Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals • Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals • Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [ • Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. • Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections. • Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80. • The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests. • Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty. • In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [ • Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy." • Muscular hypotonia is common. • Communicating hydrocephalus can occur at any age. • Spastic paraplegia has also been described [ • Genu valgum is common and contributes to the gait disturbance. • Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [ • Conventional radiographs may reveal: • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Cranial MRI, including sagittal T • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations]. • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary. • The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines. • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean. • Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm. • In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals. • Narrow shoulders and convex chest were characteristic of the individuals in the study populations. • Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population. • A study from Australia reported a prevalence of 1:500,000 [ • Studies from Norway reported six individuals in a population of 4.5 million [ • A prevalence of 1:300,000 was reported in the Czech Republic [ ## Clinical Description The clinical phenotype of alpha-mannosidosis varies considerably, with a wide spectrum of clinical findings and broad variability in individual presentation. Designating clinical types can be useful in prognosis and management. At least three clinical types (mild, moderate, and severe) have been suggested [ However, with the advent of ERT, the natural history of this condition may change. Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [ With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [ All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. The prognosis for individuals receiving VA treatment is not yet known. Post-transplant mannosidase activity was within normal limits in all eight affected individuals tested [ Developmental improvement in all affected individuals, though none have reached typical development levels for age; Preservation of previously learned skills in all affected individuals; Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently; Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [ Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved. HSCT has shown beneficial effects on the central nervous system pathology in individuals with alpha-mannosidosis, as follows [ Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals The morbidity and mortality rate associated with HSCT must be balanced against the benefits and is comparable to other non-malignant disases (88% survival rate). The benefits are greater in younger affected individuals before disease-related complications have developed. The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and, more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial [ The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described and can be seen in affected individuals post-HSCT as an immune-mediated mechanism [ Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [ Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections. Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80. The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests. Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty. In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [ In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one sib but not the other [ Follow-up observations have also suggested progressive impairment of motor function with age (see also A longitudinal study of a brother and sister indicated no progression over a period of 25 years [ Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy." Muscular hypotonia is common. Communicating hydrocephalus can occur at any age. Spastic paraplegia has also been described [ In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [ Genu valgum is common and contributes to the gait disturbance. Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [ Conventional radiographs may reveal: Thickened calvaria; Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; Hypoplasia of the inferior portions of the ilia; Mild expansion of the short tubular bones of the hands. Cranial MRI, including sagittal T Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations]. D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary. The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines. Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean. Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm. In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals. Narrow shoulders and convex chest were characteristic of the individuals in the study populations. Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population. A number of other ocular findings have also been reported in affected individuals, including hyperopia, myopia, strabismus, lenticular changes, superficial corneal opacities, and blurred discs. Fortunately, many ophthalmologic findings can be remedied (see Parenchymal lung disease was evident in three of five individuals with alpha-mannosidosis on CT [ In a literature review, • Treatment with VA reduced serum oligosaccharide levels and elevated serum immunoglobulin G levels in affected individuals [ • With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). • Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. • With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). • Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. • In a study of six individuals younger than age six years who received 1 mg/kg of VA intravenously (IV) once a week for at least 24 months [ • All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; • It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. • All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; • It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. • The prognosis for individuals receiving VA treatment is not yet known. • With up to 48 months of VA treatment, only 12% (4/33) of individuals with alpha-mannosidosis developed treatment-related anti-drug antibodies (ADAs). • Clinical outcomes assessed by the three-minute stair climb test (3MSCT) and the six-minute walk test (6MWT) were similar regardless of genotype or ADA status. • All children improved in one or more efficacy assessments of serum oligosaccharide concentrations (decreased), hearing, immunologic profile, and quality of life, suggesting a beneficial effect of early treatment; • It was suggested that long-term VA treatment has an acceptable safety profile, is well tolerated, and may provide potential benefits to individuals with alpha-mannosidosis younger than age six years. • Developmental improvement in all affected individuals, though none have reached typical development levels for age; • Preservation of previously learned skills in all affected individuals; • Ability to participate in activities of daily living, with one affected plerson reported to be able to live independently; • Stabilization or improvement in skeletal abnormalities, despite difficulties in quantifying changes in a growing skeleton [ • Improvement in hearing ability in some affected individuals, though hearing disability was not completely resolved. • Diminished white matter abnormalities, reduced demyelination, and decreased gliosis compared to untreated affected individuals • Normalization of abnormal signals on cerebral magnetic resonance spectroscopy (MRS) that are present in untreated affected individuals • Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [ • Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. • Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections. • Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80. • The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests. • Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty. • In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [ • Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy." • Muscular hypotonia is common. • Communicating hydrocephalus can occur at any age. • Spastic paraplegia has also been described [ • Genu valgum is common and contributes to the gait disturbance. • Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [ • Conventional radiographs may reveal: • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Cranial MRI, including sagittal T • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations]. • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary. • The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines. • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean. • Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm. • In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals. • Narrow shoulders and convex chest were characteristic of the individuals in the study populations. • Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population. ## Clinical Features in Treatment-Naïve Individuals The first decade of life is characterized by a high incidence of recurrent infections, including the common cold, pneumonia, gastroenteritis, and, more rarely, infections of the urinary tract. Serous otitis media is common and is usually not bacterial [ The infections diminish in the second and third decade, when ataxia and muscular weakness are more prominent. However, many individuals are able to ski, ride a bike, or play soccer up to the third decade. At any time, individuals risk setbacks in the form of acute necrotizing arthritis or acute hydrocephalus, both requiring surgery. Worsening of the myopathy has also been described and can be seen in affected individuals post-HSCT as an immune-mediated mechanism [ Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [ Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections. Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80. The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests. Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty. In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [ In a longitudinal study of a brother and sister over a period of 25 years, decreased speech capacity was seen in one sib but not the other [ Follow-up observations have also suggested progressive impairment of motor function with age (see also A longitudinal study of a brother and sister indicated no progression over a period of 25 years [ Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy." Muscular hypotonia is common. Communicating hydrocephalus can occur at any age. Spastic paraplegia has also been described [ In nine individuals with alpha-mannosidosis and psychiatric symptoms, a physical or psychological stressor preceded the rapid development of confusion, delusions, hallucinations, anxiety, and often depression, leading to severe loss of function usually lasting three to 12 weeks, and followed by a period of somnolence, asthenia, and prolonged sleep [ Genu valgum is common and contributes to the gait disturbance. Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [ Conventional radiographs may reveal: Thickened calvaria; Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; Hypoplasia of the inferior portions of the ilia; Mild expansion of the short tubular bones of the hands. Cranial MRI, including sagittal T Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations]. D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary. The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines. Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean. Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm. In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals. Narrow shoulders and convex chest were characteristic of the individuals in the study populations. Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population. A number of other ocular findings have also been reported in affected individuals, including hyperopia, myopia, strabismus, lenticular changes, superficial corneal opacities, and blurred discs. Fortunately, many ophthalmologic findings can be remedied (see Parenchymal lung disease was evident in three of five individuals with alpha-mannosidosis on CT [ In a literature review, • Individuals with alpha-mannosidosis appear to have decreased ability to produce specific antibodies in response to antigen presentation compared to typical individuals [ • Although infections generate compensatory mechanisms in leukocytes to improve phagocytosis, these mechanisms are inadequate because of disease-induced phagocyte-blocking agents in the serum or because of the lack of specific antibodies. • Leukocytes in affected individuals have a decreased capacity for intracellular killing, which may contribute to the often serious outcome of bacterial infections. • Individuals with adult onset typically have mild-to-moderate intellectual disability with an IQ of 60-80. • The measurement of total cognitive performance is very complex, and individuals tend to score better in nonverbal tests. • Some investigators suggest that intellectual disability progresses slowly, whereas others suggest that disease progression ceases after puberty. • In a few individuals undergoing neurodevelopmental assessment, general intelligence, language skills, visual-spatial skills, and overall adaptive abilities appeared stable over a period of two years [ • Ataxia is the most characteristic and specific motor disturbance and affected children are often noted to be "clumsy." • Muscular hypotonia is common. • Communicating hydrocephalus can occur at any age. • Spastic paraplegia has also been described [ • Genu valgum is common and contributes to the gait disturbance. • Hip pathology includes osteoarthritis, dysplasia of the hip, subarticular cystic changes in the femoral head and acetabulum with loss of joint space, and mild flattening of the femoral head. These findings point toward degenerative disease with possible ischemic changes [C Ficicioglu & K Stepien, personal observations] and may lead to hip joint destruction if not surgically corrected [ • Conventional radiographs may reveal: • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Cranial MRI, including sagittal T • Thickened calvaria; • Ovoid configuration, flattening, and hook-shaped deformity of the vertebral bodies; • Hypoplasia of the inferior portions of the ilia; • Mild expansion of the short tubular bones of the hands. • Untreated affected individuals often report increased frequency of bowel movements or diarrhea [C Ficicioglu & K Stepien, personal observations]. • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • Affected individuals may develop swallowing issues and experience aspiration; in some, a more permanent gastrostomy tube may be necessary. • The liver and spleen are often enlarged, especially in more severely affected individuals who have not been treated with ERT or HSCT; however, this has no clinical significance. Liver function is typically normal, and liver biopsy reveals the same vacuoles in hepatocytes as is described in several hematologic cell lines. • D-mannose has a laxative effect, and clinical evidence demonstrates that this significantly increases the gastrointestinal transit ratio in people with alpha-mannosidosis. • In one case of a 13-year-old boy, HSCT led to resolution of diarrhea and recurrent infections [ • Only four out of 45 individuals with alpha-mannosidosis had a height that was two standard deviations (SD) below the mean. • Mean height of adults with alpha-mannosidosis was 162 cm, with a SD of ±9 cm, encompassing a broad range from 145 cm to 179 cm. • In some affected individuals, shorter length of the lower extremities was noted with normal trunk length, which could contribute to the short stature observed in adolescent individuals. • Narrow shoulders and convex chest were characteristic of the individuals in the study populations. • Craniometric analysis showed that head circumference did not differ from typical unaffected peers but had a tendency to be slightly shorter and broader than in the general population. ## Genotype-Phenotype Correlations No genotype-phenotype correlations are known. ## Nomenclature Alpha-mannosidosis may also be referred to as lysosomal alpha-d-mannosidase deficiency. ## Prevalence General estimates for the prevalence of alpha-mannosidosis vary. The most recent study estimated the prevalence to be 1:1,000,000 [ A study from Australia reported a prevalence of 1:500,000 [ Studies from Norway reported six individuals in a population of 4.5 million [ A prevalence of 1:300,000 was reported in the Czech Republic [ The disease is not specific to individuals of any specific ancestry; individuals from all parts of the world have been described [ • A study from Australia reported a prevalence of 1:500,000 [ • Studies from Norway reported six individuals in a population of 4.5 million [ • A prevalence of 1:300,000 was reported in the Czech Republic [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Alpha-Mannosidosis Coarse facial features Thickened ribs Heart defects Hypertrichosis Coarse facial features Dysostosis multiplex ID Short stature Contractures Hypotonia Coarse facial features DD Frequent upper respiratory infections Joint stiffness Seizures Microcytic anemia Coarse facial features Dysostosis multiplex Short stature Failure to thrive Short stature Normal-to-mildly impaired cognitive development Coarse facial features Dysostosis multiplex ID Similar to MPS II DD Poor feeding Retinopathy AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked The mucopolysaccharidoses are inherited in an autosomal recessive manner with the exception of mucopolysaccharidosis type II, which is associated with pathogenic variants in • Coarse facial features • Thickened ribs • Heart defects • Hypertrichosis • Coarse facial features • Dysostosis multiplex • ID • Short stature • Contractures • Hypotonia • Coarse facial features • DD • Frequent upper respiratory infections • Joint stiffness • Seizures • Microcytic anemia • Coarse facial features • Dysostosis multiplex • Short stature • Failure to thrive • Short stature • Normal-to-mildly impaired cognitive development • Coarse facial features • Dysostosis multiplex • ID • Similar to MPS II • DD • Poor feeding • Retinopathy ## Management No clinical practice guidelines for alpha-mannosidosis have been published. To establish the extent of disease and needs in an individual diagnosed with alpha-mannosidosis, the evaluations summarized in Alpha-Mannosidosis: Recommended Evaluations Following Initial Diagnosis To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies Consider referral to rheumatologist. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Assess for asthenia Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present. Assess for signs/symptoms of ataxia & gait abnormalities. Gross motor & fine motor skills Muscle pain, joint aches, reduced range of motion, & bone pain 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. Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes. Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response. To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy Consider referral to cardiologist. Community or Social work involvement for parental support Home nursing referral Based on ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLE = systemic lupus erythematosus Such as change in social, domestic, or school- or work-related activities or in ability to walk distances Including headache, increasing gait ataxia, nausea, and/or papilledema Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for alpha-mannosidosis. Velmanase alfa (Lamzede Alpha-Mannosidosis: Targeted Treatment Improvement in both biochemical & functional parameters have been reported. Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis. ERT = enzyme replacement therapy For individuals who weigh less than 49 kg, IV infusion is typically given over a minimum of 60 minutes; for those who weigh 50 kg or more, infusion rate is typically 25 mL/hour. The key points are: In a study by Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [ While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [ The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [ HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable. Note: Most affected individuals are clinically normal at birth. Since alpha-mannosidosis can be treated with ERT or HSCT, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology [ 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 Alpha-Mannosidosis: Treatment of Manifestations Early antibiotics for bacterial infections Bacterial & viral infections must be treated w/vigilance. This typically includes consideration of a ventriculocaval shunt. Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity. Hydrotherapy helps to avoid strain on joints. Special shoes may help w/ankle & foot support. Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard. Standard treatment per gastroenterologist &/or endocrinologist Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis. Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices). More complex findings (e.g., retinal dystrophy) may require further input from subspecialists. 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 OT = occupational therapy; PT = physical therapy Regular cardiopulmonary evaluations and a careful airway evaluation prior to any surgical intervention under general anesthesia is recommended. Authors, personal observations 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about confusion, delusions, hallucinations, anxiety, and depression 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 Alpha-Mannosidosis: Recommended Surveillance Assess for new manifestations such ataxia & gait abnormalities. Evaluate for asthenia Every 6-12 mos in childhood Annually in adults Consider DXA bone densitometry scan Radiographs of hips/spine may be indicated. Monitoring for diarrhea Assessment of liver & spleen size through physical exam 3MSCT = three-minute stair climb test; 6MWT = six-minute walk test; BMI = body mass index; DXA = dual-energy x-ray absorptiometry; ERT = enzyme replacement therapy; ESR = erythrocyte sedimentation rate; HSCT = hematopoietic stem cell transplant; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia It is unclear how many of the medical complications will improve or resolve with targeted ERT/HSCT. In those over age two years; in those younger than age two years, assessment of weight for length may be more appropriate. For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ Such as change in social, domestic, or school- or work-related activities or in ability to walk distances Including headache, increasing gait ataxia, nausea, and/or papilledema Consider plain radiographs of the head, knees (AP view), spine (lateral view), and any symptomatic sites. Typically done after age four years Testing of all at-risk sibs of any age (including prenatal diagnosis) is warranted to allow for early diagnosis and targeted treatment of alpha-mannosidosis (see Molecular genetic testing if the pathogenic variants in the family are known; Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known. See Search Because of the limited number of affected individuals with psychiatric symptoms, no conclusion about the benefit of various psychotropic drugs can be made at this time. However, to date, 5-15 mg of olanzapine at bedtime has been used in several affected individuals with some success [D Malm, personal observations]. • To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies • Consider referral to rheumatologist. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Assess for asthenia • Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present. • Assess for signs/symptoms of ataxia & gait abnormalities. • Gross motor & fine motor skills • Muscle pain, joint aches, reduced range of motion, & bone pain • 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. • Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes. • Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response. • To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy • Consider referral to cardiologist. • Community or • Social work involvement for parental support • Home nursing referral • Improvement in both biochemical & functional parameters have been reported. • Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis. • In a study by • Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [ • While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [ • The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [ • HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable. • Early antibiotics for bacterial infections • Bacterial & viral infections must be treated w/vigilance. • This typically includes consideration of a ventriculocaval shunt. • Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity. • Hydrotherapy helps to avoid strain on joints. • Special shoes may help w/ankle & foot support. • Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard. • Standard treatment per gastroenterologist &/or endocrinologist • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. • Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis. • Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices). • More complex findings (e.g., retinal dystrophy) may require further input from subspecialists. • 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ • Assess for new manifestations such ataxia & gait abnormalities. • Evaluate for asthenia • Every 6-12 mos in childhood • Annually in adults • Consider DXA bone densitometry scan • Radiographs of hips/spine may be indicated. • Monitoring for diarrhea • Assessment of liver & spleen size through physical exam • Molecular genetic testing if the pathogenic variants in the family are known; • Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with alpha-mannosidosis, the evaluations summarized in Alpha-Mannosidosis: Recommended Evaluations Following Initial Diagnosis To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies Consider referral to rheumatologist. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Assess for asthenia Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present. Assess for signs/symptoms of ataxia & gait abnormalities. Gross motor & fine motor skills Muscle pain, joint aches, reduced range of motion, & bone pain 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. Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes. Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response. To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy Consider referral to cardiologist. Community or Social work involvement for parental support Home nursing referral Based on ADL = activities of daily living; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLE = systemic lupus erythematosus Such as change in social, domestic, or school- or work-related activities or in ability to walk distances Including headache, increasing gait ataxia, nausea, and/or papilledema Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl immunologic testing such as anti-nuclear antibodies & anti-double-stranded-DNA antibodies • Consider referral to rheumatologist. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Assess for asthenia • Consider head CT to assess size of ventricles & shape/size of cerebellum, particularly if signs/symptoms of hydrocephalus are present. • Assess for signs/symptoms of ataxia & gait abnormalities. • Gross motor & fine motor skills • Muscle pain, joint aches, reduced range of motion, & bone pain • 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. • Ultrasound is often done, although abdominal MRI may be more informative to calculate organ volumes. • Although organomegaly typically does not cause clinical symptoms, this finding can be used as a clinical marker to assess treatment response. • To assess for aortic or mitral stenosis/regurgitation &/or cardiomyopathy • Consider referral to cardiologist. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for alpha-mannosidosis. Velmanase alfa (Lamzede Alpha-Mannosidosis: Targeted Treatment Improvement in both biochemical & functional parameters have been reported. Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis. ERT = enzyme replacement therapy For individuals who weigh less than 49 kg, IV infusion is typically given over a minimum of 60 minutes; for those who weigh 50 kg or more, infusion rate is typically 25 mL/hour. The key points are: In a study by Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [ While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [ The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [ HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable. Note: Most affected individuals are clinically normal at birth. Since alpha-mannosidosis can be treated with ERT or HSCT, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology [ 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 Alpha-Mannosidosis: Treatment of Manifestations Early antibiotics for bacterial infections Bacterial & viral infections must be treated w/vigilance. This typically includes consideration of a ventriculocaval shunt. Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity. Hydrotherapy helps to avoid strain on joints. Special shoes may help w/ankle & foot support. Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard. Standard treatment per gastroenterologist &/or endocrinologist Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis. Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices). More complex findings (e.g., retinal dystrophy) may require further input from subspecialists. 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 OT = occupational therapy; PT = physical therapy Regular cardiopulmonary evaluations and a careful airway evaluation prior to any surgical intervention under general anesthesia is recommended. Authors, personal observations 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about confusion, delusions, hallucinations, anxiety, and depression can be addressed by a pediatric psychiatrist. • Improvement in both biochemical & functional parameters have been reported. • Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis. • In a study by • Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [ • While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [ • The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [ • HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable. • Early antibiotics for bacterial infections • Bacterial & viral infections must be treated w/vigilance. • This typically includes consideration of a ventriculocaval shunt. • Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity. • Hydrotherapy helps to avoid strain on joints. • Special shoes may help w/ankle & foot support. • Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard. • Standard treatment per gastroenterologist &/or endocrinologist • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. • Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis. • Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices). • More complex findings (e.g., retinal dystrophy) may require further input from subspecialists. • 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ ## Targeted Therapies Velmanase alfa (Lamzede Alpha-Mannosidosis: Targeted Treatment Improvement in both biochemical & functional parameters have been reported. Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis. ERT = enzyme replacement therapy For individuals who weigh less than 49 kg, IV infusion is typically given over a minimum of 60 minutes; for those who weigh 50 kg or more, infusion rate is typically 25 mL/hour. The key points are: In a study by Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [ While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [ The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [ HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable. Note: Most affected individuals are clinically normal at birth. Since alpha-mannosidosis can be treated with ERT or HSCT, there is a pressing need for newborn screening to identify affected individuals early, before the onset of severe irreversible pathology [ • Improvement in both biochemical & functional parameters have been reported. • Velmanase alfa has been very well tolerated & is now regarded as standard treatment for alpha-mannosidosis. • In a study by • Two affected individuals died within five months post-HSCT, likely due to transplant-related complications [ • While normal development was not achieved, affected individuals showed developmental progress after HSCT, with some improvements in hearing ability [ • The benefits of HSCT are greater in younger individuals before the disease has significantly progressed, as transplant-related risks increase with age [ • HSCT can halt the progressive cognitive decline in individuals with alpha-mannosidosis when performed early, though the outcomes have been variable. ## 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 Alpha-Mannosidosis: Treatment of Manifestations Early antibiotics for bacterial infections Bacterial & viral infections must be treated w/vigilance. This typically includes consideration of a ventriculocaval shunt. Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity. Hydrotherapy helps to avoid strain on joints. Special shoes may help w/ankle & foot support. Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard. Standard treatment per gastroenterologist &/or endocrinologist Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis. Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices). More complex findings (e.g., retinal dystrophy) may require further input from subspecialists. 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 OT = occupational therapy; PT = physical therapy Regular cardiopulmonary evaluations and a careful airway evaluation prior to any surgical intervention under general anesthesia is recommended. Authors, personal observations 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about confusion, delusions, hallucinations, anxiety, and depression can be addressed by a pediatric psychiatrist. • Early antibiotics for bacterial infections • Bacterial & viral infections must be treated w/vigilance. • This typically includes consideration of a ventriculocaval shunt. • Ventriculoperitoneal shunts may cause ascites because of reduced absorptive capacity of peritoneal cavity. • Hydrotherapy helps to avoid strain on joints. • Special shoes may help w/ankle & foot support. • Consider need for mobility devices (incl wheelchair, if needed) & disability parking placard. • Standard treatment per gastroenterologist &/or endocrinologist • Feeding therapy; gastrostomy tube placement may be required for persistent feeding issues. • Although lens replacement for cataract is a standard procedure, corneal transplantation can be difficult in persons w/alpha-mannosidosis. • Postoperative complications incl astigmatism (which may be correctable w/repeat surgery, laser treatment, or optical devices). • More complex findings (e.g., retinal dystrophy) may require further input from subspecialists. • 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ ## 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ • 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 affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ ## Consultation with a developmental pediatrician may be helpful in guiding parents/caregivers through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about confusion, delusions, hallucinations, anxiety, and depression 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 Alpha-Mannosidosis: Recommended Surveillance Assess for new manifestations such ataxia & gait abnormalities. Evaluate for asthenia Every 6-12 mos in childhood Annually in adults Consider DXA bone densitometry scan Radiographs of hips/spine may be indicated. Monitoring for diarrhea Assessment of liver & spleen size through physical exam 3MSCT = three-minute stair climb test; 6MWT = six-minute walk test; BMI = body mass index; DXA = dual-energy x-ray absorptiometry; ERT = enzyme replacement therapy; ESR = erythrocyte sedimentation rate; HSCT = hematopoietic stem cell transplant; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia It is unclear how many of the medical complications will improve or resolve with targeted ERT/HSCT. In those over age two years; in those younger than age two years, assessment of weight for length may be more appropriate. For affected individuals on ERT, a Bruininks-Oseretsky test can be used to assess motor proficiency in children and young adults [ Such as change in social, domestic, or school- or work-related activities or in ability to walk distances Including headache, increasing gait ataxia, nausea, and/or papilledema Consider plain radiographs of the head, knees (AP view), spine (lateral view), and any symptomatic sites. Typically done after age four years • Assess for new manifestations such ataxia & gait abnormalities. • Evaluate for asthenia • Every 6-12 mos in childhood • Annually in adults • Consider DXA bone densitometry scan • Radiographs of hips/spine may be indicated. • Monitoring for diarrhea • Assessment of liver & spleen size through physical exam ## Evaluation of Relatives at Risk Testing of all at-risk sibs of any age (including prenatal diagnosis) is warranted to allow for early diagnosis and targeted treatment of alpha-mannosidosis (see Molecular genetic testing if the pathogenic variants in the family are known; Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known. See • Molecular genetic testing if the pathogenic variants in the family are known; • Assay of acid alpha-mannosidase enzyme activity in leukocytes or other nucleated cells if the pathogenic variants in the family are not known. ## Therapies Under Investigation Search ## Other Because of the limited number of affected individuals with psychiatric symptoms, no conclusion about the benefit of various psychotropic drugs can be made at this time. However, to date, 5-15 mg of olanzapine at bedtime has been used in several affected individuals with some success [D Malm, personal observations]. ## Genetic Counseling Alpha-mannosidosis 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 Affected sibs (with identical pathogenic variants) may present with different phenotypes [ 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. It is appropriate to offer molecular genetic testing of Note: Given the wide variability in phenotype and lack of genotype-phenotype correlation, severity of disease cannot be predicted based on the results of molecular genetic or biochemical testing. 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. • 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 • Affected sibs (with identical pathogenic variants) may present with different phenotypes [ • 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. • It is appropriate to offer molecular genetic testing of ## Mode of Inheritance Alpha-mannosidosis 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 Affected sibs (with identical pathogenic variants) may present with different phenotypes [ 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 • Affected sibs (with identical pathogenic variants) may present with different phenotypes [ • 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. It is appropriate to offer molecular genetic testing 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, are carriers, or are at risk of being carriers. • It is appropriate to offer molecular genetic testing of ## Prenatal Testing and Preimplantation Genetic Testing Note: Given the wide variability in phenotype and lack of genotype-phenotype correlation, severity of disease cannot be predicted based on the results of molecular genetic or biochemical testing. 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 United Kingdom • • • • United Kingdom • • • ## Molecular Genetics Alpha-Mannosidosis: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alpha-Mannosidosis ( Alpha-mannosidosis belongs to a group of disorders called glycoproteinoses, which are caused by lack of one of the many enzymes required for the sequential degradation of asparagine-linked oligosaccharides from glycoproteins in the lysosomes. During normal turnover and catabolism, glycoproteins are digested by proteinases and glycosidases within the lysosomes. These enzymes degrade glycoproteins into fragments small enough to be excreted or transported to the cytosol for reuse. Lack of any one of these enzymes, including alpha-mannosidase, will compromise the degradation pathway as a whole, resulting in accumulation of oligosaccharides or glycopeptides in the lysosomes. Accumulation of storage material is thought to impair lysosomal function and thereby harm cellular functions such as vesicle maturation, endocytosis, exocytosis, and calcium homeostasis [ Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Alpha-mannosidosis belongs to a group of disorders called glycoproteinoses, which are caused by lack of one of the many enzymes required for the sequential degradation of asparagine-linked oligosaccharides from glycoproteins in the lysosomes. During normal turnover and catabolism, glycoproteins are digested by proteinases and glycosidases within the lysosomes. These enzymes degrade glycoproteins into fragments small enough to be excreted or transported to the cytosol for reuse. Lack of any one of these enzymes, including alpha-mannosidase, will compromise the degradation pathway as a whole, resulting in accumulation of oligosaccharides or glycopeptides in the lysosomes. Accumulation of storage material is thought to impair lysosomal function and thereby harm cellular functions such as vesicle maturation, endocytosis, exocytosis, and calcium homeostasis [ Variants listed in the table have been provided by the authors. ## Chapter Notes Can Ficicioglu, MD, PhD (2024-present)Dag Malm, MD, PhD; Tromsø Center of Internal Medicine (2001-2024)Øivind Nilssen, PhD; University of Tromsø (2001-2024)Karolina M Stepien, MD, PhD (2024-present) 13 June 2024 (ma) Comprehensive update posted live 21 February 2019 (sw) Comprehensive update posted live 3 May 2012 (me) Comprehensive update posted live 26 August 2008 (cg) Comprehensive update posted live 25 January 2006 (me) Comprehensive update posted live 3 December 2003 (me) Comprehensive update posted live 11 October 2001 (me) Review posted live April 2001 (dm) Original submission • 13 June 2024 (ma) Comprehensive update posted live • 21 February 2019 (sw) Comprehensive update posted live • 3 May 2012 (me) Comprehensive update posted live • 26 August 2008 (cg) Comprehensive update posted live • 25 January 2006 (me) Comprehensive update posted live • 3 December 2003 (me) Comprehensive update posted live • 11 October 2001 (me) Review posted live • April 2001 (dm) Original submission ## Author History Can Ficicioglu, MD, PhD (2024-present)Dag Malm, MD, PhD; Tromsø Center of Internal Medicine (2001-2024)Øivind Nilssen, PhD; University of Tromsø (2001-2024)Karolina M Stepien, MD, PhD (2024-present) ## Revision History 13 June 2024 (ma) Comprehensive update posted live 21 February 2019 (sw) Comprehensive update posted live 3 May 2012 (me) Comprehensive update posted live 26 August 2008 (cg) Comprehensive update posted live 25 January 2006 (me) Comprehensive update posted live 3 December 2003 (me) Comprehensive update posted live 11 October 2001 (me) Review posted live April 2001 (dm) Original submission • 13 June 2024 (ma) Comprehensive update posted live • 21 February 2019 (sw) Comprehensive update posted live • 3 May 2012 (me) Comprehensive update posted live • 26 August 2008 (cg) Comprehensive update posted live • 25 January 2006 (me) Comprehensive update posted live • 3 December 2003 (me) Comprehensive update posted live • 11 October 2001 (me) Review posted live • April 2001 (dm) Original submission ## Key Sections in This ## References Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [ Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [ • Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [ • Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [ ## Published Guidelines / Consensus Statements Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [ Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [ • Guffon N, Tylki-Szymanska A, Borgwardt L, Lund AM, Gil-Campos M, Parini R, Hennermann JB. Recognition of alpha-mannosidosis in paediatric and adult patients: presentation of a diagnostic algorithm from an international working group. Mol Genet Metab. 2019;126:470-4. [ • Nilssen Ø, Stensland HM, Malm D. Clinical utility gene card for: α-mannosidosis. Eur J Hum Genet. 2011;19. [ ## Literature Cited	[]	11/10/2001	13/6/2024	18/7/2019	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
a-thal	a-thal	[ "Hemoglobin Bart Hydrops Fetalis (Hb Bart) Syndrome", "Hemoglobin H (HbH) Disease", "a-Thalassemia Trait/Carrier", "a-Thalassemia Silent Carrier", "Hemoglobin subunit alpha", "Hemoglobin subunit zeta", "HBA1", "HBA2", "HBZ", "Alpha-Thalassemia" ]	Alpha-Thalassemia	Hannah Tamary, Orly Dgany	Summary Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome (caused by deletion/inactivation of all four alpha globin [α-globin] alleles; --/--), and hemoglobin H (HbH) disease (most frequently caused by deletion/inactivation of three α-globin alleles; --/-α). The diagnosis of Hb Bart syndrome is established in a fetus with characteristic hematologic and hemoglobin (Hb) findings and molecular genetic testing that identifies biallelic pathogenic variants in both The diagnosis of HbH disease is established in a proband with hematologic and Hb findings and molecular genetic testing that identifies biallelic pathogenic variants in Alpha-thalassemia is usually inherited in an autosomal recessive manner.	For synonyms and outdated names see In descending order of severity ## Diagnosis Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb bart) syndrome (deletion/inactivation of all four alpha globin [α-globin] alleles; --/--), and hemoglobin H (HbH) disease (most frequently caused by deletion/inactivation of three α-globin alleles; --/-α) (see An at-risk fetus with increased nuchal thickness, thickened placenta, increased cerebral media artery velocity, and increased cardiothoracic ratio on ultrasonography examination at 13-14 weeks' gestation A fetus with generalized edema, ascites, and pleural and pericardial effusions on ultrasonography examination at 22-28 weeks' gestation Mild jaundice Hepatosplenomegaly Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) Note: (1) Newborn screening for sickle cell disease offered by several states/countries may detect Hb Bart in the newborn with α-thalassemia. (2) Reference ranges may vary among laboratories performing newborn screening. (3) Low concentrations of Hb Bart (1%-8%) are indicative of the carrier states, and while this finding usually does not indicate a need for further evaluation of the newborn, The diagnosis of Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See Reticulocytosis. Variable; may be >60% Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells The diagnosis of Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See Moderate reticulocytosis (3%-6%) Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) Red blood cell supravital stain showing HbH inclusions (β Red Blood Cell Indices in Individuals with Hb Bart Syndrome and HbH Disease Reference ranges may vary among laboratories. If available, qualitative and quantitative hemoglobin (Hb) analysis by weak-cation high-performance liquid chromatography identifies the amount and type of Hb present. The Hb pattern in α-thalassemia varies by α-thalassemia type (see Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ Hemoglobin H (HbH). Four beta globin chains (β Hemoglobin A Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ Hemoglobin Patterns in Alpha-Thalassemia Reference ranges may vary among laboratories. Deletion or inactivation of all four α-globin chains makes it impossible to assemble HbF and HbA. Fetal blood contains mainly Hb Bart (γ Deletion or inactivation of three α-globin chains Note: Hematologic testing to identify α-thalassemia trait and α-thalassemia silent carrier status is addressed in Molecular testing approaches can include Note: Multiple ligation-dependent probe amplification (MLPA) assay specifically designed for the α-globin locus has been described. Common deletions of both α-globin genes include the following: Southeast Asian deletion (-- Filipino deletion (-- Mediterranean deletion (-- Note: (1) These common deletions are typically founder variants (see Common deletions of a single α-globin gene include: 3.7-kb deletion (-α 4.2-kb deletion (-α Note: In addition to these two common deletions, other deletions involving a single α-globin gene have been reported. Note: "Non-deletion" or "trait" Molecular Genetic Testing Used in Alpha-Thalassemia 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 Methods used to detect common, rare, or previously undescribed deletions/duplications within the α-globin gene cluster and regulatory elements may include Gap PCR, MLPA (also known as break-point PCR), chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays, and next-generation sequencing (NGS) for analysis of deletion breakpoints [ See • An at-risk fetus with increased nuchal thickness, thickened placenta, increased cerebral media artery velocity, and increased cardiothoracic ratio on ultrasonography examination at 13-14 weeks' gestation • A fetus with generalized edema, ascites, and pleural and pericardial effusions on ultrasonography examination at 22-28 weeks' gestation • • Mild jaundice • Hepatosplenomegaly • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) • Mild jaundice • Hepatosplenomegaly • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) • Note: (1) Newborn screening for sickle cell disease offered by several states/countries may detect Hb Bart in the newborn with α-thalassemia. (2) Reference ranges may vary among laboratories performing newborn screening. (3) Low concentrations of Hb Bart (1%-8%) are indicative of the carrier states, and while this finding usually does not indicate a need for further evaluation of the newborn, • Mild jaundice • Hepatosplenomegaly • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) • • Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See • Reticulocytosis. Variable; may be >60% • Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells • Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See • Reticulocytosis. Variable; may be >60% • Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells • Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See • Reticulocytosis. Variable; may be >60% • Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells • • Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See • Moderate reticulocytosis (3%-6%) • Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) • Red blood cell supravital stain showing HbH inclusions (β • Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See • Moderate reticulocytosis (3%-6%) • Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) • Red blood cell supravital stain showing HbH inclusions (β • Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See • Moderate reticulocytosis (3%-6%) • Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) • Red blood cell supravital stain showing HbH inclusions (β • Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α • Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α • Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ • Hemoglobin H (HbH). Four beta globin chains (β • Hemoglobin A • Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ • Common deletions of both α-globin genes include the following: • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • Note: (1) These common deletions are typically founder variants (see • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • Common deletions of a single α-globin gene include: • 3.7-kb deletion (-α • 4.2-kb deletion (-α • Note: In addition to these two common deletions, other deletions involving a single α-globin gene have been reported. • 3.7-kb deletion (-α • 4.2-kb deletion (-α • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • 3.7-kb deletion (-α • 4.2-kb deletion (-α ## Suggestive Findings Alpha-thalassemia (α-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb bart) syndrome (deletion/inactivation of all four alpha globin [α-globin] alleles; --/--), and hemoglobin H (HbH) disease (most frequently caused by deletion/inactivation of three α-globin alleles; --/-α) (see An at-risk fetus with increased nuchal thickness, thickened placenta, increased cerebral media artery velocity, and increased cardiothoracic ratio on ultrasonography examination at 13-14 weeks' gestation A fetus with generalized edema, ascites, and pleural and pericardial effusions on ultrasonography examination at 22-28 weeks' gestation Mild jaundice Hepatosplenomegaly Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) Note: (1) Newborn screening for sickle cell disease offered by several states/countries may detect Hb Bart in the newborn with α-thalassemia. (2) Reference ranges may vary among laboratories performing newborn screening. (3) Low concentrations of Hb Bart (1%-8%) are indicative of the carrier states, and while this finding usually does not indicate a need for further evaluation of the newborn, • An at-risk fetus with increased nuchal thickness, thickened placenta, increased cerebral media artery velocity, and increased cardiothoracic ratio on ultrasonography examination at 13-14 weeks' gestation • A fetus with generalized edema, ascites, and pleural and pericardial effusions on ultrasonography examination at 22-28 weeks' gestation • • Mild jaundice • Hepatosplenomegaly • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) • Mild jaundice • Hepatosplenomegaly • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) • Note: (1) Newborn screening for sickle cell disease offered by several states/countries may detect Hb Bart in the newborn with α-thalassemia. (2) Reference ranges may vary among laboratories performing newborn screening. (3) Low concentrations of Hb Bart (1%-8%) are indicative of the carrier states, and while this finding usually does not indicate a need for further evaluation of the newborn, • Mild jaundice • Hepatosplenomegaly • Mild thalassemia-like bone changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) ## Establishing the Diagnosis The diagnosis of Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See Reticulocytosis. Variable; may be >60% Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells The diagnosis of Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See Moderate reticulocytosis (3%-6%) Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) Red blood cell supravital stain showing HbH inclusions (β Red Blood Cell Indices in Individuals with Hb Bart Syndrome and HbH Disease Reference ranges may vary among laboratories. If available, qualitative and quantitative hemoglobin (Hb) analysis by weak-cation high-performance liquid chromatography identifies the amount and type of Hb present. The Hb pattern in α-thalassemia varies by α-thalassemia type (see Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ Hemoglobin H (HbH). Four beta globin chains (β Hemoglobin A Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ Hemoglobin Patterns in Alpha-Thalassemia Reference ranges may vary among laboratories. Deletion or inactivation of all four α-globin chains makes it impossible to assemble HbF and HbA. Fetal blood contains mainly Hb Bart (γ Deletion or inactivation of three α-globin chains Note: Hematologic testing to identify α-thalassemia trait and α-thalassemia silent carrier status is addressed in Molecular testing approaches can include Note: Multiple ligation-dependent probe amplification (MLPA) assay specifically designed for the α-globin locus has been described. Common deletions of both α-globin genes include the following: Southeast Asian deletion (-- Filipino deletion (-- Mediterranean deletion (-- Note: (1) These common deletions are typically founder variants (see Common deletions of a single α-globin gene include: 3.7-kb deletion (-α 4.2-kb deletion (-α Note: In addition to these two common deletions, other deletions involving a single α-globin gene have been reported. Note: "Non-deletion" or "trait" Molecular Genetic Testing Used in Alpha-Thalassemia 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 Methods used to detect common, rare, or previously undescribed deletions/duplications within the α-globin gene cluster and regulatory elements may include Gap PCR, MLPA (also known as break-point PCR), chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays, and next-generation sequencing (NGS) for analysis of deletion breakpoints [ See • • Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See • Reticulocytosis. Variable; may be >60% • Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells • Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See • Reticulocytosis. Variable; may be >60% • Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells • Red blood cell indices. Severe macrocytic hypochromic anemia, in the absence of ABO or Rh blood group incompatibility (See • Reticulocytosis. Variable; may be >60% • Peripheral blood smear with large, hypochromic red cells, severe anisopoikilocytosis, and numerous nucleated red cells • • Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See • Moderate reticulocytosis (3%-6%) • Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) • Red blood cell supravital stain showing HbH inclusions (β • Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See • Moderate reticulocytosis (3%-6%) • Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) • Red blood cell supravital stain showing HbH inclusions (β • Red blood cell indices. Mild-to-moderate (rarely severe) microcytic hypochromic hemolytic anemia (See • Moderate reticulocytosis (3%-6%) • Peripheral blood smear with anisopoikilocytosis, and very rarely nucleated red blood cells (i.e., erythroblasts) • Red blood cell supravital stain showing HbH inclusions (β • Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α • Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α • Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ • Hemoglobin H (HbH). Four beta globin chains (β • Hemoglobin A • Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ • Common deletions of both α-globin genes include the following: • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • Note: (1) These common deletions are typically founder variants (see • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • Common deletions of a single α-globin gene include: • 3.7-kb deletion (-α • 4.2-kb deletion (-α • Note: In addition to these two common deletions, other deletions involving a single α-globin gene have been reported. • 3.7-kb deletion (-α • 4.2-kb deletion (-α • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • 3.7-kb deletion (-α • 4.2-kb deletion (-α ## Hematologic Findings Red Blood Cell Indices in Individuals with Hb Bart Syndrome and HbH Disease Reference ranges may vary among laboratories. ## Hemoglobin Analysis If available, qualitative and quantitative hemoglobin (Hb) analysis by weak-cation high-performance liquid chromatography identifies the amount and type of Hb present. The Hb pattern in α-thalassemia varies by α-thalassemia type (see Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ Hemoglobin H (HbH). Four beta globin chains (β Hemoglobin A Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ Hemoglobin Patterns in Alpha-Thalassemia Reference ranges may vary among laboratories. Deletion or inactivation of all four α-globin chains makes it impossible to assemble HbF and HbA. Fetal blood contains mainly Hb Bart (γ Deletion or inactivation of three α-globin chains Note: Hematologic testing to identify α-thalassemia trait and α-thalassemia silent carrier status is addressed in • Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α • Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α • Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ • Hemoglobin H (HbH). Four beta globin chains (β • Hemoglobin A • Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ ## Molecular Genetic Testing Molecular testing approaches can include Note: Multiple ligation-dependent probe amplification (MLPA) assay specifically designed for the α-globin locus has been described. Common deletions of both α-globin genes include the following: Southeast Asian deletion (-- Filipino deletion (-- Mediterranean deletion (-- Note: (1) These common deletions are typically founder variants (see Common deletions of a single α-globin gene include: 3.7-kb deletion (-α 4.2-kb deletion (-α Note: In addition to these two common deletions, other deletions involving a single α-globin gene have been reported. Note: "Non-deletion" or "trait" Molecular Genetic Testing Used in Alpha-Thalassemia 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 Methods used to detect common, rare, or previously undescribed deletions/duplications within the α-globin gene cluster and regulatory elements may include Gap PCR, MLPA (also known as break-point PCR), chromosomal microarray analysis (CMA) using oligonucleotide or SNP arrays, and next-generation sequencing (NGS) for analysis of deletion breakpoints [ See • Common deletions of both α-globin genes include the following: • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • Note: (1) These common deletions are typically founder variants (see • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • Common deletions of a single α-globin gene include: • 3.7-kb deletion (-α • 4.2-kb deletion (-α • Note: In addition to these two common deletions, other deletions involving a single α-globin gene have been reported. • 3.7-kb deletion (-α • 4.2-kb deletion (-α • Southeast Asian deletion (-- • Filipino deletion (-- • Mediterranean deletion (-- • 3.7-kb deletion (-α • 4.2-kb deletion (-α ## Clinical Characteristics The clinically significant phenotypes of alpha-thalassemia (α-thalassemia) are hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease. The severity of the α-thalassemia syndromes depends on the extent of the alpha globin (α-globin) chain defect (see The main clinical features are generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia. Notably, red cells with Hb Bart have an extremely high oxygen affinity and are incapable of effective oxygen delivery. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common. Retardation in brain growth, hydrocephalus, cardiovascular deformities, and urogenital defects have been reported. A very small number of newborns survive following intrauterine transfusions and repeated frequent transfusions after birth. Maternal complications during pregnancy commonly include preeclampsia, polyhydramnios or oligohydramnios, antepartum hemorrhage, and premature delivery. The majority of individuals have enlargement of the spleen and less commonly of the liver, mild jaundice, and sometimes mild-to-moderate thalassemia-like skeletal changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) that affect the facial features. Leg ulcers are rare. Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to oxidant drugs and infections. Rarely, infection with parvovirus B19 can cause an aplastic crisis. While the majority of individuals with HbH disease have minor disability, some are severely affected, requiring regular blood transfusions; in very rare cases hydrops fetalis is present [ Significant iron overload is uncommon but has been reported in older individuals, usually resulting from repeated blood transfusions or increased iron absorption [ The phenotype of the α-thalassemia syndromes depends on the degree of α-globin chain deficiency relative to beta globin chain production. The correlation between α-thalassemia pathogenic variants, α-globin mRNA levels, α-globin synthesis, and clinical manifestations of α-thalassemia is well documented. Most often caused by large deletions on both chromosomes (--/--) Rarely, an individual with Hb Bart syndrome will have a non-deletion variant (--/α Most often caused by a large deletion on one chromosome with a single α-globin allele deletion (--/-α) or other non-deletion inactivating variant (--/α Individuals homozygous for Individuals who are homozygous or compound heterozygous for highly unstable α-globin gene variants may have HbH disease. Rarely, HbH disease is caused by compound heterozygosity for an MCS-R2 (see The α-thalassemia carrier states have been classified on the basis of the total globin protein produced from each of the two α-globin genes and by the number of globin genes that are missing or abnormal (see Carrier State Nomenclature Both α-globin genes on one chromosome 16 are deleted or inactivated by a non-deletion variant. One α-globin gene on each chromosome 16 is deleted or inactivated by a non-deletion variant. The terms " MCS-R2, a Since the early 1960s, prevalence of α-thalassemia has been determined in several populations using the percent of Hb Bart in cord blood. However, because not all newborns with α-thalassemia (mainly α-thalassemia silent carriers) have increased Hb Bart, the prevalence of α-thalassemia derived from this measure may be underestimated. Data that are more precise have been obtained using molecular testing. For detailed references for the frequency of α-thalassemia in each population, see The highest allele frequency (0.30-0.40) of the -α Deletion of the two α-globin genes on the same chromosome (--/αα) has been reported very rarely in North Africa and in the African American population. Alpha-thalassemia trait caused by two α Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare (0.002); thus, Hb Bart hydrops fetalis is only rarely reported. A remarkable aspect of α-thalassemia variants identified in the Mediterranean population is the heterogeneity of variants, particularly the non-deletion variants. Frequency of the -α Deletion of the two α-globin genes on the same chromosome (--/αα) is extremely rare. Alpha-thalassemia trait reaches very high allele frequency (0.35-0.92) in the Indian tribal population of Andra Pradesh; in other tribes, the frequency is much lower (0.03-0.12). Both the -α Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare. Alpha Alpha-thalassemia caused by Hb Constant Spring alleles is also common. The incidence of Hb Bart hydrops fetalis is expected to be in the range of 0.5-5:1,000 births and HbH disease the range of 4-20:1,000 births. The distribution of α-thalassemia, extensively studied by DNA-based methods, follows a pattern consistent with the degree of malaria endemicity. The prevalence of α-thalassemia is low in the highlands and high in the coastal areas and the lowlands where malaria is hyperendemic. Some α-thalassemias have unusual mutation mechanisms; for example, some affected individuals on the island of Vanuatu who have normal α-globin genes without deletions or variants have a variant in a regulatory element that creates a GATA-1 site and activates a cryptic promoter [ Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare. • Most often caused by large deletions on both chromosomes (--/--) • Rarely, an individual with Hb Bart syndrome will have a non-deletion variant (--/α • Most often caused by a large deletion on one chromosome with a single α-globin allele deletion (--/-α) or other non-deletion inactivating variant (--/α • Individuals homozygous for • Individuals who are homozygous or compound heterozygous for highly unstable α-globin gene variants may have HbH disease. • Rarely, HbH disease is caused by compound heterozygosity for an MCS-R2 (see ## Clinical Description The clinically significant phenotypes of alpha-thalassemia (α-thalassemia) are hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease. The severity of the α-thalassemia syndromes depends on the extent of the alpha globin (α-globin) chain defect (see The main clinical features are generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia. Notably, red cells with Hb Bart have an extremely high oxygen affinity and are incapable of effective oxygen delivery. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common. Retardation in brain growth, hydrocephalus, cardiovascular deformities, and urogenital defects have been reported. A very small number of newborns survive following intrauterine transfusions and repeated frequent transfusions after birth. Maternal complications during pregnancy commonly include preeclampsia, polyhydramnios or oligohydramnios, antepartum hemorrhage, and premature delivery. The majority of individuals have enlargement of the spleen and less commonly of the liver, mild jaundice, and sometimes mild-to-moderate thalassemia-like skeletal changes (e.g., hypertrophy of the maxilla, bossing of the skull, and prominence of the malar eminences) that affect the facial features. Leg ulcers are rare. Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to oxidant drugs and infections. Rarely, infection with parvovirus B19 can cause an aplastic crisis. While the majority of individuals with HbH disease have minor disability, some are severely affected, requiring regular blood transfusions; in very rare cases hydrops fetalis is present [ Significant iron overload is uncommon but has been reported in older individuals, usually resulting from repeated blood transfusions or increased iron absorption [ ## Genotype-Phenotype Correlations The phenotype of the α-thalassemia syndromes depends on the degree of α-globin chain deficiency relative to beta globin chain production. The correlation between α-thalassemia pathogenic variants, α-globin mRNA levels, α-globin synthesis, and clinical manifestations of α-thalassemia is well documented. Most often caused by large deletions on both chromosomes (--/--) Rarely, an individual with Hb Bart syndrome will have a non-deletion variant (--/α Most often caused by a large deletion on one chromosome with a single α-globin allele deletion (--/-α) or other non-deletion inactivating variant (--/α Individuals homozygous for Individuals who are homozygous or compound heterozygous for highly unstable α-globin gene variants may have HbH disease. Rarely, HbH disease is caused by compound heterozygosity for an MCS-R2 (see • Most often caused by large deletions on both chromosomes (--/--) • Rarely, an individual with Hb Bart syndrome will have a non-deletion variant (--/α • Most often caused by a large deletion on one chromosome with a single α-globin allele deletion (--/-α) or other non-deletion inactivating variant (--/α • Individuals homozygous for • Individuals who are homozygous or compound heterozygous for highly unstable α-globin gene variants may have HbH disease. • Rarely, HbH disease is caused by compound heterozygosity for an MCS-R2 (see ## Nomenclature The α-thalassemia carrier states have been classified on the basis of the total globin protein produced from each of the two α-globin genes and by the number of globin genes that are missing or abnormal (see Carrier State Nomenclature Both α-globin genes on one chromosome 16 are deleted or inactivated by a non-deletion variant. One α-globin gene on each chromosome 16 is deleted or inactivated by a non-deletion variant. The terms " MCS-R2, a ## Prevalence Since the early 1960s, prevalence of α-thalassemia has been determined in several populations using the percent of Hb Bart in cord blood. However, because not all newborns with α-thalassemia (mainly α-thalassemia silent carriers) have increased Hb Bart, the prevalence of α-thalassemia derived from this measure may be underestimated. Data that are more precise have been obtained using molecular testing. For detailed references for the frequency of α-thalassemia in each population, see The highest allele frequency (0.30-0.40) of the -α Deletion of the two α-globin genes on the same chromosome (--/αα) has been reported very rarely in North Africa and in the African American population. Alpha-thalassemia trait caused by two α Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare (0.002); thus, Hb Bart hydrops fetalis is only rarely reported. A remarkable aspect of α-thalassemia variants identified in the Mediterranean population is the heterogeneity of variants, particularly the non-deletion variants. Frequency of the -α Deletion of the two α-globin genes on the same chromosome (--/αα) is extremely rare. Alpha-thalassemia trait reaches very high allele frequency (0.35-0.92) in the Indian tribal population of Andra Pradesh; in other tribes, the frequency is much lower (0.03-0.12). Both the -α Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare. Alpha Alpha-thalassemia caused by Hb Constant Spring alleles is also common. The incidence of Hb Bart hydrops fetalis is expected to be in the range of 0.5-5:1,000 births and HbH disease the range of 4-20:1,000 births. The distribution of α-thalassemia, extensively studied by DNA-based methods, follows a pattern consistent with the degree of malaria endemicity. The prevalence of α-thalassemia is low in the highlands and high in the coastal areas and the lowlands where malaria is hyperendemic. Some α-thalassemias have unusual mutation mechanisms; for example, some affected individuals on the island of Vanuatu who have normal α-globin genes without deletions or variants have a variant in a regulatory element that creates a GATA-1 site and activates a cryptic promoter [ Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare. ## Africa The highest allele frequency (0.30-0.40) of the -α Deletion of the two α-globin genes on the same chromosome (--/αα) has been reported very rarely in North Africa and in the African American population. ## The Mediterranean Alpha-thalassemia trait caused by two α Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare (0.002); thus, Hb Bart hydrops fetalis is only rarely reported. A remarkable aspect of α-thalassemia variants identified in the Mediterranean population is the heterogeneity of variants, particularly the non-deletion variants. ## The Arabian Peninsula Frequency of the -α Deletion of the two α-globin genes on the same chromosome (--/αα) is extremely rare. ## India Alpha-thalassemia trait reaches very high allele frequency (0.35-0.92) in the Indian tribal population of Andra Pradesh; in other tribes, the frequency is much lower (0.03-0.12). Both the -α Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare. ## Southeast Asia Alpha Alpha-thalassemia caused by Hb Constant Spring alleles is also common. The incidence of Hb Bart hydrops fetalis is expected to be in the range of 0.5-5:1,000 births and HbH disease the range of 4-20:1,000 births. ## Oceania The distribution of α-thalassemia, extensively studied by DNA-based methods, follows a pattern consistent with the degree of malaria endemicity. The prevalence of α-thalassemia is low in the highlands and high in the coastal areas and the lowlands where malaria is hyperendemic. Some α-thalassemias have unusual mutation mechanisms; for example, some affected individuals on the island of Vanuatu who have normal α-globin genes without deletions or variants have a variant in a regulatory element that creates a GATA-1 site and activates a cryptic promoter [ Deletion of the two α-globin genes on the same chromosome (--/αα) is very rare. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Hydrops fetalis is associated with many conditions in addition to Hb Bart, including immune-related disorders (e.g., alloimmune hemolytic disease, Rh isoimmunization), fetal cardiac anomalies, chromosome abnormalities, fetal infections, genetic disorders, and maternal and placental disorders. The combination of a hydropic fetus with a very high proportion of Hb Bart, however, is found in no other condition. An unknown percent of 46,XY individuals with ATRX syndrome have a mild form of HbH disease, evident as HbH inclusions (β Acquired variants in ## Hydrops Fetalis Hydrops fetalis is associated with many conditions in addition to Hb Bart, including immune-related disorders (e.g., alloimmune hemolytic disease, Rh isoimmunization), fetal cardiac anomalies, chromosome abnormalities, fetal infections, genetic disorders, and maternal and placental disorders. The combination of a hydropic fetus with a very high proportion of Hb Bart, however, is found in no other condition. ## Hemoglobin H (HbH) Disease An unknown percent of 46,XY individuals with ATRX syndrome have a mild form of HbH disease, evident as HbH inclusions (β Acquired variants in ## Carrier States (α ## Management In 2017, the Thalassemia International Federation updated its To establish the extent of disease and needs in an individual diagnosed with alpha-thalassemia (α-thalassemia), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Differentiation of deletion (mild) from non-deletion (moderate to severe) forms of HbH disease by appropriate molecular genetic testing of Referral to a hematologist 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 α-thalassemia in order to facilitate medical and personal decision making More recently, Because such advances in intrauterine and postnatal therapy often result in ethical dilemmas for the family and health care provider, consultation with a clinical ethics service may be helpful in assessing health care decisions in the context of the best interest of the child and the values and preferences of the family. Individuals with deletional HbH disease may need occasional red blood cell transfusions if the hemoglobin (Hb) level suddenly drops because of hemolytic or aplastic crises. Clear indications for red blood cell transfusions are severe anemia affecting cardiac function and massive erythroid expansion, resulting in severe bone changes and extramedullary erythropoiesis. Note: These events are quite rare in HbH disease. Iron chelation therapy may be needed in individuals with iron loading caused by regular blood transfusion, inappropriate iron therapy, or abnormal iron absorption. Splenectomy should be performed only in individuals with massive splenomegaly or hypersplenism; the associated risks for severe, life-threatening sepsis and venous thrombosis should be considered. Other complications, such as gallstones and leg ulcers, require appropriate medical or surgical treatment. When chronic red blood cell transfusions are instituted for individuals with HbH disease, the management should be the same as for all individuals who have been polytransfused, including use of iron chelation therapy (see In individuals with HbH disease who are not red blood cell transfusion dependent, the only iron chelator specifically approved is deferasirox, shown to be superior to placebo in reducing liver iron concentration in those older than age ten years with β-thalassemia intermedia, hemoglobin E/β-thalassemia, or HbH disease [ Regular folic acid supplementation should be recommended, as for other hemolytic anemias. If splenectomy is required, antimicrobial prophylaxis is usually provided, at least until age five years, to decrease the risk for overwhelming sepsis caused by encapsulated organisms. Use of antimicrobial prophylaxis notwithstanding, a careful clinical evaluation of individuals who have undergone splenectomy and have a fever is recommended. Hematologic evaluation every six to 12 months to determine the steady state levels of Hb In children, assessment of growth and development every six to 12 months Monitoring of iron load with annual determination of serum ferritin concentration in individuals who have been transfused, in older individuals, and in those given inappropriate iron supplementation. Since serum ferritin may underestimate the degree of iron overload, a periodic noninvasive quantitative measurement of liver iron concentration by MRI is also recommended [ Inappropriate iron therapy Oxidant drugs according to recommendations for G6PD deficiency [ The sibs of a proband should be evaluated as soon as possible after birth to determine if they have HbH disease so that appropriate management (including agents/circumstances to avoid) can be implemented. Evaluations can include: Evaluation of red blood cell indices, red blood cell supravital stain for HbH inclusions, and hemoglobin analysis by high-performance liquid chromatography Targeted molecular analysis if the pathogenic variants in the family are known Molecular genetic analysis (according to the frequency of alpha globin gene pathogenic variants by geographic area) if the pathogenic variants in the family are not known See During pregnancy, complications reported in women with HbH disease include worsening of anemia (with occasional need for red cell transfusions), preeclampsia, congestive heart failure, and threatened miscarriage [ Search • Differentiation of deletion (mild) from non-deletion (moderate to severe) forms of HbH disease by appropriate molecular genetic testing of • Referral to a hematologist • 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 α-thalassemia in order to facilitate medical and personal decision making • Individuals with deletional HbH disease may need occasional red blood cell transfusions if the hemoglobin (Hb) level suddenly drops because of hemolytic or aplastic crises. • Clear indications for red blood cell transfusions are severe anemia affecting cardiac function and massive erythroid expansion, resulting in severe bone changes and extramedullary erythropoiesis. Note: These events are quite rare in HbH disease. • Iron chelation therapy may be needed in individuals with iron loading caused by regular blood transfusion, inappropriate iron therapy, or abnormal iron absorption. • Splenectomy should be performed only in individuals with massive splenomegaly or hypersplenism; the associated risks for severe, life-threatening sepsis and venous thrombosis should be considered. • Other complications, such as gallstones and leg ulcers, require appropriate medical or surgical treatment. • Hematologic evaluation every six to 12 months to determine the steady state levels of Hb • In children, assessment of growth and development every six to 12 months • Monitoring of iron load with annual determination of serum ferritin concentration in individuals who have been transfused, in older individuals, and in those given inappropriate iron supplementation. Since serum ferritin may underestimate the degree of iron overload, a periodic noninvasive quantitative measurement of liver iron concentration by MRI is also recommended [ • Inappropriate iron therapy • Oxidant drugs according to recommendations for G6PD deficiency [ • Evaluation of red blood cell indices, red blood cell supravital stain for HbH inclusions, and hemoglobin analysis by high-performance liquid chromatography • Targeted molecular analysis if the pathogenic variants in the family are known • Molecular genetic analysis (according to the frequency of alpha globin gene pathogenic variants by geographic area) 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 alpha-thalassemia (α-thalassemia), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Differentiation of deletion (mild) from non-deletion (moderate to severe) forms of HbH disease by appropriate molecular genetic testing of Referral to a hematologist 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 α-thalassemia in order to facilitate medical and personal decision making • Differentiation of deletion (mild) from non-deletion (moderate to severe) forms of HbH disease by appropriate molecular genetic testing of • Referral to a hematologist • 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 α-thalassemia in order to facilitate medical and personal decision making ## Treatment of Manifestations More recently, Because such advances in intrauterine and postnatal therapy often result in ethical dilemmas for the family and health care provider, consultation with a clinical ethics service may be helpful in assessing health care decisions in the context of the best interest of the child and the values and preferences of the family. Individuals with deletional HbH disease may need occasional red blood cell transfusions if the hemoglobin (Hb) level suddenly drops because of hemolytic or aplastic crises. Clear indications for red blood cell transfusions are severe anemia affecting cardiac function and massive erythroid expansion, resulting in severe bone changes and extramedullary erythropoiesis. Note: These events are quite rare in HbH disease. Iron chelation therapy may be needed in individuals with iron loading caused by regular blood transfusion, inappropriate iron therapy, or abnormal iron absorption. Splenectomy should be performed only in individuals with massive splenomegaly or hypersplenism; the associated risks for severe, life-threatening sepsis and venous thrombosis should be considered. Other complications, such as gallstones and leg ulcers, require appropriate medical or surgical treatment. • Individuals with deletional HbH disease may need occasional red blood cell transfusions if the hemoglobin (Hb) level suddenly drops because of hemolytic or aplastic crises. • Clear indications for red blood cell transfusions are severe anemia affecting cardiac function and massive erythroid expansion, resulting in severe bone changes and extramedullary erythropoiesis. Note: These events are quite rare in HbH disease. • Iron chelation therapy may be needed in individuals with iron loading caused by regular blood transfusion, inappropriate iron therapy, or abnormal iron absorption. • Splenectomy should be performed only in individuals with massive splenomegaly or hypersplenism; the associated risks for severe, life-threatening sepsis and venous thrombosis should be considered. • Other complications, such as gallstones and leg ulcers, require appropriate medical or surgical treatment. ## Prevention of Primary Manifestations ## Prevention of Secondary Complications When chronic red blood cell transfusions are instituted for individuals with HbH disease, the management should be the same as for all individuals who have been polytransfused, including use of iron chelation therapy (see In individuals with HbH disease who are not red blood cell transfusion dependent, the only iron chelator specifically approved is deferasirox, shown to be superior to placebo in reducing liver iron concentration in those older than age ten years with β-thalassemia intermedia, hemoglobin E/β-thalassemia, or HbH disease [ Regular folic acid supplementation should be recommended, as for other hemolytic anemias. If splenectomy is required, antimicrobial prophylaxis is usually provided, at least until age five years, to decrease the risk for overwhelming sepsis caused by encapsulated organisms. Use of antimicrobial prophylaxis notwithstanding, a careful clinical evaluation of individuals who have undergone splenectomy and have a fever is recommended. ## Surveillance Hematologic evaluation every six to 12 months to determine the steady state levels of Hb In children, assessment of growth and development every six to 12 months Monitoring of iron load with annual determination of serum ferritin concentration in individuals who have been transfused, in older individuals, and in those given inappropriate iron supplementation. Since serum ferritin may underestimate the degree of iron overload, a periodic noninvasive quantitative measurement of liver iron concentration by MRI is also recommended [ • Hematologic evaluation every six to 12 months to determine the steady state levels of Hb • In children, assessment of growth and development every six to 12 months • Monitoring of iron load with annual determination of serum ferritin concentration in individuals who have been transfused, in older individuals, and in those given inappropriate iron supplementation. Since serum ferritin may underestimate the degree of iron overload, a periodic noninvasive quantitative measurement of liver iron concentration by MRI is also recommended [ ## Agents/Circumstances to Avoid Inappropriate iron therapy Oxidant drugs according to recommendations for G6PD deficiency [ • Inappropriate iron therapy • Oxidant drugs according to recommendations for G6PD deficiency [ ## Evaluation of Relatives at Risk The sibs of a proband should be evaluated as soon as possible after birth to determine if they have HbH disease so that appropriate management (including agents/circumstances to avoid) can be implemented. Evaluations can include: Evaluation of red blood cell indices, red blood cell supravital stain for HbH inclusions, and hemoglobin analysis by high-performance liquid chromatography Targeted molecular analysis if the pathogenic variants in the family are known Molecular genetic analysis (according to the frequency of alpha globin gene pathogenic variants by geographic area) if the pathogenic variants in the family are not known See • Evaluation of red blood cell indices, red blood cell supravital stain for HbH inclusions, and hemoglobin analysis by high-performance liquid chromatography • Targeted molecular analysis if the pathogenic variants in the family are known • Molecular genetic analysis (according to the frequency of alpha globin gene pathogenic variants by geographic area) if the pathogenic variants in the family are not known ## Pregnancy Management During pregnancy, complications reported in women with HbH disease include worsening of anemia (with occasional need for red cell transfusions), preeclampsia, congestive heart failure, and threatened miscarriage [ ## Therapies Under Investigation Search ## Genetic Counseling Alpha-thalassemia (α-thalassemia) is usually inherited in an autosomal recessive manner. Possible Parental Genotypes and Corresponding Outcomes in Sibs of a Proband with HbH Disease 25% HbH disease 25% silent carrier 25% α 25% normal Hb 50% silent carrier 50% α 25% HbH disease [α 50% α-thalassemia trait [α 25% normal Hb 25% HbH disease 25% silent carrier 25% α 25% normal Hb Hb = hemoglobin Genotype frequency depends on geographic region (e.g., in the Mediterranean region, single-nucleotide variants are relatively frequent, while they are rare in the Far East). Each child of an individual with HbH disease inherits: Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); OR Non-deletion inactivation of Given the high carrier rate of α-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with: HbH disease OR Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α Molecular genetic testing of the α-globin genes Alpha-Thalassemia Carrier States Single-nucleotide variants are usually more severe than a 1-gene deletion due to lack of compensatory increase of α-globin production assoc with a 1-gene deletion. Moreover, pathogenic variants in RBC = red blood cell Moderate thalassemia-like hematologic picture refers to mild hypochromic (low mean corpuscular hemoglobin), microcytic (low mean corpuscular volume) anemia and normal hemoglobin A Individuals with this genotype may be referred to as α Because of the high carrier rate for the two-gene deletion on the same chromosome (--/αα) in certain populations and the availability of genetic counseling and prenatal testing, it is ideal to screen (prior to or early in pregnancy) couples who are members of at-risk populations to identify those at risk of conceiving a fetus with Hb Bart syndrome. Note: Since -- Note: Prospective identification of α-thalassemia silent carriers (i.e., -α/αα or αα Hematologic Findings in Alpha-Thalassemia Trait and Alpha-Thalassemia Silent Carriers Reference ranges may vary by laboratory. Alpha-thalassemia carriers with the two-gene deletion on the same chromosome (--/αα) have slightly lower red blood cell indices. Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α Hemoglobin H (HbH). Four beta globin chains (β Hemoglobin A2 (HbA Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ Hemoglobin Analysis in Alpha-Thalassemia Trait and Alpha-Thalassemia Silent Carriers Deletion or inactivation of two α-globin alleles on either the same chromosome (--/αα) or opposite homologous chromosomes (-α/-α) Deletion or inactivation of one α-globin allele (-α/αα) 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 have HbH disease, are carriers, or are at risk of being carriers. One parent has an α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the other has an α-thalassemia-like hematologic picture but no α-thalassemia variant identified by molecular genetic testing. The mother has a known α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the father is unknown or unavailable for testing. This is of concern if the father belongs to a population with a high carrier rate for α-thalassemia In both instances, the options for prenatal testing should be discussed in the context of formal genetic counseling. Analysis of fetal DNA for the known α-thalassemia variant is recommended as the first step in prenatal testing for indeterminate-risk pregnancies; if the known α-thalassemia variant is present, globin chain synthesis analysis is performed using a fetal blood sample obtained by percutaneous umbilical blood sampling. 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. • 25% HbH disease • 25% silent carrier • 25% α • 25% normal Hb • 50% silent carrier • 50% α • 25% HbH disease [α • 50% α-thalassemia trait [α • 25% normal Hb • 25% HbH disease • 25% silent carrier • 25% α • 25% normal Hb • Each child of an individual with HbH disease inherits: • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • Given the high carrier rate of α-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with: • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • Single-nucleotide variants are usually more severe than a 1-gene deletion due to lack of compensatory increase of α-globin production assoc with a 1-gene deletion. • Moreover, pathogenic variants in • Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α • Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α • Hemoglobin H (HbH). Four beta globin chains (β • Hemoglobin A2 (HbA • Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ • Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ • 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 HbH disease, are carriers, or are at risk of being carriers. • One parent has an α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the other has an α-thalassemia-like hematologic picture but no α-thalassemia variant identified by molecular genetic testing. • The mother has a known α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the father is unknown or unavailable for testing. This is of concern if the father belongs to a population with a high carrier rate for α-thalassemia ## Mode of Inheritance Alpha-thalassemia (α-thalassemia) is usually inherited in an autosomal recessive manner. ## Risk to Family Members Possible Parental Genotypes and Corresponding Outcomes in Sibs of a Proband with HbH Disease 25% HbH disease 25% silent carrier 25% α 25% normal Hb 50% silent carrier 50% α 25% HbH disease [α 50% α-thalassemia trait [α 25% normal Hb 25% HbH disease 25% silent carrier 25% α 25% normal Hb Hb = hemoglobin Genotype frequency depends on geographic region (e.g., in the Mediterranean region, single-nucleotide variants are relatively frequent, while they are rare in the Far East). Each child of an individual with HbH disease inherits: Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); OR Non-deletion inactivation of Given the high carrier rate of α-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with: HbH disease OR Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α Molecular genetic testing of the α-globin genes Alpha-Thalassemia Carrier States Single-nucleotide variants are usually more severe than a 1-gene deletion due to lack of compensatory increase of α-globin production assoc with a 1-gene deletion. Moreover, pathogenic variants in RBC = red blood cell Moderate thalassemia-like hematologic picture refers to mild hypochromic (low mean corpuscular hemoglobin), microcytic (low mean corpuscular volume) anemia and normal hemoglobin A Individuals with this genotype may be referred to as α • 25% HbH disease • 25% silent carrier • 25% α • 25% normal Hb • 50% silent carrier • 50% α • 25% HbH disease [α • 50% α-thalassemia trait [α • 25% normal Hb • 25% HbH disease • 25% silent carrier • 25% α • 25% normal Hb • Each child of an individual with HbH disease inherits: • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • Given the high carrier rate of α-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with: • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • Single-nucleotide variants are usually more severe than a 1-gene deletion due to lack of compensatory increase of α-globin production assoc with a 1-gene deletion. • Moreover, pathogenic variants in ## Hemoglobin Bart Hydrops Fetalis (Hb Bart) Syndrome ## Hemoglobin H (HbH) Disease Possible Parental Genotypes and Corresponding Outcomes in Sibs of a Proband with HbH Disease 25% HbH disease 25% silent carrier 25% α 25% normal Hb 50% silent carrier 50% α 25% HbH disease [α 50% α-thalassemia trait [α 25% normal Hb 25% HbH disease 25% silent carrier 25% α 25% normal Hb Hb = hemoglobin Genotype frequency depends on geographic region (e.g., in the Mediterranean region, single-nucleotide variants are relatively frequent, while they are rare in the Far East). Each child of an individual with HbH disease inherits: Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); OR Non-deletion inactivation of Given the high carrier rate of α-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with: HbH disease OR Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • 25% HbH disease • 25% silent carrier • 25% α • 25% normal Hb • 50% silent carrier • 50% α • 25% HbH disease [α • 50% α-thalassemia trait [α • 25% normal Hb • 25% HbH disease • 25% silent carrier • 25% α • 25% normal Hb • Each child of an individual with HbH disease inherits: • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • Given the high carrier rate of α-thalassemia in certain populations, it is appropriate to offer carrier testing to the reproductive partner of an individual with: • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α • Deletion or inactivation of two α-globin genes on the same chromosome (e.g. ,--/αα, α-thalassemia trait/carrier); • OR • Non-deletion inactivation of • HbH disease • OR • Alpha-thalassemia trait/carrier associated with either deletion of the two α-globin genes on the same chromosome (--/αα) or a non-deletional variant (α ## Carrier Detection for Individuals with a Positive Family History of Hb Bart Syndrome or HbH Disease Molecular genetic testing of the α-globin genes Alpha-Thalassemia Carrier States Single-nucleotide variants are usually more severe than a 1-gene deletion due to lack of compensatory increase of α-globin production assoc with a 1-gene deletion. Moreover, pathogenic variants in RBC = red blood cell Moderate thalassemia-like hematologic picture refers to mild hypochromic (low mean corpuscular hemoglobin), microcytic (low mean corpuscular volume) anemia and normal hemoglobin A Individuals with this genotype may be referred to as α • Single-nucleotide variants are usually more severe than a 1-gene deletion due to lack of compensatory increase of α-globin production assoc with a 1-gene deletion. • Moreover, pathogenic variants in ## Population Screening for α-Thalassemia Trait Because of the high carrier rate for the two-gene deletion on the same chromosome (--/αα) in certain populations and the availability of genetic counseling and prenatal testing, it is ideal to screen (prior to or early in pregnancy) couples who are members of at-risk populations to identify those at risk of conceiving a fetus with Hb Bart syndrome. Note: Since -- Note: Prospective identification of α-thalassemia silent carriers (i.e., -α/αα or αα Hematologic Findings in Alpha-Thalassemia Trait and Alpha-Thalassemia Silent Carriers Reference ranges may vary by laboratory. Alpha-thalassemia carriers with the two-gene deletion on the same chromosome (--/αα) have slightly lower red blood cell indices. Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α Hemoglobin H (HbH). Four beta globin chains (β Hemoglobin A2 (HbA Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ Hemoglobin Analysis in Alpha-Thalassemia Trait and Alpha-Thalassemia Silent Carriers Deletion or inactivation of two α-globin alleles on either the same chromosome (--/αα) or opposite homologous chromosomes (-α/-α) Deletion or inactivation of one α-globin allele (-α/αα) • Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α • Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α • Hemoglobin H (HbH). Four beta globin chains (β • Hemoglobin A2 (HbA • Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ • Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ ## Evaluations to Detect Carrier States Hematologic Findings in Alpha-Thalassemia Trait and Alpha-Thalassemia Silent Carriers Reference ranges may vary by laboratory. Alpha-thalassemia carriers with the two-gene deletion on the same chromosome (--/αα) have slightly lower red blood cell indices. Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α Hemoglobin H (HbH). Four beta globin chains (β Hemoglobin A2 (HbA Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ Hemoglobin Analysis in Alpha-Thalassemia Trait and Alpha-Thalassemia Silent Carriers Deletion or inactivation of two α-globin alleles on either the same chromosome (--/αα) or opposite homologous chromosomes (-α/-α) Deletion or inactivation of one α-globin allele (-α/αα) • Hemoglobin A (HbA). Two alpha globin chains and two beta globin chains (α • Hemoglobin F (HbF). Two alpha globin chains and two gamma globin chains (α • Hemoglobin H (HbH). Four beta globin chains (β • Hemoglobin A2 (HbA • Hemoglobin Bart (Hb Bart). Four gamma globin chains (γ • Hemoglobin Portland. Two zeta globin chains and two gamma globin chains (ζ ## 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 have HbH disease, 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 HbH disease, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing One parent has an α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the other has an α-thalassemia-like hematologic picture but no α-thalassemia variant identified by molecular genetic testing. The mother has a known α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the father is unknown or unavailable for testing. This is of concern if the father belongs to a population with a high carrier rate for α-thalassemia In both instances, the options for prenatal testing should be discussed in the context of formal genetic counseling. Analysis of fetal DNA for the known α-thalassemia variant is recommended as the first step in prenatal testing for indeterminate-risk pregnancies; if the known α-thalassemia variant is present, globin chain synthesis analysis is performed using a fetal blood sample obtained by percutaneous umbilical blood sampling. 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. • One parent has an α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the other has an α-thalassemia-like hematologic picture but no α-thalassemia variant identified by molecular genetic testing. • The mother has a known α-thalassemia trait with a two-gene deletion on the same chromosome (--/αα) and the father is unknown or unavailable for testing. This is of concern if the father belongs to a population with a high carrier rate for α-thalassemia ## Resources 330 Seventh Avenue #200 New York NY 10001 Cyprus • • 330 Seventh Avenue • #200 • New York NY 10001 • • • • • Cyprus • ## Molecular Genetics Alpha-Thalassemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alpha-Thalassemia ( The level of transcription of Gene-Specific Laboratory Technical Considerations: Genes Causing Alpha-Thalassemia Judicious primer/probe design is required due to marked nucleotide homology between Note that locus-specific databases (see Notable Pathogenic Variants in Genes Causing Alpha-Thalassemia Variants listed in the table have been provided by the authors. General references for data in this table are the For deletions, only functional globin genes are included; deleted pseudogenes are omitted. For nucleotide variants, For predicted protein variants, The Variant forms of hemoglobin typically detected in the laboratory by altered electrophoretic properties. Name, protein characteristics, and hematologic findings are detailed in The nucleotide coordinates for globin gene deletions vary and typically are not designated; however, a few breakpoints have been reported (see Because deletions involve partial or whole-gene deletions, predicted protein changes are not applicable. • Judicious primer/probe design is required due to marked nucleotide homology between • Note that locus-specific databases (see ## Molecular Pathogenesis The level of transcription of Gene-Specific Laboratory Technical Considerations: Genes Causing Alpha-Thalassemia Judicious primer/probe design is required due to marked nucleotide homology between Note that locus-specific databases (see Notable Pathogenic Variants in Genes Causing Alpha-Thalassemia Variants listed in the table have been provided by the authors. General references for data in this table are the For deletions, only functional globin genes are included; deleted pseudogenes are omitted. For nucleotide variants, For predicted protein variants, The Variant forms of hemoglobin typically detected in the laboratory by altered electrophoretic properties. Name, protein characteristics, and hematologic findings are detailed in The nucleotide coordinates for globin gene deletions vary and typically are not designated; however, a few breakpoints have been reported (see Because deletions involve partial or whole-gene deletions, predicted protein changes are not applicable. • Judicious primer/probe design is required due to marked nucleotide homology between • Note that locus-specific databases (see ## Chapter Notes Hannah Tamary, MD, was the head of Hematology Unit in Schneider Children's Medical Center of Israel for more than 20 years. Currently she is the director of the Pediatric Molecular Hematology Laboratory there, the only laboratory in Israel using next-generation sequencing technology and providing diagnosis for all types of anemias, as well as inherited predisposition to myelodysplastic syndrome/leukemias and bone marrow failure syndromes. She also investigates erythropoiesis through the study of congenital dyserythropoietic anemia. Antonio Cao, MD; Consiglio Nazionale delle Ricerche (2005-2012)Orly Dgany, PhD (2020-present)Renzo Galanello, MD; Ospedale Regionale Microcitemie (2005-2013)Paolo Moi, MD; Università degli Studi di Cagliari (2013-2020)Raffaella Origa, MD; Università degli Studi di Cagliari (2013-2020)Hannah Tamary, MD (2020-present) 23 May 2024 (aa) Revision: 1 October 2020 (bp) Comprehensive update posted live 29 December 2016 (sw) Comprehensive update posted live 21 November 2013 (me) Comprehensive update posted live 7 June 2011 (me) Comprehensive update posted live 14 July 2008 (me) Comprehensive update posted live 1 November 2005 (me) Review posted live 3 January 2005 (rg) Original submission • 23 May 2024 (aa) Revision: • 1 October 2020 (bp) Comprehensive update posted live • 29 December 2016 (sw) Comprehensive update posted live • 21 November 2013 (me) Comprehensive update posted live • 7 June 2011 (me) Comprehensive update posted live • 14 July 2008 (me) Comprehensive update posted live • 1 November 2005 (me) Review posted live • 3 January 2005 (rg) Original submission ## Author Notes Hannah Tamary, MD, was the head of Hematology Unit in Schneider Children's Medical Center of Israel for more than 20 years. Currently she is the director of the Pediatric Molecular Hematology Laboratory there, the only laboratory in Israel using next-generation sequencing technology and providing diagnosis for all types of anemias, as well as inherited predisposition to myelodysplastic syndrome/leukemias and bone marrow failure syndromes. She also investigates erythropoiesis through the study of congenital dyserythropoietic anemia. ## Author History Antonio Cao, MD; Consiglio Nazionale delle Ricerche (2005-2012)Orly Dgany, PhD (2020-present)Renzo Galanello, MD; Ospedale Regionale Microcitemie (2005-2013)Paolo Moi, MD; Università degli Studi di Cagliari (2013-2020)Raffaella Origa, MD; Università degli Studi di Cagliari (2013-2020)Hannah Tamary, MD (2020-present) ## Revision History 23 May 2024 (aa) Revision: 1 October 2020 (bp) Comprehensive update posted live 29 December 2016 (sw) Comprehensive update posted live 21 November 2013 (me) Comprehensive update posted live 7 June 2011 (me) Comprehensive update posted live 14 July 2008 (me) Comprehensive update posted live 1 November 2005 (me) Review posted live 3 January 2005 (rg) Original submission • 23 May 2024 (aa) Revision: • 1 October 2020 (bp) Comprehensive update posted live • 29 December 2016 (sw) Comprehensive update posted live • 21 November 2013 (me) Comprehensive update posted live • 7 June 2011 (me) Comprehensive update posted live • 14 July 2008 (me) Comprehensive update posted live • 1 November 2005 (me) Review posted live • 3 January 2005 (rg) Original submission ## References Taher A, Musallam K, Cappellini MD, eds. • Taher A, Musallam K, Cappellini MD, eds. ## Published Guidelines / Consensus Statements Taher A, Musallam K, Cappellini MD, eds. • Taher A, Musallam K, Cappellini MD, eds. ## Literature Cited Schematic presentation of the chromosomal location of the alpha globin gene cluster on chromosome 16p. The genes are indicated as boxes; gene symbols are above and the hemoglobin is expressed below. The alpha globin regulatory region (MCS-R1 to -R4; also known as HS-40) is indicated. Modified from	[]	1/11/2005	1/10/2020	23/5/2024	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aadc-def	aadc-def	[ "AADC Deficiency", "AADC Deficiency", "Aromatic-L-amino-acid decarboxylase", "DDC", "Aromatic L-Amino Acid Decarboxylase Deficiency" ]	Aromatic L-Amino Acid Decarboxylase Deficiency	Nenad Blau, Toni S Pearson, Manju A Kurian, Sarah H Elsea	Summary Individuals with aromatic L-amino acid decarboxylase (AADC) deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life. The most common initial symptoms are often nonspecific, and include feeding difficulties, hypotonia, and developmental delay. More specific symptoms include oculogyric crises (which occur in the vast majority of affected individuals, typically starting in infancy), movement disorders (especially dystonia), and autonomic dysfunction (excessive sweating, temperature instability, ptosis, nasal congestion, hypoglycemic episodes). Sleep disturbance is present in a majority of affected individuals and can include insomnia, hypersomnia, or both. Mood disturbance, including irritability and anxiety, are also common. Brain MRI is typically either normal or may demonstrate nonspecific abnormalities, such as mild diffuse cerebral atrophy or delayed myelination. Seizures are an uncommon finding, occurring in fewer than 5% of affected individuals. The diagnosis of AADC deficiency is established in a proband who has the following core diagnostic testing results: biallelic pathogenic variants in AADC deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis Consensus clinical diagnostic criteria for aromatic L-amino acid decarboxylase (AADC) deficiency have been published [ AADC deficiency Infantile hypotonia Ptosis Oculogyric crises (an involuntary and prolonged upward deviation of the eyes, often precipitated by such factors as fatigue, diurnal variation, intercurrent illness, or metabolic stress) Dystonia and other hyperkinetic movement disorders Hypokinesia and other features of parkinsonism Excessive sweating Stridor and nasal congestion Sleep disorder (hypersomnolence or insomnia) Autonomic dysfunction Developmental delay / intellectual disability, most often in the severe to profound range Cerebrospinal fluid (CSF) neurotransmitter profile typically demonstrates: Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); Normal concentrations of pterins (neopterin and biopterin); High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). Plasma neurotransmitter (untargeted metabolomics) profile typically demonstrates: High level of 3-OMD; Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); Low to normal level of 3-methoxytyramine sulfate (3-MTS). Increased urinary concentration of vanillactic acid (VLA) Low whole-blood serotonin concentration Increased serum prolactin concentration, which is nonspecific Note: Because elevations of these metabolites individually are not entirely specific to AADC deficiency, more specific testing is required to establish or rule out the diagnosis of AADC deficiency (see The diagnosis of AADC deficiency Biallelic pathogenic (or likely pathogenic) variants in OR CSF or plasma neurotransmitter profile consistent with AADC deficiency (see above) AND Significantly reduced activity of the enzyme AADC in plasma Because of its relatively high sensitivity, 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 clinical and preliminary laboratory findings suggest the diagnosis of AADC deficiency, molecular genetic testing approaches can include Sequence analysis of If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. Note: Targeted analysis for the For an introduction to multigene panels click When the diagnosis of AADC deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aromatic L-Amino Acid Decarboxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ The spectrum of variants identified in A pathogenic founder variant, Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One single large deletion has been reported [ • Infantile hypotonia • Ptosis • Oculogyric crises (an involuntary and prolonged upward deviation of the eyes, often precipitated by such factors as fatigue, diurnal variation, intercurrent illness, or metabolic stress) • Dystonia and other hyperkinetic movement disorders • Hypokinesia and other features of parkinsonism • Excessive sweating • Stridor and nasal congestion • Sleep disorder (hypersomnolence or insomnia) • Autonomic dysfunction • Developmental delay / intellectual disability, most often in the severe to profound range • Cerebrospinal fluid (CSF) neurotransmitter profile typically demonstrates: • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). • Plasma neurotransmitter (untargeted metabolomics) profile typically demonstrates: • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS). • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS). • Increased urinary concentration of vanillactic acid (VLA) • Low whole-blood serotonin concentration • Increased serum prolactin concentration, which is nonspecific • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS). • Biallelic pathogenic (or likely pathogenic) variants in • CSF or plasma neurotransmitter profile consistent with AADC deficiency (see above) AND • Significantly reduced activity of the enzyme AADC in plasma • • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • Note: Targeted analysis for the • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. ## Suggestive Findings AADC deficiency Infantile hypotonia Ptosis Oculogyric crises (an involuntary and prolonged upward deviation of the eyes, often precipitated by such factors as fatigue, diurnal variation, intercurrent illness, or metabolic stress) Dystonia and other hyperkinetic movement disorders Hypokinesia and other features of parkinsonism Excessive sweating Stridor and nasal congestion Sleep disorder (hypersomnolence or insomnia) Autonomic dysfunction Developmental delay / intellectual disability, most often in the severe to profound range Cerebrospinal fluid (CSF) neurotransmitter profile typically demonstrates: Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); Normal concentrations of pterins (neopterin and biopterin); High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). Plasma neurotransmitter (untargeted metabolomics) profile typically demonstrates: High level of 3-OMD; Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); Low to normal level of 3-methoxytyramine sulfate (3-MTS). Increased urinary concentration of vanillactic acid (VLA) Low whole-blood serotonin concentration Increased serum prolactin concentration, which is nonspecific Note: Because elevations of these metabolites individually are not entirely specific to AADC deficiency, more specific testing is required to establish or rule out the diagnosis of AADC deficiency (see • Infantile hypotonia • Ptosis • Oculogyric crises (an involuntary and prolonged upward deviation of the eyes, often precipitated by such factors as fatigue, diurnal variation, intercurrent illness, or metabolic stress) • Dystonia and other hyperkinetic movement disorders • Hypokinesia and other features of parkinsonism • Excessive sweating • Stridor and nasal congestion • Sleep disorder (hypersomnolence or insomnia) • Autonomic dysfunction • Developmental delay / intellectual disability, most often in the severe to profound range • Cerebrospinal fluid (CSF) neurotransmitter profile typically demonstrates: • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). • Plasma neurotransmitter (untargeted metabolomics) profile typically demonstrates: • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS). • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS). • Increased urinary concentration of vanillactic acid (VLA) • Low whole-blood serotonin concentration • Increased serum prolactin concentration, which is nonspecific • Low levels of 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), and 3-methoxy-4-hydroxyphenylglycol (MHPG); • Normal concentrations of pterins (neopterin and biopterin); • High concentrations of levodopa, 3-O-methyldopa (3-methoxytyrosine; 3-OMD), and 5-hydroxytryptophan (5-HT). • High level of 3-OMD; • Low levels of 5-HIAA, vanillylmandelate (VMA), HVA, and dopamine-3-O-sulfate (D3OS); • Low to normal level of 3-methoxytyramine sulfate (3-MTS). ## Establishing the Diagnosis The diagnosis of AADC deficiency Biallelic pathogenic (or likely pathogenic) variants in OR CSF or plasma neurotransmitter profile consistent with AADC deficiency (see above) AND Significantly reduced activity of the enzyme AADC in plasma Because of its relatively high sensitivity, 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 clinical and preliminary laboratory findings suggest the diagnosis of AADC deficiency, molecular genetic testing approaches can include Sequence analysis of If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. Note: Targeted analysis for the For an introduction to multigene panels click When the diagnosis of AADC deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aromatic L-Amino Acid Decarboxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ The spectrum of variants identified in A pathogenic founder variant, Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One single large deletion has been reported [ • Biallelic pathogenic (or likely pathogenic) variants in • CSF or plasma neurotransmitter profile consistent with AADC deficiency (see above) AND • Significantly reduced activity of the enzyme AADC in plasma • • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • Note: Targeted analysis for the • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. ## Option 1 When the clinical and preliminary laboratory findings suggest the diagnosis of AADC deficiency, molecular genetic testing approaches can include Sequence analysis of If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. Note: Targeted analysis for the For an introduction to multigene panels click • • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • Note: Targeted analysis for the • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • Sequence analysis of • If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. ## Option 2 When the diagnosis of AADC deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aromatic L-Amino Acid Decarboxylase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ The spectrum of variants identified in A pathogenic founder variant, Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. One single large deletion has been reported [ ## Clinical Characteristics The aromatic L-amino acid decarboxylase (AADC) enzyme catalyzes the last step in the biosynthesis of the monoamine neurotransmitters dopamine and serotonin. Dopamine itself is a precursor for the synthesis of epinephrine and norepinephrine. Therefore, the clinical features of AADC deficiency are caused by a severe combined deficiency of dopamine, serotonin, epinephrine, and norepinephrine. Individuals with AADC deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life [ Select Features of Aromatic L-Amino Acid Decarboxylase Deficiency Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. Excessive sweating Temperature instability Ptosis, miosis Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances Upper airway obstruction (see below) Hypoglycemic episodes (see below) Gastrointestinal symptoms (see below) Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. No clinically relevant genotype-phenotype correlations for AADC deficiency has also been referred to as dopa decarboxylase deficiency. The worldwide incidence of AADC deficiency is not known. The condition is thought to be more prevalent in certain populations that originate from Asia, particularly Taiwan, Japan, and China, due to a founder pathogenic variant ( • • Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. • Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. • Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. • Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. • Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. • Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. • Excessive sweating • Temperature instability • Ptosis, miosis • Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances • Upper airway obstruction (see below) • Hypoglycemic episodes (see below) • Gastrointestinal symptoms (see below) • Excessive sweating • Temperature instability • Ptosis, miosis • Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances • Upper airway obstruction (see below) • Hypoglycemic episodes (see below) • Gastrointestinal symptoms (see below) • Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. • Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. • Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. • Excessive sweating • Temperature instability • Ptosis, miosis • Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances • Upper airway obstruction (see below) • Hypoglycemic episodes (see below) • Gastrointestinal symptoms (see below) • • Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. • Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. • Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. • Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. • Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. • Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. ## Clinical Description The aromatic L-amino acid decarboxylase (AADC) enzyme catalyzes the last step in the biosynthesis of the monoamine neurotransmitters dopamine and serotonin. Dopamine itself is a precursor for the synthesis of epinephrine and norepinephrine. Therefore, the clinical features of AADC deficiency are caused by a severe combined deficiency of dopamine, serotonin, epinephrine, and norepinephrine. Individuals with AADC deficiency typically have complex symptoms, including motor, behavioral, cognitive, and autonomic findings. Symptom onset is in early infancy, typically within the first six months of life [ Select Features of Aromatic L-Amino Acid Decarboxylase Deficiency Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. Excessive sweating Temperature instability Ptosis, miosis Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances Upper airway obstruction (see below) Hypoglycemic episodes (see below) Gastrointestinal symptoms (see below) Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. • • Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. • Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. • Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. • Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. • Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. • Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. • Excessive sweating • Temperature instability • Ptosis, miosis • Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances • Upper airway obstruction (see below) • Hypoglycemic episodes (see below) • Gastrointestinal symptoms (see below) • Excessive sweating • Temperature instability • Ptosis, miosis • Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances • Upper airway obstruction (see below) • Hypoglycemic episodes (see below) • Gastrointestinal symptoms (see below) • Hypokinesia is common. The combination of hypotonia, hypokinesia, and ptosis (see below) in infancy may be mistaken for a neuromuscular condition. Differentiating features of AADC deficiency on neurologic examination are the presence of normal or brisk deep tendon reflexes and recognition of dystonia in the limbs, if present. • Dystonia (involuntary movements or postures) is the most common hyperkinetic movement disorder experienced by affected individuals. Dystonia typically fluctuates with activity and state, worsening in the context of action, stress, discomfort, and fatigue. Older children may experience a pattern of diurnal variation, with worsening at the end of the day and improvement following sleep. • Other hyperkinetic movement disorders including chorea, athetosis, myoclonus, and tremor may occur, usually intermittently. • Excessive sweating • Temperature instability • Ptosis, miosis • Cardiovascular abnormalities, including hypotension, bradycardia, and other heart rhythm disturbances • Upper airway obstruction (see below) • Hypoglycemic episodes (see below) • Gastrointestinal symptoms (see below) • • Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. • Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. • Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. • Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. • Upper airway obstruction. Nasal congestion and stridor are common (due to a combination of airway hypotonia and catecholamine deficiency). This symptom is most pronounced in infants and young children, who can have audible breathing. • Acute worsening of upper airway obstruction may occur during an oculogyric crisis, leading to a need for airway support in some affected individuals. ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations for ## Nomenclature AADC deficiency has also been referred to as dopa decarboxylase deficiency. ## Prevalence The worldwide incidence of AADC deficiency is not known. The condition is thought to be more prevalent in certain populations that originate from Asia, particularly Taiwan, Japan, and China, due to a founder pathogenic variant ( ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Monoamine neurotransmitter deficiencies associated with defects in the synthesis of dopamine ( Broad categories of disorders with clinical features that may resemble those of AADC deficiency are summarized in Clinical Differential Diagnosis of Aromatic L-Amino Acid Decarboxylase Deficiency Hypotonia Hypokinesia Ptosis Dystonia Oculogyric crises Autonomic features (ptosis, nasal congestion, excessive sweating) Presence of normal or brisk deep tendon reflexes Hypotonia Hypokinesia Dystonia Oculogyric crises AADC = aromatic L-amino acid decarboxylase Pyridoxine-dependent epilepsy (PDE) syndromes associated with • Hypotonia • Hypokinesia • Ptosis • Dystonia • Oculogyric crises • Autonomic features (ptosis, nasal congestion, excessive sweating) • Presence of normal or brisk deep tendon reflexes • Hypotonia • Hypokinesia • Dystonia • Oculogyric crises ## Management Consensus clinical practice guidelines for aromatic L-amino acid decarboxylase (AADC) deficiency have been published [ To establish the extent of disease and needs in an individual diagnosed with AADC deficiency, the evaluations summarized in Aromatic L-Amino Acid Decarboxylase Deficiency: Recommended Evaluations Following Initial Diagnosis Consider brain MRI scan. Consider EEG if seizures are a concern. Consider EMG/nerve conduction studies based on symptoms (e.g., reduced limb use, absent reflexes, concerns about pyridoxine-induced neuropathy). Evaluate clinical impact of any nasal congestion, sweating, & temperature instability. See also To incl motor, adaptive, cognitive, & speech-language eval (incl assessment for communication aids) Eval for early intervention / special education needs Gross motor & fine motor skills Contractures 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 To evaluate nutritional status to meet caloric requirements Consider eval for gastrostomy tube / jejunal feeding system / Nissen fundoplication in those w/dysphagia, severe GERD, &/or aspiration risk. Evaluate for GI dysmotility: GERD, constipation, diarrhea, abdominal discomfort To assess cardiac rhythm & function Consider referral to cardiologist. To assess for respiratory risk & susceptibility to chest infections Consider need for prophylactic antibiotics, winter viral vaccines, & chest PT. To assess for hypoglycemia Consider referral to endocrinologist for monitoring & treatment (see Community or online Social work involvement for parental support; Home nursing referral; Respite provision. ADL = activities of daily living; ASD = autism spectrum disorder; EKG = electrocardiography; EMG = electromyography; GERD = gastroesophageal reflux disease; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for AADC deficiency; however, gene therapy is available for a subset of individuals with genetically confirmed AADC deficiency who meet certain clinical criteria (see Aromatic L-Amino Acid Decarboxylase Deficiency: Targeted Therapies Approved in European Union & United Kingdom for treatment of persons age >18 mos w/clinical, molecular, & genetically confirmed diagnosis of AADC deficiency w/severe phenotype (i.e., persons who cannot sit, stand, or walk), & in US for persons of any disease severity who have sufficient skull maturity to tolerate the neurosurgical procedure. Oculogyric crises were reported to ↓ in severity after gene therapy, & by 2 years after surgery 63% had gained head control & 50% could sit w/o support. 3/24 persons who had long-term follow up (2-10 years) gained ability to walk independently. Starting dose of 5 µg/kg/day of base in 1-3 divided doses Increase dose every 3-7 days by 5 µg/kg/day Max dose usually around 75 µg/kg/day, but higher doses have been anecdotally used (up to 100-110 µg/kg/day) Distinction in salt & base content (base dosages provided) Non-ergot D2 agonist, w/preference for D3 receptor Drug-induced dyskinesias may be evident, so low starting dose & slow incremental dosage increases are recommended. Start 0.25 mg/day once daily, a few hours before bedtime. Increase gradually every 3-7 days to 0.5-4.0 mg/day in 3 divided doses Max dose 0.3 mg/kg/day or 24 mg/day Non-ergot D2 agonist w/preference for D3 receptor Avoid in severe kidney failure. Risk of drug-induced dyskinesia Very limited experience in AADC deficiency Start 1-2 mg/day patch Increase weekly by 1-2 mg Max 8 mg/day patch Non-ergot D2 agonist w/preference for D3 receptor; also has effect on other dopamine receptors (D1, D2, & D5; & α2B & 5-HT1A agonist) Do not cut patches. Risk of drug-induced dyskinesias; if evident, aim for lower daily dose &/or slower increase Skin reactions occur sometimes (in around one third of persons). Sulfite can lead to allergic reactions. Remove patch during MRI/electrocardioversion due to aluminum content. Start 0.1 mg/kg/day (max 1.25 mg/day) Increase weekly by 0.1 mg/kg/day (max 1.25 mg/day) up to target dose of 0.5 mg/kg/day (max 30 mg/day) in 2-3 divided doses Start 0.1 mg/kg/day in 2-3 divided doses Increase incrementally every 2 wks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. Start 0.1 mg/kg/day in 2 doses Increase every 2 wks by 0.1 mg/kg/day up to 0.5 mg/kg/day Max dose 30 mg/day Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. Occurrence of "cheese effect" (hypertensive crises when foods w/high content of tyramine are ingested) is very unlikely in persons w/AADC deficiency due to their low levels of dopamine, norepinephrine, & epinephrine. Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. Start at 100 mg/day in 2 doses Max dose 200 mg/day Pyridoxine may be drug of choice over PLP due to its lower cost & increased availability. Chronic use in high doses can cause severe sensorimotor polyneuropathy. Start at 100 mg/day in 2 doses Max dose 200 mg/day Consider if pyridoxine is not tolerated. Dose limits should be followed due to concerns about side effects (e.g., chronic use in high doses can cause severe sensorimotor polyneuropathy). 1-2 mg/kg/day Usual dose 15 mg 1x/day, but can be titrated upward according to CSF 5-MTHF levels May be used if evidence of low 5-MTHF on CSF neurotransmitter analysis Generally well tolerated Anecdotally, some affected persons are given prophylactic calcium folinate, as it is postulated that the raised 3-OMD levels seen in AADC deficiency can deplete cerebral folate levels. Start 0.5-1 mg/kg/day in 3 divided doses Increase fortnightly by 1 mg/kg to 5 mg/kg/day only if clinical effective. Further increase to max 15 mg/kg/day may be considered. Substrate for AADC to form dopamine; effective in certain persons w/substrate binding site variants. Start as first-line treatment only if known binding site variant. Monitor CSF neurotransmitters, incl 5-MTHF levels, during treatment (see 3-OMD = 3-O-methyldopa; AADC = aromatic L-amino acid decarboxylase; CSF = cerebrospinal fluid; MAO = monoamine oxidase; MTHF = methylenetetrahydrofolate; vg = vector genome Note that medications often have limited benefit, especially in individuals who have severe symptoms. Approval of the treatment in Europe and the UK followed reported improvements in symptoms and motor function in 22 affected individuals (ages 1.7-8.5 years) who were enrolled in three clinical studies [ Pergolide and cabergoline should be avoided because of the risk of fibrotic complications (see Considered a first-line treatment Individuals who have a specific pathogenic variant affecting the levodopa binding site may be levodopa responsive. Most individuals with AADC deficiency do not respond to levodopa treatment. Levodopa in combination with carbidopa is avoided because carbidopa inhibits the AADC enzyme (see 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 Aromatic L-Amino Acid Decarboxylase Deficiency: Supportive Care Feeding therapy Gastrostomy tube placement or jejunal feeding may be required for persistent feeding issues. Anticholinergic drugs (benztropine, trihexyphenidyl, etc.) Sleep induction Benzodiazepines can be considered in certain circumstances (i.e., as needed for dystonic or sustained oculogyric crises). Other medications used for hyperkinetic movement disorders incl gabapentin, clonidine. Do not use for more than 5-7 days in a row to prevent habituation. Hypertensive crises if used in tandem w/MAO inhibitors is unlikely in AADC deficiency given monoamine deficiency. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Stool softeners, prokinetics, osmotic agents, or laxatives for constipation, as needed Anti-reflux medication may be indicated. Initial dose typically starts at 1 µg/kg at night (w/blood pressure monitoring) before bed up to max of 0.3 mg/day May have some benefit in also treating irritability 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 AADC = aromatic L-amino acid decarboxylase; ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; GERD = gastroesophageal reflux disease; MAO = monoamine oxidase; 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 dystonia, consider involving appropriate specialists to aid in management of baclofen, 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 Aromatic L-Amino Acid Decarboxylase Deficiency: Recommended Surveillance Measurement of growth parameters (height, weight, head circumference) Eval of nutritional status & safety of oral intake ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; EKG = electrocardiography; MTHF = methyltetrahydrofolate To screen for cardiac valvulopathy caused by valve fibrosis (the risk is lower than with other ergot-derived dopamine agonists such as pergolide, but not absent). Avoid the following: Ergot-derived dopamine agonists with strong serotonergic (5-HT2B) agonist action (pergolide and cabergoline) due to risk of cardiac valvulopathy caused by valve fibrosis [ Levodopa in most affected individuals who do not have ligand binding site pathogenic variants Dopamine receptor antagonists (e.g., metoclopramide, antipsychotic medications), which may worsen primary disease symptoms Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of AADC deficiency. For at-risk sibs when prenatal testing was not performed: Molecular genetic testing is recommended, if the pathogenic variants in the family are known; and/or Measure CSF neurotransmitters (to evaluate for the characteristic profile) and plasma AADC enzyme activity. See Successful pregnancy has been documented in a 26-year-old female with a mild phenotype [ In general, selegiline use during pregnancy is often avoided due to concerns about potential vasoconstrictive effects. One infant in a set of twins exposed to this medication and to levodopa/carbidopa and entacapone for the treatment of Parkinson disease during pregnancy was found to have a ventricular septal defect [ In general, pramipexole is not anticipated to increase the rate of malformations in exposed human pregnancies, and there have been limited reports of normal birth outcomes in exposed infants [ See Midbrain gene delivery is being studied in an ongoing Phase I/II trial ( Both delivery approaches to gene therapy lead to detectable increases in the concentration of the dopamine metabolite homovanillic acid in cerebrospinal fluid. Greater increases are observed following midbrain gene delivery, which directly targets dopaminergic neurons. Neither approach addresses the serotonin deficiency that is also part of AADC deficiency. Search • Consider brain MRI scan. • Consider EEG if seizures are a concern. • Consider EMG/nerve conduction studies based on symptoms (e.g., reduced limb use, absent reflexes, concerns about pyridoxine-induced neuropathy). • Evaluate clinical impact of any nasal congestion, sweating, & temperature instability. • See also • To incl motor, adaptive, cognitive, & speech-language eval (incl assessment for communication aids) • Eval for early intervention / special education needs • Gross motor & fine motor skills • Contractures • 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 • To evaluate nutritional status to meet caloric requirements • Consider eval for gastrostomy tube / jejunal feeding system / Nissen fundoplication in those w/dysphagia, severe GERD, &/or aspiration risk. • Evaluate for GI dysmotility: GERD, constipation, diarrhea, abdominal discomfort • To assess cardiac rhythm & function • Consider referral to cardiologist. • To assess for respiratory risk & susceptibility to chest infections • Consider need for prophylactic antibiotics, winter viral vaccines, & chest PT. • To assess for hypoglycemia • Consider referral to endocrinologist for monitoring & treatment (see • Community or online • Social work involvement for parental support; • Home nursing referral; • Respite provision. • Approved in European Union & United Kingdom for treatment of persons age >18 mos w/clinical, molecular, & genetically confirmed diagnosis of AADC deficiency w/severe phenotype (i.e., persons who cannot sit, stand, or walk), & in US for persons of any disease severity who have sufficient skull maturity to tolerate the neurosurgical procedure. • Oculogyric crises were reported to ↓ in severity after gene therapy, & by 2 years after surgery 63% had gained head control & 50% could sit w/o support. 3/24 persons who had long-term follow up (2-10 years) gained ability to walk independently. • Starting dose of 5 µg/kg/day of base in 1-3 divided doses • Increase dose every 3-7 days by 5 µg/kg/day • Max dose usually around 75 µg/kg/day, but higher doses have been anecdotally used (up to 100-110 µg/kg/day) • Distinction in salt & base content (base dosages provided) • Non-ergot D2 agonist, w/preference for D3 receptor • Drug-induced dyskinesias may be evident, so low starting dose & slow incremental dosage increases are recommended. • Start 0.25 mg/day once daily, a few hours before bedtime. • Increase gradually every 3-7 days to 0.5-4.0 mg/day in 3 divided doses • Max dose 0.3 mg/kg/day or 24 mg/day • Non-ergot D2 agonist w/preference for D3 receptor • Avoid in severe kidney failure. • Risk of drug-induced dyskinesia • Very limited experience in AADC deficiency • Start 1-2 mg/day patch • Increase weekly by 1-2 mg • Max 8 mg/day patch • Non-ergot D2 agonist w/preference for D3 receptor; also has effect on other dopamine receptors (D1, D2, & D5; & α2B & 5-HT1A agonist) • Do not cut patches. • Risk of drug-induced dyskinesias; if evident, aim for lower daily dose &/or slower increase • Skin reactions occur sometimes (in around one third of persons). • Sulfite can lead to allergic reactions. • Remove patch during MRI/electrocardioversion due to aluminum content. • Start 0.1 mg/kg/day (max 1.25 mg/day) • Increase weekly by 0.1 mg/kg/day (max 1.25 mg/day) up to target dose of 0.5 mg/kg/day (max 30 mg/day) in 2-3 divided doses • Start 0.1 mg/kg/day in 2-3 divided doses • Increase incrementally every 2 wks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day • Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. • Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. • Start 0.1 mg/kg/day in 2 doses • Increase every 2 wks by 0.1 mg/kg/day up to 0.5 mg/kg/day • Max dose 30 mg/day • Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. • Occurrence of "cheese effect" (hypertensive crises when foods w/high content of tyramine are ingested) is very unlikely in persons w/AADC deficiency due to their low levels of dopamine, norepinephrine, & epinephrine. • Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. • Start at 100 mg/day in 2 doses • Max dose 200 mg/day • Pyridoxine may be drug of choice over PLP due to its lower cost & increased availability. • Chronic use in high doses can cause severe sensorimotor polyneuropathy. • Start at 100 mg/day in 2 doses • Max dose 200 mg/day • Consider if pyridoxine is not tolerated. • Dose limits should be followed due to concerns about side effects (e.g., chronic use in high doses can cause severe sensorimotor polyneuropathy). • 1-2 mg/kg/day • Usual dose 15 mg 1x/day, but can be titrated upward according to CSF 5-MTHF levels • May be used if evidence of low 5-MTHF on CSF neurotransmitter analysis • Generally well tolerated • Anecdotally, some affected persons are given prophylactic calcium folinate, as it is postulated that the raised 3-OMD levels seen in AADC deficiency can deplete cerebral folate levels. • Start 0.5-1 mg/kg/day in 3 divided doses • Increase fortnightly by 1 mg/kg to 5 mg/kg/day only if clinical effective. • Further increase to max 15 mg/kg/day may be considered. • Substrate for AADC to form dopamine; effective in certain persons w/substrate binding site variants. • Start as first-line treatment only if known binding site variant. • Monitor CSF neurotransmitters, incl 5-MTHF levels, during treatment (see • Feeding therapy • Gastrostomy tube placement or jejunal feeding may be required for persistent feeding issues. • Anticholinergic drugs (benztropine, trihexyphenidyl, etc.) • Sleep induction • Benzodiazepines can be considered in certain circumstances (i.e., as needed for dystonic or sustained oculogyric crises). • Other medications used for hyperkinetic movement disorders incl gabapentin, clonidine. • Do not use for more than 5-7 days in a row to prevent habituation. • Hypertensive crises if used in tandem w/MAO inhibitors is unlikely in AADC deficiency given monoamine deficiency. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Stool softeners, prokinetics, osmotic agents, or laxatives for constipation, as needed • Anti-reflux medication may be indicated. • Initial dose typically starts at 1 µg/kg at night (w/blood pressure monitoring) before bed up to max of 0.3 mg/day • May have some benefit in also treating irritability • 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 dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox • Measurement of growth parameters (height, weight, head circumference) • Eval of nutritional status & safety of oral intake • Ergot-derived dopamine agonists with strong serotonergic (5-HT2B) agonist action (pergolide and cabergoline) due to risk of cardiac valvulopathy caused by valve fibrosis [ • Levodopa in most affected individuals who do not have ligand binding site pathogenic variants • Dopamine receptor antagonists (e.g., metoclopramide, antipsychotic medications), which may worsen primary disease symptoms • Molecular genetic testing is recommended, if the pathogenic variants in the family are known; and/or • Measure CSF neurotransmitters (to evaluate for the characteristic profile) and plasma AADC enzyme activity. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with AADC deficiency, the evaluations summarized in Aromatic L-Amino Acid Decarboxylase Deficiency: Recommended Evaluations Following Initial Diagnosis Consider brain MRI scan. Consider EEG if seizures are a concern. Consider EMG/nerve conduction studies based on symptoms (e.g., reduced limb use, absent reflexes, concerns about pyridoxine-induced neuropathy). Evaluate clinical impact of any nasal congestion, sweating, & temperature instability. See also To incl motor, adaptive, cognitive, & speech-language eval (incl assessment for communication aids) Eval for early intervention / special education needs Gross motor & fine motor skills Contractures 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 To evaluate nutritional status to meet caloric requirements Consider eval for gastrostomy tube / jejunal feeding system / Nissen fundoplication in those w/dysphagia, severe GERD, &/or aspiration risk. Evaluate for GI dysmotility: GERD, constipation, diarrhea, abdominal discomfort To assess cardiac rhythm & function Consider referral to cardiologist. To assess for respiratory risk & susceptibility to chest infections Consider need for prophylactic antibiotics, winter viral vaccines, & chest PT. To assess for hypoglycemia Consider referral to endocrinologist for monitoring & treatment (see Community or online Social work involvement for parental support; Home nursing referral; Respite provision. ADL = activities of daily living; ASD = autism spectrum disorder; EKG = electrocardiography; EMG = electromyography; GERD = gastroesophageal reflux disease; GI = gastrointestinal; 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) • Consider brain MRI scan. • Consider EEG if seizures are a concern. • Consider EMG/nerve conduction studies based on symptoms (e.g., reduced limb use, absent reflexes, concerns about pyridoxine-induced neuropathy). • Evaluate clinical impact of any nasal congestion, sweating, & temperature instability. • See also • To incl motor, adaptive, cognitive, & speech-language eval (incl assessment for communication aids) • Eval for early intervention / special education needs • Gross motor & fine motor skills • Contractures • 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 • To evaluate nutritional status to meet caloric requirements • Consider eval for gastrostomy tube / jejunal feeding system / Nissen fundoplication in those w/dysphagia, severe GERD, &/or aspiration risk. • Evaluate for GI dysmotility: GERD, constipation, diarrhea, abdominal discomfort • To assess cardiac rhythm & function • Consider referral to cardiologist. • To assess for respiratory risk & susceptibility to chest infections • Consider need for prophylactic antibiotics, winter viral vaccines, & chest PT. • To assess for hypoglycemia • Consider referral to endocrinologist for monitoring & treatment (see • Community or online • Social work involvement for parental support; • Home nursing referral; • Respite provision. ## Treatment of Manifestations There is no cure for AADC deficiency; however, gene therapy is available for a subset of individuals with genetically confirmed AADC deficiency who meet certain clinical criteria (see Aromatic L-Amino Acid Decarboxylase Deficiency: Targeted Therapies Approved in European Union & United Kingdom for treatment of persons age >18 mos w/clinical, molecular, & genetically confirmed diagnosis of AADC deficiency w/severe phenotype (i.e., persons who cannot sit, stand, or walk), & in US for persons of any disease severity who have sufficient skull maturity to tolerate the neurosurgical procedure. Oculogyric crises were reported to ↓ in severity after gene therapy, & by 2 years after surgery 63% had gained head control & 50% could sit w/o support. 3/24 persons who had long-term follow up (2-10 years) gained ability to walk independently. Starting dose of 5 µg/kg/day of base in 1-3 divided doses Increase dose every 3-7 days by 5 µg/kg/day Max dose usually around 75 µg/kg/day, but higher doses have been anecdotally used (up to 100-110 µg/kg/day) Distinction in salt & base content (base dosages provided) Non-ergot D2 agonist, w/preference for D3 receptor Drug-induced dyskinesias may be evident, so low starting dose & slow incremental dosage increases are recommended. Start 0.25 mg/day once daily, a few hours before bedtime. Increase gradually every 3-7 days to 0.5-4.0 mg/day in 3 divided doses Max dose 0.3 mg/kg/day or 24 mg/day Non-ergot D2 agonist w/preference for D3 receptor Avoid in severe kidney failure. Risk of drug-induced dyskinesia Very limited experience in AADC deficiency Start 1-2 mg/day patch Increase weekly by 1-2 mg Max 8 mg/day patch Non-ergot D2 agonist w/preference for D3 receptor; also has effect on other dopamine receptors (D1, D2, & D5; & α2B & 5-HT1A agonist) Do not cut patches. Risk of drug-induced dyskinesias; if evident, aim for lower daily dose &/or slower increase Skin reactions occur sometimes (in around one third of persons). Sulfite can lead to allergic reactions. Remove patch during MRI/electrocardioversion due to aluminum content. Start 0.1 mg/kg/day (max 1.25 mg/day) Increase weekly by 0.1 mg/kg/day (max 1.25 mg/day) up to target dose of 0.5 mg/kg/day (max 30 mg/day) in 2-3 divided doses Start 0.1 mg/kg/day in 2-3 divided doses Increase incrementally every 2 wks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. Start 0.1 mg/kg/day in 2 doses Increase every 2 wks by 0.1 mg/kg/day up to 0.5 mg/kg/day Max dose 30 mg/day Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. Occurrence of "cheese effect" (hypertensive crises when foods w/high content of tyramine are ingested) is very unlikely in persons w/AADC deficiency due to their low levels of dopamine, norepinephrine, & epinephrine. Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. Start at 100 mg/day in 2 doses Max dose 200 mg/day Pyridoxine may be drug of choice over PLP due to its lower cost & increased availability. Chronic use in high doses can cause severe sensorimotor polyneuropathy. Start at 100 mg/day in 2 doses Max dose 200 mg/day Consider if pyridoxine is not tolerated. Dose limits should be followed due to concerns about side effects (e.g., chronic use in high doses can cause severe sensorimotor polyneuropathy). 1-2 mg/kg/day Usual dose 15 mg 1x/day, but can be titrated upward according to CSF 5-MTHF levels May be used if evidence of low 5-MTHF on CSF neurotransmitter analysis Generally well tolerated Anecdotally, some affected persons are given prophylactic calcium folinate, as it is postulated that the raised 3-OMD levels seen in AADC deficiency can deplete cerebral folate levels. Start 0.5-1 mg/kg/day in 3 divided doses Increase fortnightly by 1 mg/kg to 5 mg/kg/day only if clinical effective. Further increase to max 15 mg/kg/day may be considered. Substrate for AADC to form dopamine; effective in certain persons w/substrate binding site variants. Start as first-line treatment only if known binding site variant. Monitor CSF neurotransmitters, incl 5-MTHF levels, during treatment (see 3-OMD = 3-O-methyldopa; AADC = aromatic L-amino acid decarboxylase; CSF = cerebrospinal fluid; MAO = monoamine oxidase; MTHF = methylenetetrahydrofolate; vg = vector genome Note that medications often have limited benefit, especially in individuals who have severe symptoms. Approval of the treatment in Europe and the UK followed reported improvements in symptoms and motor function in 22 affected individuals (ages 1.7-8.5 years) who were enrolled in three clinical studies [ Pergolide and cabergoline should be avoided because of the risk of fibrotic complications (see Considered a first-line treatment Individuals who have a specific pathogenic variant affecting the levodopa binding site may be levodopa responsive. Most individuals with AADC deficiency do not respond to levodopa treatment. Levodopa in combination with carbidopa is avoided because carbidopa inhibits the AADC enzyme (see 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 Aromatic L-Amino Acid Decarboxylase Deficiency: Supportive Care Feeding therapy Gastrostomy tube placement or jejunal feeding may be required for persistent feeding issues. Anticholinergic drugs (benztropine, trihexyphenidyl, etc.) Sleep induction Benzodiazepines can be considered in certain circumstances (i.e., as needed for dystonic or sustained oculogyric crises). Other medications used for hyperkinetic movement disorders incl gabapentin, clonidine. Do not use for more than 5-7 days in a row to prevent habituation. Hypertensive crises if used in tandem w/MAO inhibitors is unlikely in AADC deficiency given monoamine deficiency. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Stool softeners, prokinetics, osmotic agents, or laxatives for constipation, as needed Anti-reflux medication may be indicated. Initial dose typically starts at 1 µg/kg at night (w/blood pressure monitoring) before bed up to max of 0.3 mg/day May have some benefit in also treating irritability 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 AADC = aromatic L-amino acid decarboxylase; ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; GERD = gastroesophageal reflux disease; MAO = monoamine oxidase; 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 dystonia, consider involving appropriate specialists to aid in management of baclofen, 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. • Approved in European Union & United Kingdom for treatment of persons age >18 mos w/clinical, molecular, & genetically confirmed diagnosis of AADC deficiency w/severe phenotype (i.e., persons who cannot sit, stand, or walk), & in US for persons of any disease severity who have sufficient skull maturity to tolerate the neurosurgical procedure. • Oculogyric crises were reported to ↓ in severity after gene therapy, & by 2 years after surgery 63% had gained head control & 50% could sit w/o support. 3/24 persons who had long-term follow up (2-10 years) gained ability to walk independently. • Starting dose of 5 µg/kg/day of base in 1-3 divided doses • Increase dose every 3-7 days by 5 µg/kg/day • Max dose usually around 75 µg/kg/day, but higher doses have been anecdotally used (up to 100-110 µg/kg/day) • Distinction in salt & base content (base dosages provided) • Non-ergot D2 agonist, w/preference for D3 receptor • Drug-induced dyskinesias may be evident, so low starting dose & slow incremental dosage increases are recommended. • Start 0.25 mg/day once daily, a few hours before bedtime. • Increase gradually every 3-7 days to 0.5-4.0 mg/day in 3 divided doses • Max dose 0.3 mg/kg/day or 24 mg/day • Non-ergot D2 agonist w/preference for D3 receptor • Avoid in severe kidney failure. • Risk of drug-induced dyskinesia • Very limited experience in AADC deficiency • Start 1-2 mg/day patch • Increase weekly by 1-2 mg • Max 8 mg/day patch • Non-ergot D2 agonist w/preference for D3 receptor; also has effect on other dopamine receptors (D1, D2, & D5; & α2B & 5-HT1A agonist) • Do not cut patches. • Risk of drug-induced dyskinesias; if evident, aim for lower daily dose &/or slower increase • Skin reactions occur sometimes (in around one third of persons). • Sulfite can lead to allergic reactions. • Remove patch during MRI/electrocardioversion due to aluminum content. • Start 0.1 mg/kg/day (max 1.25 mg/day) • Increase weekly by 0.1 mg/kg/day (max 1.25 mg/day) up to target dose of 0.5 mg/kg/day (max 30 mg/day) in 2-3 divided doses • Start 0.1 mg/kg/day in 2-3 divided doses • Increase incrementally every 2 wks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day • Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. • Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. • Start 0.1 mg/kg/day in 2 doses • Increase every 2 wks by 0.1 mg/kg/day up to 0.5 mg/kg/day • Max dose 30 mg/day • Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. • Occurrence of "cheese effect" (hypertensive crises when foods w/high content of tyramine are ingested) is very unlikely in persons w/AADC deficiency due to their low levels of dopamine, norepinephrine, & epinephrine. • Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. • Start at 100 mg/day in 2 doses • Max dose 200 mg/day • Pyridoxine may be drug of choice over PLP due to its lower cost & increased availability. • Chronic use in high doses can cause severe sensorimotor polyneuropathy. • Start at 100 mg/day in 2 doses • Max dose 200 mg/day • Consider if pyridoxine is not tolerated. • Dose limits should be followed due to concerns about side effects (e.g., chronic use in high doses can cause severe sensorimotor polyneuropathy). • 1-2 mg/kg/day • Usual dose 15 mg 1x/day, but can be titrated upward according to CSF 5-MTHF levels • May be used if evidence of low 5-MTHF on CSF neurotransmitter analysis • Generally well tolerated • Anecdotally, some affected persons are given prophylactic calcium folinate, as it is postulated that the raised 3-OMD levels seen in AADC deficiency can deplete cerebral folate levels. • Start 0.5-1 mg/kg/day in 3 divided doses • Increase fortnightly by 1 mg/kg to 5 mg/kg/day only if clinical effective. • Further increase to max 15 mg/kg/day may be considered. • Substrate for AADC to form dopamine; effective in certain persons w/substrate binding site variants. • Start as first-line treatment only if known binding site variant. • Monitor CSF neurotransmitters, incl 5-MTHF levels, during treatment (see • Feeding therapy • Gastrostomy tube placement or jejunal feeding may be required for persistent feeding issues. • Anticholinergic drugs (benztropine, trihexyphenidyl, etc.) • Sleep induction • Benzodiazepines can be considered in certain circumstances (i.e., as needed for dystonic or sustained oculogyric crises). • Other medications used for hyperkinetic movement disorders incl gabapentin, clonidine. • Do not use for more than 5-7 days in a row to prevent habituation. • Hypertensive crises if used in tandem w/MAO inhibitors is unlikely in AADC deficiency given monoamine deficiency. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Stool softeners, prokinetics, osmotic agents, or laxatives for constipation, as needed • Anti-reflux medication may be indicated. • Initial dose typically starts at 1 µg/kg at night (w/blood pressure monitoring) before bed up to max of 0.3 mg/day • May have some benefit in also treating irritability • 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 dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox ## Targeted Therapies Aromatic L-Amino Acid Decarboxylase Deficiency: Targeted Therapies Approved in European Union & United Kingdom for treatment of persons age >18 mos w/clinical, molecular, & genetically confirmed diagnosis of AADC deficiency w/severe phenotype (i.e., persons who cannot sit, stand, or walk), & in US for persons of any disease severity who have sufficient skull maturity to tolerate the neurosurgical procedure. Oculogyric crises were reported to ↓ in severity after gene therapy, & by 2 years after surgery 63% had gained head control & 50% could sit w/o support. 3/24 persons who had long-term follow up (2-10 years) gained ability to walk independently. Starting dose of 5 µg/kg/day of base in 1-3 divided doses Increase dose every 3-7 days by 5 µg/kg/day Max dose usually around 75 µg/kg/day, but higher doses have been anecdotally used (up to 100-110 µg/kg/day) Distinction in salt & base content (base dosages provided) Non-ergot D2 agonist, w/preference for D3 receptor Drug-induced dyskinesias may be evident, so low starting dose & slow incremental dosage increases are recommended. Start 0.25 mg/day once daily, a few hours before bedtime. Increase gradually every 3-7 days to 0.5-4.0 mg/day in 3 divided doses Max dose 0.3 mg/kg/day or 24 mg/day Non-ergot D2 agonist w/preference for D3 receptor Avoid in severe kidney failure. Risk of drug-induced dyskinesia Very limited experience in AADC deficiency Start 1-2 mg/day patch Increase weekly by 1-2 mg Max 8 mg/day patch Non-ergot D2 agonist w/preference for D3 receptor; also has effect on other dopamine receptors (D1, D2, & D5; & α2B & 5-HT1A agonist) Do not cut patches. Risk of drug-induced dyskinesias; if evident, aim for lower daily dose &/or slower increase Skin reactions occur sometimes (in around one third of persons). Sulfite can lead to allergic reactions. Remove patch during MRI/electrocardioversion due to aluminum content. Start 0.1 mg/kg/day (max 1.25 mg/day) Increase weekly by 0.1 mg/kg/day (max 1.25 mg/day) up to target dose of 0.5 mg/kg/day (max 30 mg/day) in 2-3 divided doses Start 0.1 mg/kg/day in 2-3 divided doses Increase incrementally every 2 wks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. Start 0.1 mg/kg/day in 2 doses Increase every 2 wks by 0.1 mg/kg/day up to 0.5 mg/kg/day Max dose 30 mg/day Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. Occurrence of "cheese effect" (hypertensive crises when foods w/high content of tyramine are ingested) is very unlikely in persons w/AADC deficiency due to their low levels of dopamine, norepinephrine, & epinephrine. Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. Start at 100 mg/day in 2 doses Max dose 200 mg/day Pyridoxine may be drug of choice over PLP due to its lower cost & increased availability. Chronic use in high doses can cause severe sensorimotor polyneuropathy. Start at 100 mg/day in 2 doses Max dose 200 mg/day Consider if pyridoxine is not tolerated. Dose limits should be followed due to concerns about side effects (e.g., chronic use in high doses can cause severe sensorimotor polyneuropathy). 1-2 mg/kg/day Usual dose 15 mg 1x/day, but can be titrated upward according to CSF 5-MTHF levels May be used if evidence of low 5-MTHF on CSF neurotransmitter analysis Generally well tolerated Anecdotally, some affected persons are given prophylactic calcium folinate, as it is postulated that the raised 3-OMD levels seen in AADC deficiency can deplete cerebral folate levels. Start 0.5-1 mg/kg/day in 3 divided doses Increase fortnightly by 1 mg/kg to 5 mg/kg/day only if clinical effective. Further increase to max 15 mg/kg/day may be considered. Substrate for AADC to form dopamine; effective in certain persons w/substrate binding site variants. Start as first-line treatment only if known binding site variant. Monitor CSF neurotransmitters, incl 5-MTHF levels, during treatment (see 3-OMD = 3-O-methyldopa; AADC = aromatic L-amino acid decarboxylase; CSF = cerebrospinal fluid; MAO = monoamine oxidase; MTHF = methylenetetrahydrofolate; vg = vector genome Note that medications often have limited benefit, especially in individuals who have severe symptoms. Approval of the treatment in Europe and the UK followed reported improvements in symptoms and motor function in 22 affected individuals (ages 1.7-8.5 years) who were enrolled in three clinical studies [ Pergolide and cabergoline should be avoided because of the risk of fibrotic complications (see Considered a first-line treatment Individuals who have a specific pathogenic variant affecting the levodopa binding site may be levodopa responsive. Most individuals with AADC deficiency do not respond to levodopa treatment. Levodopa in combination with carbidopa is avoided because carbidopa inhibits the AADC enzyme (see • Approved in European Union & United Kingdom for treatment of persons age >18 mos w/clinical, molecular, & genetically confirmed diagnosis of AADC deficiency w/severe phenotype (i.e., persons who cannot sit, stand, or walk), & in US for persons of any disease severity who have sufficient skull maturity to tolerate the neurosurgical procedure. • Oculogyric crises were reported to ↓ in severity after gene therapy, & by 2 years after surgery 63% had gained head control & 50% could sit w/o support. 3/24 persons who had long-term follow up (2-10 years) gained ability to walk independently. • Starting dose of 5 µg/kg/day of base in 1-3 divided doses • Increase dose every 3-7 days by 5 µg/kg/day • Max dose usually around 75 µg/kg/day, but higher doses have been anecdotally used (up to 100-110 µg/kg/day) • Distinction in salt & base content (base dosages provided) • Non-ergot D2 agonist, w/preference for D3 receptor • Drug-induced dyskinesias may be evident, so low starting dose & slow incremental dosage increases are recommended. • Start 0.25 mg/day once daily, a few hours before bedtime. • Increase gradually every 3-7 days to 0.5-4.0 mg/day in 3 divided doses • Max dose 0.3 mg/kg/day or 24 mg/day • Non-ergot D2 agonist w/preference for D3 receptor • Avoid in severe kidney failure. • Risk of drug-induced dyskinesia • Very limited experience in AADC deficiency • Start 1-2 mg/day patch • Increase weekly by 1-2 mg • Max 8 mg/day patch • Non-ergot D2 agonist w/preference for D3 receptor; also has effect on other dopamine receptors (D1, D2, & D5; & α2B & 5-HT1A agonist) • Do not cut patches. • Risk of drug-induced dyskinesias; if evident, aim for lower daily dose &/or slower increase • Skin reactions occur sometimes (in around one third of persons). • Sulfite can lead to allergic reactions. • Remove patch during MRI/electrocardioversion due to aluminum content. • Start 0.1 mg/kg/day (max 1.25 mg/day) • Increase weekly by 0.1 mg/kg/day (max 1.25 mg/day) up to target dose of 0.5 mg/kg/day (max 30 mg/day) in 2-3 divided doses • Start 0.1 mg/kg/day in 2-3 divided doses • Increase incrementally every 2 wks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day • Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. • Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. • Start 0.1 mg/kg/day in 2 doses • Increase every 2 wks by 0.1 mg/kg/day up to 0.5 mg/kg/day • Max dose 30 mg/day • Give final dose of the day no later than mid-afternoon, as it can affect sleeping pattern. • Occurrence of "cheese effect" (hypertensive crises when foods w/high content of tyramine are ingested) is very unlikely in persons w/AADC deficiency due to their low levels of dopamine, norepinephrine, & epinephrine. • Most persons treated w/this drug also receive dopamine agonists &/or pyridoxine. • Start at 100 mg/day in 2 doses • Max dose 200 mg/day • Pyridoxine may be drug of choice over PLP due to its lower cost & increased availability. • Chronic use in high doses can cause severe sensorimotor polyneuropathy. • Start at 100 mg/day in 2 doses • Max dose 200 mg/day • Consider if pyridoxine is not tolerated. • Dose limits should be followed due to concerns about side effects (e.g., chronic use in high doses can cause severe sensorimotor polyneuropathy). • 1-2 mg/kg/day • Usual dose 15 mg 1x/day, but can be titrated upward according to CSF 5-MTHF levels • May be used if evidence of low 5-MTHF on CSF neurotransmitter analysis • Generally well tolerated • Anecdotally, some affected persons are given prophylactic calcium folinate, as it is postulated that the raised 3-OMD levels seen in AADC deficiency can deplete cerebral folate levels. • Start 0.5-1 mg/kg/day in 3 divided doses • Increase fortnightly by 1 mg/kg to 5 mg/kg/day only if clinical effective. • Further increase to max 15 mg/kg/day may be considered. • Substrate for AADC to form dopamine; effective in certain persons w/substrate binding site variants. • Start as first-line treatment only if known binding site variant. • Monitor CSF neurotransmitters, incl 5-MTHF levels, during treatment (see ## Supportive Care Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Aromatic L-Amino Acid Decarboxylase Deficiency: Supportive Care Feeding therapy Gastrostomy tube placement or jejunal feeding may be required for persistent feeding issues. Anticholinergic drugs (benztropine, trihexyphenidyl, etc.) Sleep induction Benzodiazepines can be considered in certain circumstances (i.e., as needed for dystonic or sustained oculogyric crises). Other medications used for hyperkinetic movement disorders incl gabapentin, clonidine. Do not use for more than 5-7 days in a row to prevent habituation. Hypertensive crises if used in tandem w/MAO inhibitors is unlikely in AADC deficiency given monoamine deficiency. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Stool softeners, prokinetics, osmotic agents, or laxatives for constipation, as needed Anti-reflux medication may be indicated. Initial dose typically starts at 1 µg/kg at night (w/blood pressure monitoring) before bed up to max of 0.3 mg/day May have some benefit in also treating irritability 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 AADC = aromatic L-amino acid decarboxylase; ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; GERD = gastroesophageal reflux disease; MAO = monoamine oxidase; 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 dystonia, consider involving appropriate specialists to aid in management of baclofen, 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 or jejunal feeding may be required for persistent feeding issues. • Anticholinergic drugs (benztropine, trihexyphenidyl, etc.) • Sleep induction • Benzodiazepines can be considered in certain circumstances (i.e., as needed for dystonic or sustained oculogyric crises). • Other medications used for hyperkinetic movement disorders incl gabapentin, clonidine. • Do not use for more than 5-7 days in a row to prevent habituation. • Hypertensive crises if used in tandem w/MAO inhibitors is unlikely in AADC deficiency given monoamine deficiency. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Stool softeners, prokinetics, osmotic agents, or laxatives for constipation, as needed • Anti-reflux medication may be indicated. • Initial dose typically starts at 1 µg/kg at night (w/blood pressure monitoring) before bed up to max of 0.3 mg/day • May have some benefit in also treating irritability • 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 dystonia, consider involving appropriate specialists to aid in management of baclofen, Botox ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of baclofen, 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 dystonia, consider involving appropriate specialists to aid in management of baclofen, 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 Aromatic L-Amino Acid Decarboxylase Deficiency: Recommended Surveillance Measurement of growth parameters (height, weight, head circumference) Eval of nutritional status & safety of oral intake ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CSF = cerebrospinal fluid; EKG = electrocardiography; MTHF = methyltetrahydrofolate To screen for cardiac valvulopathy caused by valve fibrosis (the risk is lower than with other ergot-derived dopamine agonists such as pergolide, but not absent). • Measurement of growth parameters (height, weight, head circumference) • Eval of nutritional status & safety of oral intake ## Agents/Circumstances to Avoid Avoid the following: Ergot-derived dopamine agonists with strong serotonergic (5-HT2B) agonist action (pergolide and cabergoline) due to risk of cardiac valvulopathy caused by valve fibrosis [ Levodopa in most affected individuals who do not have ligand binding site pathogenic variants Dopamine receptor antagonists (e.g., metoclopramide, antipsychotic medications), which may worsen primary disease symptoms • Ergot-derived dopamine agonists with strong serotonergic (5-HT2B) agonist action (pergolide and cabergoline) due to risk of cardiac valvulopathy caused by valve fibrosis [ • Levodopa in most affected individuals who do not have ligand binding site pathogenic variants • Dopamine receptor antagonists (e.g., metoclopramide, antipsychotic medications), which may worsen primary disease symptoms ## Evaluation of Relatives at Risk Testing of all at-risk sibs of any age is warranted to allow for early diagnosis and treatment of AADC deficiency. For at-risk sibs when prenatal testing was not performed: Molecular genetic testing is recommended, if the pathogenic variants in the family are known; and/or Measure CSF neurotransmitters (to evaluate for the characteristic profile) and plasma AADC enzyme activity. See • Molecular genetic testing is recommended, if the pathogenic variants in the family are known; and/or • Measure CSF neurotransmitters (to evaluate for the characteristic profile) and plasma AADC enzyme activity. ## Pregnancy Management Successful pregnancy has been documented in a 26-year-old female with a mild phenotype [ In general, selegiline use during pregnancy is often avoided due to concerns about potential vasoconstrictive effects. One infant in a set of twins exposed to this medication and to levodopa/carbidopa and entacapone for the treatment of Parkinson disease during pregnancy was found to have a ventricular septal defect [ In general, pramipexole is not anticipated to increase the rate of malformations in exposed human pregnancies, and there have been limited reports of normal birth outcomes in exposed infants [ See ## Therapies Under Investigation Midbrain gene delivery is being studied in an ongoing Phase I/II trial ( Both delivery approaches to gene therapy lead to detectable increases in the concentration of the dopamine metabolite homovanillic acid in cerebrospinal fluid. Greater increases are observed following midbrain gene delivery, which directly targets dopaminergic neurons. Neither approach addresses the serotonin deficiency that is also part of AADC deficiency. Search ## Genetic Counseling Aromatic L-amino acid decarboxylase (AADC) 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, 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 Affected sibs tend to have similar clinical disease severity, although some variability has been observed (e.g., mild and moderate phenotypes described in the same family) [ 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 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 should be considered for the reproductive partners of individuals known to be carriers of AADC deficiency, particularly if both partners are of the same ancestral background. A pathogenic founder variant has been observed in individuals of Asian (particularly Chinese, Taiwanese, or Japanese) ancestry (see 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 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 • Affected sibs tend to have similar clinical disease severity, although some variability has been observed (e.g., mild and moderate phenotypes described in the same family) [ • 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 individuals known to be carriers of AADC deficiency, particularly if both partners are of the same ancestral background. A pathogenic founder variant has been observed in individuals of Asian (particularly Chinese, Taiwanese, or Japanese) ancestry (see ## Mode of Inheritance Aromatic L-amino acid decarboxylase (AADC) 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, 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 Affected sibs tend to have similar clinical disease severity, although some variability has been observed (e.g., mild and moderate phenotypes described in the same family) [ 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, 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 • Affected sibs tend to have similar clinical disease severity, although some variability has been observed (e.g., mild and moderate phenotypes described in the same family) [ • 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 ## 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 should be considered for the reproductive partners of individuals known to be carriers of AADC deficiency, particularly if both partners are of the same ancestral background. A pathogenic founder variant has been observed in individuals of Asian (particularly Chinese, Taiwanese, or Japanese) 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 individuals known to be carriers of AADC deficiency, particularly if both partners are of the same ancestral background. A pathogenic founder variant has been observed in individuals of Asian (particularly Chinese, Taiwanese, or Japanese) ancestry (see ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom United Kingdom • • • • United Kingdom • • • • • • • United Kingdom • ## Molecular Genetics Aromatic L-Amino Acid Decarboxylase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Aromatic L-Amino Acid Decarboxylase Deficiency ( Other Molecular Resources: IEMbase Entries for Aromatic L-Amino Acid Decarboxylase Deficiency ( AF = allele frequency Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis AF = allele frequency Variants listed in the table have been provided by the authors. ## Chapter Notes This work was supported in part by Nenad Blau IEMbase Endowment Fund of the MCF, Marin County, CA, USA. Sarah Elsea acknowledges research support for AADC deficiency research from PTC Therapeutics, support for metabolomics, genomics, and newborn screening research and development in neurotransmitter deficiencies from Speragen, Inc., and the SSADH Association. 23 January 2025 (ma) Revision: eladocagene exuparvovec approved by FDA ( 12 October 2023 (ma) Review posted live 9 January 2023 (nb) Original submission • 23 January 2025 (ma) Revision: eladocagene exuparvovec approved by FDA ( • 12 October 2023 (ma) Review posted live • 9 January 2023 (nb) Original submission ## Author Notes ## Acknowledgments This work was supported in part by Nenad Blau IEMbase Endowment Fund of the MCF, Marin County, CA, USA. Sarah Elsea acknowledges research support for AADC deficiency research from PTC Therapeutics, support for metabolomics, genomics, and newborn screening research and development in neurotransmitter deficiencies from Speragen, Inc., and the SSADH Association. ## Revision History 23 January 2025 (ma) Revision: eladocagene exuparvovec approved by FDA ( 12 October 2023 (ma) Review posted live 9 January 2023 (nb) Original submission • 23 January 2025 (ma) Revision: eladocagene exuparvovec approved by FDA ( • 12 October 2023 (ma) Review posted live • 9 January 2023 (nb) Original submission ## Key Sections in this ## References ## Literature Cited Diagnostic flowchart to establish a diagnosis of AADC deficiency	[]	12/10/2023		23/1/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aars2-dis	aars2-dis	[ "AARS2-Related Infant-Onset Cardiomyopathy", "AARS2-Related Neurodegeneration With or Without Leukoencephalopathy", "Alanine--tRNA ligase, mitochondrial", "AARS2", "AARS2-Related Disorder" ]		Tomasz Chmiela, Zbigniew K Wszolek	Summary The diagnosis of In In	Infantile-onset cardiomyopathy Neurodegeneration with or without leukoencephalopathy For other genetic causes of these phenotypes, see • Infantile-onset cardiomyopathy • Neurodegeneration with or without leukoencephalopathy ## Diagnosis Formal diagnostic criteria for Hypertrophic cardiomyopathy Hypotonia Muscle weakness Lung hypoplasia Nonimmune hydrops fetalis Motor disorders, including ataxia, dystonia, chorea, parkinsonism, tremor spasticity, and/or hyperreflexia Cognitive decline Endocrine manifestations (in females) such as hypogonadism and premature ovarian failure Psychiatric manifestations, including depression, psychosis, anxiety, and/or behavioral changes Ocular manifestations such as nystagmus and ophthalmoplegia Progressive bilateral white matter lesions, hyperintense in T Linear or punctate lesions on diffusion-weighted imaging. Partly confluent lesions are typically present. Lesions may be found in the corona radiata and centrum semiovale. Brain atrophy and thinning of corpus callosum Absence of white matter calcifications White matter demonstrates rarefaction with suppression on fluid-attenuated inversion recovery MRI sequences. Note: In 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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. • Hypertrophic cardiomyopathy • Hypotonia • Muscle weakness • Lung hypoplasia • Nonimmune hydrops fetalis • Motor disorders, including ataxia, dystonia, chorea, parkinsonism, tremor spasticity, and/or hyperreflexia • Cognitive decline • Endocrine manifestations (in females) such as hypogonadism and premature ovarian failure • Psychiatric manifestations, including depression, psychosis, anxiety, and/or behavioral changes • Ocular manifestations such as nystagmus and ophthalmoplegia • Progressive bilateral white matter lesions, hyperintense in T • Linear or punctate lesions on diffusion-weighted imaging. Partly confluent lesions are typically present. Lesions may be found in the corona radiata and centrum semiovale. • Brain atrophy and thinning of corpus callosum • Absence of white matter calcifications • White matter demonstrates rarefaction with suppression on fluid-attenuated inversion recovery MRI sequences. ## Suggestive Findings Hypertrophic cardiomyopathy Hypotonia Muscle weakness Lung hypoplasia Nonimmune hydrops fetalis Motor disorders, including ataxia, dystonia, chorea, parkinsonism, tremor spasticity, and/or hyperreflexia Cognitive decline Endocrine manifestations (in females) such as hypogonadism and premature ovarian failure Psychiatric manifestations, including depression, psychosis, anxiety, and/or behavioral changes Ocular manifestations such as nystagmus and ophthalmoplegia Progressive bilateral white matter lesions, hyperintense in T Linear or punctate lesions on diffusion-weighted imaging. Partly confluent lesions are typically present. Lesions may be found in the corona radiata and centrum semiovale. Brain atrophy and thinning of corpus callosum Absence of white matter calcifications White matter demonstrates rarefaction with suppression on fluid-attenuated inversion recovery MRI sequences. Note: In • Hypertrophic cardiomyopathy • Hypotonia • Muscle weakness • Lung hypoplasia • Nonimmune hydrops fetalis • Motor disorders, including ataxia, dystonia, chorea, parkinsonism, tremor spasticity, and/or hyperreflexia • Cognitive decline • Endocrine manifestations (in females) such as hypogonadism and premature ovarian failure • Psychiatric manifestations, including depression, psychosis, anxiety, and/or behavioral changes • Ocular manifestations such as nystagmus and ophthalmoplegia • Progressive bilateral white matter lesions, hyperintense in T • Linear or punctate lesions on diffusion-weighted imaging. Partly confluent lesions are typically present. Lesions may be found in the corona radiata and centrum semiovale. • Brain atrophy and thinning of corpus callosum • Absence of white matter calcifications • White matter demonstrates rarefaction with suppression on fluid-attenuated inversion recovery MRI sequences. Hypertrophic cardiomyopathy Hypotonia Muscle weakness Lung hypoplasia Nonimmune hydrops fetalis • Hypertrophic cardiomyopathy • Hypotonia • Muscle weakness • Lung hypoplasia • Nonimmune hydrops fetalis Motor disorders, including ataxia, dystonia, chorea, parkinsonism, tremor spasticity, and/or hyperreflexia Cognitive decline Endocrine manifestations (in females) such as hypogonadism and premature ovarian failure Psychiatric manifestations, including depression, psychosis, anxiety, and/or behavioral changes Ocular manifestations such as nystagmus and ophthalmoplegia Progressive bilateral white matter lesions, hyperintense in T Linear or punctate lesions on diffusion-weighted imaging. Partly confluent lesions are typically present. Lesions may be found in the corona radiata and centrum semiovale. Brain atrophy and thinning of corpus callosum Absence of white matter calcifications White matter demonstrates rarefaction with suppression on fluid-attenuated inversion recovery MRI sequences. Note: In • Motor disorders, including ataxia, dystonia, chorea, parkinsonism, tremor spasticity, and/or hyperreflexia • Cognitive decline • Endocrine manifestations (in females) such as hypogonadism and premature ovarian failure • Psychiatric manifestations, including depression, psychosis, anxiety, and/or behavioral changes • Ocular manifestations such as nystagmus and ophthalmoplegia • Progressive bilateral white matter lesions, hyperintense in T • Linear or punctate lesions on diffusion-weighted imaging. Partly confluent lesions are typically present. Lesions may be found in the corona radiata and centrum semiovale. • Brain atrophy and thinning of corpus callosum • Absence of white matter calcifications • White matter demonstrates rarefaction with suppression on fluid-attenuated inversion recovery MRI sequences. ## 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 Percentages are based on 18 individuals with Percentages are based on 48 individuals with Pathogenic variants affecting the aminoacylation domain (residues 24-477) have been shown to cause leukoencephalopathy and premature ovarian failure in women [ No other genotype-phenotype correlations have been identified. ## Clinical Description Percentages are based on 18 individuals with Percentages are based on 48 individuals with Percentages are based on 18 individuals with ## AARS2-Related Neurodegeneration with or without Leukoencephalopathy Percentages are based on 48 individuals with ## Genotype-Phenotype Correlations Pathogenic variants affecting the aminoacylation domain (residues 24-477) have been shown to cause leukoencephalopathy and premature ovarian failure in women [ No other genotype-phenotype correlations have been identified. ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Hypertrophic CM Muscle weakness Respiratory deficiency Macroglossia Less severe manifestations Angiokeratomas Hypohidrosis Proteinuria Kidney disease Hypertrophic CM Skeletal muscle weakness Fatal early-onset CM Lactic acidosis Neonatal hypoglycemia Dysmorphic facies Phenotype of spinal muscular atrophy Less severe manifestations Hypertrophic CM Hypotonia Hyperammonemia Characteristic pattern of facial features AD = autosomal dominant; AR = autosomal recessive; CM = cardiomyopathy; Mat = maternal; MOI = mode of inheritance; XL = X-linked See also Genetic Disorders in the Differential Diagnosis of Older age of onset No premature ovarian failure in females White matter calcification on brain MRI Cognitive decline Behavioral changes Presence of ovarian failure in females Cognitive decline Executive dysfunction Cognitive impairment (late manifestation) Ataxia Pyramidal signs Early autonomic dysfunction Periventricular rims of lateral ventricles normal or mildly affected on brain MRI Neurodegeneration Ataxia Pyramidal signs Normal cognitive function in adults Palatal myoclonus Cognitive decline Pyramidal signs Seizures Psychiatric features Peripheral neuropathy No WML in cerebellum Peripheral neuropathy MRI changes predominantly in posterior white matter Demyelination in brain stem & cerebellum Cognitive decline Pyramidal signs Neuropathy WML are contrast enhancing. Frontal & temporal atrophy Fewer WML Motor neuron disease Skin changes, hepatosplenomegaly (GM1) Early-childhood onset, cherry-red spots of macula (GM2) Frontal & temporal atrophy Fewer WMLs Stroke-like clinical signs Multiple clinical infarcts Neurologic dysfunction Ataxia Tremor Delayed or arrested puberty Growth hormone deficiency Hypogonadotropic hypogonadism Clinical decline Psychiatric & neurologic features Polycystic osseous lesions Pathologic fractures AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; WML = white matter lesions; XL = X-linked Neuronal ceroid lipofuscinosis (NCL) is inherited in an autosomal recessive manner with the exception of Aicardi-Goutières syndrome is most frequently inherited in an autosomal recessive manner; in a few instances the disease can result from specific Infectious disease (e.g., HIV, syphilis, hepatitis B and C, and tuberculosis) Drug use (e.g., heroin and methanol) Inflammatory disease (e.g., systemic lupus erythematosus) Progressive multifocal leukoencephalopathy associated with JC virus in immunosuppressed individuals Primary central nervous system lymphoma and gliomatosis and treatment with chemo- or radiotherapy Small vessel disease (typically associated with an older age of onset and significant cardiovascular risk factors) • Hypertrophic CM • Muscle weakness • Respiratory deficiency • Macroglossia • Less severe manifestations • Angiokeratomas • Hypohidrosis • Proteinuria • Kidney disease • Hypertrophic CM • Skeletal muscle weakness • Fatal early-onset CM • Lactic acidosis • Neonatal hypoglycemia • Dysmorphic facies • Phenotype of spinal muscular atrophy • Less severe manifestations • Hypertrophic CM • Hypotonia • Hyperammonemia • Characteristic pattern of facial features • Older age of onset • No premature ovarian failure in females • White matter calcification on brain MRI • Cognitive decline • Behavioral changes • Presence of ovarian failure in females • Cognitive decline • Executive dysfunction • Cognitive impairment (late manifestation) • Ataxia • Pyramidal signs • Early autonomic dysfunction • Periventricular rims of lateral ventricles normal or mildly affected on brain MRI • Neurodegeneration • Ataxia • Pyramidal signs • Normal cognitive function in adults • Palatal myoclonus • Cognitive decline • Pyramidal signs • Seizures • Psychiatric features • Peripheral neuropathy • No WML in cerebellum • Peripheral neuropathy • MRI changes predominantly in posterior white matter • Demyelination in brain stem & cerebellum • Cognitive decline • Pyramidal signs • Neuropathy • WML are contrast enhancing. • Frontal & temporal atrophy • Fewer WML • Motor neuron disease • Skin changes, hepatosplenomegaly (GM1) • Early-childhood onset, cherry-red spots of macula (GM2) • Frontal & temporal atrophy • Fewer WMLs • Stroke-like clinical signs • Multiple clinical infarcts • Neurologic dysfunction • Ataxia • Tremor • Delayed or arrested puberty • Growth hormone deficiency • Hypogonadotropic hypogonadism • Clinical decline • Psychiatric & neurologic features • Polycystic osseous lesions • Pathologic fractures • Infectious disease (e.g., HIV, syphilis, hepatitis B and C, and tuberculosis) • Drug use (e.g., heroin and methanol) • Inflammatory disease (e.g., systemic lupus erythematosus) • Progressive multifocal leukoencephalopathy associated with JC virus in immunosuppressed individuals • Primary central nervous system lymphoma and gliomatosis and treatment with chemo- or radiotherapy • Small vessel disease (typically associated with an older age of onset and significant cardiovascular risk factors) Genes of Interest in the Differential Diagnosis of Hypertrophic CM Muscle weakness Respiratory deficiency Macroglossia Less severe manifestations Angiokeratomas Hypohidrosis Proteinuria Kidney disease Hypertrophic CM Skeletal muscle weakness Fatal early-onset CM Lactic acidosis Neonatal hypoglycemia Dysmorphic facies Phenotype of spinal muscular atrophy Less severe manifestations Hypertrophic CM Hypotonia Hyperammonemia Characteristic pattern of facial features AD = autosomal dominant; AR = autosomal recessive; CM = cardiomyopathy; Mat = maternal; MOI = mode of inheritance; XL = X-linked See also • Hypertrophic CM • Muscle weakness • Respiratory deficiency • Macroglossia • Less severe manifestations • Angiokeratomas • Hypohidrosis • Proteinuria • Kidney disease • Hypertrophic CM • Skeletal muscle weakness • Fatal early-onset CM • Lactic acidosis • Neonatal hypoglycemia • Dysmorphic facies • Phenotype of spinal muscular atrophy • Less severe manifestations • Hypertrophic CM • Hypotonia • Hyperammonemia • Characteristic pattern of facial features Genetic Disorders in the Differential Diagnosis of Older age of onset No premature ovarian failure in females White matter calcification on brain MRI Cognitive decline Behavioral changes Presence of ovarian failure in females Cognitive decline Executive dysfunction Cognitive impairment (late manifestation) Ataxia Pyramidal signs Early autonomic dysfunction Periventricular rims of lateral ventricles normal or mildly affected on brain MRI Neurodegeneration Ataxia Pyramidal signs Normal cognitive function in adults Palatal myoclonus Cognitive decline Pyramidal signs Seizures Psychiatric features Peripheral neuropathy No WML in cerebellum Peripheral neuropathy MRI changes predominantly in posterior white matter Demyelination in brain stem & cerebellum Cognitive decline Pyramidal signs Neuropathy WML are contrast enhancing. Frontal & temporal atrophy Fewer WML Motor neuron disease Skin changes, hepatosplenomegaly (GM1) Early-childhood onset, cherry-red spots of macula (GM2) Frontal & temporal atrophy Fewer WMLs Stroke-like clinical signs Multiple clinical infarcts Neurologic dysfunction Ataxia Tremor Delayed or arrested puberty Growth hormone deficiency Hypogonadotropic hypogonadism Clinical decline Psychiatric & neurologic features Polycystic osseous lesions Pathologic fractures AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; WML = white matter lesions; XL = X-linked Neuronal ceroid lipofuscinosis (NCL) is inherited in an autosomal recessive manner with the exception of Aicardi-Goutières syndrome is most frequently inherited in an autosomal recessive manner; in a few instances the disease can result from specific Infectious disease (e.g., HIV, syphilis, hepatitis B and C, and tuberculosis) Drug use (e.g., heroin and methanol) Inflammatory disease (e.g., systemic lupus erythematosus) Progressive multifocal leukoencephalopathy associated with JC virus in immunosuppressed individuals Primary central nervous system lymphoma and gliomatosis and treatment with chemo- or radiotherapy Small vessel disease (typically associated with an older age of onset and significant cardiovascular risk factors) • Older age of onset • No premature ovarian failure in females • White matter calcification on brain MRI • Cognitive decline • Behavioral changes • Presence of ovarian failure in females • Cognitive decline • Executive dysfunction • Cognitive impairment (late manifestation) • Ataxia • Pyramidal signs • Early autonomic dysfunction • Periventricular rims of lateral ventricles normal or mildly affected on brain MRI • Neurodegeneration • Ataxia • Pyramidal signs • Normal cognitive function in adults • Palatal myoclonus • Cognitive decline • Pyramidal signs • Seizures • Psychiatric features • Peripheral neuropathy • No WML in cerebellum • Peripheral neuropathy • MRI changes predominantly in posterior white matter • Demyelination in brain stem & cerebellum • Cognitive decline • Pyramidal signs • Neuropathy • WML are contrast enhancing. • Frontal & temporal atrophy • Fewer WML • Motor neuron disease • Skin changes, hepatosplenomegaly (GM1) • Early-childhood onset, cherry-red spots of macula (GM2) • Frontal & temporal atrophy • Fewer WMLs • Stroke-like clinical signs • Multiple clinical infarcts • Neurologic dysfunction • Ataxia • Tremor • Delayed or arrested puberty • Growth hormone deficiency • Hypogonadotropic hypogonadism • Clinical decline • Psychiatric & neurologic features • Polycystic osseous lesions • Pathologic fractures • Infectious disease (e.g., HIV, syphilis, hepatitis B and C, and tuberculosis) • Drug use (e.g., heroin and methanol) • Inflammatory disease (e.g., systemic lupus erythematosus) • Progressive multifocal leukoencephalopathy associated with JC virus in immunosuppressed individuals • Primary central nervous system lymphoma and gliomatosis and treatment with chemo- or radiotherapy • Small vessel disease (typically associated with an older age of onset and significant cardiovascular risk factors) ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Assessment of weight, length, & head circumference Feeding assessment Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse To establish the extent of disease and needs in an individual diagnosed with Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes Referral to psychologist &/or neuropsychologist as needed Community or Social work involvement Home nursing referral MOI = mode of inheritance 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 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 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 Levodopa or other dopaminergic therapies for parkinsonism Botulinum toxin for spasticity Cognitive behavioral therapy Psychoeducational interventions There are no data on long-term efficacy of psychiatric treatments for depression, suicidal tendencies, anxiety, & psychosis. The use of antipsychotic drugs should be discussed w/individual &/or family due to potential risk of extrapyramidal symptoms. They may be considered in persons w/aggression. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Cardiology eval to assess cardiac function EKG & echocardiogram per cardiologist Assessment of growth parameters Feeding assessment Neurologic eval Brain MRI EEG OT = occupational therapy; PT = physical therapy Many individuals with See Search • Assessment of weight, length, & head circumference • Feeding assessment • Community or • Social work involvement for parental support • Home nursing referral • Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes • Referral to psychologist &/or neuropsychologist as needed • Community or • Social work involvement • 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 • Levodopa or other dopaminergic therapies for parkinsonism • Botulinum toxin for spasticity • Cognitive behavioral therapy • Psychoeducational interventions • There are no data on long-term efficacy of psychiatric treatments for depression, suicidal tendencies, anxiety, & psychosis. • The use of antipsychotic drugs should be discussed w/individual &/or family due to potential risk of extrapyramidal symptoms. They may be considered in persons w/aggression. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Cardiology eval to assess cardiac function • EKG & echocardiogram per cardiologist • Assessment of growth parameters • Feeding assessment • Neurologic eval • Brain MRI • EEG ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Assessment of weight, length, & head circumference Feeding assessment Community or Social work involvement for parental support Home nursing referral MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse To establish the extent of disease and needs in an individual diagnosed with Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes Referral to psychologist &/or neuropsychologist as needed Community or Social work involvement Home nursing referral MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Assessment of weight, length, & head circumference • Feeding assessment • Community or • Social work involvement for parental support • Home nursing referral • Assessment for anxiety, depression, apathy, indifference, abulia, disinhibition, distraction, & other behavioral or personality changes • Referral to psychologist &/or neuropsychologist as needed • Community or • Social work involvement • 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 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 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 Levodopa or other dopaminergic therapies for parkinsonism Botulinum toxin for spasticity Cognitive behavioral therapy Psychoeducational interventions There are no data on long-term efficacy of psychiatric treatments for depression, suicidal tendencies, anxiety, & psychosis. The use of antipsychotic drugs should be discussed w/individual &/or family due to potential risk of extrapyramidal symptoms. They may be considered in persons w/aggression. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see • 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 • Levodopa or other dopaminergic therapies for parkinsonism • Botulinum toxin for spasticity • Cognitive behavioral therapy • Psychoeducational interventions • There are no data on long-term efficacy of psychiatric treatments for depression, suicidal tendencies, anxiety, & psychosis. • The use of antipsychotic drugs should be discussed w/individual &/or family due to potential risk of extrapyramidal symptoms. They may be considered in persons w/aggression. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Cardiology eval to assess cardiac function EKG & echocardiogram per cardiologist Assessment of growth parameters Feeding assessment Neurologic eval Brain MRI EEG OT = occupational therapy; PT = physical therapy • Cardiology eval to assess cardiac function • EKG & echocardiogram per cardiologist • Assessment of growth parameters • Feeding assessment • Neurologic eval • Brain MRI • EEG ## Agents/Circumstances to Avoid Many individuals with ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected individual are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate. • The parents of an affected individual 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 ## Risk to Family Members The parents of an affected individual 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 individual are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 decisions regarding prenatal and preimplantation genetic testing to be the choice of the parents, discussion of these issues is appropriate. ## Resources • • • • • • • ## Molecular Genetics AARS2-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for AARS2-Related Disorder ( ## Molecular Pathogenesis ## Chapter Notes Dr Chmiela ( Dr Chmiela and Dr Wszolek are also interested in hearing from clinicians treating families affected by hereditary leukoencephalopathies 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 Chmiela and Dr Wszolek and to inquire about review of Dr Wszolek serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206), Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia), ONO-2808-03, and Amylyx AMX0035-009 projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc, and as a consultant for Eli Lilly & Company and for NovoGlia, Inc Dr Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), the Haworth Family Professorship in Neurodegenerative Diseases fund, the Albertson Parkinson's Research Foundation, PPND Family Foundation, and the Margaret N and John Wilchek Family. 31 October 2024 (sw) Review posted live 25 July 2024 (zw) Original submission • 31 October 2024 (sw) Review posted live • 25 July 2024 (zw) Original submission ## Author Notes Dr Chmiela ( Dr Chmiela and Dr Wszolek are also interested in hearing from clinicians treating families affected by hereditary leukoencephalopathies 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 Chmiela and Dr Wszolek and to inquire about review of Dr Wszolek serves as PI or Co-PI on Biohaven Pharmaceuticals, Inc. (BHV4157-206), Vigil Neuroscience, Inc (VGL101-01.002, VGL101-01.201, PET tracer development protocol, Csf1r biomarker and repository project, and ultra-high field MRI in the diagnosis and management of CSF1R-related adult-onset leukoencephalopathy with axonal spheroids and pigmented glia), ONO-2808-03, and Amylyx AMX0035-009 projects/grants. He serves as Co-PI of the Mayo Clinic APDA Center for Advanced Research and as an external advisory board member for the Vigil Neuroscience, Inc, and as a consultant for Eli Lilly & Company and for NovoGlia, Inc ## Acknowledgments Dr Wszolek is partially supported by the NIH/NIA and NIH/NINDS (1U19AG063911, FAIN: U19AG063911), the Haworth Family Professorship in Neurodegenerative Diseases fund, the Albertson Parkinson's Research Foundation, PPND Family Foundation, and the Margaret N and John Wilchek Family. ## Revision History 31 October 2024 (sw) Review posted live 25 July 2024 (zw) Original submission • 31 October 2024 (sw) Review posted live • 25 July 2024 (zw) Original submission ## References ## Literature Cited	[]	31/10/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ab-lipo-p	ab-lipo-p	[ "Bassen-Kornzweig Syndrome", "Bassen-Kornzweig Syndrome", "Microsomal triglyceride transfer protein large subunit", "MTTP", "Abetalipoproteinemia" ]	Abetalipoproteinemia	John R Burnett, Amanda J Hooper, Robert A Hegele	Summary Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. Hematologic manifestations may include acanthocytosis (irregularly spiculated erythrocytes), anemia, reticulocytosis, and hemolysis with resultant hyperbilirubinemia. Malabsorption of fat-soluble vitamins (A, D, E, and K) can result in an increased international normalized ratio (INR). Untreated individuals may develop atypical pigmentation of the retina that may present with progressive loss of night vision and/or color vision in adulthood. Neuromuscular findings in untreated individuals including progressive loss of deep tendon reflexes, vibratory sense, and proprioception; muscle weakness; dysarthria; and ataxia typically manifest in the first or second decades of life. The diagnosis of abetalipoproteinemia is established in a proband with absent or extremely low LDL-cholesterol, triglyceride, and apolipoprotein (apo) B levels and biallelic pathogenic variants in Abetalipoproteinemia 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 and preimplantation genetic testing are possible if the pathogenic	## Diagnosis No formal clinical diagnostic criteria for abetalipoproteinemia have been published. Classic abetalipoproteinemia presents from birth with failure to thrive, severe diarrhea and vomiting, and malabsorption of fat. Abetalipoproteinemia Failure to thrive, with diarrhea and vomiting Fat malabsorption with steatorrhea Hepatomegaly Loss of night and/or color vision Acquired atypical pigmentation of the retina Spinocerebellar ataxia and myopathy Marked hypocholesterolemia (total cholesterol ~1 mmol/L [~40 mg/dL]) Plasma LDL-cholesterol (measured or calculated) absent or extremely low Plasma apo B absent or very low Plasma triglyceride very low Plasma HDL-cholesterol at a low to average level Acanthocytosis Abnormal liver transaminases (AST and ALT 1-1.5 times the upper reference limit) Prolonged international normalized ratio (INR) Low serum concentrations of fat-soluble vitamins (A, D, E, and K) The diagnosis of abetalipoproteinemia 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 [ When the phenotypic and laboratory findings suggest the diagnosis of abetalipoproteinemia, molecular genetic testing approaches can include Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For an introduction to multigene panels click Molecular Genetic Testing Used in Abetalipoproteinemia 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. R Hegele, personal observation • Failure to thrive, with diarrhea and vomiting • Fat malabsorption with steatorrhea • Hepatomegaly • Loss of night and/or color vision • Acquired atypical pigmentation of the retina • Spinocerebellar ataxia and myopathy • Marked hypocholesterolemia (total cholesterol ~1 mmol/L [~40 mg/dL]) • Plasma LDL-cholesterol (measured or calculated) absent or extremely low • Plasma apo B absent or very low • Plasma triglyceride very low • Plasma HDL-cholesterol at a low to average level • Acanthocytosis • Abnormal liver transaminases (AST and ALT 1-1.5 times the upper reference limit) • Prolonged international normalized ratio (INR) • Low serum concentrations of fat-soluble vitamins (A, D, E, and K) • Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For an introduction to multigene panels click ## Suggestive Findings Classic abetalipoproteinemia presents from birth with failure to thrive, severe diarrhea and vomiting, and malabsorption of fat. Abetalipoproteinemia Failure to thrive, with diarrhea and vomiting Fat malabsorption with steatorrhea Hepatomegaly Loss of night and/or color vision Acquired atypical pigmentation of the retina Spinocerebellar ataxia and myopathy Marked hypocholesterolemia (total cholesterol ~1 mmol/L [~40 mg/dL]) Plasma LDL-cholesterol (measured or calculated) absent or extremely low Plasma apo B absent or very low Plasma triglyceride very low Plasma HDL-cholesterol at a low to average level Acanthocytosis Abnormal liver transaminases (AST and ALT 1-1.5 times the upper reference limit) Prolonged international normalized ratio (INR) Low serum concentrations of fat-soluble vitamins (A, D, E, and K) • Failure to thrive, with diarrhea and vomiting • Fat malabsorption with steatorrhea • Hepatomegaly • Loss of night and/or color vision • Acquired atypical pigmentation of the retina • Spinocerebellar ataxia and myopathy • Marked hypocholesterolemia (total cholesterol ~1 mmol/L [~40 mg/dL]) • Plasma LDL-cholesterol (measured or calculated) absent or extremely low • Plasma apo B absent or very low • Plasma triglyceride very low • Plasma HDL-cholesterol at a low to average level • Acanthocytosis • Abnormal liver transaminases (AST and ALT 1-1.5 times the upper reference limit) • Prolonged international normalized ratio (INR) • Low serum concentrations of fat-soluble vitamins (A, D, E, and K) ## Establishing the Diagnosis The diagnosis of abetalipoproteinemia 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 [ When the phenotypic and laboratory findings suggest the diagnosis of abetalipoproteinemia, molecular genetic testing approaches can include Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For an introduction to multigene panels click Molecular Genetic Testing Used in Abetalipoproteinemia 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. R Hegele, personal observation • Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • For an introduction to multigene panels click ## Clinical Characteristics Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. The absence of apo B-containing lipoproteins and resulting deficiency of fat-soluble vitamins lead to multisystem manifestations as the affected individual ages. As affected individuals age they learn to avoid dietary fat, which improves steatorrhea [ Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant [ Hepatomegaly and hepatic steatosis can be observed, which rarely may progress to steatohepatitis, fibrosis, and cirrhosis [ On a typical diet (e.g., no dietary fat restriction), the intestinal mucosa may have a "gelee blanche" or "white hoar frosting" appearance on endoscopy. Biopsy of the intestinal epithelium may demonstrate lipid-laden intestinal epithelial cells. Acanthocytosis, defined as irregularly spiculated erythrocytes Low erythrocyte sedimentation rate Anemia Reticulocytosis Hyperbilirubinemia Hemolysis Prolonged INR due to vitamin K deficiency [ Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. As the disease progresses, affected individuals may experience progressively expanding scotomas. Without treatment, progression to complete visual loss may occur. Other rare, typically acquired, ophthalmologic findings include the following: Ptosis Ophthalmoplegia Corneal ulcers It is hypothesized that the possible cause of ptosis and ophthalmoplegia is vitamin E deficiency leading to cranial nerve demyelination. Corneal ulcers may be caused or exacerbated by vitamin A deficiency [ Progressive loss of deep tendon reflexes, vibratory sense, and proprioception Muscle weakness Dysarthria Eventually, a Friedrich's-like ataxia, with a broad base and high stepping gait, can develop in early adulthood in untreated individuals [ Due to the small number of individuals with abetalipoproteinemia reported in the literature, reliable data on genotype-phenotype correlations are lacking. While 100% of individuals either homozygous or compound heterozygous for pathogenic Abetalipoproteinemia was initially named Bassen-Kornzweig syndrome. Abetalipoproteinemia is rare; fewer than 100 individuals have been described in the literature. • As affected individuals age they learn to avoid dietary fat, which improves steatorrhea [ • Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant [ • Hepatomegaly and hepatic steatosis can be observed, which rarely may progress to steatohepatitis, fibrosis, and cirrhosis [ • On a typical diet (e.g., no dietary fat restriction), the intestinal mucosa may have a "gelee blanche" or "white hoar frosting" appearance on endoscopy. • Biopsy of the intestinal epithelium may demonstrate lipid-laden intestinal epithelial cells. • Acanthocytosis, defined as irregularly spiculated erythrocytes • Low erythrocyte sedimentation rate • Anemia • Reticulocytosis • Hyperbilirubinemia • Hemolysis • Prolonged INR due to vitamin K deficiency [ • Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. • As the disease progresses, affected individuals may experience progressively expanding scotomas. • Without treatment, progression to complete visual loss may occur. • Other rare, typically acquired, ophthalmologic findings include the following: • Ptosis • Ophthalmoplegia • Corneal ulcers • Ptosis • Ophthalmoplegia • Corneal ulcers • Ptosis • Ophthalmoplegia • Corneal ulcers • Progressive loss of deep tendon reflexes, vibratory sense, and proprioception • Muscle weakness • Dysarthria • Eventually, a Friedrich's-like ataxia, with a broad base and high stepping gait, can develop in early adulthood in untreated individuals [ ## Clinical Description Abetalipoproteinemia typically presents in infancy with failure to thrive, diarrhea, vomiting, and malabsorption of fat. The absence of apo B-containing lipoproteins and resulting deficiency of fat-soluble vitamins lead to multisystem manifestations as the affected individual ages. As affected individuals age they learn to avoid dietary fat, which improves steatorrhea [ Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant [ Hepatomegaly and hepatic steatosis can be observed, which rarely may progress to steatohepatitis, fibrosis, and cirrhosis [ On a typical diet (e.g., no dietary fat restriction), the intestinal mucosa may have a "gelee blanche" or "white hoar frosting" appearance on endoscopy. Biopsy of the intestinal epithelium may demonstrate lipid-laden intestinal epithelial cells. Acanthocytosis, defined as irregularly spiculated erythrocytes Low erythrocyte sedimentation rate Anemia Reticulocytosis Hyperbilirubinemia Hemolysis Prolonged INR due to vitamin K deficiency [ Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. As the disease progresses, affected individuals may experience progressively expanding scotomas. Without treatment, progression to complete visual loss may occur. Other rare, typically acquired, ophthalmologic findings include the following: Ptosis Ophthalmoplegia Corneal ulcers It is hypothesized that the possible cause of ptosis and ophthalmoplegia is vitamin E deficiency leading to cranial nerve demyelination. Corneal ulcers may be caused or exacerbated by vitamin A deficiency [ Progressive loss of deep tendon reflexes, vibratory sense, and proprioception Muscle weakness Dysarthria Eventually, a Friedrich's-like ataxia, with a broad base and high stepping gait, can develop in early adulthood in untreated individuals [ • As affected individuals age they learn to avoid dietary fat, which improves steatorrhea [ • Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant [ • Hepatomegaly and hepatic steatosis can be observed, which rarely may progress to steatohepatitis, fibrosis, and cirrhosis [ • On a typical diet (e.g., no dietary fat restriction), the intestinal mucosa may have a "gelee blanche" or "white hoar frosting" appearance on endoscopy. • Biopsy of the intestinal epithelium may demonstrate lipid-laden intestinal epithelial cells. • Acanthocytosis, defined as irregularly spiculated erythrocytes • Low erythrocyte sedimentation rate • Anemia • Reticulocytosis • Hyperbilirubinemia • Hemolysis • Prolonged INR due to vitamin K deficiency [ • Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. • As the disease progresses, affected individuals may experience progressively expanding scotomas. • Without treatment, progression to complete visual loss may occur. • Other rare, typically acquired, ophthalmologic findings include the following: • Ptosis • Ophthalmoplegia • Corneal ulcers • Ptosis • Ophthalmoplegia • Corneal ulcers • Ptosis • Ophthalmoplegia • Corneal ulcers • Progressive loss of deep tendon reflexes, vibratory sense, and proprioception • Muscle weakness • Dysarthria • Eventually, a Friedrich's-like ataxia, with a broad base and high stepping gait, can develop in early adulthood in untreated individuals [ ## Genotype-Phenotype Correlations Due to the small number of individuals with abetalipoproteinemia reported in the literature, reliable data on genotype-phenotype correlations are lacking. ## Penetrance While 100% of individuals either homozygous or compound heterozygous for pathogenic ## Nomenclature Abetalipoproteinemia was initially named Bassen-Kornzweig syndrome. ## Prevalence Abetalipoproteinemia is rare; fewer than 100 individuals have been described in the literature. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Abetalipoproteinemia Normal lipid levels in abetalipoproteinemia; LDL-cholesterol levels <50% of normal in hypobetalipoproteinemia. Acanthocytosis Peripheral neuropathy Broad-based, high stepping gait Loss of proprioception Loss of deep tendon reflexes AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked • Normal lipid levels in abetalipoproteinemia; • LDL-cholesterol levels <50% of normal in hypobetalipoproteinemia. • Acanthocytosis • Peripheral neuropathy • Broad-based, high stepping gait • Loss of proprioception • Loss of deep tendon reflexes ## Management To establish the extent of disease and needs in an individual diagnosed with abetalipoproteinemia, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Abetalipoproteinemia Fecal fat Serum lipid profile (LDL, HDL, & total cholesterol; triglyceride; ApoB; Apo-A-I) Serum concentrations of fat-soluble vitamins (A, D, E, K) Liver transaminases & bilirubin levels HDL = high-density lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein The following treatment is recommended for abetalipoproteinemia to address symptoms and prevent complications [ Treatment of Manifestations in Individuals with Abetalipoproteinemia Vitamin A (100-400 IU/kg/day) Vitamin D (800-1,200 IU/day) Vitamin E (100-300 IU/kg/day) Vitamin K (5-35 mg/wk) Intensive rehab (or coordinative physiotherapy) Canes/walkers to prevent falls Home modifications to accommodate motorized chairs as needed Weighted eating utensils & dressing hooks Weight control, as obesity can exacerbate problems w/ambulation & mobility INR = international normalized ratio; OT = occupational therapist; PT = physical therapist With proper treatment, a normal growth velocity can be achieved in affected persons; however, affected persons may not meet their full growth potential, even after treatment [ Long-chain fatty acids should be avoided (see Vitamin A dosing should be titrated to serum beta-carotene concentrations (see While vitamin A toxicity is unlikely, it has been reported in one affected person with a normal serum vitamin A level who initiated vitamin A supplementation [ The target goal for vitamin A levels should be low normal to avoid hepatotoxicity. Despite supplementation, an affected person will always have low vitamin E levels. Early treatment with vitamin E (100-300 IU/kg/day) may delay or prevent the development of neurologic dysfunction [ Vitamin E supplementation may also delay or prevent the development of ophthalmoplegia and/or ptosis. Vitamin A supplementation (100-400 IU/kg/day) may help to prevent corneal ulcers from developing. See See Clinical evaluation every six to 12 months, including assessment of diet and any gastrointestinal or neurologic symptoms, is recommended. The following evaluations are also recommended for abetalipoproteinemia [ Recommended Surveillance for Individuals with Abetalipoproteinemia Liver function tests Fat-soluble vitamin levels Complete blood count INR Reticulocyte count Serum calcium, phosphate, & uric acid Serum TSH INR = international normalized ratio; TSH = thyroid stimulating hormone Lipid profile typically includes total cholesterol, triglyceride concentration, LDL-cholesterol, HDL-cholesterol, apo B, and apo A-I. Annual lipid profile evaluation is not absolutely necessary, as lipid levels often remain stable over long periods of time. AST, ALT, GGT, total and direct bilirubin, alkaline phosphatase, and albumin Vitamin A (retinol), 25-OH vitamin D, and plasma or red blood cell (RBC) vitamin E Vitamin A dosing should be titrated to serum beta-carotene concentrations. In affected persons age >10 years Avoid fatty foods, particularly those rich in long-chain fatty acids. It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: A full lipid profile and apo B determination; Molecular genetic testing if the pathogenic variants in the family are known. Note: In classic abetalipoproteinemia, affected sibs will present shortly after birth with failure to thrive, diarrhea, vomiting, and malabsorption of fat. See Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum beta carotene levels throughout pregnancy is recommended [ Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity. See Search • Fecal fat • Serum lipid profile (LDL, HDL, & total cholesterol; triglyceride; ApoB; Apo-A-I) • Serum concentrations of fat-soluble vitamins (A, D, E, K) • Liver transaminases & bilirubin levels • Vitamin A (100-400 IU/kg/day) • Vitamin D (800-1,200 IU/day) • Vitamin E (100-300 IU/kg/day) • Vitamin K (5-35 mg/wk) • Intensive rehab (or coordinative physiotherapy) • Canes/walkers to prevent falls • Home modifications to accommodate motorized chairs as needed • Weighted eating utensils & dressing hooks • Weight control, as obesity can exacerbate problems w/ambulation & mobility • Liver function tests • Fat-soluble vitamin levels • Complete blood count • INR • Reticulocyte count • Serum calcium, phosphate, & uric acid • Serum TSH • A full lipid profile and apo B determination; • Molecular genetic testing if the pathogenic variants in the family are known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with abetalipoproteinemia, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Abetalipoproteinemia Fecal fat Serum lipid profile (LDL, HDL, & total cholesterol; triglyceride; ApoB; Apo-A-I) Serum concentrations of fat-soluble vitamins (A, D, E, K) Liver transaminases & bilirubin levels HDL = high-density lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein • Fecal fat • Serum lipid profile (LDL, HDL, & total cholesterol; triglyceride; ApoB; Apo-A-I) • Serum concentrations of fat-soluble vitamins (A, D, E, K) • Liver transaminases & bilirubin levels ## Treatment of Manifestations The following treatment is recommended for abetalipoproteinemia to address symptoms and prevent complications [ Treatment of Manifestations in Individuals with Abetalipoproteinemia Vitamin A (100-400 IU/kg/day) Vitamin D (800-1,200 IU/day) Vitamin E (100-300 IU/kg/day) Vitamin K (5-35 mg/wk) Intensive rehab (or coordinative physiotherapy) Canes/walkers to prevent falls Home modifications to accommodate motorized chairs as needed Weighted eating utensils & dressing hooks Weight control, as obesity can exacerbate problems w/ambulation & mobility INR = international normalized ratio; OT = occupational therapist; PT = physical therapist With proper treatment, a normal growth velocity can be achieved in affected persons; however, affected persons may not meet their full growth potential, even after treatment [ Long-chain fatty acids should be avoided (see Vitamin A dosing should be titrated to serum beta-carotene concentrations (see While vitamin A toxicity is unlikely, it has been reported in one affected person with a normal serum vitamin A level who initiated vitamin A supplementation [ The target goal for vitamin A levels should be low normal to avoid hepatotoxicity. Despite supplementation, an affected person will always have low vitamin E levels. • Vitamin A (100-400 IU/kg/day) • Vitamin D (800-1,200 IU/day) • Vitamin E (100-300 IU/kg/day) • Vitamin K (5-35 mg/wk) • Intensive rehab (or coordinative physiotherapy) • Canes/walkers to prevent falls • Home modifications to accommodate motorized chairs as needed • Weighted eating utensils & dressing hooks • Weight control, as obesity can exacerbate problems w/ambulation & mobility ## Prevention of Primary Manifestations Early treatment with vitamin E (100-300 IU/kg/day) may delay or prevent the development of neurologic dysfunction [ Vitamin E supplementation may also delay or prevent the development of ophthalmoplegia and/or ptosis. Vitamin A supplementation (100-400 IU/kg/day) may help to prevent corneal ulcers from developing. See ## Prevention of Secondary Complications See ## Surveillance Clinical evaluation every six to 12 months, including assessment of diet and any gastrointestinal or neurologic symptoms, is recommended. The following evaluations are also recommended for abetalipoproteinemia [ Recommended Surveillance for Individuals with Abetalipoproteinemia Liver function tests Fat-soluble vitamin levels Complete blood count INR Reticulocyte count Serum calcium, phosphate, & uric acid Serum TSH INR = international normalized ratio; TSH = thyroid stimulating hormone Lipid profile typically includes total cholesterol, triglyceride concentration, LDL-cholesterol, HDL-cholesterol, apo B, and apo A-I. Annual lipid profile evaluation is not absolutely necessary, as lipid levels often remain stable over long periods of time. AST, ALT, GGT, total and direct bilirubin, alkaline phosphatase, and albumin Vitamin A (retinol), 25-OH vitamin D, and plasma or red blood cell (RBC) vitamin E Vitamin A dosing should be titrated to serum beta-carotene concentrations. In affected persons age >10 years • Liver function tests • Fat-soluble vitamin levels • Complete blood count • INR • Reticulocyte count • Serum calcium, phosphate, & uric acid • Serum TSH ## Agents/Circumstances to Avoid Avoid fatty foods, particularly those rich in long-chain fatty acids. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: A full lipid profile and apo B determination; Molecular genetic testing if the pathogenic variants in the family are known. Note: In classic abetalipoproteinemia, affected sibs will present shortly after birth with failure to thrive, diarrhea, vomiting, and malabsorption of fat. See • A full lipid profile and apo B determination; • Molecular genetic testing if the pathogenic variants in the family are known. ## Pregnancy Management Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum beta carotene levels throughout pregnancy is recommended [ Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity. See ## Therapies Under Investigation Search ## Genetic Counseling Abetalipoproteinemia 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, have normal lipid profiles, and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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, have normal lipid profiles, and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Abetalipoproteinemia 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, have normal lipid profiles, 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, have normal lipid profiles, and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 Abetalipoproteinemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Abetalipoproteinemia ( The microsomal triglyceride transfer protein is an essential cofactor for the assembly and secretion of the apolipoprotein (apo) B-containing lipoproteins: chylomicrons from the intestine and very low-density lipoprotein from the liver. Active microsomal triglyceride transfer protein consists of two subunits, the unique MTTP subunit (encoded by Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The microsomal triglyceride transfer protein is an essential cofactor for the assembly and secretion of the apolipoprotein (apo) B-containing lipoproteins: chylomicrons from the intestine and very low-density lipoprotein from the liver. Active microsomal triglyceride transfer protein consists of two subunits, the unique MTTP subunit (encoded by Variants listed in the table have been provided by the authors. ## Chapter Notes RAH has received operating grants from the Canadian Institutes of Health Research (Foundation Grant), the Heart and Stroke Foundation of Ontario (G-15-0009214), and Genome Canada through Genome Quebec (award 4530). 19 May 2022 (aa) Revision: 25 October 2018 (ma) Review posted live 23 January 2018 (jb) Original submission • 19 May 2022 (aa) Revision: • 25 October 2018 (ma) Review posted live • 23 January 2018 (jb) Original submission ## Acknowledgments RAH has received operating grants from the Canadian Institutes of Health Research (Foundation Grant), the Heart and Stroke Foundation of Ontario (G-15-0009214), and Genome Canada through Genome Quebec (award 4530). ## Revision History 19 May 2022 (aa) Revision: 25 October 2018 (ma) Review posted live 23 January 2018 (jb) Original submission • 19 May 2022 (aa) Revision: • 25 October 2018 (ma) Review posted live • 23 January 2018 (jb) Original submission ## References ## Literature Cited	[ "S Bishara, S Merin, M Cooper, E Azizi, G Delpre, RJ Deckelbaum. Combined vitamin A and E therapy prevents retinal electrophysiological deterioration in abetalipoproteinemia.. Br J Ophthalmol. 1982;66:767-70", "DD Black, RV Hay, PL Rohwer-Nutter, H Ellinas, JK Stephens, H Sherman, BB Teng, PF Whitington, NO Davidson. Intestinal and hepatic apolipoprotein B gene expression in abetalipoproteinemia.. Gastroenterology. 1991;101:520-8", "DG Cogan, M Rodrigues, FC Chu, EJ Schaefer. Ocular abnormalities in abetalipoproteinemia. A clinicopathologic correlation.. Ophthalmology. 1984;91:991-8", "M Di Filippo, H Créhalet, ME Samson-Bouma, V Bonnet, LP Aggerbeck, JP Rabès, F Gottrand, G Luc, D Bozon, A Sassolas. Molecular and functional analysis of two new MTTP gene mutations in an atypical case of abetalipoproteinemia.. J Lipid Res. 2012;53:548-55", "M Di Filippo, P Moulin, P Roy, ME Samson-Bouma, S Collardeau-Frachon, S Chebel-Dumont, N Peretti, J Dumortier, F Zoulim, T Fontanges, R Parini, M Rigoldi, F Furlan, G Mancini, D Bonnefont-Rousselot, E Bruckert, J Schmitz, JY Scoazec, S Charrière, S Villar-Fimbel, F Gottrand, B Dubern, D Doummar, F Joly, ME Liard-Meillon, A Lachaux, A Sassolas. Homozygous MTTP and APOB mutations may lead to hepatic steatosis and fibrosis despite metabolic differences in congenital hypocholesterolemia.. J Hepatol. 2014;61:891-902", "I Khatun, MT Walsh, MM Hussain. Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia.. J Lipid Res. 2013;54:1541-9", "J Lee, RA Hegele. Abetalipoproteinemia and homozygous hypobetalipoproteinemia: a framework for diagnosis and management.. J Inherit Metab Dis. 2014;37:333-9", "K Ohashi, S Ishibashi, J Osuga, R Tozawa, K Harada, N Yahagi, F Shionoiri, Y Iizuka, Y Tamura, R Nagai, DR Illingworth, T Gotoda, N Yamada. Novel mutations in the microsomal triglyceride transfer protein gene causing abetalipoproteinemia.. J Lipid Res. 2000;41:1199-204", "M Paquette, R Dufour, RA Hegele, A Baass. A tale of 2 cousins: an atypical and a typical case of abetalipoproteinemia.. J Clin Lipidol. 2016;10:1030-4", "EF Rehberg, ME Samson-Bouma, B Kienzle, L Blinderman, H Jamil, JR Wetterau, LP Aggerbeck, DA Gordon. A novel abetalipoproteinemia genotype. Identification of a missense mutation in the 97-kDa subunit of the microsomal triglyceride transfer protein that prevents complex formation with protein disulfide isomerase.. J Biol Chem. 1996;271:29945-52", "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", "MC Tanyel, LD Mancano. Neurologic findings in vitamin E deficiency.. Am Fam Physician. 1997;55:197-201", "R Zamel, R Kand, RL Pollex, RA Hegele. Abetalipoproteinemia: two cases and literature review.. Orphanet J Rare Dis. 2008;3:19" ]	25/10/2018		19/5/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
abs	abs	[ "POR Deficiency", "PORD", "POR Deficiency", "PORD", "Antley-Bixler Syndrome", "Congenital Adrenal Hyperplasia due to Apparent Combined CYP17A1 and CYP21A2 Enzymatic Deficiency", "NADPH--cytochrome P450 reductase", "POR", "Cytochrome P450 Oxidoreductase Deficiency" ]	Cytochrome P450 Oxidoreductase Deficiency	Jan Idkowiak, Deborah Cragun, Robert J Hopkin, Wiebke Arlt	Summary Cytochrome P450 oxidoreductase deficiency (PORD) is a disorder of steroidogenesis with a broad phenotypic spectrum including cortisol deficiency, altered sex steroid synthesis, disorders of sex development (DSD), and skeletal malformations of the Antley-Bixler syndrome (ABS) phenotype. Cortisol deficiency is usually partial, with some baseline cortisol production but failure to mount an adequate cortisol response in stress. Mild mineralocorticoid excess can be present and causes arterial hypertension, usually presenting in young adulthood. Manifestations of altered sex steroid synthesis include ambiguous genitalia/DSD in both males and females, large ovarian cysts in females, poor masculinization and delayed puberty in males, and maternal virilization during pregnancy with an affected fetus. Skeletal malformations can manifest as craniosynostosis, mid-face retrusion with proptosis and choanal stenosis or atresia, low-set dysplastic ears with stenotic external auditory canals, hydrocephalus, radiohumeral synostosis, neonatal fractures, congenital bowing of the long bones, joint contractures, arachnodactyly, and clubfeet; other anomalies observed include urinary tract anomalies (renal pelvic dilatation, vesicoureteral reflux). Cognitive impairment is of minor concern and likely associated with the severity of malformations; studies of developmental outcomes are lacking. The diagnosis of PORD can be established by urinary steroid profiling using gas chromatography / mass spectrometry (GC/MS), which documents combined impairment of 17α-hydroxylase (CYP17A1) and 21-hydroxylase (CYP21A2) enzymatic activity located at key branch points of cortisol, aldosterone, and sex steroid synthesis. Identification of biallelic PORD 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 family members and prenatal genetic testing for pregnancies at increased risk are possible if the	Antley-Bixler syndrome Congenital adrenal hyperplasia due to apparent combined CYP17A1 and CYP21A2 enzymatic deficiency For synonyms and outdated names see For other genetic causes of these phenotypes see • Antley-Bixler syndrome • Congenital adrenal hyperplasia due to apparent combined CYP17A1 and CYP21A2 enzymatic deficiency ## Diagnosis Cytochrome P450 oxidoreductase deficiency (PORD) is an autosomal recessive disorder with a broad phenotypic spectrum including skeletal malformations resembling the Antley-Bixler syndrome (ABS) phenotype and abnormalities in adrenal steroid biosynthesis resulting in congenital adrenal hyperplasia (CAH). Midface retrusion Craniosynostosis (i.e. brachycephaly or turricephaly) Hand and feet malformations (arachnodactyly, clinodactyly, camptodactyly, metacarpal and metatarsal synostoses, wrist deviation, rocker-bottom feet, talipes) Large joint synostosis, predominantly radiohumeral or radioulnar synostosis, in severely affected individuals. Other large joints (e.g., knees, ankles) can also be affected. Femoral bowing Females may present with masculinized genitalia (46,XX DSD; e.g., enlarged clitoris, labial fusion). Males can present undermasculinized (46,XY DSD; e.g., hypospadias, micropenis). Because POR is required for normal enzymatic function at various steps within the cholesterol and steroid synthesis pathways, individuals with PORD exhibit characteristic abnormalities in both sterol and steroid metabolism (see Increased concentration of pregnenediol (metabolite of pregnenolone) and pregnanediol (metabolite of progesterone); Significantly elevated ratio of metabolites associated with: Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). Note: The term "apparent pregnene hydroxylation deficiency (APHD)" refers to individuals with this unique urinary steroid profile [ The diagnosis of PORD Increased concentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) Significantly elevated metabolites associated with: Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) Identification of biallelic pathogenic (or likely pathogenic) variants in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Cytochrome P450 Oxidoreductase 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 The results 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. Affected individuals have been reported with a single pathogenic variant and nearly complete absence of mRNA made from the allele in which no pathogenic variant was found [ • Midface retrusion • Craniosynostosis (i.e. brachycephaly or turricephaly) • Hand and feet malformations (arachnodactyly, clinodactyly, camptodactyly, metacarpal and metatarsal synostoses, wrist deviation, rocker-bottom feet, talipes) • Large joint synostosis, predominantly radiohumeral or radioulnar synostosis, in severely affected individuals. Other large joints (e.g., knees, ankles) can also be affected. • Femoral bowing • Females may present with masculinized genitalia (46,XX DSD; e.g., enlarged clitoris, labial fusion). • Males can present undermasculinized (46,XY DSD; e.g., hypospadias, micropenis). • Increased concentration of pregnenediol (metabolite of pregnenolone) and pregnanediol (metabolite of progesterone); • Significantly elevated ratio of metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). • Increased concentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • For an introduction to multigene panels click ## Suggestive Findings Cytochrome P450 oxidoreductase deficiency (PORD) is an autosomal recessive disorder with a broad phenotypic spectrum including skeletal malformations resembling the Antley-Bixler syndrome (ABS) phenotype and abnormalities in adrenal steroid biosynthesis resulting in congenital adrenal hyperplasia (CAH). Midface retrusion Craniosynostosis (i.e. brachycephaly or turricephaly) Hand and feet malformations (arachnodactyly, clinodactyly, camptodactyly, metacarpal and metatarsal synostoses, wrist deviation, rocker-bottom feet, talipes) Large joint synostosis, predominantly radiohumeral or radioulnar synostosis, in severely affected individuals. Other large joints (e.g., knees, ankles) can also be affected. Femoral bowing Females may present with masculinized genitalia (46,XX DSD; e.g., enlarged clitoris, labial fusion). Males can present undermasculinized (46,XY DSD; e.g., hypospadias, micropenis). Because POR is required for normal enzymatic function at various steps within the cholesterol and steroid synthesis pathways, individuals with PORD exhibit characteristic abnormalities in both sterol and steroid metabolism (see Increased concentration of pregnenediol (metabolite of pregnenolone) and pregnanediol (metabolite of progesterone); Significantly elevated ratio of metabolites associated with: Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). Note: The term "apparent pregnene hydroxylation deficiency (APHD)" refers to individuals with this unique urinary steroid profile [ • Midface retrusion • Craniosynostosis (i.e. brachycephaly or turricephaly) • Hand and feet malformations (arachnodactyly, clinodactyly, camptodactyly, metacarpal and metatarsal synostoses, wrist deviation, rocker-bottom feet, talipes) • Large joint synostosis, predominantly radiohumeral or radioulnar synostosis, in severely affected individuals. Other large joints (e.g., knees, ankles) can also be affected. • Femoral bowing • Females may present with masculinized genitalia (46,XX DSD; e.g., enlarged clitoris, labial fusion). • Males can present undermasculinized (46,XY DSD; e.g., hypospadias, micropenis). • Increased concentration of pregnenediol (metabolite of pregnenolone) and pregnanediol (metabolite of progesterone); • Significantly elevated ratio of metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). ## Clinical Findings Midface retrusion Craniosynostosis (i.e. brachycephaly or turricephaly) Hand and feet malformations (arachnodactyly, clinodactyly, camptodactyly, metacarpal and metatarsal synostoses, wrist deviation, rocker-bottom feet, talipes) Large joint synostosis, predominantly radiohumeral or radioulnar synostosis, in severely affected individuals. Other large joints (e.g., knees, ankles) can also be affected. Femoral bowing Females may present with masculinized genitalia (46,XX DSD; e.g., enlarged clitoris, labial fusion). Males can present undermasculinized (46,XY DSD; e.g., hypospadias, micropenis). • Midface retrusion • Craniosynostosis (i.e. brachycephaly or turricephaly) • Hand and feet malformations (arachnodactyly, clinodactyly, camptodactyly, metacarpal and metatarsal synostoses, wrist deviation, rocker-bottom feet, talipes) • Large joint synostosis, predominantly radiohumeral or radioulnar synostosis, in severely affected individuals. Other large joints (e.g., knees, ankles) can also be affected. • Femoral bowing • Females may present with masculinized genitalia (46,XX DSD; e.g., enlarged clitoris, labial fusion). • Males can present undermasculinized (46,XY DSD; e.g., hypospadias, micropenis). ## Laboratory Findings Because POR is required for normal enzymatic function at various steps within the cholesterol and steroid synthesis pathways, individuals with PORD exhibit characteristic abnormalities in both sterol and steroid metabolism (see Increased concentration of pregnenediol (metabolite of pregnenolone) and pregnanediol (metabolite of progesterone); Significantly elevated ratio of metabolites associated with: Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). Note: The term "apparent pregnene hydroxylation deficiency (APHD)" refers to individuals with this unique urinary steroid profile [ • Increased concentration of pregnenediol (metabolite of pregnenolone) and pregnanediol (metabolite of progesterone); • Significantly elevated ratio of metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11-dehydro metabolites); • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone). ## Establishing the Diagnosis The diagnosis of PORD Increased concentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) Significantly elevated metabolites associated with: Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) Identification of biallelic pathogenic (or likely pathogenic) variants in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Cytochrome P450 Oxidoreductase 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 The results 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. Affected individuals have been reported with a single pathogenic variant and nearly complete absence of mRNA made from the allele in which no pathogenic variant was found [ • Increased concentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • For an introduction to multigene panels click ## Clinical Characteristics The natural history of cytochrome P450 oxidoreductase deficiency (PORD) varies because it encompasses a wide phenotypic spectrum. However, steroid abnormalities, which occur in all individuals with PORD, can be associated with a number of characteristics. The summary of clinical characteristics is based on 26 studies on 140 individuals with molecularly confirmed PORD published to date (June 2017). Based on ACTH stimulation tests, PORD Skeletal Malformation Scoring System Classifying the Major Features of the Antley-Bixler Syndrome Phenotype Proposed in The maximum score is 16. A score of 1-4 has been proposed as "mild," 5-8 as "moderate," and >9 as "severe." VP = ventriculoperitoneal While individuals with the same pathogenic variants (even sibs) can show phenotypic variations, some commonalities are observed among individuals with the same genotype. The broad phenotypic spectrum of PORD may be caused by the effect of various Three studies report the investigation of genotype-phenotype correlations in larger cohorts of individuals with PORD [ The overall reported frequency of skeletal malformations in genetically confirmed PORD is about 85%. Homozygotes for Compound heterozygosity for p.Arg457His and a severe loss-of-function pathogenic variant on the other allele is associated with a more severe skeletal phenotype. Homozygotes for Compound heterozygosity for p.Ala287Pro and a severe loss-of-function pathogenic variant on the other allele is associated with a severe skeletal phenotype. An abnormal urinary steroid pattern has been found in Adrenal insufficiency is present in most persons with PORD: based on ACTH stimulation tests, However, a prediction of the overall severity of glucocorticoid deficiency based on genotype is not possible. The prevalence of PORD has yet to be determined, however it is a very rare condition. Since The most prevalent pathogenic variant in individuals with PORD of Japanese ancestry is • The overall reported frequency of skeletal malformations in genetically confirmed PORD is about 85%. • Homozygotes for • Compound heterozygosity for p.Arg457His and a severe loss-of-function pathogenic variant on the other allele is associated with a more severe skeletal phenotype. • Homozygotes for • Compound heterozygosity for p.Ala287Pro and a severe loss-of-function pathogenic variant on the other allele is associated with a severe skeletal phenotype. • An abnormal urinary steroid pattern has been found in • Adrenal insufficiency is present in most persons with PORD: based on ACTH stimulation tests, • However, a prediction of the overall severity of glucocorticoid deficiency based on genotype is not possible. ## Clinical Description The natural history of cytochrome P450 oxidoreductase deficiency (PORD) varies because it encompasses a wide phenotypic spectrum. However, steroid abnormalities, which occur in all individuals with PORD, can be associated with a number of characteristics. The summary of clinical characteristics is based on 26 studies on 140 individuals with molecularly confirmed PORD published to date (June 2017). Based on ACTH stimulation tests, PORD Skeletal Malformation Scoring System Classifying the Major Features of the Antley-Bixler Syndrome Phenotype Proposed in The maximum score is 16. A score of 1-4 has been proposed as "mild," 5-8 as "moderate," and >9 as "severe." VP = ventriculoperitoneal ## Genotype-Phenotype Correlations While individuals with the same pathogenic variants (even sibs) can show phenotypic variations, some commonalities are observed among individuals with the same genotype. The broad phenotypic spectrum of PORD may be caused by the effect of various Three studies report the investigation of genotype-phenotype correlations in larger cohorts of individuals with PORD [ The overall reported frequency of skeletal malformations in genetically confirmed PORD is about 85%. Homozygotes for Compound heterozygosity for p.Arg457His and a severe loss-of-function pathogenic variant on the other allele is associated with a more severe skeletal phenotype. Homozygotes for Compound heterozygosity for p.Ala287Pro and a severe loss-of-function pathogenic variant on the other allele is associated with a severe skeletal phenotype. An abnormal urinary steroid pattern has been found in Adrenal insufficiency is present in most persons with PORD: based on ACTH stimulation tests, However, a prediction of the overall severity of glucocorticoid deficiency based on genotype is not possible. • The overall reported frequency of skeletal malformations in genetically confirmed PORD is about 85%. • Homozygotes for • Compound heterozygosity for p.Arg457His and a severe loss-of-function pathogenic variant on the other allele is associated with a more severe skeletal phenotype. • Homozygotes for • Compound heterozygosity for p.Ala287Pro and a severe loss-of-function pathogenic variant on the other allele is associated with a severe skeletal phenotype. • An abnormal urinary steroid pattern has been found in • Adrenal insufficiency is present in most persons with PORD: based on ACTH stimulation tests, • However, a prediction of the overall severity of glucocorticoid deficiency based on genotype is not possible. ## Nomenclature ## Prevalence The prevalence of PORD has yet to be determined, however it is a very rare condition. Since The most prevalent pathogenic variant in individuals with PORD of Japanese ancestry is ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis ## Management To establish the extent of disease and needs in an individual diagnosed with PORD, the following evaluations are recommended: Evaluations by appropriate specialists in endocrinology, clinical genetics, neurosurgery, otolaryngology, and cardiology Assessment for airway problems in individuals with skeletal malformations Functional adrenal studies (cosyntropin test) to assess glucocorticoid deficiency, regardless of the presence or absence of genital abnormalities Additional studies that may be indicated: Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures Echocardiogram if a heart defect is suspected Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. Regular hydrocortisone replacement therapy is indicated if baseline serum cortisol concentrations are low. Stress-dose steroids should be provided perioperatively and during times of physiologic stress in individuals in whom cortisol response to ACTH stimulation (cosyntropin test) is below normal [ Hypospadias and cryptorchidism may be corrected with surgery. When clitoromegaly is severe, surgical reduction and plastic reconstruction of the clitoris may be considered. Vaginal reconstruction may be performed in females with vaginal hypoplasia. Dihydrotestosterone treatment has been successful in some males with micropenis [ Testosterone replacement has been initiated in males in whom testosterone levels remained relatively low after onset of puberty [ Endotracheal intubation is often required in the first minutes after delivery. Nasal stints or tracheotomy may be required. Tracheostomy may be necessary until age three to five years when the pharyngeal encroachment can be corrected. Supplementation with appropriate steroid hormones in individuals who are deficient has helped alleviate: Adrenal crisis Lack of or poor pubertal development in males and females Sleepiness and fatigue Early intervention services may improve the outcome for individuals at risk for developmental delays and learning difficulties. Individuals with PORD should be seen by a specialist tertiary pediatric endocrine service throughout childhood to closely monitor their development and adjust steroid supplementation. Because of the presence of developmental delays in many individuals with ABS, periodic formal developmental assessments may be indicated. However, interpretation of these assessments may be complicated by the physical limitations of the disorder. Screening evaluations are likely to underestimate cognitive abilities. Therefore, evaluations should be done in centers with expertise and experience in developmental testing. It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Urinary steroid profiling using gas chromatography / mass spectrometry (GC/MS) can be done if the pathogenic variants in the family are not known. The characteristic urinary steroid profile: Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) Significantly elevated metabolites associated with: Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) See Search In vitro activity assays on major drug-metabolizing enzymes and in vivo investigations to assess the impact of various pathogenic and non-pathogenic variants of In brief, the different pathogenic variations have different effects on microsomal P450 drug metabolizing enzymes. The common pathogenic variant • Evaluations by appropriate specialists in endocrinology, clinical genetics, neurosurgery, otolaryngology, and cardiology • Assessment for airway problems in individuals with skeletal malformations • Functional adrenal studies (cosyntropin test) to assess glucocorticoid deficiency, regardless of the presence or absence of genital abnormalities • Additional studies that may be indicated: • Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth • Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures • Echocardiogram if a heart defect is suspected • Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. • Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth • Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures • Echocardiogram if a heart defect is suspected • Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. • Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth • Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures • Echocardiogram if a heart defect is suspected • Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. • Regular hydrocortisone replacement therapy is indicated if baseline serum cortisol concentrations are low. • Stress-dose steroids should be provided perioperatively and during times of physiologic stress in individuals in whom cortisol response to ACTH stimulation (cosyntropin test) is below normal [ • Hypospadias and cryptorchidism may be corrected with surgery. • When clitoromegaly is severe, surgical reduction and plastic reconstruction of the clitoris may be considered. • Vaginal reconstruction may be performed in females with vaginal hypoplasia. • Dihydrotestosterone treatment has been successful in some males with micropenis [ • Testosterone replacement has been initiated in males in whom testosterone levels remained relatively low after onset of puberty [ • Endotracheal intubation is often required in the first minutes after delivery. • Nasal stints or tracheotomy may be required. • Tracheostomy may be necessary until age three to five years when the pharyngeal encroachment can be corrected. • Adrenal crisis • Lack of or poor pubertal development in males and females • Sleepiness and fatigue • Molecular genetic testing if the pathogenic variants in the family are known; • Urinary steroid profiling using gas chromatography / mass spectrometry (GC/MS) can be done if the pathogenic variants in the family are not known. The characteristic urinary steroid profile: • Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PORD, the following evaluations are recommended: Evaluations by appropriate specialists in endocrinology, clinical genetics, neurosurgery, otolaryngology, and cardiology Assessment for airway problems in individuals with skeletal malformations Functional adrenal studies (cosyntropin test) to assess glucocorticoid deficiency, regardless of the presence or absence of genital abnormalities Additional studies that may be indicated: Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures Echocardiogram if a heart defect is suspected Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. • Evaluations by appropriate specialists in endocrinology, clinical genetics, neurosurgery, otolaryngology, and cardiology • Assessment for airway problems in individuals with skeletal malformations • Functional adrenal studies (cosyntropin test) to assess glucocorticoid deficiency, regardless of the presence or absence of genital abnormalities • Additional studies that may be indicated: • Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth • Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures • Echocardiogram if a heart defect is suspected • Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. • Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth • Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures • Echocardiogram if a heart defect is suspected • Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. • Cranial CT scan and/or MRI to determine the degree of craniosynostosis, hydrocephaly, choanal stenosis, and orbital depth • Radiographs to identify long-bone fractures and/or bowing, bony synostoses, and/or joint contractures • Echocardiogram if a heart defect is suspected • Abdominal and pelvic ultrasound examination to identify internal sex organs, detect any renal anomalies, and detect and monitor ovarian cysts in adolescent girls. ## Treatment of Manifestations Regular hydrocortisone replacement therapy is indicated if baseline serum cortisol concentrations are low. Stress-dose steroids should be provided perioperatively and during times of physiologic stress in individuals in whom cortisol response to ACTH stimulation (cosyntropin test) is below normal [ Hypospadias and cryptorchidism may be corrected with surgery. When clitoromegaly is severe, surgical reduction and plastic reconstruction of the clitoris may be considered. Vaginal reconstruction may be performed in females with vaginal hypoplasia. Dihydrotestosterone treatment has been successful in some males with micropenis [ Testosterone replacement has been initiated in males in whom testosterone levels remained relatively low after onset of puberty [ Endotracheal intubation is often required in the first minutes after delivery. Nasal stints or tracheotomy may be required. Tracheostomy may be necessary until age three to five years when the pharyngeal encroachment can be corrected. • Regular hydrocortisone replacement therapy is indicated if baseline serum cortisol concentrations are low. • Stress-dose steroids should be provided perioperatively and during times of physiologic stress in individuals in whom cortisol response to ACTH stimulation (cosyntropin test) is below normal [ • Hypospadias and cryptorchidism may be corrected with surgery. • When clitoromegaly is severe, surgical reduction and plastic reconstruction of the clitoris may be considered. • Vaginal reconstruction may be performed in females with vaginal hypoplasia. • Dihydrotestosterone treatment has been successful in some males with micropenis [ • Testosterone replacement has been initiated in males in whom testosterone levels remained relatively low after onset of puberty [ • Endotracheal intubation is often required in the first minutes after delivery. • Nasal stints or tracheotomy may be required. • Tracheostomy may be necessary until age three to five years when the pharyngeal encroachment can be corrected. ## Prevention of Secondary Complications Supplementation with appropriate steroid hormones in individuals who are deficient has helped alleviate: Adrenal crisis Lack of or poor pubertal development in males and females Sleepiness and fatigue Early intervention services may improve the outcome for individuals at risk for developmental delays and learning difficulties. • Adrenal crisis • Lack of or poor pubertal development in males and females • Sleepiness and fatigue ## Surveillance Individuals with PORD should be seen by a specialist tertiary pediatric endocrine service throughout childhood to closely monitor their development and adjust steroid supplementation. Because of the presence of developmental delays in many individuals with ABS, periodic formal developmental assessments may be indicated. However, interpretation of these assessments may be complicated by the physical limitations of the disorder. Screening evaluations are likely to underestimate cognitive abilities. Therefore, evaluations should be done in centers with expertise and experience in developmental testing. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Urinary steroid profiling using gas chromatography / mass spectrometry (GC/MS) can be done if the pathogenic variants in the family are not known. The characteristic urinary steroid profile: Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) Significantly elevated metabolites associated with: Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) See • Molecular genetic testing if the pathogenic variants in the family are known; • Urinary steroid profiling using gas chromatography / mass spectrometry (GC/MS) can be done if the pathogenic variants in the family are not known. The characteristic urinary steroid profile: • Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Increased coancentration of metabolites of pregnenolone (pregnenediol) and progesterone (pregnanediol) • Significantly elevated metabolites associated with: • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) • Deficiency of 17α-hydroxylase (5α-tetrahydrocorticosterone, tetrahydrocorticosterone, and 11 dehydrometabolites) • Deficiency of 21-hydroxylase (17α-hydroxypregnanolone, pregnanetriol, and pregnanetriolone) ## Pregnancy Management ## Therapies Under Investigation Search ## Other In vitro activity assays on major drug-metabolizing enzymes and in vivo investigations to assess the impact of various pathogenic and non-pathogenic variants of In brief, the different pathogenic variations have different effects on microsomal P450 drug metabolizing enzymes. The common pathogenic variant ## Genetic Counseling Cytochrome P450 oxidoreductase deficiency (PORD) is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are typically asymptomatic but may have altered hepatic drug metabolism [ 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 typically asymptomatic but may have altered hepatic drug metabolism [ 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 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, 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 typically asymptomatic but may have altered hepatic drug metabolism [ • 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 typically asymptomatic but may have altered hepatic drug metabolism [ • 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 Cytochrome P450 oxidoreductase deficiency (PORD) 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 typically asymptomatic but may have altered hepatic drug metabolism [ 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 typically asymptomatic but may have altered hepatic drug metabolism [ • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are typically asymptomatic but may have altered hepatic drug metabolism [ • 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 typically asymptomatic but may have altered hepatic drug metabolism [ ## 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 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, 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 2414 Morris Ave Suite 110 Union NJ 07083 CLIMB Congenital Adrenal Hyperplasia Support Group United Kingdom • • 2414 Morris Ave • Suite 110 • Union NJ 07083 • • • CLIMB Congenital Adrenal Hyperplasia Support Group • • • • • United Kingdom • • • ## Molecular Genetics Cytochrome P450 Oxidoreductase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Cytochrome P450 Oxidoreductase Deficiency ( Two pathogenic variants, p.Ala287Pro and p.Arg457His, are common in distinct ethnic groups: p.Ala287Pro accounts for about 40% of pathogenic variants among individuals of European ancestry and p.Arg457His accounts for about 60% of pathogenic variants among individuals of Japanese ancestry, although it is important to note that p.Arg457His has also been reported in individuals of European and African ancestry [ Variants listed in the table have been provided by the authors. See Pathogenic variants that create a premature stop codon are predicted to result in a truncated nonfunctional protein [ A murine knockout of ## Molecular Pathogenesis Two pathogenic variants, p.Ala287Pro and p.Arg457His, are common in distinct ethnic groups: p.Ala287Pro accounts for about 40% of pathogenic variants among individuals of European ancestry and p.Arg457His accounts for about 60% of pathogenic variants among individuals of Japanese ancestry, although it is important to note that p.Arg457His has also been reported in individuals of European and African ancestry [ Variants listed in the table have been provided by the authors. See Pathogenic variants that create a premature stop codon are predicted to result in a truncated nonfunctional protein [ A murine knockout of ## References ## Literature Cited ## Chapter Notes The authors would like to thank Dr Cedric Shackleton and Dr Richard Kelley for providing information and inspiration for this project. 3 August 2017 (sw) Comprehensive update posted live 18 August 2009 (me) Comprehensive update posted live 8 September 2005 (me) Review posted live 9 September 2004 (dlc) Original submission • 3 August 2017 (sw) Comprehensive update posted live • 18 August 2009 (me) Comprehensive update posted live • 8 September 2005 (me) Review posted live • 9 September 2004 (dlc) Original submission ## Acknowledgments The authors would like to thank Dr Cedric Shackleton and Dr Richard Kelley for providing information and inspiration for this project. ## Revision History 3 August 2017 (sw) Comprehensive update posted live 18 August 2009 (me) Comprehensive update posted live 8 September 2005 (me) Review posted live 9 September 2004 (dlc) Original submission • 3 August 2017 (sw) Comprehensive update posted live • 18 August 2009 (me) Comprehensive update posted live • 8 September 2005 (me) Review posted live • 9 September 2004 (dlc) Original submission Steroid synthesis Principal intermediates of steroidogenesis illustrating the location of multiple partial biochemical blocks at steps that rely on cytochrome p450 oxidoreductase. These partial blocks lead to increased serum pregnenolone, progesterone, and 17-alpha-OH-progesterone. Steroid anomalies and pregnancy Partial blockages, which occur at each step catalyzed by cytochrome p450 (CYP) dependent enzymes, presumably explain the finding of low maternal serum unconjugated estriol (uE3) during pregnancies with an affected fetus. Impaired aromatization of fetal androgens may also help explain why some mothers experience maternal virilization during pregnancy with an affected fetus. Impaired aromatization of fetal androgens may also contribute to the virilization of affected female infants. The proposed alternative (or "backdoor") pathway of androgen synthesis, which is believed to be active only during fetal life, is also illustrated. This alternative pathway has been proposed as an explanation for ambiguous genitalia present in some affected females. Note: It is unknown if low maternal serum concentration of uE3 is a consistent finding among all individuals with cytochrome P450 oxidoreductase deficiency. Cholesterol synthesis pathway (distal portion) Evidence for a partial biochemical block in sterol synthesis at the level of 14- α-demethylase comes from the finding of significantly increased levels of lanosterol and dihydrolanosterol when lymphoblasts are grown in the absence of cholesterol [	[ "M Adachi, K Tachibana, Y Asakura, T Yamamoto, K Hanaki, A Oka. Compound heterozygous mutations of cytochrome P450 oxidoreductase gene (POR) in two patients with Antley-Bixler syndrome.. Am J Med Genet A 2004;128A:333-9", "V Agrawal, JH Choi, KM Giacomini, WL Miller. Substrate-specific modulation of CYP3A4 activity by genetic variants of cytochrome P450 oxidoreductase.. Pharmacogenet Genomics 2010;20:611-8", "V Agrawal, N Huang, WL Miller. 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Am J Med Genet A 2006;140A:1797-803" ]	8/9/2005	3/8/2017	2/11/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
accpn	accpn	[ "Agenesis of Corpus Callosum with Peripheral Neuropathy (ACCPN)", "Andermann Syndrome", "Agenesis of Corpus Callosum with Peripheral Neuropathy (ACCPN)", "Andermann Syndrome", "Solute carrier family 12 member 6", "SLC12A6", "Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum" ]	Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum	Claudie Gauvreau, Jean-Denis Brisson, Nicolas Dupré	Summary Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), a neurodevelopmental and neurodegenerative disorder, is characterized by severe progressive sensorimotor neuropathy with resulting hypotonia, areflexia, and amyotrophy, and by variable degrees of dysgenesis of the corpus callosum. Mild-to-severe intellectual disability and "psychotic episodes" during adolescence are observed. Sensory modalities are moderately to severely affected beginning in infancy. The average age of onset of walking is 3.8 years; the average age of loss of walking is 13.8 years; the average age of death is 33 years. The diagnosis of HMSN/ACC is established in a proband with suggestive findings and biallelic pathogenic variants in HMSN/ACC 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. Heterozygotes (carriers) are asymptomatic. Once the	## Diagnosis Consensus diagnostic criteria for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) have not been established. Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) Severe progressive sensorimotor neuropathy with areflexia Developmental delay / intellectual disability ranging from mild to severe Sensory nerve action potentials cannot be recorded at the median, ulnar, or sural nerves even in children in their first year of life. Compound motor action potentials usually show diminished amplitudes. Nerve conduction velocities for the median, ulnar, and tibial nerves are variable. Needle electromyography may show mild signs of active denervation (e.g., fibrillation potentials). Brain MRI showing complete agenesis of the corpus callosum in 60% of individuals ( Mild cortical or cerebellar atrophy at a later age The diagnosis of hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) 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: In individuals of French Canadian origin who have the typical phenotype, targeted analysis for the 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 Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum 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 Nearly all (>99%) individuals of French Canadian descent, who make up most of the affected population, have 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. • Severe progressive sensorimotor neuropathy with areflexia • Developmental delay / intellectual disability ranging from mild to severe • Sensory nerve action potentials cannot be recorded at the median, ulnar, or sural nerves even in children in their first year of life. • Compound motor action potentials usually show diminished amplitudes. • Nerve conduction velocities for the median, ulnar, and tibial nerves are variable. • Needle electromyography may show mild signs of active denervation (e.g., fibrillation potentials). • Brain MRI showing complete agenesis of the corpus callosum in 60% of individuals ( • Mild cortical or cerebellar atrophy at a later age ## Suggestive Findings Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) Severe progressive sensorimotor neuropathy with areflexia Developmental delay / intellectual disability ranging from mild to severe Sensory nerve action potentials cannot be recorded at the median, ulnar, or sural nerves even in children in their first year of life. Compound motor action potentials usually show diminished amplitudes. Nerve conduction velocities for the median, ulnar, and tibial nerves are variable. Needle electromyography may show mild signs of active denervation (e.g., fibrillation potentials). Brain MRI showing complete agenesis of the corpus callosum in 60% of individuals ( Mild cortical or cerebellar atrophy at a later age • Severe progressive sensorimotor neuropathy with areflexia • Developmental delay / intellectual disability ranging from mild to severe • Sensory nerve action potentials cannot be recorded at the median, ulnar, or sural nerves even in children in their first year of life. • Compound motor action potentials usually show diminished amplitudes. • Nerve conduction velocities for the median, ulnar, and tibial nerves are variable. • Needle electromyography may show mild signs of active denervation (e.g., fibrillation potentials). • Brain MRI showing complete agenesis of the corpus callosum in 60% of individuals ( • Mild cortical or cerebellar atrophy at a later age ## Establishing the Diagnosis The diagnosis of hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) 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: In individuals of French Canadian origin who have the typical phenotype, targeted analysis for the 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 Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum 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 Nearly all (>99%) individuals of French Canadian descent, who make up most of the affected population, have 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 Note: In individuals of French Canadian origin who have the typical phenotype, targeted analysis for the 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 Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum 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 Nearly all (>99%) individuals of French Canadian descent, who make up most of the affected population, have 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 Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is both a neurodevelopmental disorder (with variable degrees of dysgenesis of the corpus callosum and mild-to-severe intellectual disability) and a neurodegenerative disorder (severe progressive sensorimotor neuropathy). The neurologic findings of HMSN/ACC in 64 individuals (ages 2 to 34 years) in the French Canadian population reported by Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum: Select Features ID = intellectual disability; MCP = metacarpophalangeal Based on Reflexes invariably absent from infancy Hypotonia invariably present in the first year of life Progressive distal and proximal symmetric limb weakness Muscle atrophy Diffuse limb tremor (probably secondary to polyneuropathy) Contractures Loss of sensation to touch and pinprick in a glove and stocking distribution; easier to evaluate in older children The average age of onset for sitting alone is 2.1 years, for standing is more than two years, for walking is 3.8 years, and average age of loss of ability to walk is 13.8 years. Note: Sural nerve biopsy is unnecessary to confirm the diagnosis, now that molecular genetic testing is possible. The data from affected individuals are insufficient to establish genotype-phenotype correlations. HMSN/ACC may also be referred to as Charlevoix disease. In the French Canadian population of the Saguenay and Lac-St-Jean regions of Quebec, Canada, the overall incidence of HMSN/ACC is 1:2,117 live births; the carrier rate is 1:23 inhabitants due to the • Reflexes invariably absent from infancy • Hypotonia invariably present in the first year of life • Progressive distal and proximal symmetric limb weakness • Muscle atrophy • Diffuse limb tremor (probably secondary to polyneuropathy) • Contractures • Loss of sensation to touch and pinprick in a glove and stocking distribution; easier to evaluate in older children • Note: Sural nerve biopsy is unnecessary to confirm the diagnosis, now that molecular genetic testing is possible. ## Clinical Description Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is both a neurodevelopmental disorder (with variable degrees of dysgenesis of the corpus callosum and mild-to-severe intellectual disability) and a neurodegenerative disorder (severe progressive sensorimotor neuropathy). The neurologic findings of HMSN/ACC in 64 individuals (ages 2 to 34 years) in the French Canadian population reported by Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum: Select Features ID = intellectual disability; MCP = metacarpophalangeal Based on Reflexes invariably absent from infancy Hypotonia invariably present in the first year of life Progressive distal and proximal symmetric limb weakness Muscle atrophy Diffuse limb tremor (probably secondary to polyneuropathy) Contractures Loss of sensation to touch and pinprick in a glove and stocking distribution; easier to evaluate in older children The average age of onset for sitting alone is 2.1 years, for standing is more than two years, for walking is 3.8 years, and average age of loss of ability to walk is 13.8 years. Note: Sural nerve biopsy is unnecessary to confirm the diagnosis, now that molecular genetic testing is possible. • Reflexes invariably absent from infancy • Hypotonia invariably present in the first year of life • Progressive distal and proximal symmetric limb weakness • Muscle atrophy • Diffuse limb tremor (probably secondary to polyneuropathy) • Contractures • Loss of sensation to touch and pinprick in a glove and stocking distribution; easier to evaluate in older children • Note: Sural nerve biopsy is unnecessary to confirm the diagnosis, now that molecular genetic testing is possible. ## Genotype-Phenotype Correlations The data from affected individuals are insufficient to establish genotype-phenotype correlations. ## Nomenclature HMSN/ACC may also be referred to as Charlevoix disease. ## Prevalence In the French Canadian population of the Saguenay and Lac-St-Jean regions of Quebec, Canada, the overall incidence of HMSN/ACC is 1:2,117 live births; the carrier rate is 1:23 inhabitants due to the ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Autosomal Recessive Neurodegenerative Disorders in the Differential Diagnosis of Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Classic INAD: typical onset age 6 mos to 3 yrs w/developmental regression, hypotonia, progressive psychomotor delay, & progressive spastic tetraparesis; strabismus, nystagmus, & optic atrophy common; ± partial ACC Rapid disease progression: many affected children never learn to walk or lose this ability shortly after attaining it; severe spasticity, progressive cognitive decline, & visual impairment typically → death in 1st decade. Atypical NAD: see footnote 1. Faster & more severe regression of motor skills Spasticity Infantile- & early-juvenile-onset MLD present w/CNS &/or peripheral nervous system manifestations; affected persons eventually lose motor & intellectual functions. Disease course is ~3-10 yrs in late-infantile-onset MLD & ~20 yrs in juvenile-onset MLD; death is most commonly from pneumonia or other infection. Absence (typically) of ACC Leukodystrophy Presents w/severe peripheral motor & sensory neuropathy in infancy; evolves into CNS impairment (ID, seizures, cerebellar signs, & pyramidal tract signs); pathologic hallmark is "giant axons" assoc w/massive disorganization & aggregation of neurofilaments. Most persons become wheelchair dependent in 2nd decade of life & eventually bedridden w/severe polyneuropathy, ataxia, & dementia; death usually occurs in 3rd decade. Absence (typically) of ACC Atrophy of CC in some affected persons Progressive spasticity & weakness of lower limbs frequently assoc w/mild ID w/learning difficulties in childhood &/or progressive cognitive decline, peripheral neuropathy, pseudobulbar involvement, & ↑ reflexes in upper limbs. Less frequent findings: cerebellar signs (ataxia, nystagmus, saccadic pursuit), retinal degeneration, pes cavus, scoliosis, parkinsonism Onset occurs mainly in infancy or adolescence; most affected persons become wheelchair bound 1-2 decades after disease onset. Hyperreflexia of upper limbs & spasticity Thin CC in some affected persons Infantile form presents before age 12 mos w/extreme irritability, axial hypotonia, spasticity, loss of acquired milestones, & peripheral neuropathy; average age at death is 24 mos. Late-onset form presents after age 12 mos (childhood-7th decade) & may present as DD or regression; disease course is variable & may be assoc w/spastic paraparesis, peripheral neuropathy, seizures, & vision loss. Spastic paraparesis (in late onset form) Thin CC in some affected persons ACC = agenesis of corpus callosum; CC = corpus callosum; CNS = central nervous system; DD = developmental delay; DiffDx = differential diagnosis; HMSN = hereditary motor and sensory neuropathy; ID = intellectual disability Atypical neuroaxonal dystrophy is more varied than the classic form. In general, onset is in early childhood, but can be as late as the late teens. The presenting signs may be similar to the classic form with gait instability or ataxia, but may be speech delay and autistic features, which may remain as the only evidence of disease for a year or more. The course is fairly stable during early childhood and resembles static encephalopathy, but is followed by neurologic deterioration between ages seven and 12 years. • Classic INAD: typical onset age 6 mos to 3 yrs w/developmental regression, hypotonia, progressive psychomotor delay, & progressive spastic tetraparesis; strabismus, nystagmus, & optic atrophy common; ± partial ACC • Rapid disease progression: many affected children never learn to walk or lose this ability shortly after attaining it; severe spasticity, progressive cognitive decline, & visual impairment typically → death in 1st decade. • Atypical NAD: see footnote 1. • Faster & more severe regression of motor skills • Spasticity • Infantile- & early-juvenile-onset MLD present w/CNS &/or peripheral nervous system manifestations; affected persons eventually lose motor & intellectual functions. • Disease course is ~3-10 yrs in late-infantile-onset MLD & ~20 yrs in juvenile-onset MLD; death is most commonly from pneumonia or other infection. • Absence (typically) of ACC • Leukodystrophy • Presents w/severe peripheral motor & sensory neuropathy in infancy; evolves into CNS impairment (ID, seizures, cerebellar signs, & pyramidal tract signs); pathologic hallmark is "giant axons" assoc w/massive disorganization & aggregation of neurofilaments. • Most persons become wheelchair dependent in 2nd decade of life & eventually bedridden w/severe polyneuropathy, ataxia, & dementia; death usually occurs in 3rd decade. • Absence (typically) of ACC • Atrophy of CC in some affected persons • Progressive spasticity & weakness of lower limbs frequently assoc w/mild ID w/learning difficulties in childhood &/or progressive cognitive decline, peripheral neuropathy, pseudobulbar involvement, & ↑ reflexes in upper limbs. • Less frequent findings: cerebellar signs (ataxia, nystagmus, saccadic pursuit), retinal degeneration, pes cavus, scoliosis, parkinsonism • Onset occurs mainly in infancy or adolescence; most affected persons become wheelchair bound 1-2 decades after disease onset. • Hyperreflexia of upper limbs & spasticity • Thin CC in some affected persons • Infantile form presents before age 12 mos w/extreme irritability, axial hypotonia, spasticity, loss of acquired milestones, & peripheral neuropathy; average age at death is 24 mos. • Late-onset form presents after age 12 mos (childhood-7th decade) & may present as DD or regression; disease course is variable & may be assoc w/spastic paraparesis, peripheral neuropathy, seizures, & vision loss. • Spastic paraparesis (in late onset form) • Thin CC in some affected persons ## Management Consensus clinical management recommendations for hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) have not been published. To establish the extent of disease and needs in an individual diagnosed with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Obtain EEG. Consider MRI if not previously performed. Gross motor & fine motor skills Possible contractures (esp Achilles tendon) Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Mobility, self-help skills, ADL, & need for adaptive devices Baseline eval for scoliosis Baseline pulmonary function assessment given ↑ risk for restrictive lung disease To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education / community & social activities Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Care is best provided by a multidisciplinary team that comprises a pediatrician or pediatric neurologist, developmental pediatrician, psychiatrist, orthopedist, physiotherapist, and occupational therapist. Treatment of Manifestations in Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Valproate may also be beneficial for behavioral problems. Education of parents/caregivers Regular physiotherapy to maximize mobility & ↓ risk for later orthopedic complications (e.g., hand & foot contractures, scoliosis) Walking aids incl canes or walkers when appropriate Use of orthoses for upper & lower limbs as needed Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) Disability parking placard for 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; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical 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. Recommended Surveillance for Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Esp in early teen yrs when significant scoliosis is likely to appear Annual or biannual As needed Refer to psychiatrist. OT = occupational therapist; PT = physical therapist See Search • Obtain EEG. • Consider MRI if not previously performed. • Gross motor & fine motor skills • Possible contractures (esp Achilles tendon) • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Mobility, self-help skills, ADL, & need for adaptive devices • Baseline eval for scoliosis • Baseline pulmonary function assessment given ↑ risk for restrictive lung disease • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education / community & social activities • 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. • Valproate may also be beneficial for behavioral problems. • Education of parents/caregivers • Regular physiotherapy to maximize mobility & ↓ risk for later orthopedic complications (e.g., hand & foot contractures, scoliosis) • Walking aids incl canes or walkers when appropriate • Use of orthoses for upper & lower limbs as needed • Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) • Disability parking placard for caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Esp in early teen yrs when significant scoliosis is likely to appear • Annual or biannual • As needed • Refer to psychiatrist. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Obtain EEG. Consider MRI if not previously performed. Gross motor & fine motor skills Possible contractures (esp Achilles tendon) Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Mobility, self-help skills, ADL, & need for adaptive devices Baseline eval for scoliosis Baseline pulmonary function assessment given ↑ risk for restrictive lung disease To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education / community & social activities Community or Social work involvement for parental support; Home nursing referral. ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Obtain EEG. • Consider MRI if not previously performed. • Gross motor & fine motor skills • Possible contractures (esp Achilles tendon) • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Mobility, self-help skills, ADL, & need for adaptive devices • Baseline eval for scoliosis • Baseline pulmonary function assessment given ↑ risk for restrictive lung disease • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education / community & social activities • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Care is best provided by a multidisciplinary team that comprises a pediatrician or pediatric neurologist, developmental pediatrician, psychiatrist, orthopedist, physiotherapist, and occupational therapist. Treatment of Manifestations in Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Valproate may also be beneficial for behavioral problems. Education of parents/caregivers Regular physiotherapy to maximize mobility & ↓ risk for later orthopedic complications (e.g., hand & foot contractures, scoliosis) Walking aids incl canes or walkers when appropriate Use of orthoses for upper & lower limbs as needed Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) Disability parking placard for 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; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on nonmedical 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. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Valproate may also be beneficial for behavioral problems. • Education of parents/caregivers • Regular physiotherapy to maximize mobility & ↓ risk for later orthopedic complications (e.g., hand & foot contractures, scoliosis) • Walking aids incl canes or walkers when appropriate • Use of orthoses for upper & lower limbs as needed • Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) • Disability parking placard for caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## 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 Recommended Surveillance for Individuals with Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum Esp in early teen yrs when significant scoliosis is likely to appear Annual or biannual As needed Refer to psychiatrist. OT = occupational therapist; PT = physical therapist • Esp in early teen yrs when significant scoliosis is likely to appear • Annual or biannual • As needed • Refer to psychiatrist. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the 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 carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of 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 carriers or are at risk of being carriers. ## Mode of Inheritance Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the See ## Related Genetic Counseling Issues 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 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 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 Canada PO Box 5801 Bethesda MD 20824 • • • • • • Canada • • • PO Box 5801 • Bethesda MD 20824 • ## Molecular Genetics Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Hereditary Motor and Sensory Neuropathy with Agenesis of the Corpus Callosum ( 12 putative membrane-spanning helices with large NH2 and COOH termini; A large extracellular loop between transmembrane domains 7 and 8 with five potential sites for N-linked glycosylation; Two consensus cAMP-dependent protein kinase phosphorylation sites; Four consensus protein kinase C phosphorylation sites in the COOH terminus. KCC3, a cell cotransporter of the peripheral and central nervous system throughout neurologic development and adulthood, is necessary for the transport of chloride and potassium for the regulation of axonal cell volume [ KCC3 is also involved in the precise propagation of the paranodal action potential [ Although both loss of function and gain of function of KCC3 can cause peripheral neuropathy, gain of KCC3 function causes peripheral neuropathy without abnormalities of the corpus callosum or cognitive abilities [ Studies on mice lacking Notable Variants listed in the table have been provided by the authors. Alternate designation • 12 putative membrane-spanning helices with large NH2 and COOH termini; • A large extracellular loop between transmembrane domains 7 and 8 with five potential sites for N-linked glycosylation; • Two consensus cAMP-dependent protein kinase phosphorylation sites; • Four consensus protein kinase C phosphorylation sites in the COOH terminus. ## Molecular Pathogenesis 12 putative membrane-spanning helices with large NH2 and COOH termini; A large extracellular loop between transmembrane domains 7 and 8 with five potential sites for N-linked glycosylation; Two consensus cAMP-dependent protein kinase phosphorylation sites; Four consensus protein kinase C phosphorylation sites in the COOH terminus. KCC3, a cell cotransporter of the peripheral and central nervous system throughout neurologic development and adulthood, is necessary for the transport of chloride and potassium for the regulation of axonal cell volume [ KCC3 is also involved in the precise propagation of the paranodal action potential [ Although both loss of function and gain of function of KCC3 can cause peripheral neuropathy, gain of KCC3 function causes peripheral neuropathy without abnormalities of the corpus callosum or cognitive abilities [ Studies on mice lacking Notable Variants listed in the table have been provided by the authors. Alternate designation • 12 putative membrane-spanning helices with large NH2 and COOH termini; • A large extracellular loop between transmembrane domains 7 and 8 with five potential sites for N-linked glycosylation; • Two consensus cAMP-dependent protein kinase phosphorylation sites; • Four consensus protein kinase C phosphorylation sites in the COOH terminus. ## Chapter Notes This work was supported by Additionally, the authors would like to acknowledge the very significant contributions of Dr Jean Mathieu and Dr Jean-Pierre Bouchard to the understanding of HMSN/ACC, which have been the cornerstone of its phenotypic and genotypic characterization in the last decade. Jean-Denis Brisson, MD, FRCP(C) (2020-present)Nicolas Dupré, MD, MSc, FRCP(C) (2006-present)Claudie Gauvreau, MD, MSc (2020-present)Heidi C Howard, PhD; Radboud University Medical Center (2006-2020)Guy A Rouleau, MD, PhD, FRCP(C); McGill University (2006-2020) 17 September 2020 (bp) Comprehensive update posted live 12 June 2014 (me) Comprehensive update posted live 18 June 2009 (me) Comprehensive update posted live 2 February 2006 (me) Review posted live 2 September 2005 (gr) Original submission • 17 September 2020 (bp) Comprehensive update posted live • 12 June 2014 (me) Comprehensive update posted live • 18 June 2009 (me) Comprehensive update posted live • 2 February 2006 (me) Review posted live • 2 September 2005 (gr) Original submission ## Acknowledgments This work was supported by Additionally, the authors would like to acknowledge the very significant contributions of Dr Jean Mathieu and Dr Jean-Pierre Bouchard to the understanding of HMSN/ACC, which have been the cornerstone of its phenotypic and genotypic characterization in the last decade. ## Author History Jean-Denis Brisson, MD, FRCP(C) (2020-present)Nicolas Dupré, MD, MSc, FRCP(C) (2006-present)Claudie Gauvreau, MD, MSc (2020-present)Heidi C Howard, PhD; Radboud University Medical Center (2006-2020)Guy A Rouleau, MD, PhD, FRCP(C); McGill University (2006-2020) ## Revision History 17 September 2020 (bp) Comprehensive update posted live 12 June 2014 (me) Comprehensive update posted live 18 June 2009 (me) Comprehensive update posted live 2 February 2006 (me) Review posted live 2 September 2005 (gr) Original submission • 17 September 2020 (bp) Comprehensive update posted live • 12 June 2014 (me) Comprehensive update posted live • 18 June 2009 (me) Comprehensive update posted live • 2 February 2006 (me) Review posted live • 2 September 2005 (gr) Original submission ## References ## Literature Cited Sagittal T A. Complete agenesis of the corpus callosum B. Normal corpus callosum (arrow) Axial T A. Agenesis of the corpus callosum with parallelism of the ventricles B. Normal ventricles	[]	2/2/2006	17/9/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
achm	achm	[ "Complete Achromatopsia (Rod Monochromatism, Total Color Blindness)", "Incomplete Achromatopsia", "Cone cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha'", "Cyclic AMP-dependent transcription factor ATF-6 alpha", "Cyclic nucleotide-gated channel alpha-3", "Cyclic nucleotide-gated channel beta-3", "Guanine nucleotide-binding protein G(t) subunit alpha-2", "Retinal cone rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma", "ATF6", "CNGA3", "CNGB3", "GNAT2", "PDE6C", "PDE6H", "Achromatopsia" ]	Achromatopsia	Susanne Kohl, Herbert Jägle, Bernd Wissinger, Ditta Zobor	Summary Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination. All individuals with achromatopsia (achromats) have impaired color discrimination along all three axes of color vision corresponding to the three cone classes: the protan or long-wavelength-sensitive cone axis (red), the deutan or middle-wavelength-sensitive cone axis (green), and the tritan or short-wavelength-sensitive cone axis (blue). Most individuals have Hyperopia is common in achromatopsia. Nystagmus develops during the first few weeks after birth followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time; both nystagmus and sensitivity to bright light may improve slightly. Although the fundus is usually normal, macular changes (which may show early signs of progression) and vessel narrowing may be present in some affected individuals. Defects in the macula are visible on optical coherence tomography. The diagnosis of achromatopsia is established in a proband through clinical and family history, examination for nystagmus, visual acuity testing, color vision assessment, and fundoscopic examination. If achromatopsia is suspected, additional testing may include optical coherence tomography, fundus autofluorescence, visual fields, and electroretinogram. Identification of biallelic pathogenic (or likely pathogenic) variants in Achromatopsia 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 pathogenic variants have been identified in the family.	Complete achromatopsia (rod monochromatism, total color blindness) Incomplete achromatopsia For synonyms and outdated names see For other genetic causes of these phenotypes see • Complete achromatopsia (rod monochromatism, total color blindness) • Incomplete achromatopsia ## Diagnosis Achromatopsia Pendular nystagmus Increased sensitivity to light (photophobia) Eccentric fixation Reduced visual acuity Reduced or complete lack of color discrimination Small central scotoma Fundus appearance: normal in many affected individuals, but can show subtle bilateral macular changes such as absence of the foveal reflex, pigment mottling, or narrowing of the retinal vessels. Frank atrophy of the retinal pigment epithelium (RPE) in the fovea can occur in older individuals. Generally, no specific axis of color confusion is found on the Farnsworth Munsell 100-hue test. An achromat axis (in which the constituent color chips are arranged according to their rod-perceived lightness) is characteristic for complete achromatopsia on both the saturated and desaturated versions of the Panel D-15 test. The most important and diagnostic test is red-green color discrimination with the Rayleigh anomaloscope equation. Although a complete achromat can always fully color-match the spectral yellow primary to any mixture of the spectral red and green primaries, a brightness match is only possible to red primary-dominated mixtures. The clinical diagnosis of achromatopsia 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 For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Achromatopsia 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. Larger deletions, insertions, or duplications have either not been reported or are confined to single reports or families [ Of 163 individuals with pathogenic variants in A single nonsense variant has been reported in three families [ • Pendular nystagmus • Increased sensitivity to light (photophobia) • Eccentric fixation • Reduced visual acuity • Reduced or complete lack of color discrimination • Small central scotoma • Fundus appearance: normal in many affected individuals, but can show subtle bilateral macular changes such as absence of the foveal reflex, pigment mottling, or narrowing of the retinal vessels. Frank atrophy of the retinal pigment epithelium (RPE) in the fovea can occur in older individuals. • Generally, no specific axis of color confusion is found on the Farnsworth Munsell 100-hue test. • An achromat axis (in which the constituent color chips are arranged according to their rod-perceived lightness) is characteristic for complete achromatopsia on both the saturated and desaturated versions of the Panel D-15 test. • The most important and diagnostic test is red-green color discrimination with the Rayleigh anomaloscope equation. Although a complete achromat can always fully color-match the spectral yellow primary to any mixture of the spectral red and green primaries, a brightness match is only possible to red primary-dominated mixtures. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Achromatopsia Pendular nystagmus Increased sensitivity to light (photophobia) Eccentric fixation Reduced visual acuity Reduced or complete lack of color discrimination Small central scotoma Fundus appearance: normal in many affected individuals, but can show subtle bilateral macular changes such as absence of the foveal reflex, pigment mottling, or narrowing of the retinal vessels. Frank atrophy of the retinal pigment epithelium (RPE) in the fovea can occur in older individuals. Generally, no specific axis of color confusion is found on the Farnsworth Munsell 100-hue test. An achromat axis (in which the constituent color chips are arranged according to their rod-perceived lightness) is characteristic for complete achromatopsia on both the saturated and desaturated versions of the Panel D-15 test. The most important and diagnostic test is red-green color discrimination with the Rayleigh anomaloscope equation. Although a complete achromat can always fully color-match the spectral yellow primary to any mixture of the spectral red and green primaries, a brightness match is only possible to red primary-dominated mixtures. • Pendular nystagmus • Increased sensitivity to light (photophobia) • Eccentric fixation • Reduced visual acuity • Reduced or complete lack of color discrimination • Small central scotoma • Fundus appearance: normal in many affected individuals, but can show subtle bilateral macular changes such as absence of the foveal reflex, pigment mottling, or narrowing of the retinal vessels. Frank atrophy of the retinal pigment epithelium (RPE) in the fovea can occur in older individuals. • Generally, no specific axis of color confusion is found on the Farnsworth Munsell 100-hue test. • An achromat axis (in which the constituent color chips are arranged according to their rod-perceived lightness) is characteristic for complete achromatopsia on both the saturated and desaturated versions of the Panel D-15 test. • The most important and diagnostic test is red-green color discrimination with the Rayleigh anomaloscope equation. Although a complete achromat can always fully color-match the spectral yellow primary to any mixture of the spectral red and green primaries, a brightness match is only possible to red primary-dominated mixtures. ## Establishing the Diagnosis The clinical diagnosis of achromatopsia 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 For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Achromatopsia 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. Larger deletions, insertions, or duplications have either not been reported or are confined to single reports or families [ Of 163 individuals with pathogenic variants in A single nonsense variant has been reported in three families [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma (which is often difficult to demonstrate), eccentric fixation, and reduced or complete lack of color discrimination. Hyperopia is common. Nystagmus develops during the first few weeks after birth and is followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time, but both nystagmus and sensitivity to bright light may improve slightly. The fundus is usually normal, but macular changes and vessel narrowing may be present in some individuals, and optical coherence tomography (OCT) reveals macular changes that can progress with time [ Most individuals have Rarely, individuals have Certain Pathogenic variants in Cone-rod dystrophy and macular dystrophy have been reported for pathogenic variants in The The Achromatopsia is a rare disorder with an estimated prevalence of fewer than 1:30,000 [ Parental consanguinity is common in certain geographic regions. On the island of Pingelap in the eastern Caroline Islands in Micronesia, the prevalence of achromatopsia is between 4% and 10%, secondary to the founder variant • Certain • Pathogenic variants in • Cone-rod dystrophy and macular dystrophy have been reported for pathogenic variants in ## Clinical Description Achromatopsia is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma (which is often difficult to demonstrate), eccentric fixation, and reduced or complete lack of color discrimination. Hyperopia is common. Nystagmus develops during the first few weeks after birth and is followed by increased sensitivity to bright light. Best visual acuity varies with severity of the disease; it is 20/200 or less in complete achromatopsia and may be as high as 20/80 in incomplete achromatopsia. Visual acuity is usually stable over time, but both nystagmus and sensitivity to bright light may improve slightly. The fundus is usually normal, but macular changes and vessel narrowing may be present in some individuals, and optical coherence tomography (OCT) reveals macular changes that can progress with time [ Most individuals have Rarely, individuals have ## Phenotype Correlations by Gene Certain Pathogenic variants in Cone-rod dystrophy and macular dystrophy have been reported for pathogenic variants in • Certain • Pathogenic variants in • Cone-rod dystrophy and macular dystrophy have been reported for pathogenic variants in ## Nomenclature The The ## Prevalence Achromatopsia is a rare disorder with an estimated prevalence of fewer than 1:30,000 [ Parental consanguinity is common in certain geographic regions. On the island of Pingelap in the eastern Caroline Islands in Micronesia, the prevalence of achromatopsia is between 4% and 10%, secondary to the founder variant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Allelic disorders observed in the other five achromatopsia-associated genes are discussed in Allelic Disorders to Consider in the Differential Diagnosis of Achromatopsia Often only distinguishable from achromatopsia by evidence of disease progression over time AR = autosomal recessive ; MOI = mode of inheritance Allelic Disorders (Not in the Differential Diagnosis of Achromatopsia) ## Differential Diagnosis Achromatopsia is readily recognized by its characteristic features (see Inherited retinal dystrophies that may be confused with achromatopsia are summarized in Inherited Retinal Dystrophies to Consider in the Differential Diagnosis of Achromatopsia Severely ↓ visual acuity Eccentric fixation ± Infantile nystagmus No obvious fundus abnormalities Poor or no color discrimination Peak of photopic luminosity function is near 440 nm (the peak sensitivity of the S cones), not 507 nm (the peak sensitivity of the rods). Mostly males are affected. A special 4-color plate test or a 2-color filter test can clinically distinguish blue-cone monochromats from achromats (rod monochromats). Cone ERG responses can be elicited by presenting blue flashes on a yellow background (because the S cones are functioning in addition to the rods). Absence of ophthalmologic or other associated clinical abnormalities Most individuals w/protanomalous & deuteranomalous color vision defects (i.e., anomalous trichromats) have no major problems in naming colors. Mostly males are affected. Clinical chart tests widely used to detect red-green color vision defects include Ishihara plates & the American Optical HRR pseudoisochromatic plates. Definitive classification of color vision defects known as protanopia, deuteranopia, protanomaly, & deuteranomaly requires use of anomaloscope, which involves color matching. In tritan & yellow-blue defects: color confusion is limited to blues & greens. Cone function may be normal at birth. Typical symptoms (↓ visual acuity, photophobia, ↑ sensitivity to glare, abnormal color vision) appear later. Age of onset of vision loss may be as early as childhood or as late as 7th decade. Dark-adapted rod thresholds may be elevated. Differentiating between achromatopsia & cone dystrophy can be difficult, particularly in individuals w/early-childhood onset. Best clinical discriminator is disease progression. Infantile nystagmus Photophobia Severely reduced visual acuity No obvious fundus abnormalities Poor or no color discrimination Prolonged electroretinal response suppression leading to difficulties adjusting to changes in luminance Normal to subnormal visual acuity Photophobia Infantile nystagmus Photophobia Severely reduced visual acuity Poor or no color discrimination AD = autosomal dominant; AR = autosomal recessive; ERG = electroretinogram; MOI = mode of inheritance; XL = X-linked Blue-cone monochromacy may also be referred to as S-cone monochromacy or X-chromosome-linked achromatopsia. The dysfunction of the L (red) and M (green) cones is caused by pathogenic variants leading to the loss of the X-linked red ( Blue-cone monochromacy affects mostly males. Some males with mildly defective red-green color vision may not be aware of it until they are tested. Among individuals of northern European origin, about 8% of males and 0.5% of females have red-green color vision defects; these defects are less frequent among males of African (3%-4%) or Asian (3%) origin. Often referred to as yellow-blue disorders, although the color confusion is typically between blues & greens, tritan defects affect the S (blue) cones. See • Severely ↓ visual acuity • Eccentric fixation • ± Infantile nystagmus • No obvious fundus abnormalities • Poor or no color discrimination • Peak of photopic luminosity function is near 440 nm (the peak sensitivity of the S cones), not 507 nm (the peak sensitivity of the rods). • Mostly males are affected. • A special 4-color plate test or a 2-color filter test can clinically distinguish blue-cone monochromats from achromats (rod monochromats). • Cone ERG responses can be elicited by presenting blue flashes on a yellow background (because the S cones are functioning in addition to the rods). • Absence of ophthalmologic or other associated clinical abnormalities • Most individuals w/protanomalous & deuteranomalous color vision defects (i.e., anomalous trichromats) have no major problems in naming colors. • Mostly males are affected. • Clinical chart tests widely used to detect red-green color vision defects include Ishihara plates & the American Optical HRR pseudoisochromatic plates. • Definitive classification of color vision defects known as protanopia, deuteranopia, protanomaly, & deuteranomaly requires use of anomaloscope, which involves color matching. • Cone function may be normal at birth. • Typical symptoms (↓ visual acuity, photophobia, ↑ sensitivity to glare, abnormal color vision) appear later. • Age of onset of vision loss may be as early as childhood or as late as 7th decade. • Dark-adapted rod thresholds may be elevated. • Differentiating between achromatopsia & cone dystrophy can be difficult, particularly in individuals w/early-childhood onset. • Best clinical discriminator is disease progression. • Infantile nystagmus • Photophobia • Severely reduced visual acuity • No obvious fundus abnormalities • Poor or no color discrimination • Prolonged electroretinal response suppression leading to difficulties adjusting to changes in luminance • Normal to subnormal visual acuity • Photophobia • Infantile nystagmus • Photophobia • Severely reduced visual acuity • Poor or no color discrimination ## Management To establish the extent of disease and needs in an individual diagnosed with achromatopsia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Standard clinical ophthalmologic evaluation and testing with attention to visual acuity and use of spectacles and/or contact lenses to achieve the best possible corrected visual acuity Color vision evaluation Consultation with a clinical geneticist and/or genetic counselor as treatment could be possible in the near future (See Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity. Low vision aids include high-powered magnifiers for reading as well as digital/electronic devices. Children with achromatopsia should have preferential seating in the classroom (i.e., in the front to benefit maximally from magnifying devices and away from windows to reduce the effects of glare on vision). Extensive information about learning and occupational aids is available from the Achromatopsia Network ( Ophthalmologic examination is indicated: Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity; Every two to three years in adults. To avoid additional light damage to the retina, it is recommended that individuals wear appropriate protective (dark) glasses in bright light. See In July 2012 a Phase I/II clinical trial (NCT01846052) investigating the therapeutic effects and safety of an intraocular implant releasing ciliary neurotrophic factor (CNTF) in individuals with Several interventional Phase I/II clinical safety and efficacy trials for gene replacement therapy using viral AAV vectors for In addition, clinical observational trials have been or are recruiting individuals for clinical assessment to establish the natural history of achromatopsia (NCT02435940, NCT01846052). Search • Standard clinical ophthalmologic evaluation and testing with attention to visual acuity and use of spectacles and/or contact lenses to achieve the best possible corrected visual acuity • Color vision evaluation • Consultation with a clinical geneticist and/or genetic counselor as treatment could be possible in the near future (See • Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity; • Every two to three years in adults. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with achromatopsia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Standard clinical ophthalmologic evaluation and testing with attention to visual acuity and use of spectacles and/or contact lenses to achieve the best possible corrected visual acuity Color vision evaluation Consultation with a clinical geneticist and/or genetic counselor as treatment could be possible in the near future (See • Standard clinical ophthalmologic evaluation and testing with attention to visual acuity and use of spectacles and/or contact lenses to achieve the best possible corrected visual acuity • Color vision evaluation • Consultation with a clinical geneticist and/or genetic counselor as treatment could be possible in the near future (See ## Treatment of Manifestations Dark or special filter glasses or red-tinted contact lenses reduce photophobia and may improve visual acuity. Low vision aids include high-powered magnifiers for reading as well as digital/electronic devices. Children with achromatopsia should have preferential seating in the classroom (i.e., in the front to benefit maximally from magnifying devices and away from windows to reduce the effects of glare on vision). Extensive information about learning and occupational aids is available from the Achromatopsia Network ( ## Surveillance Ophthalmologic examination is indicated: Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity; Every two to three years in adults. • Every six to 12 months in children to monitor changes in refraction in order to achieve the best possible corrected visual acuity; • Every two to three years in adults. ## Agents/Circumstances to Avoid To avoid additional light damage to the retina, it is recommended that individuals wear appropriate protective (dark) glasses in bright light. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation In July 2012 a Phase I/II clinical trial (NCT01846052) investigating the therapeutic effects and safety of an intraocular implant releasing ciliary neurotrophic factor (CNTF) in individuals with Several interventional Phase I/II clinical safety and efficacy trials for gene replacement therapy using viral AAV vectors for In addition, clinical observational trials have been or are recruiting individuals for clinical assessment to establish the natural history of achromatopsia (NCT02435940, NCT01846052). Search ## Genetic Counseling Achromatopsia is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one achromatopsia-related pathogenic variant). 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 achromatopsia-related pathogenic variants 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 achromatopsia-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for achromatopsia 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 obligate heterozygotes (i.e., carriers of one achromatopsia-related pathogenic variant). • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Achromatopsia 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 achromatopsia-related pathogenic variant). 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 achromatopsia-related pathogenic variant). • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the achromatopsia-related pathogenic variants in the family. ## 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 achromatopsia-related pathogenic variants have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for achromatopsia 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 Germany Italy • • • • Germany • • • Italy • • • • • ## Molecular Genetics Achromatopsia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Achromatopsia ( Light-excited cone visual pigment molecules induce the exchange of GDP to GTP on the transducin alpha subunit ( The activated GTP-transducin then binds and activates the alpha' subunit of the retinal cone photoreceptor phosphodiesterase ( Retinal cone photoreceptor PDE6C hydrolyzes cGMP, reducing its intracellular concentration and causing closure of the heterotetrameric cGMP-gated cation channels ( Transducin thus mediates the first step, the phosphodiesterase the intermediate, and the cGMP-gated channel represents the final step in the phototransduction cascade. In contrast, the most recently identified ACHM-related gene, Six individuals (from 2 unrelated families of Irish/British descent) who are homozygous for c.970C>T have been identified; the families were shown to have a common haplotype of 0.7 Mb suggestive of a founder variant [ Variants listed in the table have been provided by the authors. Two cDNAs were identified, one with partial intron retention and one with exon skipping [ Other missense changes have been studied and divided into class I, 2, or 3: Class 1. Disease-associated Class 2. Disease-associated Class 3. ATF6 missense variants with complete loss of transcriptional activity because of absent or defective bZIP domains Primary fibroblasts from patients with class 1 or class 3 Of note, the Some pathogenic variants in the pore region and the cGMP binding domain are associated with incomplete achromatopsia. These abnormal proteins can form functional channels, but with grossly altered properties, including altered affinity for cGMP and/or cAMP, and changes in the gating properties of the cone CNG channels, like Ca Animal models have helped to clarify the underlying pathogenic mechanisms: One, resulting in the p.Ser435Phe mutated protein, causes "Pingelapese blindness" in achromats originating from the island of Pingelap in Micronesia [ The recurrent single base-pair deletion Variants listed in the table have been provided by the authors. Animal models have helped to clarify the underlying pathogenic mechanisms. Two naturally occurring Variants listed in the table have been provided by the authors. Animal models have helped to clarify the underlying pathogenic mechanisms. An achromatopsia mouse model is homozygous for the murine Animal models have helped to clarify the underlying pathogenic mechanisms. The cone photoreceptor function loss 1 ( Variants listed in the table have been provided by the authors. Of note, the • Light-excited cone visual pigment molecules induce the exchange of GDP to GTP on the transducin alpha subunit ( • The activated GTP-transducin then binds and activates the alpha' subunit of the retinal cone photoreceptor phosphodiesterase ( • Retinal cone photoreceptor PDE6C hydrolyzes cGMP, reducing its intracellular concentration and causing closure of the heterotetrameric cGMP-gated cation channels ( • Class 1. Disease-associated • Class 2. Disease-associated • Class 3. ATF6 missense variants with complete loss of transcriptional activity because of absent or defective bZIP domains ## Molecular Pathogenesis Light-excited cone visual pigment molecules induce the exchange of GDP to GTP on the transducin alpha subunit ( The activated GTP-transducin then binds and activates the alpha' subunit of the retinal cone photoreceptor phosphodiesterase ( Retinal cone photoreceptor PDE6C hydrolyzes cGMP, reducing its intracellular concentration and causing closure of the heterotetrameric cGMP-gated cation channels ( Transducin thus mediates the first step, the phosphodiesterase the intermediate, and the cGMP-gated channel represents the final step in the phototransduction cascade. In contrast, the most recently identified ACHM-related gene, Six individuals (from 2 unrelated families of Irish/British descent) who are homozygous for c.970C>T have been identified; the families were shown to have a common haplotype of 0.7 Mb suggestive of a founder variant [ Variants listed in the table have been provided by the authors. Two cDNAs were identified, one with partial intron retention and one with exon skipping [ Other missense changes have been studied and divided into class I, 2, or 3: Class 1. Disease-associated Class 2. Disease-associated Class 3. ATF6 missense variants with complete loss of transcriptional activity because of absent or defective bZIP domains Primary fibroblasts from patients with class 1 or class 3 Of note, the Some pathogenic variants in the pore region and the cGMP binding domain are associated with incomplete achromatopsia. These abnormal proteins can form functional channels, but with grossly altered properties, including altered affinity for cGMP and/or cAMP, and changes in the gating properties of the cone CNG channels, like Ca Animal models have helped to clarify the underlying pathogenic mechanisms: One, resulting in the p.Ser435Phe mutated protein, causes "Pingelapese blindness" in achromats originating from the island of Pingelap in Micronesia [ The recurrent single base-pair deletion Variants listed in the table have been provided by the authors. Animal models have helped to clarify the underlying pathogenic mechanisms. Two naturally occurring Variants listed in the table have been provided by the authors. Animal models have helped to clarify the underlying pathogenic mechanisms. An achromatopsia mouse model is homozygous for the murine Animal models have helped to clarify the underlying pathogenic mechanisms. The cone photoreceptor function loss 1 ( Variants listed in the table have been provided by the authors. Of note, the • Light-excited cone visual pigment molecules induce the exchange of GDP to GTP on the transducin alpha subunit ( • The activated GTP-transducin then binds and activates the alpha' subunit of the retinal cone photoreceptor phosphodiesterase ( • Retinal cone photoreceptor PDE6C hydrolyzes cGMP, reducing its intracellular concentration and causing closure of the heterotetrameric cGMP-gated cation channels ( • Class 1. Disease-associated • Class 2. Disease-associated • Class 3. ATF6 missense variants with complete loss of transcriptional activity because of absent or defective bZIP domains ## Six individuals (from 2 unrelated families of Irish/British descent) who are homozygous for c.970C>T have been identified; the families were shown to have a common haplotype of 0.7 Mb suggestive of a founder variant [ Variants listed in the table have been provided by the authors. Two cDNAs were identified, one with partial intron retention and one with exon skipping [ Other missense changes have been studied and divided into class I, 2, or 3: Class 1. Disease-associated Class 2. Disease-associated Class 3. ATF6 missense variants with complete loss of transcriptional activity because of absent or defective bZIP domains Primary fibroblasts from patients with class 1 or class 3 Of note, the • Class 1. Disease-associated • Class 2. Disease-associated • Class 3. ATF6 missense variants with complete loss of transcriptional activity because of absent or defective bZIP domains ## Some pathogenic variants in the pore region and the cGMP binding domain are associated with incomplete achromatopsia. These abnormal proteins can form functional channels, but with grossly altered properties, including altered affinity for cGMP and/or cAMP, and changes in the gating properties of the cone CNG channels, like Ca Animal models have helped to clarify the underlying pathogenic mechanisms: ## One, resulting in the p.Ser435Phe mutated protein, causes "Pingelapese blindness" in achromats originating from the island of Pingelap in Micronesia [ The recurrent single base-pair deletion Variants listed in the table have been provided by the authors. Animal models have helped to clarify the underlying pathogenic mechanisms. Two naturally occurring ## Variants listed in the table have been provided by the authors. Animal models have helped to clarify the underlying pathogenic mechanisms. An achromatopsia mouse model is homozygous for the murine ## Animal models have helped to clarify the underlying pathogenic mechanisms. The cone photoreceptor function loss 1 ( ## Variants listed in the table have been provided by the authors. Of note, the ## Chapter Notes Herbert Jägle, MD, FEBO, Dhabil Prof (2004-present)Susanne Kohl, Bsc, MSc, PhD (2004-present)Lindsay T Sharpe, BA (Hons), MA, PhD, Dhabil (med); Institute of Ophthalmology, UK (2004-2013)Ditta Zobor, MD, PhD, FEBO, Dhabil (2018-present)Bernd Wissinger, BSc, MSc, PhD, Prof (2004-present) 20 September 2018 (bp) Comprehensive update posted live 25 February 2016 (sk) Revision: Therapies Under Investigation 29 October 2015 (me) Comprehensive update posted live 27 June 2013 (me) Comprehensive update posted live 23 December 2010 (cd) Revision: sequence analysis available clinically for mutations in 23 September 2010 (cd) Revision: prenatal testing available for achromatopsia 2 and 3; achromatopsia 5 (caused by mutations in 25 June 2009 (me) Comprehensive update posted live 23 October 2006 (me) Comprehensive update posted live 24 June 2004 (me) Review posted live 17 February 2004 (sk, bw) Original submission • 20 September 2018 (bp) Comprehensive update posted live • 25 February 2016 (sk) Revision: Therapies Under Investigation • 29 October 2015 (me) Comprehensive update posted live • 27 June 2013 (me) Comprehensive update posted live • 23 December 2010 (cd) Revision: sequence analysis available clinically for mutations in • 23 September 2010 (cd) Revision: prenatal testing available for achromatopsia 2 and 3; achromatopsia 5 (caused by mutations in • 25 June 2009 (me) Comprehensive update posted live • 23 October 2006 (me) Comprehensive update posted live • 24 June 2004 (me) Review posted live • 17 February 2004 (sk, bw) Original submission ## Author History Herbert Jägle, MD, FEBO, Dhabil Prof (2004-present)Susanne Kohl, Bsc, MSc, PhD (2004-present)Lindsay T Sharpe, BA (Hons), MA, PhD, Dhabil (med); Institute of Ophthalmology, UK (2004-2013)Ditta Zobor, MD, PhD, FEBO, Dhabil (2018-present)Bernd Wissinger, BSc, MSc, PhD, Prof (2004-present) ## Revision History 20 September 2018 (bp) Comprehensive update posted live 25 February 2016 (sk) Revision: Therapies Under Investigation 29 October 2015 (me) Comprehensive update posted live 27 June 2013 (me) Comprehensive update posted live 23 December 2010 (cd) Revision: sequence analysis available clinically for mutations in 23 September 2010 (cd) Revision: prenatal testing available for achromatopsia 2 and 3; achromatopsia 5 (caused by mutations in 25 June 2009 (me) Comprehensive update posted live 23 October 2006 (me) Comprehensive update posted live 24 June 2004 (me) Review posted live 17 February 2004 (sk, bw) Original submission • 20 September 2018 (bp) Comprehensive update posted live • 25 February 2016 (sk) Revision: Therapies Under Investigation • 29 October 2015 (me) Comprehensive update posted live • 27 June 2013 (me) Comprehensive update posted live • 23 December 2010 (cd) Revision: sequence analysis available clinically for mutations in • 23 September 2010 (cd) Revision: prenatal testing available for achromatopsia 2 and 3; achromatopsia 5 (caused by mutations in • 25 June 2009 (me) Comprehensive update posted live • 23 October 2006 (me) Comprehensive update posted live • 24 June 2004 (me) Review posted live • 17 February 2004 (sk, bw) Original submission ## References ## Literature Cited	[]	24/6/2004	20/9/2018	25/2/2016	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
achon1b	achon1b	[ "ACG1B, SLC26A2-Related Achondrogenesis", "ACG1B", "SLC26A2-Related Achondrogenesis", "Sulfate transporter", "SLC26A2", "Achondrogenesis Type 1B" ]	Achondrogenesis Type 1B	Sheila Unger, Andrea Superti-Furga	Summary Clinical features of achondrogenesis type 1B (ACG1B) include extremely short limbs with short fingers and toes, hypoplasia of the thorax, protuberant abdomen, and hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton. The face is flat, the neck is short, and the soft tissue of the neck may be thickened. Death occurs prenatally or shortly after birth. The diagnosis of ACG1B is established in a proband with characteristic clinical, radiologic, and histopathologic features. Identification of biallelic pathogenic variants in ACG1B is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis Achondrogenesis type 1B (ACG1B) is a perinatal-lethal disorder with death occurring prenatally or shortly after birth. ACG1B Extremely short limbs with short fingers and toes and clubfeet Hypoplasia of the thorax Protuberant abdomen Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton Flat face with micrognathia Short neck Thickened soft tissue of the neck Disproportion between the nearly normal-sized skull and very short body length. The skull may have a normal appearance or be mildly abnormal (reduced ossification for age; lateral or superior extension of the orbits). Total lack of ossification of the vertebral bodies or only rudimentary calcification of the center. The vertebral lateral pedicles are usually ossified. Short and slightly thin (but usually not fractured) ribs Iliac bone ossification limited to the upper part, giving a crescent-shaped, "paraglider-like" appearance on x-ray. The ischium is usually not ossified. Shortening of the tubular bones such that no major axis can be recognized. Metaphyseal spurring gives the appearance of a "thorn apple" (or in hematologic terms, acanthocyte). The phalanges are poorly ossified and thus rarely identified on x-ray. Only mildly abnormal clavicles (somewhat shortened but normally shaped and ossified) and scapulae (small with irregular contours) [ The diagnosis of ACG1B can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click When the phenotype is not clearly distinguishable from other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Achondrogenesis Type 1B 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 identifies 90% of alleles in individuals with radiologic and histologic features of achondrogenesis type 1B [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ Note: It is often difficult to distinguish between the three different forms of achondrogenesis: ACG1A, ACG1B, and ACG2 (see • Extremely short limbs with short fingers and toes and clubfeet • Hypoplasia of the thorax • Protuberant abdomen • Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton • Flat face with micrognathia • Short neck • Thickened soft tissue of the neck • Disproportion between the nearly normal-sized skull and very short body length. The skull may have a normal appearance or be mildly abnormal (reduced ossification for age; lateral or superior extension of the orbits). • Total lack of ossification of the vertebral bodies or only rudimentary calcification of the center. The vertebral lateral pedicles are usually ossified. • Short and slightly thin (but usually not fractured) ribs • Iliac bone ossification limited to the upper part, giving a crescent-shaped, "paraglider-like" appearance on x-ray. The ischium is usually not ossified. • Shortening of the tubular bones such that no major axis can be recognized. Metaphyseal spurring gives the appearance of a "thorn apple" (or in hematologic terms, acanthocyte). The phalanges are poorly ossified and thus rarely identified on x-ray. • Only mildly abnormal clavicles (somewhat shortened but normally shaped and ossified) and scapulae (small with irregular contours) [ ## Suggestive Findings ACG1B Extremely short limbs with short fingers and toes and clubfeet Hypoplasia of the thorax Protuberant abdomen Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton Flat face with micrognathia Short neck Thickened soft tissue of the neck Disproportion between the nearly normal-sized skull and very short body length. The skull may have a normal appearance or be mildly abnormal (reduced ossification for age; lateral or superior extension of the orbits). Total lack of ossification of the vertebral bodies or only rudimentary calcification of the center. The vertebral lateral pedicles are usually ossified. Short and slightly thin (but usually not fractured) ribs Iliac bone ossification limited to the upper part, giving a crescent-shaped, "paraglider-like" appearance on x-ray. The ischium is usually not ossified. Shortening of the tubular bones such that no major axis can be recognized. Metaphyseal spurring gives the appearance of a "thorn apple" (or in hematologic terms, acanthocyte). The phalanges are poorly ossified and thus rarely identified on x-ray. Only mildly abnormal clavicles (somewhat shortened but normally shaped and ossified) and scapulae (small with irregular contours) [ • Extremely short limbs with short fingers and toes and clubfeet • Hypoplasia of the thorax • Protuberant abdomen • Hydropic fetal appearance caused by the abundance of soft tissue relative to the short skeleton • Flat face with micrognathia • Short neck • Thickened soft tissue of the neck • Disproportion between the nearly normal-sized skull and very short body length. The skull may have a normal appearance or be mildly abnormal (reduced ossification for age; lateral or superior extension of the orbits). • Total lack of ossification of the vertebral bodies or only rudimentary calcification of the center. The vertebral lateral pedicles are usually ossified. • Short and slightly thin (but usually not fractured) ribs • Iliac bone ossification limited to the upper part, giving a crescent-shaped, "paraglider-like" appearance on x-ray. The ischium is usually not ossified. • Shortening of the tubular bones such that no major axis can be recognized. Metaphyseal spurring gives the appearance of a "thorn apple" (or in hematologic terms, acanthocyte). The phalanges are poorly ossified and thus rarely identified on x-ray. • Only mildly abnormal clavicles (somewhat shortened but normally shaped and ossified) and scapulae (small with irregular contours) [ ## Establishing the Diagnosis The diagnosis of ACG1B can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click When the phenotype is not clearly distinguishable from other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Achondrogenesis Type 1B 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 identifies 90% of alleles in individuals with radiologic and histologic features of achondrogenesis type 1B [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ ## Option 1 For an introduction to multigene panels click ## Option 2 When the phenotype is not clearly distinguishable from other skeletal dysplasias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Achondrogenesis Type 1B 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 identifies 90% of alleles in individuals with radiologic and histologic features of achondrogenesis type 1B [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 [ ## Other Testing Note: It is often difficult to distinguish between the three different forms of achondrogenesis: ACG1A, ACG1B, and ACG2 (see ## Clinical Characteristics Achondrogenesis type 1B (ACG1B), one of the most severe chondrodysplasias, is a perinatal-lethal disorder with death occurring prenatally or shortly after birth. The mechanism of the prenatal death is unknown. In the live-born neonate, death is secondary to respiratory failure and occurs shortly after birth. Fetuses with ACG1B often present in breech position. Pregnancy complications as a result of polyhydramnios may occur (e.g., maternal breathing difficulties, preterm labor). Infants with ACG1B appear hydropic with an abundance of soft tissue relative to the short skeleton. The face is flat and the neck is short with thickened soft tissue. The limbs are extremely shortened, with inturning of the feet and toes (talipes equinovarus) and brachydactyly (short stubby fingers and toes). The thorax is narrow and the abdomen protuberant. Frequently, umbilical or inguinal hernias are present. Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders that extends from lethal ACG1B to mild Pathogenic variant Variant Variants Variant Variant The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes ( The term "achondrogenesis" (Greek for "not producing cartilage") was used by the pathologist Marco Fraccaro in 1952 to denote the condition observed in a stillborn with severe micromelia and marked histologic changes in cartilage. Subsequently, "achondrogenesis" was used to characterize the most severe forms of human chondrodysplasia, invariably lethal before or shortly after birth. In the 1980s, a new classification of achondrogenesis (types I to IV) based on radiologic criteria was proposed; the classification did not prove helpful and was later abandoned. Currently, three types of achondrogenesis are recognized and are distinguishable by molecular genetic testing and radiographic findings: ACG1A (an autosomal recessive disorder associated with pathogenic variants in In the 2023 revised Nosology of Genetic Skeletal Disorders [ No data on the prevalence of ACG1B are available. • Variant • Variant ## Clinical Description Achondrogenesis type 1B (ACG1B), one of the most severe chondrodysplasias, is a perinatal-lethal disorder with death occurring prenatally or shortly after birth. The mechanism of the prenatal death is unknown. In the live-born neonate, death is secondary to respiratory failure and occurs shortly after birth. Fetuses with ACG1B often present in breech position. Pregnancy complications as a result of polyhydramnios may occur (e.g., maternal breathing difficulties, preterm labor). Infants with ACG1B appear hydropic with an abundance of soft tissue relative to the short skeleton. The face is flat and the neck is short with thickened soft tissue. The limbs are extremely shortened, with inturning of the feet and toes (talipes equinovarus) and brachydactyly (short stubby fingers and toes). The thorax is narrow and the abdomen protuberant. Frequently, umbilical or inguinal hernias are present. ## Genotype-Phenotype Correlations Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype in this spectrum of disorders that extends from lethal ACG1B to mild Pathogenic variant Variant Variants Variant Variant The same pathogenic variants found in the ACG1B phenotype can also be found in the milder phenotypes ( • Variant • Variant ## Nomenclature The term "achondrogenesis" (Greek for "not producing cartilage") was used by the pathologist Marco Fraccaro in 1952 to denote the condition observed in a stillborn with severe micromelia and marked histologic changes in cartilage. Subsequently, "achondrogenesis" was used to characterize the most severe forms of human chondrodysplasia, invariably lethal before or shortly after birth. In the 1980s, a new classification of achondrogenesis (types I to IV) based on radiologic criteria was proposed; the classification did not prove helpful and was later abandoned. Currently, three types of achondrogenesis are recognized and are distinguishable by molecular genetic testing and radiographic findings: ACG1A (an autosomal recessive disorder associated with pathogenic variants in In the 2023 revised Nosology of Genetic Skeletal Disorders [ ## Prevalence No data on the prevalence of ACG1B are available. ## Genetically Related (Allelic) Disorders Achondrogenesis type 1B (ACG1B) is the most severe phenotype in the spectrum of Commonly lethal in perinatal period Presents around birth or before Chondrodysplasia w/clinical & histologic characteristics resembling those of DTD but more pronounced Short limb type of dwarfism assoc w/clubfeet & other joint restrictions incl "hitchhiker thumbs" Progressive scoliosis in childhood Joint pain (usually in hips & knees), deformities of hands, feet, & knees, scoliosis Abnormal finding at birth (e.g., clubfoot, cleft palate, or cystic ear swelling) in ~50% of persons Median height in adulthood at 10th %ile Usually considered as a differential diagnosis of DTD in toddlers or school-age children • Commonly lethal in perinatal period • Presents around birth or before • Chondrodysplasia w/clinical & histologic characteristics resembling those of DTD but more pronounced • Short limb type of dwarfism assoc w/clubfeet & other joint restrictions incl "hitchhiker thumbs" • Progressive scoliosis in childhood • Joint pain (usually in hips & knees), deformities of hands, feet, & knees, scoliosis • Abnormal finding at birth (e.g., clubfoot, cleft palate, or cystic ear swelling) in ~50% of persons • Median height in adulthood at 10th %ile • Usually considered as a differential diagnosis of DTD in toddlers or school-age children ## Differential Diagnosis Achondrogenesis type 1B (ACG1B) should be distinguished from other lethal chondrodysplasias and severe osteochondrodysplasias ( Selected Disorders in the Differential Diagnosis of Achondrogenesis Type 1B ACG = achondrogenesis; AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Within the achondrogenesis group, clinical and radiologic distinction between ACG1A, ACG1B, and ACG2 is not always possible. See OMIM Phenotypic Series: ## Management To establish the extent of disease in an individual diagnosed with achondrogenesis type 1B (ACG1B), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Achondrogenesis Type 1B MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Provide palliative care for live-born neonate. See Search ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with achondrogenesis type 1B (ACG1B), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Achondrogenesis Type 1B MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse ## Treatment of Manifestations Provide palliative care for live-born neonate. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Achondrogenesis type 1B (ACG1B) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of availability of prenatal/preimplantation genetic testing is 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 detection for the reproductive partner of a heterozygous individual is possible using • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • The optimal time for determination of genetic risk and discussion of availability of prenatal/preimplantation genetic testing is 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 detection for the reproductive partner of a heterozygous individual is possible using ## Mode of Inheritance Achondrogenesis type 1B (ACG1B) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. ## 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 availability of prenatal/preimplantation genetic testing is 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 detection for the reproductive partner of a heterozygous individual is possible using • The optimal time for determination of genetic risk and discussion of availability of prenatal/preimplantation genetic testing is 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 detection for the reproductive partner of a heterozygous individual is possible using ## Prenatal Testing and Preimplantation Genetic Testing ## High-Risk Pregnancies ## Low-Risk Pregnancies ## Resources • • • • • • • • • ## Molecular Genetics Achondrogenesis Type 1B: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Achondrogenesis Type 1B ( Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans, which are either not sulfated or insufficiently sulfated [ Loss of SLC26A2 sulfate transporter activity is associated with several skeletal disorders (see Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions See ## Molecular Pathogenesis Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans, which are either not sulfated or insufficiently sulfated [ Loss of SLC26A2 sulfate transporter activity is associated with several skeletal disorders (see Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions See ## Chapter Notes Diana Ballhausen, MD; Lausanne University Hospital (2002-2022)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2022)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2022)Andrea Superti-Furga, MD (2002-present)Sheila Unger, MD (2022-present) 16 March 2023 (sw) Revision: " 9 June 2022 (sw) Comprehensive update posted live 14 November 2013 (me) Comprehensive update posted live 22 September 2009 (me) Comprehensive update posted live 27 December 2006 (me) Comprehensive update posted live 21 July 2004 (me) Comprehensive update posted live 30 August 2002 (me) Review posted live 21 February 2002 (lb) Original submission • 16 March 2023 (sw) Revision: " • 9 June 2022 (sw) Comprehensive update posted live • 14 November 2013 (me) Comprehensive update posted live • 22 September 2009 (me) Comprehensive update posted live • 27 December 2006 (me) Comprehensive update posted live • 21 July 2004 (me) Comprehensive update posted live • 30 August 2002 (me) Review posted live • 21 February 2002 (lb) Original submission ## Author History Diana Ballhausen, MD; Lausanne University Hospital (2002-2022)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2022)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2022)Andrea Superti-Furga, MD (2002-present)Sheila Unger, MD (2022-present) ## Revision History 16 March 2023 (sw) Revision: " 9 June 2022 (sw) Comprehensive update posted live 14 November 2013 (me) Comprehensive update posted live 22 September 2009 (me) Comprehensive update posted live 27 December 2006 (me) Comprehensive update posted live 21 July 2004 (me) Comprehensive update posted live 30 August 2002 (me) Review posted live 21 February 2002 (lb) Original submission • 16 March 2023 (sw) Revision: " • 9 June 2022 (sw) Comprehensive update posted live • 14 November 2013 (me) Comprehensive update posted live • 22 September 2009 (me) Comprehensive update posted live • 27 December 2006 (me) Comprehensive update posted live • 21 July 2004 (me) Comprehensive update posted live • 30 August 2002 (me) Review posted live • 21 February 2002 (lb) Original submission ## References ## Literature Cited	[]	30/8/2002	9/6/2022	16/3/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
achondroplasia	achondroplasia	[ "FGFR3-Related Achondroplasia", "FGFR3-Related Achondroplasia", "Fibroblast growth factor receptor 3", "FGFR3", "Achondroplasia" ]	Achondroplasia	Janet M Legare	Summary Achondroplasia is the most common cause of disproportionate short stature. Affected individuals have rhizomelic shortening of the limbs, macrocephaly, and characteristic facial features with frontal bossing and midface retrusion. In infancy, hypotonia is typical, and acquisition of developmental motor milestones is often both aberrant in pattern and delayed. Intelligence and life span are usually near normal, although craniocervical junction compression increases the risk of death in infancy. Additional complications include obstructive sleep apnea, middle ear dysfunction, kyphosis, and spinal stenosis. Achondroplasia can be diagnosed by characteristic clinical and radiographic findings in most affected individuals. In individuals in whom there is diagnostic uncertainty or who have atypical findings, identification of a heterozygous pathogenic variant in Achondroplasia is inherited in an autosomal dominant manner. Around 80% of individuals with achondroplasia have parents with average stature and have achondroplasia as the result of a	## Diagnosis Both the clinical and radiologic features of achondroplasia have been well defined [ The diagnosis of achondroplasia Disproportionate short stature Macrocephaly with frontal bossing Midface retrusion and depressed nasal bridge Rhizomelic (proximal) shortening of the arms with redundant skin folds on limbs Limitation of elbow extension Brachydactyly Trident configuration of the hands Thoracolumbar kyphosis (principally in infancy) Exaggerated lumbar lordosis, which develops when walking begins Short, robust tubular bones Narrowing of the interpedicular distance of the caudal spine Square ilia and horizontal acetabula Narrow sacrosciatic notch Proximal femoral radiolucency Mild, generalized metaphyseal changes The diagnosis of achondroplasia Those with typical findings generally do not need molecular confirmation of the diagnosis, although confirmation may aid in receiving new treatments. In those in whom there is any uncertainty, identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Note: Since achondroplasia 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. For an introduction to multigene panels click Molecular Genetic Testing Used in Achondroplasia See See Pathogenic variant c.1138G>A (p.Gly380Arg) is identified in approximately 98% of individuals with achondroplasia; pathogenic variant c.1138G>C (p.Gly380Arg) is identified in approximately 1% of individuals with achondroplasia. 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 Includes the two pathogenic variants detected by targeted analysis • Disproportionate short stature • Macrocephaly with frontal bossing • Midface retrusion and depressed nasal bridge • Rhizomelic (proximal) shortening of the arms with redundant skin folds on limbs • Limitation of elbow extension • Brachydactyly • Trident configuration of the hands • Thoracolumbar kyphosis (principally in infancy) • Exaggerated lumbar lordosis, which develops when walking begins • Short, robust tubular bones • Narrowing of the interpedicular distance of the caudal spine • Square ilia and horizontal acetabula • Narrow sacrosciatic notch • Proximal femoral radiolucency • Mild, generalized metaphyseal changes ## Suggestive Findings The diagnosis of achondroplasia Disproportionate short stature Macrocephaly with frontal bossing Midface retrusion and depressed nasal bridge Rhizomelic (proximal) shortening of the arms with redundant skin folds on limbs Limitation of elbow extension Brachydactyly Trident configuration of the hands Thoracolumbar kyphosis (principally in infancy) Exaggerated lumbar lordosis, which develops when walking begins Short, robust tubular bones Narrowing of the interpedicular distance of the caudal spine Square ilia and horizontal acetabula Narrow sacrosciatic notch Proximal femoral radiolucency Mild, generalized metaphyseal changes • Disproportionate short stature • Macrocephaly with frontal bossing • Midface retrusion and depressed nasal bridge • Rhizomelic (proximal) shortening of the arms with redundant skin folds on limbs • Limitation of elbow extension • Brachydactyly • Trident configuration of the hands • Thoracolumbar kyphosis (principally in infancy) • Exaggerated lumbar lordosis, which develops when walking begins • Short, robust tubular bones • Narrowing of the interpedicular distance of the caudal spine • Square ilia and horizontal acetabula • Narrow sacrosciatic notch • Proximal femoral radiolucency • Mild, generalized metaphyseal changes ## Establishing the Diagnosis The diagnosis of achondroplasia Those with typical findings generally do not need molecular confirmation of the diagnosis, although confirmation may aid in receiving new treatments. In those in whom there is any uncertainty, identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include Note: Since achondroplasia 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. For an introduction to multigene panels click Molecular Genetic Testing Used in Achondroplasia See See Pathogenic variant c.1138G>A (p.Gly380Arg) is identified in approximately 98% of individuals with achondroplasia; pathogenic variant c.1138G>C (p.Gly380Arg) is identified in approximately 1% of individuals with achondroplasia. 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 Includes the two pathogenic variants detected by targeted analysis ## Clinical Characteristics Individuals with achondroplasia have short stature caused by rhizomelic shortening of the limbs, macrocephaly, characteristic facies with frontal bossing and midface retrusion, exaggerated lumbar lordosis, limitation of elbow extension and rotation, Obesity is a major problem in achondroplasia [ Clinical signs and symptoms of obstructive sleep apnea may include the following: Difficult morning waking Excessive daytime somnolence Respiratory pauses during sleep Loud snoring Glottal stops or gasping Loud sighs while sleeping Poor daytime concentration Irritability, fatigue, depression Bedwetting Clinical signs and symptoms of infantile sleep apnea include the following: Observed apnea or exaggerated periodic breathing Struggling to breathe Poor feeding Coughing Difficulty lying flat to sleep Frequent awakenings Central sleep apnea as well as obstructive sleep apnea may be present in infants. Clinical history is a poor predictor of apnea, and polysomnography should be done [ Because nearly all instances of achondroplasia arise secondary to identical amino acid substitutions, genotype-phenotype correlation related to the primary pathogenic variant is not possible. Penetrance is 100%; all individuals who have an Historically, the term "achondroplasia" was initially used to describe all individuals with short-limbed dwarfing disorders. Because achondroplasia is so common compared to other small stature processes, the term "dwarf" was previously used most often to refer to an individual with achondroplasia. Over the past 50 years diagnostic criteria have been available to distinguish true achondroplasia from other, superficially similar processes. In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ Achondroplasia is the most common form of inherited disproportionate short stature. Best estimates are that it occurs in 1:26,000-1:28,000 live births [ • Difficult morning waking • Excessive daytime somnolence • Respiratory pauses during sleep • Loud snoring • Glottal stops or gasping • Loud sighs while sleeping • Poor daytime concentration • Irritability, fatigue, depression • Bedwetting • Observed apnea or exaggerated periodic breathing • Struggling to breathe • Poor feeding • Coughing • Difficulty lying flat to sleep • Frequent awakenings ## Clinical Description Individuals with achondroplasia have short stature caused by rhizomelic shortening of the limbs, macrocephaly, characteristic facies with frontal bossing and midface retrusion, exaggerated lumbar lordosis, limitation of elbow extension and rotation, Obesity is a major problem in achondroplasia [ Clinical signs and symptoms of obstructive sleep apnea may include the following: Difficult morning waking Excessive daytime somnolence Respiratory pauses during sleep Loud snoring Glottal stops or gasping Loud sighs while sleeping Poor daytime concentration Irritability, fatigue, depression Bedwetting Clinical signs and symptoms of infantile sleep apnea include the following: Observed apnea or exaggerated periodic breathing Struggling to breathe Poor feeding Coughing Difficulty lying flat to sleep Frequent awakenings Central sleep apnea as well as obstructive sleep apnea may be present in infants. Clinical history is a poor predictor of apnea, and polysomnography should be done [ • Difficult morning waking • Excessive daytime somnolence • Respiratory pauses during sleep • Loud snoring • Glottal stops or gasping • Loud sighs while sleeping • Poor daytime concentration • Irritability, fatigue, depression • Bedwetting • Observed apnea or exaggerated periodic breathing • Struggling to breathe • Poor feeding • Coughing • Difficulty lying flat to sleep • Frequent awakenings ## Genotype-Phenotype Correlations Because nearly all instances of achondroplasia arise secondary to identical amino acid substitutions, genotype-phenotype correlation related to the primary pathogenic variant is not possible. ## Penetrance Penetrance is 100%; all individuals who have an ## Nomenclature Historically, the term "achondroplasia" was initially used to describe all individuals with short-limbed dwarfing disorders. Because achondroplasia is so common compared to other small stature processes, the term "dwarf" was previously used most often to refer to an individual with achondroplasia. Over the past 50 years diagnostic criteria have been available to distinguish true achondroplasia from other, superficially similar processes. In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ ## Prevalence Achondroplasia is the most common form of inherited disproportionate short stature. Best estimates are that it occurs in 1:26,000-1:28,000 live births [ ## Genetically Related (Allelic) Disorders Other phenotypes associated with pathogenic variants in SADDAN ( Isolated familial acanthosis nigricans [ CATSHL syndrome ( For other phenotypes associated with pathogenic variants in • • SADDAN ( • Isolated familial acanthosis nigricans [ • CATSHL syndrome ( ## Differential Diagnosis While more than 450 skeletal dysplasias that cause short stature are recognized [ SADDAN syndrome (OMIM Other metaphyseal dysplasias • • SADDAN syndrome (OMIM • Other metaphyseal dysplasias ## Management Clinical manifestations in achondroplasia vary modestly. In order to establish the extent of disease in an individual diagnosed with achondroplasia, the following evaluations are recommended if they have not already been completed: Clinical genetics consultation including neurologic exam and, if feasible, consultation with a clinician experienced in caring for children with bone dysplasias Documentation of length, weight, and head circumference compared with achondroplasia-specific growth standards Assessment of the craniocervical junction including neurologic history and examination, neuroimaging of the craniocervical junction using either CT or MR, and polysomnography as soon after birth as possible. If CT is obtained, compare it to published standards for achondroplasia. When both sagittal and transverse dimensions are greater than 1 SD below the mean for achondroplasia, and clinical features are also present, the individual is at increased risk of requiring decompression surgery [ Baseline neuroimaging of the brain as soon after diagnosis as possible to assess ventricular size Audiologic evaluation as a newborn and repeated at age one year. In those in whom diagnosis is delayed, audiologic screen should be completed at diagnosis and if concerns arise [ Vosoritide, a C-type natriuretic peptide (CNP) analog, has recently been approved to increase height in children with achondroplasia from age five years until growth plates close. Phase III studies showed an increase in annualized growth velocity of 1.57 cm/year when given at doses of 15 µg/kg subcutaneously daily. The most common side effects were injection site reactions and transient hypotension. Injections should be given after a meal and drinking 8-12 oz of fluids to minimize hypotension. Studies in younger age groups are ongoing, as are studies looking at possible medical benefits of the drug [ Recommendations for health supervision of children with achondroplasia were outlined by the American Academy of Pediatrics Committee on Genetics [ The recommendations include (but are not limited to) the following. The presumed etiology of hydrocephalus in achondroplasia is increased intracranial venous pressure secondary to stenosis of the jugular foramina. Therefore, ventriculoperitoneal shunting has been the standard treatment. However, endoscopic third ventriculostomy may be beneficial in some individuals [ Lower-limb hyperreflexia or clonus Central hypopnea demonstrated by polysomnography Reduced foramen magnum size, determined by CT examination of the craniocervical junction and by comparison with the norms for children with achondroplasia [ Evidence of spinal cord compression and/or T If there is clear indication of symptomatic compression, urgent referral to a pediatric neurosurgeon for decompression surgery should be initiated [ Adenotonsillectomy Positive airway pressure Tracheostomy for extreme cases Weight reduction Improvement in disturbed sleep and some improvement in neurologic function can result from these interventions [ In rare instances in which the obstruction is severe enough to require tracheostomy, surgical intervention to advance the midface has been used to alleviate upper airway obstruction [ Implementation of appropriate therapies is warranted at any age if concerns arise [ In general, these and other series show initial acceleration of growth, but with lessening effect over time. On average, only about 3 cm of additional adult height can be expected [ Extended limb lengthening using various techniques remains an option for some. Increases in height of up to 30-35 cm may be obtained [ Although some have advocated performing these procedures as early as ages six to eight years, many pediatricians, clinical geneticists, and ethicists have advocated postponing such surgery until the young person is able to participate in making an informed decision. At least in North America, only a tiny proportion of affected individuals elect to undergo extended limb lengthening. The Medical Advisory Board of Little People of America has published a Standard weight and weight-by-height grids specific for achondroplasia [ Body mass index (BMI) standards have been generated for children age 16 and under [ Presence of progressive, symptomatic bowing should prompt referral to an orthopedist. Varus deformity alone, without symptoms, does not usually warrant surgical correction. Various interventions may be elected (e.g., guided growth using eight-Plates, valgus-producing and derotational osteotomies). No controlled studies comparing outcomes of treatment options have been completed. Kyphosis improves significantly or resolves in the majority of children upon assuming an orthograde posture and beginning to walk [ In children in whom spontaneous remission does not arise after trunk strength increases and the child begins to walk, bracing is usually sufficient to prevent persistence of the thoracolumbar kyphosis [ If a severe kyphosis persists, spinal surgery may be necessary to prevent neurologic complications [ Extended and wide laminectomies [ Pedal extenders for driving are almost always needed. Also needed may be workplace modification such as lower desks, smaller keyboards, step stools, and toileting access. Support groups (see Information on employment, education, disability rights, adoption of children with short stature, medical issues, suitable clothing, adaptive devices, and parenting is available through a national newsletter, seminars, and workshops. Recommendations for surveillance are incorporated into the American Academy of Pediatrics guidelines [ Head circumference should be measured at every physician contact until around age six years given that sutural closure is markedly delayed (as evidenced by anterior fontanelle closure as late as age 5-6 years). Occipitofrontal circumference should continue to be measured throughout childhood at well checks and genetics visits, plotting it on growth curves standardized for achondroplasia [ Overnight polysomnography should also be completed as soon as possible after initial diagnosis in infancy, and interpreted with consideration of features important in assessing the craniocervical junction. Increased central apnea is indicative of cord compression at the craniocervical junction. Neurologic examination including monitoring for signs of cervical myelopathy such as persistent hypotonia, hyperreflexia, clonus, and asymmetries should be incorporated into each physical examination in infancy and childhood. Difficult morning waking Excessive daytime somnolence Respiratory pauses during sleep Loud snoring Glottal stops or gasping Loud sighs while sleeping Poor daytime concentration Irritability, fatigue, depression Bedwetting If worrisome nighttime or daytime features arise, polysomnography should be repeated. Evidence for middle ear problems or hearing loss should be sought throughout childhood. Audiologic evaluations should be completed yearly throughout childhood. Children with achondroplasia should remain rear-facing in car seats as long as possible. Large heads with relatively lax neck ligaments place children at more risk in a motor vehicle accident. Avoid soft-back infant seats, which increase the likelihood of developing kyphosis. Front carriers without a firm back should also be avoided. Particularly in childhood, care must be taken to limit risk for injury to the spinal cord at the craniocervical junction. This should include prohibition of activities including collision sports (e.g., American football, ice hockey, rugby), use of a trampoline, diving from diving boards, vaulting in gymnastics, and hanging upside down from knees or feet on playground equipment. Protocols have been published regarding positioning that should be avoided in order to decrease the likelihood of development of a fixed, angular kyphosis [ There is no increased risk for bone fragility or joint degeneration, and there are no related circumstances to avoid. See When the pregnant woman is of average stature and the fetus has achondroplasia, fetal macrocephaly may cause cephalopelvic disproportion, potentially requiring delivery by cesarean section. Pregnant women with achondroplasia must always be delivered by cesarean section because of the small size of the pelvis. Pregnancy in a woman with achondroplasia is considered higher risk because of the slightly increased risk of respiratory failure. An initial consultation with a pulmonologist is recommended in early pregnancy. Administration of C-type natriuretic peptide analog attached to a depot protein is in clinical trial ( Search • Clinical genetics consultation including neurologic exam and, if feasible, consultation with a clinician experienced in caring for children with bone dysplasias • Documentation of length, weight, and head circumference compared with achondroplasia-specific growth standards • Assessment of the craniocervical junction including neurologic history and examination, neuroimaging of the craniocervical junction using either CT or MR, and polysomnography as soon after birth as possible. If CT is obtained, compare it to published standards for achondroplasia. When both sagittal and transverse dimensions are greater than 1 SD below the mean for achondroplasia, and clinical features are also present, the individual is at increased risk of requiring decompression surgery [ • Baseline neuroimaging of the brain as soon after diagnosis as possible to assess ventricular size • Audiologic evaluation as a newborn and repeated at age one year. In those in whom diagnosis is delayed, audiologic screen should be completed at diagnosis and if concerns arise [ • Lower-limb hyperreflexia or clonus • Central hypopnea demonstrated by polysomnography • Reduced foramen magnum size, determined by CT examination of the craniocervical junction and by comparison with the norms for children with achondroplasia [ • Evidence of spinal cord compression and/or T • Adenotonsillectomy • Positive airway pressure • Tracheostomy for extreme cases • Weight reduction • In general, these and other series show initial acceleration of growth, but with lessening effect over time. • On average, only about 3 cm of additional adult height can be expected [ • Although some have advocated performing these procedures as early as ages six to eight years, many pediatricians, clinical geneticists, and ethicists have advocated postponing such surgery until the young person is able to participate in making an informed decision. • At least in North America, only a tiny proportion of affected individuals elect to undergo extended limb lengthening. The Medical Advisory Board of Little People of America has published a • Standard weight and weight-by-height grids specific for achondroplasia [ • Body mass index (BMI) standards have been generated for children age 16 and under [ • Kyphosis improves significantly or resolves in the majority of children upon assuming an orthograde posture and beginning to walk [ • In children in whom spontaneous remission does not arise after trunk strength increases and the child begins to walk, bracing is usually sufficient to prevent persistence of the thoracolumbar kyphosis [ • If a severe kyphosis persists, spinal surgery may be necessary to prevent neurologic complications [ • Difficult morning waking • Excessive daytime somnolence • Respiratory pauses during sleep • Loud snoring • Glottal stops or gasping • Loud sighs while sleeping • Poor daytime concentration • Irritability, fatigue, depression • Bedwetting ## Evaluations Following Initial Diagnosis Clinical manifestations in achondroplasia vary modestly. In order to establish the extent of disease in an individual diagnosed with achondroplasia, the following evaluations are recommended if they have not already been completed: Clinical genetics consultation including neurologic exam and, if feasible, consultation with a clinician experienced in caring for children with bone dysplasias Documentation of length, weight, and head circumference compared with achondroplasia-specific growth standards Assessment of the craniocervical junction including neurologic history and examination, neuroimaging of the craniocervical junction using either CT or MR, and polysomnography as soon after birth as possible. If CT is obtained, compare it to published standards for achondroplasia. When both sagittal and transverse dimensions are greater than 1 SD below the mean for achondroplasia, and clinical features are also present, the individual is at increased risk of requiring decompression surgery [ Baseline neuroimaging of the brain as soon after diagnosis as possible to assess ventricular size Audiologic evaluation as a newborn and repeated at age one year. In those in whom diagnosis is delayed, audiologic screen should be completed at diagnosis and if concerns arise [ • Clinical genetics consultation including neurologic exam and, if feasible, consultation with a clinician experienced in caring for children with bone dysplasias • Documentation of length, weight, and head circumference compared with achondroplasia-specific growth standards • Assessment of the craniocervical junction including neurologic history and examination, neuroimaging of the craniocervical junction using either CT or MR, and polysomnography as soon after birth as possible. If CT is obtained, compare it to published standards for achondroplasia. When both sagittal and transverse dimensions are greater than 1 SD below the mean for achondroplasia, and clinical features are also present, the individual is at increased risk of requiring decompression surgery [ • Baseline neuroimaging of the brain as soon after diagnosis as possible to assess ventricular size • Audiologic evaluation as a newborn and repeated at age one year. In those in whom diagnosis is delayed, audiologic screen should be completed at diagnosis and if concerns arise [ ## Treatment of Manifestations Vosoritide, a C-type natriuretic peptide (CNP) analog, has recently been approved to increase height in children with achondroplasia from age five years until growth plates close. Phase III studies showed an increase in annualized growth velocity of 1.57 cm/year when given at doses of 15 µg/kg subcutaneously daily. The most common side effects were injection site reactions and transient hypotension. Injections should be given after a meal and drinking 8-12 oz of fluids to minimize hypotension. Studies in younger age groups are ongoing, as are studies looking at possible medical benefits of the drug [ Recommendations for health supervision of children with achondroplasia were outlined by the American Academy of Pediatrics Committee on Genetics [ The recommendations include (but are not limited to) the following. The presumed etiology of hydrocephalus in achondroplasia is increased intracranial venous pressure secondary to stenosis of the jugular foramina. Therefore, ventriculoperitoneal shunting has been the standard treatment. However, endoscopic third ventriculostomy may be beneficial in some individuals [ Lower-limb hyperreflexia or clonus Central hypopnea demonstrated by polysomnography Reduced foramen magnum size, determined by CT examination of the craniocervical junction and by comparison with the norms for children with achondroplasia [ Evidence of spinal cord compression and/or T If there is clear indication of symptomatic compression, urgent referral to a pediatric neurosurgeon for decompression surgery should be initiated [ Adenotonsillectomy Positive airway pressure Tracheostomy for extreme cases Weight reduction Improvement in disturbed sleep and some improvement in neurologic function can result from these interventions [ In rare instances in which the obstruction is severe enough to require tracheostomy, surgical intervention to advance the midface has been used to alleviate upper airway obstruction [ Implementation of appropriate therapies is warranted at any age if concerns arise [ In general, these and other series show initial acceleration of growth, but with lessening effect over time. On average, only about 3 cm of additional adult height can be expected [ Extended limb lengthening using various techniques remains an option for some. Increases in height of up to 30-35 cm may be obtained [ Although some have advocated performing these procedures as early as ages six to eight years, many pediatricians, clinical geneticists, and ethicists have advocated postponing such surgery until the young person is able to participate in making an informed decision. At least in North America, only a tiny proportion of affected individuals elect to undergo extended limb lengthening. The Medical Advisory Board of Little People of America has published a Standard weight and weight-by-height grids specific for achondroplasia [ Body mass index (BMI) standards have been generated for children age 16 and under [ Presence of progressive, symptomatic bowing should prompt referral to an orthopedist. Varus deformity alone, without symptoms, does not usually warrant surgical correction. Various interventions may be elected (e.g., guided growth using eight-Plates, valgus-producing and derotational osteotomies). No controlled studies comparing outcomes of treatment options have been completed. Kyphosis improves significantly or resolves in the majority of children upon assuming an orthograde posture and beginning to walk [ In children in whom spontaneous remission does not arise after trunk strength increases and the child begins to walk, bracing is usually sufficient to prevent persistence of the thoracolumbar kyphosis [ If a severe kyphosis persists, spinal surgery may be necessary to prevent neurologic complications [ Extended and wide laminectomies [ Pedal extenders for driving are almost always needed. Also needed may be workplace modification such as lower desks, smaller keyboards, step stools, and toileting access. Support groups (see Information on employment, education, disability rights, adoption of children with short stature, medical issues, suitable clothing, adaptive devices, and parenting is available through a national newsletter, seminars, and workshops. • Lower-limb hyperreflexia or clonus • Central hypopnea demonstrated by polysomnography • Reduced foramen magnum size, determined by CT examination of the craniocervical junction and by comparison with the norms for children with achondroplasia [ • Evidence of spinal cord compression and/or T • Adenotonsillectomy • Positive airway pressure • Tracheostomy for extreme cases • Weight reduction • In general, these and other series show initial acceleration of growth, but with lessening effect over time. • On average, only about 3 cm of additional adult height can be expected [ • Although some have advocated performing these procedures as early as ages six to eight years, many pediatricians, clinical geneticists, and ethicists have advocated postponing such surgery until the young person is able to participate in making an informed decision. • At least in North America, only a tiny proportion of affected individuals elect to undergo extended limb lengthening. The Medical Advisory Board of Little People of America has published a • Standard weight and weight-by-height grids specific for achondroplasia [ • Body mass index (BMI) standards have been generated for children age 16 and under [ • Kyphosis improves significantly or resolves in the majority of children upon assuming an orthograde posture and beginning to walk [ • In children in whom spontaneous remission does not arise after trunk strength increases and the child begins to walk, bracing is usually sufficient to prevent persistence of the thoracolumbar kyphosis [ • If a severe kyphosis persists, spinal surgery may be necessary to prevent neurologic complications [ ## Surveillance Recommendations for surveillance are incorporated into the American Academy of Pediatrics guidelines [ Head circumference should be measured at every physician contact until around age six years given that sutural closure is markedly delayed (as evidenced by anterior fontanelle closure as late as age 5-6 years). Occipitofrontal circumference should continue to be measured throughout childhood at well checks and genetics visits, plotting it on growth curves standardized for achondroplasia [ Overnight polysomnography should also be completed as soon as possible after initial diagnosis in infancy, and interpreted with consideration of features important in assessing the craniocervical junction. Increased central apnea is indicative of cord compression at the craniocervical junction. Neurologic examination including monitoring for signs of cervical myelopathy such as persistent hypotonia, hyperreflexia, clonus, and asymmetries should be incorporated into each physical examination in infancy and childhood. Difficult morning waking Excessive daytime somnolence Respiratory pauses during sleep Loud snoring Glottal stops or gasping Loud sighs while sleeping Poor daytime concentration Irritability, fatigue, depression Bedwetting If worrisome nighttime or daytime features arise, polysomnography should be repeated. Evidence for middle ear problems or hearing loss should be sought throughout childhood. Audiologic evaluations should be completed yearly throughout childhood. • Difficult morning waking • Excessive daytime somnolence • Respiratory pauses during sleep • Loud snoring • Glottal stops or gasping • Loud sighs while sleeping • Poor daytime concentration • Irritability, fatigue, depression • Bedwetting ## Agents/Circumstances to Avoid Children with achondroplasia should remain rear-facing in car seats as long as possible. Large heads with relatively lax neck ligaments place children at more risk in a motor vehicle accident. Avoid soft-back infant seats, which increase the likelihood of developing kyphosis. Front carriers without a firm back should also be avoided. Particularly in childhood, care must be taken to limit risk for injury to the spinal cord at the craniocervical junction. This should include prohibition of activities including collision sports (e.g., American football, ice hockey, rugby), use of a trampoline, diving from diving boards, vaulting in gymnastics, and hanging upside down from knees or feet on playground equipment. Protocols have been published regarding positioning that should be avoided in order to decrease the likelihood of development of a fixed, angular kyphosis [ There is no increased risk for bone fragility or joint degeneration, and there are no related circumstances to avoid. ## Evaluation of Relatives at Risk See ## Pregnancy Management When the pregnant woman is of average stature and the fetus has achondroplasia, fetal macrocephaly may cause cephalopelvic disproportion, potentially requiring delivery by cesarean section. Pregnant women with achondroplasia must always be delivered by cesarean section because of the small size of the pelvis. Pregnancy in a woman with achondroplasia is considered higher risk because of the slightly increased risk of respiratory failure. An initial consultation with a pulmonologist is recommended in early pregnancy. ## Therapies Under Investigation Administration of C-type natriuretic peptide analog attached to a depot protein is in clinical trial ( Search ## Genetic Counseling Achondroplasia is inherited in an autosomal dominant manner. Approximately 80% of individuals with achondroplasia have parents of average stature and have achondroplasia as a result of a The remaining 20% of individuals with achondroplasia have at least one affected parent. Presumed parental germline mosaicism [ If the parents are of average stature, the risk to sibs of having achondroplasia is very low but appears to exceed that in the general, comparable population because of the possibility of parental germline mosaicism [ If one parent has achondroplasia, the risk to sibs is 50%. The risk to offspring of an individual with achondroplasia of inheriting the An individual with achondroplasia who has a partner of average stature is at 50% risk of having a child with achondroplasia. When both parents have achondroplasia, their offspring have a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a lethal condition). Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with achondroplasia 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 [ When the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child is at 25% risk of having average stature, 25% risk of having the same skeletal dysplasia as the father, 25% risk of having the same skeletal dysplasia as the mother, and 25% risk of inheriting a pathogenic variant from both parents and being at risk for a poor outcome. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. Genetic counseling is recommended when both parents have a skeletal dysplasia. Guidelines for prenatal diagnosis of skeletal dysplasias are available [ • Approximately 80% of individuals with achondroplasia have parents of average stature and have achondroplasia as a result of a • The remaining 20% of individuals with achondroplasia have at least one affected parent. • Presumed parental germline mosaicism [ • If the parents are of average stature, the risk to sibs of having achondroplasia is very low but appears to exceed that in the general, comparable population because of the possibility of parental germline mosaicism [ • If one parent has achondroplasia, the risk to sibs is 50%. • The risk to offspring of an individual with achondroplasia of inheriting the • An individual with achondroplasia who has a partner of average stature is at 50% risk of having a child with achondroplasia. • When both parents have achondroplasia, their offspring have a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a lethal condition). • Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with achondroplasia 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 [ • When the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child is at 25% risk of having average stature, 25% risk of having the same skeletal dysplasia as the father, 25% risk of having the same skeletal dysplasia as the mother, and 25% risk of inheriting a pathogenic variant from both parents and being at risk for a poor outcome. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • Genetic counseling is recommended when both parents have a skeletal dysplasia. ## Mode of Inheritance Achondroplasia is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 80% of individuals with achondroplasia have parents of average stature and have achondroplasia as a result of a The remaining 20% of individuals with achondroplasia have at least one affected parent. Presumed parental germline mosaicism [ If the parents are of average stature, the risk to sibs of having achondroplasia is very low but appears to exceed that in the general, comparable population because of the possibility of parental germline mosaicism [ If one parent has achondroplasia, the risk to sibs is 50%. The risk to offspring of an individual with achondroplasia of inheriting the An individual with achondroplasia who has a partner of average stature is at 50% risk of having a child with achondroplasia. When both parents have achondroplasia, their offspring have a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a lethal condition). Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with achondroplasia 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 [ When the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child is at 25% risk of having average stature, 25% risk of having the same skeletal dysplasia as the father, 25% risk of having the same skeletal dysplasia as the mother, and 25% risk of inheriting a pathogenic variant from both parents and being at risk for a poor outcome. • Approximately 80% of individuals with achondroplasia have parents of average stature and have achondroplasia as a result of a • The remaining 20% of individuals with achondroplasia have at least one affected parent. • Presumed parental germline mosaicism [ • If the parents are of average stature, the risk to sibs of having achondroplasia is very low but appears to exceed that in the general, comparable population because of the possibility of parental germline mosaicism [ • If one parent has achondroplasia, the risk to sibs is 50%. • The risk to offspring of an individual with achondroplasia of inheriting the • An individual with achondroplasia who has a partner of average stature is at 50% risk of having a child with achondroplasia. • When both parents have achondroplasia, their offspring have a 25% chance of having average stature, a 50% chance of having achondroplasia, and a 25% chance of having homozygous achondroplasia (a lethal condition). • Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with achondroplasia 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 [ • When the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child is at 25% risk of having average stature, 25% risk of having the same skeletal dysplasia as the father, 25% risk of having the same skeletal dysplasia as the mother, and 25% risk of inheriting a pathogenic variant from both parents and being at risk for a poor outcome. ## 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. Genetic counseling is recommended when both parents have a skeletal dysplasia. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • Genetic counseling is recommended when both parents have a skeletal dysplasia. ## Prenatal Testing and Preimplantation Genetic Testing Guidelines for prenatal diagnosis of skeletal dysplasias are available [ ## Resources United Kingdom • • • • • • United Kingdom • • • • • • • • • ## Molecular Genetics Achondroplasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Achondroplasia ( Variants listed in the table have been provided by the author. FGFR-3 is activated by various fibroblast growth factors (FGFs) [ ## Chapter Notes Clair A Francomano, MD; National Institutes of Health (1998-2012)Janet M Legare, MD (2018-present)Richard M Pauli, MD, PhD; University of Wisconsin (2012-2020)Douglas J Wilkin, PhD; Federal Bureau of Investigation (1998-2001) 11 May 2023 (sw) Revision: " 6 January 2022 (aa) Revision: new treatments 6 August 2020 (sw) Comprehensive update posted live 10 May 2018 (sw) Comprehensive update posted live 16 February 2012 (me) Comprehensive update posted live 9 January 2006 (me) Comprehensive update posted live 31 July 2003 (me) Comprehensive update posted live 8 March 2001 (me) Comprehensive update posted live 12 October 1998 (pb) Review posted live 26 June 1998 (cf) Original submission • 11 May 2023 (sw) Revision: " • 6 January 2022 (aa) Revision: new treatments • 6 August 2020 (sw) Comprehensive update posted live • 10 May 2018 (sw) Comprehensive update posted live • 16 February 2012 (me) Comprehensive update posted live • 9 January 2006 (me) Comprehensive update posted live • 31 July 2003 (me) Comprehensive update posted live • 8 March 2001 (me) Comprehensive update posted live • 12 October 1998 (pb) Review posted live • 26 June 1998 (cf) Original submission ## Author History Clair A Francomano, MD; National Institutes of Health (1998-2012)Janet M Legare, MD (2018-present)Richard M Pauli, MD, PhD; University of Wisconsin (2012-2020)Douglas J Wilkin, PhD; Federal Bureau of Investigation (1998-2001) ## Revision History 11 May 2023 (sw) Revision: " 6 January 2022 (aa) Revision: new treatments 6 August 2020 (sw) Comprehensive update posted live 10 May 2018 (sw) Comprehensive update posted live 16 February 2012 (me) Comprehensive update posted live 9 January 2006 (me) Comprehensive update posted live 31 July 2003 (me) Comprehensive update posted live 8 March 2001 (me) Comprehensive update posted live 12 October 1998 (pb) Review posted live 26 June 1998 (cf) Original submission • 11 May 2023 (sw) Revision: " • 6 January 2022 (aa) Revision: new treatments • 6 August 2020 (sw) Comprehensive update posted live • 10 May 2018 (sw) Comprehensive update posted live • 16 February 2012 (me) Comprehensive update posted live • 9 January 2006 (me) Comprehensive update posted live • 31 July 2003 (me) Comprehensive update posted live • 8 March 2001 (me) Comprehensive update posted live • 12 October 1998 (pb) Review posted live • 26 June 1998 (cf) Original submission ## References ## Literature Cited	[ "MC Ain, JA Browne. 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Am J Med Genet A 2016;170:2882-8", "DJ Wilkin, JK Szabo, R Cameron, S Henderson, GA Bellus, ML Mack, I Kaitila, J Loughlin, A Munnich, B Sykes, J Bonaventure, CA Francomano. Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome.. Am J Hum Genet 1998;63:711-6", "J Wynn, TM King, MJ Gambello, DK Waller, JK Hecht. Mortality in achondroplasia study: a 42-year follow-up.. Am J Med Genet A 2007;143A:2502-11", "L Xu, Y Li, F Sheng, C Zia, Y Qui, Z Zhu. The efficacy of brace treatment for thoracolumbar kyphosis in patients with achondroplasia.. Spine (Phila Pa 1976) 2018;43:1133-8" ]	12/10/1998	6/8/2020	11/5/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
acp	acp	[ "Ceruloplasmin", "CP", "Aceruloplasminemia" ]	Aceruloplasminemia	Hiroaki Miyajima, Yasushi Hosoi	Summary Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. The clinical triad of retinal degeneration, diabetes mellitus (DM), and neurologic disease is seen in individuals ranging from age 30 years to older than 70 years. The neurologic findings of movement disorder (blepharospasm, grimacing, facial and neck dystonia, tremors, chorea) and ataxia (gait ataxia, dysarthria) correspond to regions of iron deposition in the brain. Individuals with aceruloplasminemia often present with anemia prior to onset of DM or obvious neurologic problems. Cognitive dysfunction including apathy and forgetfulness occurs in more than half of individuals with this condition. Aceruloplasminemia, a disorder of iron metabolism caused by the complete absence of ceruloplasmin ferroxidase activity, is associated with very low to absent serum ceruloplasmin and some combination of the following: Low serum copper concentration Low serum iron concentration High serum ferritin concentration Increased hepatic iron concentration The diagnosis of aceruloplasminemia is established in a proband with typical clinical findings and the identification of biallelic pathogenic variants in Aceruloplasminemia 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 a pregnancy at increased risk, and preimplantation genetic testing are possible if the	## Diagnosis Aceruloplasminemia is characterized by iron accumulation in the brain and viscera. Aceruloplasminemia Characteristic retinal degeneration findings (which differ from diabetic retinopathy [ Evidence of early-onset macular degeneration Undisturbed visual acuity Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium On fluorescein angiography: window defects corresponding to the yellowish opacities Diabetes mellitus (DM) Anemia Neurologic disturbance (ataxia, involuntary movement) The diagnosis of aceruloplasminemia 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 aceruloplasminemia is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of aceruloplasminemia, molecular genetic testing approaches can include For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click When the diagnosis of aceruloplasminemia is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aceruloplasminemia 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 Individuals of Japanese heritage [ 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. Rare single-exon deletions have been reported [ • Characteristic retinal degeneration findings (which differ from diabetic retinopathy [ • Evidence of early-onset macular degeneration • Undisturbed visual acuity • Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium • On fluorescein angiography: window defects corresponding to the yellowish opacities • Evidence of early-onset macular degeneration • Undisturbed visual acuity • Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium • On fluorescein angiography: window defects corresponding to the yellowish opacities • Diabetes mellitus (DM) • Anemia • Neurologic disturbance (ataxia, involuntary movement) • Evidence of early-onset macular degeneration • Undisturbed visual acuity • Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium • On fluorescein angiography: window defects corresponding to the yellowish opacities • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Suggestive Findings Aceruloplasminemia Characteristic retinal degeneration findings (which differ from diabetic retinopathy [ Evidence of early-onset macular degeneration Undisturbed visual acuity Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium On fluorescein angiography: window defects corresponding to the yellowish opacities Diabetes mellitus (DM) Anemia Neurologic disturbance (ataxia, involuntary movement) • Characteristic retinal degeneration findings (which differ from diabetic retinopathy [ • Evidence of early-onset macular degeneration • Undisturbed visual acuity • Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium • On fluorescein angiography: window defects corresponding to the yellowish opacities • Evidence of early-onset macular degeneration • Undisturbed visual acuity • Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium • On fluorescein angiography: window defects corresponding to the yellowish opacities • Diabetes mellitus (DM) • Anemia • Neurologic disturbance (ataxia, involuntary movement) • Evidence of early-onset macular degeneration • Undisturbed visual acuity • Several small yellowish opacities scattered over grayish atrophy of the retinal pigment epithelium • On fluorescein angiography: window defects corresponding to the yellowish opacities ## Establishing the Diagnosis The diagnosis of aceruloplasminemia 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 aceruloplasminemia is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of aceruloplasminemia, molecular genetic testing approaches can include For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click When the diagnosis of aceruloplasminemia is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aceruloplasminemia 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 Individuals of Japanese heritage [ 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. Rare single-exon deletions have been reported [ • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of aceruloplasminemia, molecular genetic testing approaches can include For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see For an introduction to multigene panels click • For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see • For an introduction to multigene panels click ## Option 2 When the diagnosis of aceruloplasminemia is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aceruloplasminemia 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 Individuals of Japanese heritage [ 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. Rare single-exon deletions have been reported [ ## Clinical Characteristics The clinical manifestations of aceruloplasminemia are retinal degeneration, diabetes mellitus (DM), and neurologic signs/symptoms [ A summary of clinical manifestations and age of onset in 71 Japanese individuals is shown in Clinical Manifestations / Age at Onset in 71 Individuals with Aceruloplasminemia From Undetectable serum ceruloplasmin Elevated serum ferritin Decreased serum iron Iron refractory microcytic anemia Low serum copper and normal urinary copper levels Excess iron accumulation (>1,200 µg/gram dry weight) within hepatocytes and reticuloendothelial cells Normal hepatic architecture and histology without cirrhosis or fibrosis Normal copper accumulation The liver shows no cirrhotic changes. The iron content in the liver is greater than the iron content in the brain. The hepatic iron concentration (HIC) is determined in µmol/g of dry weight. The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Normal individuals have an HII of 1.1 or less; more than 80% of individuals with aceruloplasminemia have an HII greater than 1.3. (HIC [µg/g dry weight] 56 = HIC [µmol/g dry weight], HIC [µmol/g dry weight]/age [years] = HII). Islet beta cells demonstrate iron deposition, which results in diabetes mellitus. The distribution in order of iron level in the brain is globus pallidus > putamen > cerebral cortex > cerebellar cortex. Severe iron overload and extensive neuronal loss are observed in the basal ganglia, while iron deposition and neuronal cell loss are trivial in the frontal cortices. The cerebellar cortex shows marked loss of Purkinje cells. Iron deposition is more prominent in the astrocytes than in the neurons. Astrocytic deformity and globular structures are characteristic features in brains of individuals with aceruloplasminemia. The globular structures in the astrocytes are seen in proportion to the degree of iron deposition [ No clear genotype-phenotype correlation exists for aceruloplasminemia. Aceruloplasminemia was originally called familial apoceruloplasmin deficiency [ The serum ceruloplasmin concentrations of about 5,000 adults undergoing medical examination were screened ( There is no data on the prevalence of this disorder outside of Japan are available. Frequencies of Aceruloplasminemia From Heterozygotes for the ceruloplasmin gene have been estimated to account for 0.1% of individuals with diabetes in Japan [ • Undetectable serum ceruloplasmin • Elevated serum ferritin • Decreased serum iron • Iron refractory microcytic anemia • Low serum copper and normal urinary copper levels • Excess iron accumulation (>1,200 µg/gram dry weight) within hepatocytes and reticuloendothelial cells • Normal hepatic architecture and histology without cirrhosis or fibrosis • Normal copper accumulation • The liver shows no cirrhotic changes. The iron content in the liver is greater than the iron content in the brain. The hepatic iron concentration (HIC) is determined in µmol/g of dry weight. The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Normal individuals have an HII of 1.1 or less; more than 80% of individuals with aceruloplasminemia have an HII greater than 1.3. (HIC [µg/g dry weight] 56 = HIC [µmol/g dry weight], HIC [µmol/g dry weight]/age [years] = HII). • Islet beta cells demonstrate iron deposition, which results in diabetes mellitus. • The distribution in order of iron level in the brain is globus pallidus > putamen > cerebral cortex > cerebellar cortex. Severe iron overload and extensive neuronal loss are observed in the basal ganglia, while iron deposition and neuronal cell loss are trivial in the frontal cortices. The cerebellar cortex shows marked loss of Purkinje cells. Iron deposition is more prominent in the astrocytes than in the neurons. Astrocytic deformity and globular structures are characteristic features in brains of individuals with aceruloplasminemia. The globular structures in the astrocytes are seen in proportion to the degree of iron deposition [ ## Clinical Description The clinical manifestations of aceruloplasminemia are retinal degeneration, diabetes mellitus (DM), and neurologic signs/symptoms [ A summary of clinical manifestations and age of onset in 71 Japanese individuals is shown in Clinical Manifestations / Age at Onset in 71 Individuals with Aceruloplasminemia From Undetectable serum ceruloplasmin Elevated serum ferritin Decreased serum iron Iron refractory microcytic anemia Low serum copper and normal urinary copper levels Excess iron accumulation (>1,200 µg/gram dry weight) within hepatocytes and reticuloendothelial cells Normal hepatic architecture and histology without cirrhosis or fibrosis Normal copper accumulation The liver shows no cirrhotic changes. The iron content in the liver is greater than the iron content in the brain. The hepatic iron concentration (HIC) is determined in µmol/g of dry weight. The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Normal individuals have an HII of 1.1 or less; more than 80% of individuals with aceruloplasminemia have an HII greater than 1.3. (HIC [µg/g dry weight] 56 = HIC [µmol/g dry weight], HIC [µmol/g dry weight]/age [years] = HII). Islet beta cells demonstrate iron deposition, which results in diabetes mellitus. The distribution in order of iron level in the brain is globus pallidus > putamen > cerebral cortex > cerebellar cortex. Severe iron overload and extensive neuronal loss are observed in the basal ganglia, while iron deposition and neuronal cell loss are trivial in the frontal cortices. The cerebellar cortex shows marked loss of Purkinje cells. Iron deposition is more prominent in the astrocytes than in the neurons. Astrocytic deformity and globular structures are characteristic features in brains of individuals with aceruloplasminemia. The globular structures in the astrocytes are seen in proportion to the degree of iron deposition [ • Undetectable serum ceruloplasmin • Elevated serum ferritin • Decreased serum iron • Iron refractory microcytic anemia • Low serum copper and normal urinary copper levels • Excess iron accumulation (>1,200 µg/gram dry weight) within hepatocytes and reticuloendothelial cells • Normal hepatic architecture and histology without cirrhosis or fibrosis • Normal copper accumulation • The liver shows no cirrhotic changes. The iron content in the liver is greater than the iron content in the brain. The hepatic iron concentration (HIC) is determined in µmol/g of dry weight. The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Normal individuals have an HII of 1.1 or less; more than 80% of individuals with aceruloplasminemia have an HII greater than 1.3. (HIC [µg/g dry weight] 56 = HIC [µmol/g dry weight], HIC [µmol/g dry weight]/age [years] = HII). • Islet beta cells demonstrate iron deposition, which results in diabetes mellitus. • The distribution in order of iron level in the brain is globus pallidus > putamen > cerebral cortex > cerebellar cortex. Severe iron overload and extensive neuronal loss are observed in the basal ganglia, while iron deposition and neuronal cell loss are trivial in the frontal cortices. The cerebellar cortex shows marked loss of Purkinje cells. Iron deposition is more prominent in the astrocytes than in the neurons. Astrocytic deformity and globular structures are characteristic features in brains of individuals with aceruloplasminemia. The globular structures in the astrocytes are seen in proportion to the degree of iron deposition [ ## Additional Findings Undetectable serum ceruloplasmin Elevated serum ferritin Decreased serum iron Iron refractory microcytic anemia Low serum copper and normal urinary copper levels Excess iron accumulation (>1,200 µg/gram dry weight) within hepatocytes and reticuloendothelial cells Normal hepatic architecture and histology without cirrhosis or fibrosis Normal copper accumulation The liver shows no cirrhotic changes. The iron content in the liver is greater than the iron content in the brain. The hepatic iron concentration (HIC) is determined in µmol/g of dry weight. The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Normal individuals have an HII of 1.1 or less; more than 80% of individuals with aceruloplasminemia have an HII greater than 1.3. (HIC [µg/g dry weight] 56 = HIC [µmol/g dry weight], HIC [µmol/g dry weight]/age [years] = HII). Islet beta cells demonstrate iron deposition, which results in diabetes mellitus. The distribution in order of iron level in the brain is globus pallidus > putamen > cerebral cortex > cerebellar cortex. Severe iron overload and extensive neuronal loss are observed in the basal ganglia, while iron deposition and neuronal cell loss are trivial in the frontal cortices. The cerebellar cortex shows marked loss of Purkinje cells. Iron deposition is more prominent in the astrocytes than in the neurons. Astrocytic deformity and globular structures are characteristic features in brains of individuals with aceruloplasminemia. The globular structures in the astrocytes are seen in proportion to the degree of iron deposition [ • Undetectable serum ceruloplasmin • Elevated serum ferritin • Decreased serum iron • Iron refractory microcytic anemia • Low serum copper and normal urinary copper levels • Excess iron accumulation (>1,200 µg/gram dry weight) within hepatocytes and reticuloendothelial cells • Normal hepatic architecture and histology without cirrhosis or fibrosis • Normal copper accumulation • The liver shows no cirrhotic changes. The iron content in the liver is greater than the iron content in the brain. The hepatic iron concentration (HIC) is determined in µmol/g of dry weight. The hepatic iron index (HII) is then calculated by dividing the hepatic iron concentration by the age (in years) of the individual. Normal individuals have an HII of 1.1 or less; more than 80% of individuals with aceruloplasminemia have an HII greater than 1.3. (HIC [µg/g dry weight] 56 = HIC [µmol/g dry weight], HIC [µmol/g dry weight]/age [years] = HII). • Islet beta cells demonstrate iron deposition, which results in diabetes mellitus. • The distribution in order of iron level in the brain is globus pallidus > putamen > cerebral cortex > cerebellar cortex. Severe iron overload and extensive neuronal loss are observed in the basal ganglia, while iron deposition and neuronal cell loss are trivial in the frontal cortices. The cerebellar cortex shows marked loss of Purkinje cells. Iron deposition is more prominent in the astrocytes than in the neurons. Astrocytic deformity and globular structures are characteristic features in brains of individuals with aceruloplasminemia. The globular structures in the astrocytes are seen in proportion to the degree of iron deposition [ ## Genotype-Phenotype Correlations No clear genotype-phenotype correlation exists for aceruloplasminemia. ## Nomenclature Aceruloplasminemia was originally called familial apoceruloplasmin deficiency [ ## Prevalence The serum ceruloplasmin concentrations of about 5,000 adults undergoing medical examination were screened ( There is no data on the prevalence of this disorder outside of Japan are available. Frequencies of Aceruloplasminemia From Heterozygotes for the ceruloplasmin gene have been estimated to account for 0.1% of individuals with diabetes in Japan [ ## Genetically Related (Allelic) Disorders No phenotype other than those discussed in this ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Aceruloplasminemia Iron accumulation in several visceral organs as well as brain Development of diabetes & retinopathy Radiographic evidence of iron accumulation in basal ganglia, especially thalamus Iron accumulation in several visceral organs as well as brain Marked iron accumulation in brain as well as visceral tissues Low serum iron concentrations Radiographic evidence of iron accumulation in basal ganglia, especially thalamus Iron accumulation in several visceral organs as well as brain No history of drug use or toxicity Radiographic evidence of iron accumulation in basal ganglia, especially thalamus Iron accumulation in several visceral organs as well as brain AD = autosomal dominant; AR = autosomal recessive; DRPLA = dentatorubral-pallidoluysian atrophy; MOI = mode of inheritance; NBIA = neurodegeneration with brain iron accumulation; XL = X-linked Aceruloplasminemia is a type of NBIA. NBIA is a group of inherited neurologic disorders in which iron accumulates in the basal ganglia resulting in progressive dystonia, spasticity, parkinsonism, neuropsychiatric abnormalities, and optic atrophy or retinal degeneration. Ten types and their associated genes are recognized ( In Wilson disease, an inability to transfer copper into the ceruloplasmin precursor protein, apoceruloplasmin, and a decrease in biliary copper excretion results in serum ceruloplasmin deficiency and excess copper accumulation. Because aceruloplasminemia has features of Wilson disease and While hereditary, isolated, and combined dystonias are usually inherited in an autosomal dominant manner, complex dystonias are often inherited in an autosomal recessive or mitochondrial manner. In general, X-linked forms are rare. • Iron accumulation in several visceral organs as well as brain • Development of diabetes & retinopathy • Radiographic evidence of iron accumulation in basal ganglia, especially thalamus • Iron accumulation in several visceral organs as well as brain • Marked iron accumulation in brain as well as visceral tissues • Low serum iron concentrations • Radiographic evidence of iron accumulation in basal ganglia, especially thalamus • Iron accumulation in several visceral organs as well as brain • No history of drug use or toxicity • Radiographic evidence of iron accumulation in basal ganglia, especially thalamus • Iron accumulation in several visceral organs as well as brain ## Management To establish the extent of disease and needs in an individual diagnosed with aceruloplasminemia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Note: Individual case reports indicate the effectiveness of treatment in individuals with aceruloplasminemia; however, no large series of symptomatic persons treated with iron chelators and zinc is available and there is no universally accepted treatment regimen. A systematic review/analysis of studies designed to evaluate the clinical effectiveness of desferrioxamine, deferiprone, deferasirox, and zinc as monotherapy for the initial treatment of various clinical presentations of aceruloplasminemia is needed. Intravenous infusions of 500 mg of desferrioxamine (desferoxamine mesylate) dissolved in 100 mL of isotonic saline solution are given over one hour. Desferrioxamine is infused twice a week for six to ten months. In the In the Zinc concentrations in affected individuals were decreased in the brain and visceral organs, and zinc showed opposing distributions to those for iron. Because zinc has antioxidant activity, treatment with an iron chelator accompanied by zinc may be useful in individuals with aceruloplasminemia to diminish iron accumulation in the brain and body and to prevent or ameliorate systemic and neurologic symptoms [ Marked accumulation of iron in parenchymal tissues including the liver, pancreas, heart, and thyroid can result in diabetes mellitus, cardiac failure, and hypothyroidism. All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus. Cardiac evaluation should be performed early in the course of the disease and repeated every year. Evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis. It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband (starting at age 15 years) in order to identify as early as possible those who would benefit from Molecular genetic testing if the pathogenic variants in the family are known; Monitoring of serum concentrations of hemoglobin and hemoglobin A1c as anemia and diabetes may precede neurologic symptoms (see also See Search • In the • In the • All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus. • Cardiac evaluation should be performed early in the course of the disease and repeated every year. • Evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis. • Molecular genetic testing if the pathogenic variants in the family are known; • Monitoring of serum concentrations of hemoglobin and hemoglobin A1c as anemia and diabetes may precede neurologic symptoms (see also ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with aceruloplasminemia, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: ## Treatment of Manifestations Note: Individual case reports indicate the effectiveness of treatment in individuals with aceruloplasminemia; however, no large series of symptomatic persons treated with iron chelators and zinc is available and there is no universally accepted treatment regimen. A systematic review/analysis of studies designed to evaluate the clinical effectiveness of desferrioxamine, deferiprone, deferasirox, and zinc as monotherapy for the initial treatment of various clinical presentations of aceruloplasminemia is needed. Intravenous infusions of 500 mg of desferrioxamine (desferoxamine mesylate) dissolved in 100 mL of isotonic saline solution are given over one hour. Desferrioxamine is infused twice a week for six to ten months. In the In the • In the • In the ## Prevention of Primary Manifestations Zinc concentrations in affected individuals were decreased in the brain and visceral organs, and zinc showed opposing distributions to those for iron. Because zinc has antioxidant activity, treatment with an iron chelator accompanied by zinc may be useful in individuals with aceruloplasminemia to diminish iron accumulation in the brain and body and to prevent or ameliorate systemic and neurologic symptoms [ ## Surveillance Marked accumulation of iron in parenchymal tissues including the liver, pancreas, heart, and thyroid can result in diabetes mellitus, cardiac failure, and hypothyroidism. All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus. Cardiac evaluation should be performed early in the course of the disease and repeated every year. Evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis. • All affected individuals should have an annual glucose tolerance test starting at age 15 years to evaluate for the onset of diabetes mellitus. • Cardiac evaluation should be performed early in the course of the disease and repeated every year. • Evaluation of thyroid and liver function and complete blood count are indicated annually starting at the time of diagnosis. ## Agents/Circumstances to Avoid ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband (starting at age 15 years) in order to identify as early as possible those who would benefit from Molecular genetic testing if the pathogenic variants in the family are known; Monitoring of serum concentrations of hemoglobin and hemoglobin A1c as anemia and diabetes may precede neurologic symptoms (see also See • Molecular genetic testing if the pathogenic variants in the family are known; • Monitoring of serum concentrations of hemoglobin and hemoglobin A1c as anemia and diabetes may precede neurologic symptoms (see also ## Therapies Under Investigation Search ## Genetic Counseling Aceruloplasminemia is inherited in an autosomal recessive manner. The parents of an individual with aceruloplasminemia are obligate heterozygotes (i.e., carriers of one Clinical disease is not known to occur in heterozygotes, although data are not adequate to exclude the possibility in older individuals. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) with clinical signs/symptoms have not been reported, although data are not adequate to exclude the possibility in older individuals. 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 individual with aceruloplasminemia are obligate heterozygotes (i.e., carriers of one • Clinical disease is not known to occur in heterozygotes, although data are not adequate to exclude the possibility in older individuals. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) with clinical signs/symptoms have not been reported, although data are not adequate to exclude the possibility in older individuals. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Aceruloplasminemia is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an individual with aceruloplasminemia are obligate heterozygotes (i.e., carriers of one Clinical disease is not known to occur in heterozygotes, although data are not adequate to exclude the possibility in older individuals. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) with clinical signs/symptoms have not been reported, although data are not adequate to exclude the possibility in older individuals. • The parents of an individual with aceruloplasminemia are obligate heterozygotes (i.e., carriers of one • Clinical disease is not known to occur in heterozygotes, although data are not adequate to exclude the possibility in older individuals. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) with clinical signs/symptoms have not been reported, although data are not adequate to exclude the possibility in older individuals. ## 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 Center of Excellence for NBIA Clinical Care and Research International Registry for NBIA and Related Disorders Oregon Health & Science University Germany • • • • Center of Excellence for NBIA Clinical Care and Research • International Registry for NBIA and Related Disorders • Oregon Health & Science University • • • Germany • ## Molecular Genetics Aceruloplasminemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Aceruloplasminemia ( More than half of the pathogenic variants in Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions; in this instance the alias refers to the length of the mature peptide. Ceruloplasmin has two forms: (1) a secreted form (1,040 amino acids) mainly produced and secreted by hepatocytes, and (2) a glycosylphosphatidylinositol (GPI)-anchored form (1,065 amino acids) mainly expressed in astrocytes as well as visceral organs (see The secreted form, alpha2-glycoprotein, is synthesized mainly in the liver; it plays an important role in iron mobilization from the tissues as a ferroxidase. The GPI-anchored form is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the five C-terminal amino acids of the secreted form with an alternative 30-amino-acid sequence that signals GPI anchor addition. The GPI-anchored form of ceruloplasmin is expressed in astrocytes and plays an important role in iron metabolism in the central nervous system through its ferroxidase activity [ • The secreted form, alpha2-glycoprotein, is synthesized mainly in the liver; it plays an important role in iron mobilization from the tissues as a ferroxidase. • The GPI-anchored form is generated by alternative RNA splicing. The splicing occurs downstream of exon 18 and replaces the five C-terminal amino acids of the secreted form with an alternative 30-amino-acid sequence that signals GPI anchor addition. The GPI-anchored form of ceruloplasmin is expressed in astrocytes and plays an important role in iron metabolism in the central nervous system through its ferroxidase activity [ ## References ## Literature Cited ## Chapter Notes Aceruloplasminemia research is funded in part by a Grant-in-Aid of Science from the Ministry of Education, Science, Culture, Sports, and Technology, Japan. 27 September 2018 (ha) Comprehensive update posted live 5 November 2015 (me) Comprehensive update posted live 18 April 2013 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 29 April 2008 (me) Comprehensive update posted live 15 August 2005 (me) Comprehensive update posted live 12 August 2003 (me) Review posted live 23 June 2003 (hm) Original submission • 27 September 2018 (ha) Comprehensive update posted live • 5 November 2015 (me) Comprehensive update posted live • 18 April 2013 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 29 April 2008 (me) Comprehensive update posted live • 15 August 2005 (me) Comprehensive update posted live • 12 August 2003 (me) Review posted live • 23 June 2003 (hm) Original submission ## Acknowledgments Aceruloplasminemia research is funded in part by a Grant-in-Aid of Science from the Ministry of Education, Science, Culture, Sports, and Technology, Japan. ## Revision History 27 September 2018 (ha) Comprehensive update posted live 5 November 2015 (me) Comprehensive update posted live 18 April 2013 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 29 April 2008 (me) Comprehensive update posted live 15 August 2005 (me) Comprehensive update posted live 12 August 2003 (me) Review posted live 23 June 2003 (hm) Original submission • 27 September 2018 (ha) Comprehensive update posted live • 5 November 2015 (me) Comprehensive update posted live • 18 April 2013 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 29 April 2008 (me) Comprehensive update posted live • 15 August 2005 (me) Comprehensive update posted live • 12 August 2003 (me) Review posted live • 23 June 2003 (hm) Original submission CT and T Pathogenic variants (mutations) characterized in individuals with aceruloplasminemia and their family members. 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acpp	acpp	[ "Long QT Syndrome Type 7 (LQTS Type 7)", "LQT7", "Long QT Syndrome Type 7", "LQTS Type 7", "G protein-activated inward rectifier potassium channel 4", "Inward rectifier potassium channel 2", "KCNJ2", "KCNJ5", "Andersen-Tawil Syndrome" ]	Andersen-Tawil Syndrome	Aravindhan Veerapandiyan, Jeffrey M Statland, Rabi Tawil	Summary Andersen-Tawil syndrome (ATS) is characterized by a triad of: episodic flaccid muscle weakness (i.e., periodic paralysis); ventricular arrhythmias and prolonged QT interval; and anomalies including low-set ears, widely spaced eyes, small mandible, fifth-digit clinodactyly, syndactyly, short stature, and scoliosis. Affected individuals present in the first or second decade with either cardiac symptoms (palpitations and/or syncope) or weakness that occurs spontaneously following prolonged rest or following rest after exertion. Mild permanent weakness is common. Mild learning difficulties and a distinct neurocognitive phenotype (i.e., deficits in executive function and abstract reasoning) have been described. The diagnosis of ATS is established in an individual with characteristic clinical and EKG findings and/or identification of a pathogenic variant in ATS is inherited in an autosomal dominant manner. At least 50% of individuals diagnosed with ATS have an affected parent. Up to 50% of affected individuals have ATS as the result of a	## Diagnosis Andersen-Tawil syndrome (ATS) A. Presence of two of the following three criteria: Periodic paralysis Symptomatic cardiac arrhythmias or electrocardiographic evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval Characteristic facies, dental anomalies, small hands and feet, AND at least two of the following: Low-set ears Widely spaced eyes Small mandible Fifth-digit clinodactyly Syndactyly of toes 2 and 3 B. One of the above three criteria AND at least one other family member who meets two of the three criteria [ Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead EKG, a 24-hour Holter monitor, and possibly the long exercise protocol. The diagnosis of ATS 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 ATS is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of ATS 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 cardiac arrhythmias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Andersen-Tawil 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions of One individual with periodic paralysis, ventricular arrhythmias, no history of hypertension, and normal plasma aldosterone levels was found to have a • Periodic paralysis • Symptomatic cardiac arrhythmias or electrocardiographic evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval • Characteristic facies, dental anomalies, small hands and feet, AND at least two of the following: • Low-set ears • Widely spaced eyes • Small mandible • Fifth-digit clinodactyly • Syndactyly of toes 2 and 3 • Low-set ears • Widely spaced eyes • Small mandible • Fifth-digit clinodactyly • Syndactyly of toes 2 and 3 • Low-set ears • Widely spaced eyes • Small mandible • Fifth-digit clinodactyly • Syndactyly of toes 2 and 3 • For an introduction to multigene panels click ## Suggestive Findings Andersen-Tawil syndrome (ATS) A. Presence of two of the following three criteria: Periodic paralysis Symptomatic cardiac arrhythmias or electrocardiographic evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval Characteristic facies, dental anomalies, small hands and feet, AND at least two of the following: Low-set ears Widely spaced eyes Small mandible Fifth-digit clinodactyly Syndactyly of toes 2 and 3 B. One of the above three criteria AND at least one other family member who meets two of the three criteria [ • Periodic paralysis • Symptomatic cardiac arrhythmias or electrocardiographic evidence of enlarged U-waves, ventricular ectopy, or a prolonged QTc or QUc interval • Characteristic facies, dental anomalies, small hands and feet, AND at least two of the following: • Low-set ears • Widely spaced eyes • Small mandible • Fifth-digit clinodactyly • Syndactyly of toes 2 and 3 • Low-set ears • Widely spaced eyes • Small mandible • Fifth-digit clinodactyly • Syndactyly of toes 2 and 3 • Low-set ears • Widely spaced eyes • Small mandible • Fifth-digit clinodactyly • Syndactyly of toes 2 and 3 ## Supportive Findings Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead EKG, a 24-hour Holter monitor, and possibly the long exercise protocol. ## Establishing the Diagnosis The diagnosis of ATS 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 ATS is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of ATS 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 cardiac arrhythmias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Andersen-Tawil 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions of One individual with periodic paralysis, ventricular arrhythmias, no history of hypertension, and normal plasma aldosterone levels was found to have a • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of ATS 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 cardiac arrhythmias, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Andersen-Tawil 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 quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions of One individual with periodic paralysis, ventricular arrhythmias, no history of hypertension, and normal plasma aldosterone levels was found to have a ## Clinical Characteristics Andersen-Tawil syndrome (ATS) is characterized by a triad of features: Episodic flaccid muscle weakness (periodic paralysis) Cardiac abnormalities (ventricular arrhythmias, prolonged QTc or QUc intervals, and prominent U waves) Distinctive dysmorphic features Affected individuals present initially with either periodic paralysis or cardiac symptoms (palpitations and/or syncope) in the first or second decade [ Detailed, prospectively collected data in ten individuals with confirmed Characteristic facies include broad forehead, short palpebral fissures, wide nasal bridge with bulbous nose, hypoplasia of maxilla and mandible, thin upper lip, and a triangular face. Dental findings include (among others) persistent primary dentition, multiple missing teeth (oligodontia), and dental crowding. Skeletal findings include mild syndactyly of toes two and three as well as fifth-digit clinodactyly. Novel findings include small hands and feet (<10th centile for age) and joint laxity. Note: Isolated reports of Whether a In a case series that evaluated for In a single large kindred with the A large five-generation family was found to have a deletion in Two pathogenic variants in A recent study examined the predictors of arrhythmias in 11 unrelated families with ATS (11 probands who were all female, 14 unaffected heterozygous family members with the Non-penetrance is evident in 6%-20% of individuals with an identifiable pathogenic variant [ Although listed in OMIM, the following names for ATS are no longer in clinical use: Periodic paralysis, potassium-sensitive cardiodysrhythmic type Andersen cardiodysrhythmic periodic paralysis The prevalence of ATS is estimated at 0.08:100,000-0.1:100,000 [ • Episodic flaccid muscle weakness (periodic paralysis) • Cardiac abnormalities (ventricular arrhythmias, prolonged QTc or QUc intervals, and prominent U waves) • Distinctive dysmorphic features • Characteristic facies include broad forehead, short palpebral fissures, wide nasal bridge with bulbous nose, hypoplasia of maxilla and mandible, thin upper lip, and a triangular face. • Dental findings include (among others) persistent primary dentition, multiple missing teeth (oligodontia), and dental crowding. • Skeletal findings include mild syndactyly of toes two and three as well as fifth-digit clinodactyly. • Novel findings include small hands and feet (<10th centile for age) and joint laxity. • Periodic paralysis, potassium-sensitive cardiodysrhythmic type • Andersen cardiodysrhythmic periodic paralysis ## Clinical Description Andersen-Tawil syndrome (ATS) is characterized by a triad of features: Episodic flaccid muscle weakness (periodic paralysis) Cardiac abnormalities (ventricular arrhythmias, prolonged QTc or QUc intervals, and prominent U waves) Distinctive dysmorphic features Affected individuals present initially with either periodic paralysis or cardiac symptoms (palpitations and/or syncope) in the first or second decade [ Detailed, prospectively collected data in ten individuals with confirmed Characteristic facies include broad forehead, short palpebral fissures, wide nasal bridge with bulbous nose, hypoplasia of maxilla and mandible, thin upper lip, and a triangular face. Dental findings include (among others) persistent primary dentition, multiple missing teeth (oligodontia), and dental crowding. Skeletal findings include mild syndactyly of toes two and three as well as fifth-digit clinodactyly. Novel findings include small hands and feet (<10th centile for age) and joint laxity. Note: Isolated reports of • Episodic flaccid muscle weakness (periodic paralysis) • Cardiac abnormalities (ventricular arrhythmias, prolonged QTc or QUc intervals, and prominent U waves) • Distinctive dysmorphic features • Characteristic facies include broad forehead, short palpebral fissures, wide nasal bridge with bulbous nose, hypoplasia of maxilla and mandible, thin upper lip, and a triangular face. • Dental findings include (among others) persistent primary dentition, multiple missing teeth (oligodontia), and dental crowding. • Skeletal findings include mild syndactyly of toes two and three as well as fifth-digit clinodactyly. • Novel findings include small hands and feet (<10th centile for age) and joint laxity. ## Genotype-Phenotype Correlations Whether a In a case series that evaluated for In a single large kindred with the A large five-generation family was found to have a deletion in Two pathogenic variants in A recent study examined the predictors of arrhythmias in 11 unrelated families with ATS (11 probands who were all female, 14 unaffected heterozygous family members with the ## Penetrance Non-penetrance is evident in 6%-20% of individuals with an identifiable pathogenic variant [ ## Nomenclature Although listed in OMIM, the following names for ATS are no longer in clinical use: Periodic paralysis, potassium-sensitive cardiodysrhythmic type Andersen cardiodysrhythmic periodic paralysis • Periodic paralysis, potassium-sensitive cardiodysrhythmic type • Andersen cardiodysrhythmic periodic paralysis ## Prevalence The prevalence of ATS is estimated at 0.08:100,000-0.1:100,000 [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Andersen-Tawil syndrome (ATS) should be considered in any individual presenting with periodic paralysis and ventricular arrhythmias or prominent U wave or prolonged QTc. Individuals with either episodic weakness or cardiac symptoms require careful evaluation by a neurologist and/or cardiologist as well as measurement of serum potassium concentration (baseline and during attacks of flaccid paralysis), a 12-lead EKG, a 24-hour Holter monitor, and possibly the long exercise protocol. The differential diagnosis depends on the initial presentation and includes the primary and secondary periodic paralyses, thyrotoxic periodic paralysis, and conditions associated with long QT. See Syncopal episodes are often interpreted as a neurologic problem rather than arrhythmia. Physical examination and EKG should be part of the evaluation of syncope. Bidirectional ventricular tachycardia demonstrated on EKG may be seen with ATS, digitalis toxicity, and ## Episodes of Flaccid Paralysis ## Long QT Syndromes See ## Palpitations, Syncope, or Cardiac Arrest Syncopal episodes are often interpreted as a neurologic problem rather than arrhythmia. Physical examination and EKG should be part of the evaluation of syncope. Bidirectional ventricular tachycardia demonstrated on EKG may be seen with ATS, digitalis toxicity, and ## Management To establish the extent of disease and needs in an individual diagnosed with Andersen-Tawil syndrome (ATS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ATS LQT = long QT; TSH = thyroid-stimulating hormone Management of individuals with ATS requires the coordinated input of a neurologist familiar with the treatment of periodic paralysis and a cardiologist familiar with the treatment of cardiac arrhythmias. To date, no randomized clinical therapeutic trials have been conducted on ATS. Management of attacks of episodic weakness depends on the associated serum potassium concentration: If the serum potassium concentration is low (<3.0 mmol/L), administer oral potassium (20-30 mEq/L) every 15-30 minutes (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes often shortens the attack. As dysphagia is almost never a problem during attacks of paralysis, oral potassium replacement is the safest route. If intravenous potassium replacement is needed, a 5% mannitol solution instead of a saline or glucose solution (both of which may exacerbate weakness) is recommended. Close monitoring of serum potassium concentrations and EKG is necessary during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia. Whether a relative drop in serum potassium within the normal range causes episodic paralysis is not clear. If such cases are suspected, affected individuals can work with their physician to devise an individual potassium replacement regimen, with a goal of maintaining serum potassium levels in the high range of normal. Attacks of weakness when serum potassium concentration is high usually resolve within 60 minutes. Episodes may be shortened by ingesting carbohydrates or continuing mild exercise. Intravenous calcium gluconate is rarely necessary for management in an individual seen in an emergency setting. Vasovagal syncope in individuals with ATS mandates a careful cardiology assessment [ Prophylactic treatment aimed at reduction of attack frequency and severity can be achieved, as in other forms of periodic paralysis, with the following: Lifestyle and dietary modification to avoid known triggers Use of carbonic anhydrase inhibitors (acetazolamide: adults 125-1,000 mg daily and children 5-10 mg/kg/day divided 1-2x/day or dichlorphenamide 50-200 mg/1-2x/day). Use of potassium-sparing diuretic should be individualized based on patient needs. Daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals prone to hypokalemia. Elevating the serum potassium concentration (>4 mEq/L) has the added benefit of narrowing the QT interval, thus reducing the risk of LQT-associated arrhythmias. An implantable cardioverter-defibrillator in individuals with tachycardia-induced syncope [ Empiric treatment with flecainide [ Cardiologists should be aware that some antiarrhythmic drugs (e.g., lidocaine, mexiletine, propafenone, quinidine), particularly Class I drugs, may paradoxically exacerbate the neuromuscular symptoms and should be used cautiously in individuals with ATS. Although For asymptomatic individuals with a Affected individuals should avoid medications known to prolong QT intervals. See Salbutamol inhalers, which may be used in the treatment of primary hyperkalemic periodic paralysis, should be avoided because of the potential for exacerbation of cardiac arrhythmias. Thiazide and other potassium-wasting diuretics may provoke drug-induced hypokalemia and could aggravate the QT interval prolongation. It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures: If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, detailed neurologic and cardiologic evaluation, 12-lead EKG, and 24-hour Holter monitoring can be used to clarify the disease status of at-risk relatives. See The rarity of ATS and the paucity of reports pertaining to pregnancy in women with ATS make an evidence-based approach to pregnancy management difficult to formulate. One case study reported an uneventful pregnancy, with increased episodes of weakness but reduced ventricular ectopy compared to the pre-pregnancy period [ Search • If the serum potassium concentration is low (<3.0 mmol/L), administer oral potassium (20-30 mEq/L) every 15-30 minutes (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes often shortens the attack. As dysphagia is almost never a problem during attacks of paralysis, oral potassium replacement is the safest route. If intravenous potassium replacement is needed, a 5% mannitol solution instead of a saline or glucose solution (both of which may exacerbate weakness) is recommended. Close monitoring of serum potassium concentrations and EKG is necessary during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia. • Whether a relative drop in serum potassium within the normal range causes episodic paralysis is not clear. If such cases are suspected, affected individuals can work with their physician to devise an individual potassium replacement regimen, with a goal of maintaining serum potassium levels in the high range of normal. • Attacks of weakness when serum potassium concentration is high usually resolve within 60 minutes. Episodes may be shortened by ingesting carbohydrates or continuing mild exercise. Intravenous calcium gluconate is rarely necessary for management in an individual seen in an emergency setting. • Lifestyle and dietary modification to avoid known triggers • Use of carbonic anhydrase inhibitors (acetazolamide: adults 125-1,000 mg daily and children 5-10 mg/kg/day divided 1-2x/day or dichlorphenamide 50-200 mg/1-2x/day). Use of potassium-sparing diuretic should be individualized based on patient needs. • Daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals prone to hypokalemia. Elevating the serum potassium concentration (>4 mEq/L) has the added benefit of narrowing the QT interval, thus reducing the risk of LQT-associated arrhythmias. • An implantable cardioverter-defibrillator in individuals with tachycardia-induced syncope [ • Empiric treatment with flecainide [ • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, detailed neurologic and cardiologic evaluation, 12-lead EKG, and 24-hour Holter monitoring can be used to clarify the disease status of at-risk relatives. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Andersen-Tawil syndrome (ATS), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ATS LQT = long QT; TSH = thyroid-stimulating hormone ## Treatment of Manifestations Management of individuals with ATS requires the coordinated input of a neurologist familiar with the treatment of periodic paralysis and a cardiologist familiar with the treatment of cardiac arrhythmias. To date, no randomized clinical therapeutic trials have been conducted on ATS. Management of attacks of episodic weakness depends on the associated serum potassium concentration: If the serum potassium concentration is low (<3.0 mmol/L), administer oral potassium (20-30 mEq/L) every 15-30 minutes (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes often shortens the attack. As dysphagia is almost never a problem during attacks of paralysis, oral potassium replacement is the safest route. If intravenous potassium replacement is needed, a 5% mannitol solution instead of a saline or glucose solution (both of which may exacerbate weakness) is recommended. Close monitoring of serum potassium concentrations and EKG is necessary during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia. Whether a relative drop in serum potassium within the normal range causes episodic paralysis is not clear. If such cases are suspected, affected individuals can work with their physician to devise an individual potassium replacement regimen, with a goal of maintaining serum potassium levels in the high range of normal. Attacks of weakness when serum potassium concentration is high usually resolve within 60 minutes. Episodes may be shortened by ingesting carbohydrates or continuing mild exercise. Intravenous calcium gluconate is rarely necessary for management in an individual seen in an emergency setting. Vasovagal syncope in individuals with ATS mandates a careful cardiology assessment [ • If the serum potassium concentration is low (<3.0 mmol/L), administer oral potassium (20-30 mEq/L) every 15-30 minutes (not to exceed 200 mEq in a 12-hour period) until the serum concentration normalizes often shortens the attack. As dysphagia is almost never a problem during attacks of paralysis, oral potassium replacement is the safest route. If intravenous potassium replacement is needed, a 5% mannitol solution instead of a saline or glucose solution (both of which may exacerbate weakness) is recommended. Close monitoring of serum potassium concentrations and EKG is necessary during potassium replacement therapy in an emergency setting to avoid secondary hyperkalemia. • Whether a relative drop in serum potassium within the normal range causes episodic paralysis is not clear. If such cases are suspected, affected individuals can work with their physician to devise an individual potassium replacement regimen, with a goal of maintaining serum potassium levels in the high range of normal. • Attacks of weakness when serum potassium concentration is high usually resolve within 60 minutes. Episodes may be shortened by ingesting carbohydrates or continuing mild exercise. Intravenous calcium gluconate is rarely necessary for management in an individual seen in an emergency setting. ## Prevention of Primary Manifestations Prophylactic treatment aimed at reduction of attack frequency and severity can be achieved, as in other forms of periodic paralysis, with the following: Lifestyle and dietary modification to avoid known triggers Use of carbonic anhydrase inhibitors (acetazolamide: adults 125-1,000 mg daily and children 5-10 mg/kg/day divided 1-2x/day or dichlorphenamide 50-200 mg/1-2x/day). Use of potassium-sparing diuretic should be individualized based on patient needs. Daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals prone to hypokalemia. Elevating the serum potassium concentration (>4 mEq/L) has the added benefit of narrowing the QT interval, thus reducing the risk of LQT-associated arrhythmias. An implantable cardioverter-defibrillator in individuals with tachycardia-induced syncope [ Empiric treatment with flecainide [ • Lifestyle and dietary modification to avoid known triggers • Use of carbonic anhydrase inhibitors (acetazolamide: adults 125-1,000 mg daily and children 5-10 mg/kg/day divided 1-2x/day or dichlorphenamide 50-200 mg/1-2x/day). Use of potassium-sparing diuretic should be individualized based on patient needs. • Daily use of slow-release potassium supplements, which may also be helpful in controlling attack rates in individuals prone to hypokalemia. Elevating the serum potassium concentration (>4 mEq/L) has the added benefit of narrowing the QT interval, thus reducing the risk of LQT-associated arrhythmias. • An implantable cardioverter-defibrillator in individuals with tachycardia-induced syncope [ • Empiric treatment with flecainide [ ## Prevention of Secondary Complications Cardiologists should be aware that some antiarrhythmic drugs (e.g., lidocaine, mexiletine, propafenone, quinidine), particularly Class I drugs, may paradoxically exacerbate the neuromuscular symptoms and should be used cautiously in individuals with ATS. Although ## Surveillance For asymptomatic individuals with a ## Agents/Circumstances to Avoid Affected individuals should avoid medications known to prolong QT intervals. See Salbutamol inhalers, which may be used in the treatment of primary hyperkalemic periodic paralysis, should be avoided because of the potential for exacerbation of cardiac arrhythmias. Thiazide and other potassium-wasting diuretics may provoke drug-induced hypokalemia and could aggravate the QT interval prolongation. ## Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures: If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, detailed neurologic and cardiologic evaluation, 12-lead EKG, and 24-hour Holter monitoring can be used to clarify the disease status of at-risk relatives. See • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, detailed neurologic and cardiologic evaluation, 12-lead EKG, and 24-hour Holter monitoring can be used to clarify the disease status of at-risk relatives. ## Pregnancy Management The rarity of ATS and the paucity of reports pertaining to pregnancy in women with ATS make an evidence-based approach to pregnancy management difficult to formulate. One case study reported an uneventful pregnancy, with increased episodes of weakness but reduced ventricular ectopy compared to the pre-pregnancy period [ ## Therapies Under Investigation Search ## Genetic Counseling Andersen-Tawil syndrome (ATS) is inherited in an autosomal dominant manner. At least 50% of individuals diagnosed with ATS have an affected parent. A proband with ATS may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent The family history of some individuals diagnosed with ATS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent not attributed to the disease, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic and cardiologic evaluations and/or molecular genetic testing has been performed on the parents of the proband. If a parent of the proband is affected and/or has the If the proband has a known ATS-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 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • At least 50% of individuals diagnosed with ATS have an affected parent. • A proband with ATS may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • The family history of some individuals diagnosed with ATS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent not attributed to the disease, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic and cardiologic evaluations and/or molecular genetic testing has been performed on the parents of the proband. • If a parent of the proband is affected and/or has the • If the proband has a known ATS-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 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 Andersen-Tawil syndrome (ATS) is inherited in an autosomal dominant manner. ## Risk to Family Members At least 50% of individuals diagnosed with ATS have an affected parent. A proband with ATS may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with an apparent The family history of some individuals diagnosed with ATS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent not attributed to the disease, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic and cardiologic evaluations and/or molecular genetic testing has been performed on the parents of the proband. If a parent of the proband is affected and/or has the If the proband has a known ATS-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 have not been tested for the • At least 50% of individuals diagnosed with ATS have an affected parent. • A proband with ATS may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with an apparent • The family history of some individuals diagnosed with ATS may appear to be negative because of failure to recognize the disorder in family members, early death of the parent not attributed to the disease, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate neurologic and cardiologic evaluations and/or molecular genetic testing has been performed on the parents of the proband. • If a parent of the proband is affected and/or has the • If the proband has a known ATS-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 have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada Heart Research Follow-Up Program • • • • Canada • • • • • • • • • Heart Research Follow-Up Program • ## Molecular Genetics Andersen-Tawil Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Andersen-Tawil Syndrome ( Variants listed in the table have been provided by the authors. See See Flaccid paralysis results from failure to propagate action potentials in the muscle membrane as a result of sustained membrane depolarization [ While the role of Kir2.1 in skeletal development remains to be clarified, consistent craniofacial, dental, and skeletal anomalies are present [ Targeted disruption of Kir2.1 in a knockout mouse is fatal, with complete cleft of the secondary palate [ Variants listed in the table have been provided by the authors. See ## References ## Literature Cited ## Chapter Notes The authors are funded in part by the Consortium for Clinical Investigation of Neurological Channelopathies (CINCH) supported by NIH 8 U54 NS59065 (NINDS/ORD). Jeffrey M Statland, MD (2013-present)Rabi Tawil, MD (2004-present)Aravindhan Veerapandiyan, MBBS (2018-present)Shannon L Venance, MD, PhD; University of Western Ontario (2004-2018) 7 June 2018 (sw) Comprehensive update posted live 3 September 2015 (rt) Revision: 6 August 2015 (me) Comprehensive update posted live 3 January 2013 (me) Comprehensive update posted live 13 May 2010 (me) Comprehensive update posted live 19 March 2007 (me) Comprehensive update posted live 27 April 2005 (cd) Revision: prenatal diagnosis available 22 November 2004 (me) Review posted live 1 June 2004 (rt) Original submission • 7 June 2018 (sw) Comprehensive update posted live • 3 September 2015 (rt) Revision: • 6 August 2015 (me) Comprehensive update posted live • 3 January 2013 (me) Comprehensive update posted live • 13 May 2010 (me) Comprehensive update posted live • 19 March 2007 (me) Comprehensive update posted live • 27 April 2005 (cd) Revision: prenatal diagnosis available • 22 November 2004 (me) Review posted live • 1 June 2004 (rt) Original submission ## Acknowledgments The authors are funded in part by the Consortium for Clinical Investigation of Neurological Channelopathies (CINCH) supported by NIH 8 U54 NS59065 (NINDS/ORD). ## Author History Jeffrey M Statland, MD (2013-present)Rabi Tawil, MD (2004-present)Aravindhan Veerapandiyan, MBBS (2018-present)Shannon L Venance, MD, PhD; University of Western Ontario (2004-2018) ## Revision History 7 June 2018 (sw) Comprehensive update posted live 3 September 2015 (rt) Revision: 6 August 2015 (me) Comprehensive update posted live 3 January 2013 (me) Comprehensive update posted live 13 May 2010 (me) Comprehensive update posted live 19 March 2007 (me) Comprehensive update posted live 27 April 2005 (cd) Revision: prenatal diagnosis available 22 November 2004 (me) Review posted live 1 June 2004 (rt) Original submission • 7 June 2018 (sw) Comprehensive update posted live • 3 September 2015 (rt) Revision: • 6 August 2015 (me) Comprehensive update posted live • 3 January 2013 (me) Comprehensive update posted live • 13 May 2010 (me) Comprehensive update posted live • 19 March 2007 (me) Comprehensive update posted live • 27 April 2005 (cd) Revision: prenatal diagnosis available • 22 November 2004 (me) Review posted live • 1 June 2004 (rt) Original submission	[ "T Ai, Y Fujiwara, K Tsuji, H Otani, S Nakano, Y Kubo, M. 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J Clin Invest. 2002;110:381-8", "S Vergult, A Dauber, B Delle Chiaie, E Van Oudenhove, M Simon, A Rihani, B Loeys, J Hirschhorn, J Pfotenhauer, JA Phillips, S Mohammed, C Ogilvie, J Crolla, G Mortier, B Menten. 17q24.2 microdeletions: a new syndromal entity with intellectual disability, truncal obesity, mood swings and hallucinations.. Eur J Hum Genet. 2012;20:534-9", "G Yoon, S Oberoi, M Tristani-Firouzi, SP Etheridge, L Quitania, JH Kramer, BL Miller, YH Fu, LJ Ptácek. Andersen-Tawil syndrome: prospective cohort analysis and expansion of the phenotype.. Am J Med Genet A. 2006a;140:312-21", "G Yoon, L Quitania, JH Kramer, YH Fu, BL Miller, LJ Ptácek. Andersen-Tawil syndrome: definition of a neurocognitive phenotype.. Neurology. 2006b;66:1703-10", "JJ Zaritsky, DM Eckman, GC Wellman, MT Nelson, TL Schwarz. Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K(+) current in K(+)-mediated vasodilation.. Circ Res. 2000;87:160-6", "L Zhang, DW Benson, M Tristani-Firouzi, LJ Ptacek, R Tawil, PJ Schwartz, AL George, M Horie, G Andelfinger, GL Snow, YH Fu, MJ Ackerman, GM Vincent. Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations: characteristic T-U-wave patterns predict the KCNJ2 genotype.. Circulation. 2005;111:2720-6" ]	22/11/2004	7/6/2018	3/9/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
actg2-dis	actg2-dis	[ "Berdon Syndrome", "Familial Visceral Myopathy", "Familial Visceral Myopathy", "Berdon Syndrome", "Megacystis-Microcolon-Intestinal Hypoperistalsis Syndrome", "Prune Belly Sequence", "Chronic Intestinal Pseudoobstruction (CIPO)", "Actin, gamma-enteric smooth muscle", "ACTG2", "ACTG2 Visceral Myopathy" ]		Pranjali K Bhagwat, Michael F Wangler	Summary Affected infants (with or without evidence of intestinal malrotation) often present with feeding intolerance and findings of non-mechanical bowel obstruction that persist after successful surgical correction of malrotation. Individuals who develop manifestations of CIPO in later childhood or adulthood often experience episodic waxing and waning of bowel motility. They may undergo frequent abdominal surgeries (perhaps related to malrotation or adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel, often becoming dependent on total parenteral nutrition (TPN). The diagnosis of For bladder and urinary tract comorbidities, monitor voiding, urinary tract anatomy, and renal function. For intestinal manifestations, monitor nutritional status and possible TPN-associated complications (line infections, liver disease) and consider need for multivisceral or isolated intestinal transplantation. Approximately 73% of individuals with If a parent is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Although penetrance of Each child of an individual with Once the	## Diagnosis No consensus clinical diagnostic criteria for Prenatal ultrasound revealing megacystis, defined according to trimester [ First trimester. Bladder diameter >6 mm Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes In neonates, prune-belly sequence (megacystis with lack of abdominal wall musculature, cryptorchidism in males, and distention of the upper urinary tract) in association with impaired gastrointestinal motility Postnatal ultrasound examination or cystogram revealing an enlarged bladder In individuals of any age, unexplained chronic functional bladder impairment of voiding without mechanical blockage Neonatal bilious emesis, abdominal distention, and feeding intolerance Intestinal malrotation and long-term intestinal motility problems often resulting in chronic abdominal pain and constipation Neonatal microcolon In individuals of any age, chronic intestinal pseudoobstruction (CIPO) (i.e., unexplained chronic functional intestinal obstruction involving small bowel and/or colon without evidence of mechanical blockage) Additional suggestive intestinal findings [ Symptoms lasting more than six months, or more than two months from birth Evidence of delayed GI transit and/or decreased GI motility Imaging studies that do not show mechanical obstruction Radiographic documentation of dilated bowel, air fluid levels without fixed obstruction [ 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 For an introduction to multigene panels click 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 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, and multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. • Prenatal ultrasound revealing megacystis, defined according to trimester [ • First trimester. Bladder diameter >6 mm • Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes • First trimester. Bladder diameter >6 mm • Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes • In neonates, prune-belly sequence (megacystis with lack of abdominal wall musculature, cryptorchidism in males, and distention of the upper urinary tract) in association with impaired gastrointestinal motility • Postnatal ultrasound examination or cystogram revealing an enlarged bladder • In individuals of any age, unexplained chronic functional bladder impairment of voiding without mechanical blockage • First trimester. Bladder diameter >6 mm • Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes • Neonatal bilious emesis, abdominal distention, and feeding intolerance • Intestinal malrotation and long-term intestinal motility problems often resulting in chronic abdominal pain and constipation • Neonatal microcolon • In individuals of any age, chronic intestinal pseudoobstruction (CIPO) (i.e., unexplained chronic functional intestinal obstruction involving small bowel and/or colon without evidence of mechanical blockage) • Symptoms lasting more than six months, or more than two months from birth • Evidence of delayed GI transit and/or decreased GI motility • Imaging studies that do not show mechanical obstruction • Radiographic documentation of dilated bowel, air fluid levels without fixed obstruction [ ## Suggestive Findings Prenatal ultrasound revealing megacystis, defined according to trimester [ First trimester. Bladder diameter >6 mm Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes In neonates, prune-belly sequence (megacystis with lack of abdominal wall musculature, cryptorchidism in males, and distention of the upper urinary tract) in association with impaired gastrointestinal motility Postnatal ultrasound examination or cystogram revealing an enlarged bladder In individuals of any age, unexplained chronic functional bladder impairment of voiding without mechanical blockage Neonatal bilious emesis, abdominal distention, and feeding intolerance Intestinal malrotation and long-term intestinal motility problems often resulting in chronic abdominal pain and constipation Neonatal microcolon In individuals of any age, chronic intestinal pseudoobstruction (CIPO) (i.e., unexplained chronic functional intestinal obstruction involving small bowel and/or colon without evidence of mechanical blockage) Additional suggestive intestinal findings [ Symptoms lasting more than six months, or more than two months from birth Evidence of delayed GI transit and/or decreased GI motility Imaging studies that do not show mechanical obstruction Radiographic documentation of dilated bowel, air fluid levels without fixed obstruction [ • Prenatal ultrasound revealing megacystis, defined according to trimester [ • First trimester. Bladder diameter >6 mm • Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes • First trimester. Bladder diameter >6 mm • Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes • In neonates, prune-belly sequence (megacystis with lack of abdominal wall musculature, cryptorchidism in males, and distention of the upper urinary tract) in association with impaired gastrointestinal motility • Postnatal ultrasound examination or cystogram revealing an enlarged bladder • In individuals of any age, unexplained chronic functional bladder impairment of voiding without mechanical blockage • First trimester. Bladder diameter >6 mm • Second and third trimesters. Enlarged bladder with failure to empty within 45 minutes • Neonatal bilious emesis, abdominal distention, and feeding intolerance • Intestinal malrotation and long-term intestinal motility problems often resulting in chronic abdominal pain and constipation • Neonatal microcolon • In individuals of any age, chronic intestinal pseudoobstruction (CIPO) (i.e., unexplained chronic functional intestinal obstruction involving small bowel and/or colon without evidence of mechanical blockage) • Symptoms lasting more than six months, or more than two months from birth • Evidence of delayed GI transit and/or decreased GI motility • Imaging studies that do not show mechanical obstruction • Radiographic documentation of dilated bowel, air fluid levels without fixed obstruction [ ## 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 For an introduction to multigene panels click 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 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, and multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 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 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, and multiplex ligation-dependent probe amplification (MLPA), and gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Individuals with The clinical severity can range within a family; mildly affected family members may not be aware of the diagnosis. For example: One individual (in a multi-generation Finnish family) with an One individual diagnosed with "spastic colon" and irritable bowel syndrome had not required surgery or intervention in middle age [ Based on CIPO = chronic intestinal pseudoobstruction The following discussion of findings from Approximately 11% of individuals have had a vesicoamniotic shunt placed prenatally [ Chronic bladder functional impairment seen in the majority of individuals with an Prune belly syndrome, characterized by lack of abdominal wall musculature, cryptorchidism in males, and distention of the urinary tract [ Affected individuals can experience episodic improvement of bowel motility, loss of bowel motility over time, or waxing and waning of reduced bowel motility. Affected individuals may undergo frequent abdominal surgeries (perhaps related to malrotation or presumed adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel. Microcolon refers to a small-caliber (but not short) colon in the neonate. The etiology is considered to be lack of use of the colon during fetal development due to proximal functional obstruction. While the caliber of the colon is often noted to be small on contrast enema, no definite radiologic criteria are established. Affected individuals in many families with a dominantly inherited Individuals with a severe outcome are more likely to have a Genotype-phenotype correlations have been identified for the following pathogenic variants (see also All 17/17 probands with missense variants at p.Arg178 had a poor outcome [ Nineteen of 20 (95%) individuals with missense variants at p.Arg178 had microcolon [ To date penetrance of Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) may also be referred to as familial visceral myopathy or Berdon syndrome. The broad term "hollow visceral myopathy" includes phenotypically related disorders caused by pathogenic variants in other genes (e.g., Prune belly sequence may also be referred to as Eagle-Barrett syndrome. To date 90 individuals with molecularly confirmed • One individual (in a multi-generation Finnish family) with an • One individual diagnosed with "spastic colon" and irritable bowel syndrome had not required surgery or intervention in middle age [ • All 17/17 probands with missense variants at p.Arg178 had a poor outcome [ • Nineteen of 20 (95%) individuals with missense variants at p.Arg178 had microcolon [ ## Clinical Description Individuals with The clinical severity can range within a family; mildly affected family members may not be aware of the diagnosis. For example: One individual (in a multi-generation Finnish family) with an One individual diagnosed with "spastic colon" and irritable bowel syndrome had not required surgery or intervention in middle age [ Based on CIPO = chronic intestinal pseudoobstruction The following discussion of findings from Approximately 11% of individuals have had a vesicoamniotic shunt placed prenatally [ Chronic bladder functional impairment seen in the majority of individuals with an Prune belly syndrome, characterized by lack of abdominal wall musculature, cryptorchidism in males, and distention of the urinary tract [ Affected individuals can experience episodic improvement of bowel motility, loss of bowel motility over time, or waxing and waning of reduced bowel motility. Affected individuals may undergo frequent abdominal surgeries (perhaps related to malrotation or presumed adhesions causing mechanical obstruction) resulting in resection of dilated segments of bowel. Microcolon refers to a small-caliber (but not short) colon in the neonate. The etiology is considered to be lack of use of the colon during fetal development due to proximal functional obstruction. While the caliber of the colon is often noted to be small on contrast enema, no definite radiologic criteria are established. Affected individuals in many families with a dominantly inherited Individuals with a severe outcome are more likely to have a • One individual (in a multi-generation Finnish family) with an • One individual diagnosed with "spastic colon" and irritable bowel syndrome had not required surgery or intervention in middle age [ ## Genotype-Phenotype Correlations Genotype-phenotype correlations have been identified for the following pathogenic variants (see also All 17/17 probands with missense variants at p.Arg178 had a poor outcome [ Nineteen of 20 (95%) individuals with missense variants at p.Arg178 had microcolon [ • All 17/17 probands with missense variants at p.Arg178 had a poor outcome [ • Nineteen of 20 (95%) individuals with missense variants at p.Arg178 had microcolon [ ## Penetrance To date penetrance of ## Nomenclature Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) may also be referred to as familial visceral myopathy or Berdon syndrome. The broad term "hollow visceral myopathy" includes phenotypically related disorders caused by pathogenic variants in other genes (e.g., Prune belly sequence may also be referred to as Eagle-Barrett syndrome. ## Prevalence To date 90 individuals with molecularly confirmed ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Approximately 62% (33/53) of individuals with a clinical diagnosis of visceral myopathy have a heterozygous pathogenic Note Inherited Disorders with Gastrointestinal/Genitourinary Visceral Myopathy in the Differential Diagnosis for MMIHS & prune belly sequence MMIHS & MSMDS AD = autosomal dominant; AR = autosomal recessive; CAKUT = congenital anomalies of the kidney and urinary tract; GI = gastrointestinal; GU = genitourinary; MMIHS = megacystis-microcolon-intestinal hypoperistalsis syndrome; MNGIE = mitochondrial neurogastrointestinal encephalopathy; MSMDS = multisystemic smooth muscle dysfunction syndrome; MOI = mode of inheritance; PDA = patent ductus arteriosus; XL = X-linked • MMIHS & prune belly sequence • MMIHS & MSMDS ## Management No clinical practice guidelines for The following recommendations are adapted from the To establish the extent of disease and needs in an individual diagnosed with Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [ Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [ Renal and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma Laboratory evaluation of renal function (e.g., BUN, creatinine, GFR) and electrolytes (potassium, phosphorus, calcium) Bowel imaging: Abdominal x-ray Contrast enema Fluoroscopic upper gastrointestinal series Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. Laboratory assessment of liver enzymes (AST, ALT, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (PT, PTT, INR, albumin) Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption Nutrition evaluation of growth parameters Treatment for When a fetus at risk for Children with Adults with Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [ Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [ TPN when appropriate for malnutrition due to intestinal failure from intestinal dysmotility Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN due to complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [ For those with chronic intestinal pseudoobstruction (CIPO), high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort [ Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period. Surveillance should be individualized using a multidisciplinary approach. Treatment/medications to be avoided or limited include those that diminish bowel and bladder motility. Opioids are known to decrease intestinal dysmotility and should be used with caution [ It is appropriate to clarify the genetic status of relatives at risk as early diagnosis may help prevent unnecessary surgery for manifestations of intestinal obstruction and may allow early evaluation of bladder and renal function, and of the urinary tract for evidence of dilatation. See Among the limited number of mothers with Search • Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [ • Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [ • Renal and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma • Laboratory evaluation of renal function (e.g., BUN, creatinine, GFR) and electrolytes (potassium, phosphorus, calcium) • Bowel imaging: • Abdominal x-ray • Contrast enema • Fluoroscopic upper gastrointestinal series • Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. • Abdominal x-ray • Contrast enema • Fluoroscopic upper gastrointestinal series • Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. • Laboratory assessment of liver enzymes (AST, ALT, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (PT, PTT, INR, albumin) • Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption • Nutrition evaluation of growth parameters • Abdominal x-ray • Contrast enema • Fluoroscopic upper gastrointestinal series • Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. • Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [ • Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [ • TPN when appropriate for malnutrition due to intestinal failure from intestinal dysmotility • Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN due to complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [ • For those with chronic intestinal pseudoobstruction (CIPO), high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort [ • Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [ Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [ Renal and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma Laboratory evaluation of renal function (e.g., BUN, creatinine, GFR) and electrolytes (potassium, phosphorus, calcium) Bowel imaging: Abdominal x-ray Contrast enema Fluoroscopic upper gastrointestinal series Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. Laboratory assessment of liver enzymes (AST, ALT, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (PT, PTT, INR, albumin) Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption Nutrition evaluation of growth parameters • Urodynamic studies to evaluate the degree of bladder dysfunction (e.g., enlarged bladder capacity for age, detrusor acontractility with failure to empty) [ • Voiding cystourethrogram to evaluate for outlet obstruction, vesicoureteral reflux (VUR), and bladder capacity [ • Renal and bladder ultrasound to evaluate for hydronephrosis and renal parenchyma • Laboratory evaluation of renal function (e.g., BUN, creatinine, GFR) and electrolytes (potassium, phosphorus, calcium) • Bowel imaging: • Abdominal x-ray • Contrast enema • Fluoroscopic upper gastrointestinal series • Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. • Abdominal x-ray • Contrast enema • Fluoroscopic upper gastrointestinal series • Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. • Laboratory assessment of liver enzymes (AST, ALT, alkaline phosphatase), cholestasis (total and direct bilirubin), and liver function (PT, PTT, INR, albumin) • Laboratory evaluation of macronutrient (carbohydrates, fat, protein) and micronutrient (vitamins, minerals) deficiencies in the setting of intestinal dysfunction and progressive malabsorption • Nutrition evaluation of growth parameters • Abdominal x-ray • Contrast enema • Fluoroscopic upper gastrointestinal series • Computed tomography examination of the abdomen as indicated to evaluate for a mechanical obstruction. ## Treatment of Manifestations Treatment for When a fetus at risk for Children with Adults with Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [ Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [ TPN when appropriate for malnutrition due to intestinal failure from intestinal dysmotility Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN due to complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [ For those with chronic intestinal pseudoobstruction (CIPO), high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort [ Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period. • Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [ • Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [ • TPN when appropriate for malnutrition due to intestinal failure from intestinal dysmotility • Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN due to complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [ • For those with chronic intestinal pseudoobstruction (CIPO), high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort [ • Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period. ## Fetal Management When a fetus at risk for ## Management of Children and Adults Children with Adults with Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [ Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [ TPN when appropriate for malnutrition due to intestinal failure from intestinal dysmotility Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN due to complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [ For those with chronic intestinal pseudoobstruction (CIPO), high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort [ Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period. • Surgical interventions such as enterostomies (e.g., gastrostomy, jejunostomy) for nutrition administration and proximal bowel decompression [ • Bowel diversion (e.g., ileostomy, colostomy) for distal bowel decompression [ • TPN when appropriate for malnutrition due to intestinal failure from intestinal dysmotility • Multivisceral or isolated intestinal transplantation should be considered for those who continue to have nutritional failure and are unable to tolerate TPN due to complications (e.g., liver dysfunction and cholestasis, lack of adequate central venous access, recurrent central line-associated bloodstream infections) [ • For those with chronic intestinal pseudoobstruction (CIPO), high-fat foods (>30% of total calories) and consumption of lactose and fructose may worsen abdominal bloating and discomfort [ • Surgical procedures associated with general anesthesia can produce a post-surgical ileus which can persist for an extended period. ## Surveillance Surveillance should be individualized using a multidisciplinary approach. ## Agents/Circumstances to Avoid Treatment/medications to be avoided or limited include those that diminish bowel and bladder motility. Opioids are known to decrease intestinal dysmotility and should be used with caution [ ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of relatives at risk as early diagnosis may help prevent unnecessary surgery for manifestations of intestinal obstruction and may allow early evaluation of bladder and renal function, and of the urinary tract for evidence of dilatation. See ## Pregnancy Management Among the limited number of mothers with ## Therapies Under Investigation Search ## Genetic Counseling Apparent autosomal recessive inheritance of The majority of individuals with Some 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, 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 [ * A parent with somatic and germline mosaicism for an An individual 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%. Although penetrance of 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 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 with • Some 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, 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 [ • * 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 [ • * A parent with somatic and germline mosaicism for an • An individual diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • * 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%. • Although penetrance of • 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 Apparent autosomal recessive inheritance of ## Risk to Family Members (Autosomal Dominant Inheritance) The majority of individuals with Some 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, 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 [ * A parent with somatic and germline mosaicism for an An individual 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%. Although penetrance of If the If the parents have not been tested for the • The majority of individuals with • Some 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, 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 [ • * 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 [ • * A parent with somatic and germline mosaicism for an • An individual diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • * 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%. • Although penetrance of • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 ACTG2 Visceral Myopathy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ACTG2 Visceral Myopathy ( Notable Based on Variants listed in the table have been provided by the authors. Poor outcome = mortality and/or multivisceral transplantation ## Molecular Pathogenesis Notable Based on Variants listed in the table have been provided by the authors. Poor outcome = mortality and/or multivisceral transplantation ## Chapter Notes The authors are currently using the latest technology including exome sequencing to understand rare mendelian disorders including disorders of intestinal motility. Pranjali K Bhagwat, MTech (Pharm) (2021-present)Arthur L Beaudet, MD; Baylor College of Medicine (2015-2021)Michael F Wangler, MD (2015-present) 6 May 2021 (bp) Comprehensive update posted live 11 June 2015 (me) Review posted live 15 July 2014 (mw) Original submission • 6 May 2021 (bp) Comprehensive update posted live • 11 June 2015 (me) Review posted live • 15 July 2014 (mw) Original submission ## Author Notes The authors are currently using the latest technology including exome sequencing to understand rare mendelian disorders including disorders of intestinal motility. ## Author History Pranjali K Bhagwat, MTech (Pharm) (2021-present)Arthur L Beaudet, MD; Baylor College of Medicine (2015-2021)Michael F Wangler, MD (2015-present) ## Revision History 6 May 2021 (bp) Comprehensive update posted live 11 June 2015 (me) Review posted live 15 July 2014 (mw) Original submission • 6 May 2021 (bp) Comprehensive update posted live • 11 June 2015 (me) Review posted live • 15 July 2014 (mw) Original submission ## References ## Literature Cited	[ "N Assia Batzir, P Kishor Bhagwat, A Larson, Z Coban Akdemir, M Bagłaj, L Bofferding, KB Bosanko, S Bouassida, B Callewaert, A Cannon, Y Enchautegui Colon, AD Garnica, MH Harr, S Heck, ACE Hurst, SN Jhangiani, B Isidor, RO Littlejohn, P Liu, P Magoulas, H Mar Fan, R Marom, S McLean, MM Nezarati, KM Nugent, MB Petersen, ML Rocha, E Roeder, R Smigiel, I Tully, J Weisfeld-Adams, KO Wells. 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Hum Genet. 2014;133:737-42", "L Tuzovic, S Tang, RS Miller, L Rohena, L Shahmirzadi, K Gonzalez, X Li, CA Leduc, J Guo, A Wilson, A Mills, K Glassberg, H Rotterdam, AR Sepulveda, W Zeng, WK Chung, K Anyane-Yeboa. New insights into the genetics of fetal megacystis: ACTG2 mutations, encoding x03B3;-2 smooth muscle actin in megacystis microcolon intestinal hypoperistalsis syndrome (Berdon syndrome).. Fetal Diagn Ther. 2015;38:296-306", "MF Wangler, C Gonzaga-Jauregui, T Gambin, S Penney, T Moss, A Chopra, FJ Probst, F Xia, Y Yang, S Werlin, I Eglite, L Kornejeva, CA Bacino, D Baldridge, J Neul, EL Lehman, A Larson, J Beuten, DM Muzny, S Jhangiani, RA Gibbs, JR Lupski, A Beaudet. Heterozygous de novo and inherited mutations in the smooth muscle actin (ACTG2) gene underlie megacystis-microcolon-intestinal hypoperistalsis syndrome.. PLoS Genet. 2014;10", "S Weber, S Mir, KP Schlingmann, G Nurnberg, C Becker, PE Kara, N Ozkayin, M Konrad, P Nurnberg, F Schaefer. Gene locus ambiguity in posterior urethral valves/prune-belly syndrome.. Pediatr Nephrol. 2005;20:1036-42", "S Weber, H Thiele, S Mir, MR Toliat, B Sozeri, H Reutter, M Draaken, M Ludwig, J Altmuller, P Frommolt, HM Stuart, P Ranjzad, NA Hanley, R Jennings, WG Newman, DT Wilcox, U Thiel, KP Schlingmann, R Beetz, PF Hoyer, M Konrad, F Schaefer, P Nurnberg, AS Woolf. Muscarinic acetylcholine receptor M3 mutation causes urinary bladder disease and a prune-belly-like syndrome.. Am J Hum Genet. 2011;89:668-74", "KM Wymer, BB Anderson, AA Wilkens, MS Gundeti. Megacystis microcolon intestinal hypoperistalsis syndrome: case series and updated review of the literature with an emphasis on urologic management.. J Pediatr Surg. 2016;51:1565-73" ]	11/6/2015	6/5/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ada	ada	[ "ADA Deficiency", "ADA1 Deficiency", "ADA-Related Immune Deficiency", "Adenosine Deaminase 1 Deficiency", "ADA Deficiency", "ADA1 Deficiency", "ADA-Related Immune Deficiency", "Adenosine Deaminase 1 Deficiency", "Less Severe Delayed/Late-Onset Combined Immunodeficiency (ADA-CID)", "Typical Early-Onset Severe Combined Immunodeficiency (ADA-SCID)", "Benign Partial ADA Deficiency", "Adenosine deaminase", "ADA", "Adenosine Deaminase Deficiency" ]	Adenosine Deaminase Deficiency	Michael Hershfield, Teresa Tarrant	Summary Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The ADA deficiency phenotypic spectrum includes typical early-onset severe combined immunodeficiency ( Newborn screening (NBS) for SCID uses extracts from Guthrie card dried blood spots to measure T-cell receptor excision circle (TREC) DNA by polymerase chain reaction (PCR). Screening specific for ADA deficiency can also be performed by detection of elevated levels of adenosine (Ado) and deoxyadenosine (dAdo) by tandem mass spectrometry (TMS). Both techniques can identify Untreated NBS for SCID does not identify individuals with the The diagnosis of ADA deficiency is established in a proband with suggestive findings either by biochemical testing showing <1% of ADA catalytic activity in red blood cells or in extracts of dried blood spots (valid in untransfused individuals), or by molecular genetic testing identifying biallelic pathogenic variants in Medications to avoid include adenine arabinoside, a substrate for ADA, as an antiviral agent and/or as chemotherapy of malignancies; and pentostatin, a potent ADA inhibitor used to treat some lymphoid malignancies, which would be ineffective in persons with ADA deficiency and would interfere with PEGylated ADA. If prenatal testing has not been performed, an at-risk newborn clinically suspected of SCID should immediately be placed in an appropriate environment to reduce the risk of infection, and the following testing should be performed before administration of a blood transfusion to allow earliest possible diagnosis and initiation of treatment: identification of the ADA deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Adenosine Deaminase Deficiency: Phenotypic Spectrum ADA = adenosine deaminase For other genetic causes of combined immunodeficiency, see For ADA enzyme levels associated with these phenotypes, see Note: Deficiency of adenosine deaminase (ADA, also referred to as adenosine deaminase 1, or ADA1) is caused by pathogenic variants in ## Diagnosis Adenosine deaminase (ADA) deficiency cannot be diagnosed solely on clinical grounds. The Primary Immune Deficiency Treatment Consortium (PIDTC) has established laboratory-based definitions for severe combined immunodeficiency (SCID) [ The two scenarios in which ADA deficiency may be considered are a Currently, SCID newborn screening (NBS) uses a blood spot to measure TRECs to detect T-cell lymphopenia [ Note: NBS for ADA deficiency by TMS, developed in Italy, is now used in several other countries in Europe and Scandinavia, as well as in several states in the US and provinces in Canada; wider use may be anticipated. Newborns with an abnormal NBS result (by either method) This chapter specifically focuses on The safety of the baby must be ensured pending establishment of the diagnosis and treatment. Parents and other care providers for all infants with a positive NBS need to avoid all of the following: Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure. Laboratory findings that support (but are not specific to) the diagnosis of Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T Virtual absence of naïve CD45RA Lymphocyte functional tests Absence of specific antibody responses to vaccines and infectious agents Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. 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. Note: Families with A symptomatic individual may present who had low TRECs on NBS or a positive TMS but did not receive recommended follow-up testing to confirm SCID, or with clinical and laboratory findings suggesting CID in whom NBS was non-diagnostic for SCID or in whom NBS was not performed. Clinical findings that support (but are not specific to) the diagnosis of Infancy (typical early-onset Failure to thrive Absence of lymphoid tissues (tonsils, lymph nodes) Opportunistic infections (viral, fungal, or bacterial) Persistent diarrhea Extensive dermatitis Recurrent pneumonia Childhood (less severe delayed or late-onset Recurrent otitis media Sinusitis Frequent/recurrent upper respiratory infections Chronic pulmonary insufficiency Frequent/recurrent viral infections including warts due to human papillomavirus Allergies or autoimmunity (serum immunoglobulin E level often elevated) Laboratory findings that support the diagnosis of Individuals with delayed or late-onset Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. Neutropenia and myeloid dysplasia have been observed [ In children less than age seven months, radiologic findings can include scapular spurring, scapular squaring, and costochondral cupping [ 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. Note: Families with The diagnosis of ADA deficiency Biochemical testing for ADA deficiency should be performed as soon as possible after a diagnosis of SCID or CID has been established following a positive NBS TREC or TMS screen, particularly when follow-up testing shows T Note: (1) In individuals who have received RBC transfusion(s) prior to biochemical testing, deficient ADA catalytic activity can be demonstrated in extracts of non-erythroid cells (e.g., fibroblasts) because individuals with SCID have insufficient blood mononuclear cells for analysis. However, this approach is now rarely used, as molecular genetic testing has become widely available. (2) Analysis of ADA catalytic activity in plasma is not useful for diagnosis of ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see The molecular diagnosis of ADA deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adenosine Deaminase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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. • Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure. • Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Lymphocyte functional tests • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Infancy (typical early-onset • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Childhood (less severe delayed or late-onset • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Note: (1) In individuals who have received RBC transfusion(s) prior to biochemical testing, deficient ADA catalytic activity can be demonstrated in extracts of non-erythroid cells (e.g., fibroblasts) because individuals with SCID have insufficient blood mononuclear cells for analysis. However, this approach is now rarely used, as molecular genetic testing has become widely available. (2) Analysis of ADA catalytic activity in plasma is not useful for diagnosis of • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see ## Suggestive Findings The two scenarios in which ADA deficiency may be considered are a Currently, SCID newborn screening (NBS) uses a blood spot to measure TRECs to detect T-cell lymphopenia [ Note: NBS for ADA deficiency by TMS, developed in Italy, is now used in several other countries in Europe and Scandinavia, as well as in several states in the US and provinces in Canada; wider use may be anticipated. Newborns with an abnormal NBS result (by either method) This chapter specifically focuses on The safety of the baby must be ensured pending establishment of the diagnosis and treatment. Parents and other care providers for all infants with a positive NBS need to avoid all of the following: Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure. Laboratory findings that support (but are not specific to) the diagnosis of Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T Virtual absence of naïve CD45RA Lymphocyte functional tests Absence of specific antibody responses to vaccines and infectious agents Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. 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. Note: Families with A symptomatic individual may present who had low TRECs on NBS or a positive TMS but did not receive recommended follow-up testing to confirm SCID, or with clinical and laboratory findings suggesting CID in whom NBS was non-diagnostic for SCID or in whom NBS was not performed. Clinical findings that support (but are not specific to) the diagnosis of Infancy (typical early-onset Failure to thrive Absence of lymphoid tissues (tonsils, lymph nodes) Opportunistic infections (viral, fungal, or bacterial) Persistent diarrhea Extensive dermatitis Recurrent pneumonia Childhood (less severe delayed or late-onset Recurrent otitis media Sinusitis Frequent/recurrent upper respiratory infections Chronic pulmonary insufficiency Frequent/recurrent viral infections including warts due to human papillomavirus Allergies or autoimmunity (serum immunoglobulin E level often elevated) Laboratory findings that support the diagnosis of Individuals with delayed or late-onset Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. Neutropenia and myeloid dysplasia have been observed [ In children less than age seven months, radiologic findings can include scapular spurring, scapular squaring, and costochondral cupping [ 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. Note: Families with • Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure. • Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Lymphocyte functional tests • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Infancy (typical early-onset • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Childhood (less severe delayed or late-onset • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ ## Scenario 1: Positive Newborn Screening Result Currently, SCID newborn screening (NBS) uses a blood spot to measure TRECs to detect T-cell lymphopenia [ Note: NBS for ADA deficiency by TMS, developed in Italy, is now used in several other countries in Europe and Scandinavia, as well as in several states in the US and provinces in Canada; wider use may be anticipated. Newborns with an abnormal NBS result (by either method) This chapter specifically focuses on The safety of the baby must be ensured pending establishment of the diagnosis and treatment. Parents and other care providers for all infants with a positive NBS need to avoid all of the following: Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure. Laboratory findings that support (but are not specific to) the diagnosis of Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T Virtual absence of naïve CD45RA Lymphocyte functional tests Absence of specific antibody responses to vaccines and infectious agents Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. 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. Note: Families with • Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure. • Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Lymphocyte functional tests • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. ## The safety of the baby must be ensured pending establishment of the diagnosis and treatment. Parents and other care providers for all infants with a positive NBS need to avoid all of the following: Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation as they increase the risk for fungal exposure. • Breast-feeding and breast milk, until maternal CMV status is established by CMV serologies. CMV is a chronic infection and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT or gene therapy • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation as they increase the risk for fungal exposure. ## Laboratory findings that support (but are not specific to) the diagnosis of Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T Virtual absence of naïve CD45RA Lymphocyte functional tests Absence of specific antibody responses to vaccines and infectious agents Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Lymphocyte subsets identified by flow cytometric analysis of confirmed autologous T cells [ • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Lymphocyte functional tests • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. • Markedly reduced numbers of T, B, and NK cell lymphocyte subsets compared to age-matched normal controls (designated T • Virtual absence of naïve CD45RA • Absence of specific antibody responses to vaccines and infectious agents • Absence of in vitro T cell responses to mitogens (i.e., <10% of normal proliferation of lymphocytes to the mitogen phytohemagglutinin [PHA] having excluded maternal engraftment) and/or anti-CD3 antibodies. ## 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. Note: Families with ## Scenario 2: Symptomatic Individual A symptomatic individual may present who had low TRECs on NBS or a positive TMS but did not receive recommended follow-up testing to confirm SCID, or with clinical and laboratory findings suggesting CID in whom NBS was non-diagnostic for SCID or in whom NBS was not performed. Clinical findings that support (but are not specific to) the diagnosis of Infancy (typical early-onset Failure to thrive Absence of lymphoid tissues (tonsils, lymph nodes) Opportunistic infections (viral, fungal, or bacterial) Persistent diarrhea Extensive dermatitis Recurrent pneumonia Childhood (less severe delayed or late-onset Recurrent otitis media Sinusitis Frequent/recurrent upper respiratory infections Chronic pulmonary insufficiency Frequent/recurrent viral infections including warts due to human papillomavirus Allergies or autoimmunity (serum immunoglobulin E level often elevated) Laboratory findings that support the diagnosis of Individuals with delayed or late-onset Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. Neutropenia and myeloid dysplasia have been observed [ In children less than age seven months, radiologic findings can include scapular spurring, scapular squaring, and costochondral cupping [ 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. Note: Families with • Infancy (typical early-onset • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Childhood (less severe delayed or late-onset • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ ## Clinical findings that support (but are not specific to) the diagnosis of Infancy (typical early-onset Failure to thrive Absence of lymphoid tissues (tonsils, lymph nodes) Opportunistic infections (viral, fungal, or bacterial) Persistent diarrhea Extensive dermatitis Recurrent pneumonia Childhood (less severe delayed or late-onset Recurrent otitis media Sinusitis Frequent/recurrent upper respiratory infections Chronic pulmonary insufficiency Frequent/recurrent viral infections including warts due to human papillomavirus Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Infancy (typical early-onset • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Childhood (less severe delayed or late-onset • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) • Failure to thrive • Absence of lymphoid tissues (tonsils, lymph nodes) • Opportunistic infections (viral, fungal, or bacterial) • Persistent diarrhea • Extensive dermatitis • Recurrent pneumonia • Recurrent otitis media • Sinusitis • Frequent/recurrent upper respiratory infections • Chronic pulmonary insufficiency • Frequent/recurrent viral infections including warts due to human papillomavirus • Allergies or autoimmunity (serum immunoglobulin E level often elevated) ## Laboratory findings that support the diagnosis of Individuals with delayed or late-onset Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. Neutropenia and myeloid dysplasia have been observed [ • • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ • Individuals with delayed or late-onset • Reduced levels of a B-cell lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from dried blood spots of individuals with delayed or late-onset • Lymphopenia: the total blood lymphocyte count is usually 5,000/µL), a finding present at birth, which at that time may not be recognized as abnormal. • All major lymphoid lineages (T, B, and NK cells) are depleted as demonstrated by flow cytometry. • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent. • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed. However, individuals with a delayed or late-onset phenotype may have elevated serum immunoglobulin E levels. • Neutropenia and myeloid dysplasia have been observed [ ## In children less than age seven months, radiologic findings can include scapular spurring, scapular squaring, and costochondral cupping [ ## 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. Note: Families with ## Establishing the Diagnosis The diagnosis of ADA deficiency Biochemical testing for ADA deficiency should be performed as soon as possible after a diagnosis of SCID or CID has been established following a positive NBS TREC or TMS screen, particularly when follow-up testing shows T Note: (1) In individuals who have received RBC transfusion(s) prior to biochemical testing, deficient ADA catalytic activity can be demonstrated in extracts of non-erythroid cells (e.g., fibroblasts) because individuals with SCID have insufficient blood mononuclear cells for analysis. However, this approach is now rarely used, as molecular genetic testing has become widely available. (2) Analysis of ADA catalytic activity in plasma is not useful for diagnosis of ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see The molecular diagnosis of ADA deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adenosine Deaminase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Note: (1) In individuals who have received RBC transfusion(s) prior to biochemical testing, deficient ADA catalytic activity can be demonstrated in extracts of non-erythroid cells (e.g., fibroblasts) because individuals with SCID have insufficient blood mononuclear cells for analysis. However, this approach is now rarely used, as molecular genetic testing has become widely available. (2) Analysis of ADA catalytic activity in plasma is not useful for diagnosis of • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see ## Biochemical Testing Biochemical testing for ADA deficiency should be performed as soon as possible after a diagnosis of SCID or CID has been established following a positive NBS TREC or TMS screen, particularly when follow-up testing shows T Note: (1) In individuals who have received RBC transfusion(s) prior to biochemical testing, deficient ADA catalytic activity can be demonstrated in extracts of non-erythroid cells (e.g., fibroblasts) because individuals with SCID have insufficient blood mononuclear cells for analysis. However, this approach is now rarely used, as molecular genetic testing has become widely available. (2) Analysis of ADA catalytic activity in plasma is not useful for diagnosis of ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see • Note: (1) In individuals who have received RBC transfusion(s) prior to biochemical testing, deficient ADA catalytic activity can be demonstrated in extracts of non-erythroid cells (e.g., fibroblasts) because individuals with SCID have insufficient blood mononuclear cells for analysis. However, this approach is now rarely used, as molecular genetic testing has become widely available. (2) Analysis of ADA catalytic activity in plasma is not useful for diagnosis of • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see • ADA catalytic activity in plasma is much lower than that in cells, even in healthy individuals; • Depending on the assay conditions, most ADA catalytic activity in plasma is due to the secreted enzyme ADA2, encoded by • Levels of dAXP >0.1 µmol/mL in packed RBCs (or >1%-2% of total adenine nucleotides) is abnormal. • Note: (1) In individuals with clinical findings of SCID or CID who have recently been transfused, any elevation of dAXP in RBCs strongly suggests ADA deficiency. (2) Analysis of dATP or dAXP in RBCs is presently performed only by specialty laboratories, including the authors' CLIA certified laboratory at Duke University (see ## Molecular Genetic Testing The molecular diagnosis of ADA deficiency Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adenosine Deaminase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 ## For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adenosine Deaminase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 Adenosine deaminase (ADA) deficiency (also referred to as adenosine deaminase 1 deficiency, or ADA1 deficiency) is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function [ The phenotypic spectrum of ADA deficiency includes typical early-onset severe combined immunodeficiency ( The clinical findings in infants with typical early-onset Persistent diarrhea, extensive dermatitis, recurrent pneumonia, and other life-threatening illnesses caused by opportunistic infections occur frequently. As a result, poor weight gain and linear growth are common. Noninfectious lung disease, frequently associated with alveolar proteinosis, appears to occur more frequently in individuals with Physical findings include growth failure and the absence of lymphoid tissues (tonsils, lymph nodes). Thymus shadow is absent on radiographs. The characteristic radiographic changes of anterior rib cupping, scapular spurring, and other skeletal abnormalities that are present at the time of diagnosis in about 50% of individuals with In addition to marked depletion of T, B, and NK cell lymphocytes, some individuals with Approximately 15%-20% of children with ADA deficiency have a "delayed" onset of clinical manifestations, usually diagnosed between ages one and ten years. Rarely, individuals with Infections in While individuals with Screening of populations and families of probands with The protein encoded by In the era of newborn screening based on detection of T-cell receptor excision circles (TRECs) / kappa-deleting recombination excision circles (KRECs) to identify lymphopenia and, increasingly, tandem mass spectrometry (TMS) to detect elevated levels of ADA substrates, ADA deficiency is often identified in asymptomatic infants. Given the broad clinical spectrum of ADA deficiency, determining the diagnosis, prognosis, and need for immediate treatment are challenges for physicians who may have limited experience with ADA deficiency. In this situation, useful guidance can be provided by understanding the correlation between The relationship between the Group I. <0.05% of normal Group II. 0.1%-0.2% of normal Group III. 0.3%-0.6% of normal Group IV. ~2%-28% of normal This ranking system was then applied to 52 clinically diverse individuals with 43 genotypes comprising 42 different Individuals with Individuals with Healthy individuals with benign partial ADA deficiency were compound heterozygotes with at least one variant from Group IV. * In individuals with compound heterozygosity for two different An inverse correlation existed between expressed ADA catalytic activity in Deoxyadenosine Nucleotides (dAXP) Levels by Phenotype CID = combined immunodeficiency; dAXP = deoxyadenosine nucleotides; RBC = red blood cell; SCID = severe combined immunodeficiency In untreated individuals Several individuals with ADA deficiency have been reported in whom the relationship of genotype to phenotype was modulated by mosaicism for reversion of ADA deficiency is estimated to occur in 1:500,000 live births [ All racial and ethnic groups are affected. Prevalence is higher in certain populations (e.g., Amish, Canadian Mennonite, Inuit, and Somali) due to founder pathogenic variants (see • Group I. <0.05% of normal • Group II. 0.1%-0.2% of normal • Group III. 0.3%-0.6% of normal • Group IV. ~2%-28% of normal • Group I. <0.05% of normal • Group II. 0.1%-0.2% of normal • Group III. 0.3%-0.6% of normal • Group IV. ~2%-28% of normal • Group I. <0.05% of normal • Group II. 0.1%-0.2% of normal • Group III. 0.3%-0.6% of normal • Group IV. ~2%-28% of normal • Individuals with • Individuals with • Healthy individuals with benign partial ADA deficiency were compound heterozygotes with at least one variant from Group IV. ## Clinical Description Adenosine deaminase (ADA) deficiency (also referred to as adenosine deaminase 1 deficiency, or ADA1 deficiency) is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function [ The phenotypic spectrum of ADA deficiency includes typical early-onset severe combined immunodeficiency ( The clinical findings in infants with typical early-onset Persistent diarrhea, extensive dermatitis, recurrent pneumonia, and other life-threatening illnesses caused by opportunistic infections occur frequently. As a result, poor weight gain and linear growth are common. Noninfectious lung disease, frequently associated with alveolar proteinosis, appears to occur more frequently in individuals with Physical findings include growth failure and the absence of lymphoid tissues (tonsils, lymph nodes). Thymus shadow is absent on radiographs. The characteristic radiographic changes of anterior rib cupping, scapular spurring, and other skeletal abnormalities that are present at the time of diagnosis in about 50% of individuals with In addition to marked depletion of T, B, and NK cell lymphocytes, some individuals with Approximately 15%-20% of children with ADA deficiency have a "delayed" onset of clinical manifestations, usually diagnosed between ages one and ten years. Rarely, individuals with Infections in While individuals with Screening of populations and families of probands with ## Typical Early-Onset Severe Combined Immunodeficiency ( The clinical findings in infants with typical early-onset Persistent diarrhea, extensive dermatitis, recurrent pneumonia, and other life-threatening illnesses caused by opportunistic infections occur frequently. As a result, poor weight gain and linear growth are common. Noninfectious lung disease, frequently associated with alveolar proteinosis, appears to occur more frequently in individuals with Physical findings include growth failure and the absence of lymphoid tissues (tonsils, lymph nodes). Thymus shadow is absent on radiographs. The characteristic radiographic changes of anterior rib cupping, scapular spurring, and other skeletal abnormalities that are present at the time of diagnosis in about 50% of individuals with In addition to marked depletion of T, B, and NK cell lymphocytes, some individuals with ## Delayed or Late-Onset Combined Immunodeficiency ( Approximately 15%-20% of children with ADA deficiency have a "delayed" onset of clinical manifestations, usually diagnosed between ages one and ten years. Rarely, individuals with Infections in While individuals with ## Benign Partial ADA Deficiency Screening of populations and families of probands with ## Nomenclature The protein encoded by ## Genotype-Phenotype Correlations In the era of newborn screening based on detection of T-cell receptor excision circles (TRECs) / kappa-deleting recombination excision circles (KRECs) to identify lymphopenia and, increasingly, tandem mass spectrometry (TMS) to detect elevated levels of ADA substrates, ADA deficiency is often identified in asymptomatic infants. Given the broad clinical spectrum of ADA deficiency, determining the diagnosis, prognosis, and need for immediate treatment are challenges for physicians who may have limited experience with ADA deficiency. In this situation, useful guidance can be provided by understanding the correlation between The relationship between the Group I. <0.05% of normal Group II. 0.1%-0.2% of normal Group III. 0.3%-0.6% of normal Group IV. ~2%-28% of normal This ranking system was then applied to 52 clinically diverse individuals with 43 genotypes comprising 42 different Individuals with Individuals with Healthy individuals with benign partial ADA deficiency were compound heterozygotes with at least one variant from Group IV. * In individuals with compound heterozygosity for two different An inverse correlation existed between expressed ADA catalytic activity in Deoxyadenosine Nucleotides (dAXP) Levels by Phenotype CID = combined immunodeficiency; dAXP = deoxyadenosine nucleotides; RBC = red blood cell; SCID = severe combined immunodeficiency In untreated individuals Several individuals with ADA deficiency have been reported in whom the relationship of genotype to phenotype was modulated by mosaicism for reversion of • Group I. <0.05% of normal • Group II. 0.1%-0.2% of normal • Group III. 0.3%-0.6% of normal • Group IV. ~2%-28% of normal • Group I. <0.05% of normal • Group II. 0.1%-0.2% of normal • Group III. 0.3%-0.6% of normal • Group IV. ~2%-28% of normal • Group I. <0.05% of normal • Group II. 0.1%-0.2% of normal • Group III. 0.3%-0.6% of normal • Group IV. ~2%-28% of normal • Individuals with • Individuals with • Healthy individuals with benign partial ADA deficiency were compound heterozygotes with at least one variant from Group IV. ## Prevalence ADA deficiency is estimated to occur in 1:500,000 live births [ All racial and ethnic groups are affected. Prevalence is higher in certain populations (e.g., Amish, Canadian Mennonite, Inuit, and Somali) due to founder pathogenic variants (see ## Genetically Related (Allelic) Disorders No phenotypes other than those described in this ## Differential Diagnosis Note: Other genes (not included in Typical Severe Combined Immunodeficiency (SCID): Genetic Causes Based on the International Union of Immunological Societies expert committee for primary immunodeficiency ADA = adenosine deaminase; AR = autosomal recessive; CID = combined immune deficiency; MOI = mode of inheritance; NBS = newborn screening; XL = X-linked For immunophenotype information, see Omenn syndrome is a clinical phenotype caused by immune dysregulation and characterized by generalized erythroderma, hepatosplenomegaly, lymphadenopathy, elevated serum immunoglobulin E, and/or increased eosinophils. The immunophenotype is CD3 Less severe delayed or late-onset PNP deficiency may be missed by NBS. PNP deficiency is detected by TMS [ Increasingly detected with newborn screening [ ## Management Consensus recommendations for managing severe combined immunodeficiency (SCID) due to adenosine deaminase (ADA) deficiency have been published [ To establish the extent of disease and needs in an individual diagnosed with ADA deficiency, the following evaluations are recommended, some of which may have been performed as part of the diagnostic evaluation. The frequency and timing of testing may vary by the treating practitioner and the individual's clinical presentation. Consultation with a clinical immunologist with expertise in the diagnosis of SCID, genetic causes of SCID, and SCID treatment protocols Identification of specific disease-causing viral, fungal, or bacterial organisms (both normal pathogens and opportunistic agents) Complete blood count with differential Flow cytometry to quantify lymphocyte subsets (T Assessment of humoral immune function by measuring serum immunoglobulins and the titer of specific antibodies related to infections and immunizations Evaluation of cellular immune function by in vitro response of blood mononuclear cells to mitogens and antigens Liver function testing to detect hepatitis Auditory testing for sensorineural hearing loss Skeletal radiographs to assess for characteristic bone abnormalities Measurement of total deoxyadenosine nucleotide (dAXP) levels in red blood cells to evaluate metabolic severity (see 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 ADA deficiency in order to facilitate medical and personal decision making Assessment of need for community or Symptomatic treatment includes: Ensuring the safety of the infant/child (see Treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against The aim of targeted therapies is to restore a functional immune system, which is essential to preventing the life-threatening manifestations of Targeted Therapy Options to Restore Immune Function Prevent opportunistic infections in asymptomatic individuals; Stabilize & improve clinical status of persons w/serious infections or other disease manifestations. Lack of an appropriate matched donor Graft-vs-host disease Graft failure Not all affected persons are suitable candidates. Limited availability Different viral vectors have had varied clinical outcomes, incl risk of malignant transformation & transfection efficiency Not all affected persons are suitable candidates. Between 1990 and 2019, ERT for The US clinical trial that supported FDA approval of Revcovi Prior to initiation of ERT, baseline levels of ADA (i.e., ADA1) catalytic activity and total deoxyadenosine nucleotides (dAXP) in red blood cells should be determined. (Note: Prior to replacement therapy with PEGylated ADA, ADA catalytic activity in plasma is negligible in individuals with The starting dose of Revcovi Biochemical monitoring of ERT, beginning about two weeks after the first dose of Revcovi It is recommended that ERT be continued for a minimum of 12 to 24 weeks until immune reconstitution is achieved. If lymphocyte counts and in vitro function are satisfactory and clinical status is stable, the dose of Revcovi In addition to permitting immune reconstitution, ERT has been associated with resolution of hepatocellular abnormalities, pulmonary alveolar proteinosis, and skeletal dysplasia; however, to date this has not been studied systematically. Additionally, in some individuals the neurologic/behavioral abnormalities associated with ADA deficiency have improved; however, it is uncertain if ERT can reverse or prevent these complications. ERT should be provided continuously until an affected individual is able to undergo definitive therapy with HSCT or HSC-GT, ideally within two years of diagnosis. Of note, the optimal time to discontinue ERT before HSCT or HSC-GT has not been systematically studied; however, in recent years, ERT has been discontinued at the time of HSCT or up to a month after HSCT or HSC-GT. Between 1990 and 2019, when Revcovi Once the diagnosis of HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. Pre-transplant cytoreductive "conditioning" of the individual with Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. Note: Universal agreement regarding the best methods for performing partially mismatched HSCT/HSC-GT does not exist [ Occasional monitoring of red blood cell ADA activity and dAXP levels may also be performed in individuals who have discontinued ERT to undergo HSCT or HSC-GT. This biochemical monitoring is not a substitute for evaluation of parameters of immune function. But when the results of biochemical monitoring are followed serially and compared with values prior to transplant or gene therapy, this information may provide an indication of the persistence of engraftment of donor or gene-corrected cells. Biochemical monitoring is usually initiated about six months after the transplant or gene therapy and repeated at one year, and yearly or less frequently thereafter, depending on clinical circumstances. Approximately 3%-5% of individuals receiving ERT with Adagen As Revcovi Breastfeeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection, and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation, as they increase the risk for fungal exposure See Looking at data on HSC-GT using either a gammaretroviral vector (see More than 100 individuals with Most of these individuals were treated with ERT for three to six months prior to HSC-GT to achieve adequate metabolic detoxification. Busulfan pre-conditioning has improved clinical outcomes [ 10%-20% of individuals receiving HSC-GT have restarted ERT or received a subsequent HSCT or HSC-GT; the other 80%-90% have normal lymphocyte subsets and are able to discontinue intravenous immunoglobulin [ In contrast to the experience with gammaretroviral gene therapy for Promising results from other lentiviral vector-based studies include: Several studies ( Lentiviral vectors are reported to have more neutral insertional sites with less risk of oncogenesis, shorter transduction time, and higher viral titers [ Search • Consultation with a clinical immunologist with expertise in the diagnosis of SCID, genetic causes of SCID, and SCID treatment protocols • Identification of specific disease-causing viral, fungal, or bacterial organisms (both normal pathogens and opportunistic agents) • Complete blood count with differential • Flow cytometry to quantify lymphocyte subsets (T • Assessment of humoral immune function by measuring serum immunoglobulins and the titer of specific antibodies related to infections and immunizations • Evaluation of cellular immune function by in vitro response of blood mononuclear cells to mitogens and antigens • Liver function testing to detect hepatitis • Auditory testing for sensorineural hearing loss • Skeletal radiographs to assess for characteristic bone abnormalities • Measurement of total deoxyadenosine nucleotide (dAXP) levels in red blood cells to evaluate metabolic severity (see • 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 ADA deficiency in order to facilitate medical and personal decision making • Assessment of need for community or • Ensuring the safety of the infant/child (see • Treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against • Prevent opportunistic infections in asymptomatic individuals; • Stabilize & improve clinical status of persons w/serious infections or other disease manifestations. • Lack of an appropriate matched donor • Graft-vs-host disease • Graft failure • Not all affected persons are suitable candidates. • Limited availability • Different viral vectors have had varied clinical outcomes, incl risk of malignant transformation & transfection efficiency • Not all affected persons are suitable candidates. • Once the diagnosis of • HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. • Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. • The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. • Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. • Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. • Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. • Pre-transplant cytoreductive "conditioning" of the individual with • Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ • Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. • Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. • Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. • Occasional monitoring of red blood cell ADA activity and dAXP levels may also be performed in individuals who have discontinued ERT to undergo HSCT or HSC-GT. This biochemical monitoring is not a substitute for evaluation of parameters of immune function. But when the results of biochemical monitoring are followed serially and compared with values prior to transplant or gene therapy, this information may provide an indication of the persistence of engraftment of donor or gene-corrected cells. Biochemical monitoring is usually initiated about six months after the transplant or gene therapy and repeated at one year, and yearly or less frequently thereafter, depending on clinical circumstances. • Approximately 3%-5% of individuals receiving ERT with Adagen • As Revcovi • Breastfeeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection, and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation, as they increase the risk for fungal exposure • More than 100 individuals with • Most of these individuals were treated with ERT for three to six months prior to HSC-GT to achieve adequate metabolic detoxification. • Busulfan pre-conditioning has improved clinical outcomes [ • 10%-20% of individuals receiving HSC-GT have restarted ERT or received a subsequent HSCT or HSC-GT; the other 80%-90% have normal lymphocyte subsets and are able to discontinue intravenous immunoglobulin [ • In contrast to the experience with gammaretroviral gene therapy for • Several studies ( • Lentiviral vectors are reported to have more neutral insertional sites with less risk of oncogenesis, shorter transduction time, and higher viral titers [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ADA deficiency, the following evaluations are recommended, some of which may have been performed as part of the diagnostic evaluation. The frequency and timing of testing may vary by the treating practitioner and the individual's clinical presentation. Consultation with a clinical immunologist with expertise in the diagnosis of SCID, genetic causes of SCID, and SCID treatment protocols Identification of specific disease-causing viral, fungal, or bacterial organisms (both normal pathogens and opportunistic agents) Complete blood count with differential Flow cytometry to quantify lymphocyte subsets (T Assessment of humoral immune function by measuring serum immunoglobulins and the titer of specific antibodies related to infections and immunizations Evaluation of cellular immune function by in vitro response of blood mononuclear cells to mitogens and antigens Liver function testing to detect hepatitis Auditory testing for sensorineural hearing loss Skeletal radiographs to assess for characteristic bone abnormalities Measurement of total deoxyadenosine nucleotide (dAXP) levels in red blood cells to evaluate metabolic severity (see 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 ADA deficiency in order to facilitate medical and personal decision making Assessment of need for community or • Consultation with a clinical immunologist with expertise in the diagnosis of SCID, genetic causes of SCID, and SCID treatment protocols • Identification of specific disease-causing viral, fungal, or bacterial organisms (both normal pathogens and opportunistic agents) • Complete blood count with differential • Flow cytometry to quantify lymphocyte subsets (T • Assessment of humoral immune function by measuring serum immunoglobulins and the titer of specific antibodies related to infections and immunizations • Evaluation of cellular immune function by in vitro response of blood mononuclear cells to mitogens and antigens • Liver function testing to detect hepatitis • Auditory testing for sensorineural hearing loss • Skeletal radiographs to assess for characteristic bone abnormalities • Measurement of total deoxyadenosine nucleotide (dAXP) levels in red blood cells to evaluate metabolic severity (see • 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 ADA deficiency in order to facilitate medical and personal decision making • Assessment of need for community or ## Treatment of Manifestations Symptomatic treatment includes: Ensuring the safety of the infant/child (see Treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against The aim of targeted therapies is to restore a functional immune system, which is essential to preventing the life-threatening manifestations of Targeted Therapy Options to Restore Immune Function Prevent opportunistic infections in asymptomatic individuals; Stabilize & improve clinical status of persons w/serious infections or other disease manifestations. Lack of an appropriate matched donor Graft-vs-host disease Graft failure Not all affected persons are suitable candidates. Limited availability Different viral vectors have had varied clinical outcomes, incl risk of malignant transformation & transfection efficiency Not all affected persons are suitable candidates. Between 1990 and 2019, ERT for The US clinical trial that supported FDA approval of Revcovi Prior to initiation of ERT, baseline levels of ADA (i.e., ADA1) catalytic activity and total deoxyadenosine nucleotides (dAXP) in red blood cells should be determined. (Note: Prior to replacement therapy with PEGylated ADA, ADA catalytic activity in plasma is negligible in individuals with The starting dose of Revcovi Biochemical monitoring of ERT, beginning about two weeks after the first dose of Revcovi It is recommended that ERT be continued for a minimum of 12 to 24 weeks until immune reconstitution is achieved. If lymphocyte counts and in vitro function are satisfactory and clinical status is stable, the dose of Revcovi In addition to permitting immune reconstitution, ERT has been associated with resolution of hepatocellular abnormalities, pulmonary alveolar proteinosis, and skeletal dysplasia; however, to date this has not been studied systematically. Additionally, in some individuals the neurologic/behavioral abnormalities associated with ADA deficiency have improved; however, it is uncertain if ERT can reverse or prevent these complications. ERT should be provided continuously until an affected individual is able to undergo definitive therapy with HSCT or HSC-GT, ideally within two years of diagnosis. Of note, the optimal time to discontinue ERT before HSCT or HSC-GT has not been systematically studied; however, in recent years, ERT has been discontinued at the time of HSCT or up to a month after HSCT or HSC-GT. Between 1990 and 2019, when Revcovi Once the diagnosis of HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. Pre-transplant cytoreductive "conditioning" of the individual with Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. Note: Universal agreement regarding the best methods for performing partially mismatched HSCT/HSC-GT does not exist [ • Ensuring the safety of the infant/child (see • Treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against • Prevent opportunistic infections in asymptomatic individuals; • Stabilize & improve clinical status of persons w/serious infections or other disease manifestations. • Lack of an appropriate matched donor • Graft-vs-host disease • Graft failure • Not all affected persons are suitable candidates. • Limited availability • Different viral vectors have had varied clinical outcomes, incl risk of malignant transformation & transfection efficiency • Not all affected persons are suitable candidates. • Once the diagnosis of • HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. • Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. • The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. • Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. • Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. • Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. • Pre-transplant cytoreductive "conditioning" of the individual with • Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ • Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. • Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. • Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. ## Symptomatic Treatment Symptomatic treatment includes: Ensuring the safety of the infant/child (see Treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against • Ensuring the safety of the infant/child (see • Treatment of infections and use of immunoglobulin infusions and antibiotics, particularly prophylaxis against ## Targeted Therapies The aim of targeted therapies is to restore a functional immune system, which is essential to preventing the life-threatening manifestations of Targeted Therapy Options to Restore Immune Function Prevent opportunistic infections in asymptomatic individuals; Stabilize & improve clinical status of persons w/serious infections or other disease manifestations. Lack of an appropriate matched donor Graft-vs-host disease Graft failure Not all affected persons are suitable candidates. Limited availability Different viral vectors have had varied clinical outcomes, incl risk of malignant transformation & transfection efficiency Not all affected persons are suitable candidates. Between 1990 and 2019, ERT for The US clinical trial that supported FDA approval of Revcovi Prior to initiation of ERT, baseline levels of ADA (i.e., ADA1) catalytic activity and total deoxyadenosine nucleotides (dAXP) in red blood cells should be determined. (Note: Prior to replacement therapy with PEGylated ADA, ADA catalytic activity in plasma is negligible in individuals with The starting dose of Revcovi Biochemical monitoring of ERT, beginning about two weeks after the first dose of Revcovi It is recommended that ERT be continued for a minimum of 12 to 24 weeks until immune reconstitution is achieved. If lymphocyte counts and in vitro function are satisfactory and clinical status is stable, the dose of Revcovi In addition to permitting immune reconstitution, ERT has been associated with resolution of hepatocellular abnormalities, pulmonary alveolar proteinosis, and skeletal dysplasia; however, to date this has not been studied systematically. Additionally, in some individuals the neurologic/behavioral abnormalities associated with ADA deficiency have improved; however, it is uncertain if ERT can reverse or prevent these complications. ERT should be provided continuously until an affected individual is able to undergo definitive therapy with HSCT or HSC-GT, ideally within two years of diagnosis. Of note, the optimal time to discontinue ERT before HSCT or HSC-GT has not been systematically studied; however, in recent years, ERT has been discontinued at the time of HSCT or up to a month after HSCT or HSC-GT. Between 1990 and 2019, when Revcovi Once the diagnosis of HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. Pre-transplant cytoreductive "conditioning" of the individual with Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. Note: Universal agreement regarding the best methods for performing partially mismatched HSCT/HSC-GT does not exist [ • Prevent opportunistic infections in asymptomatic individuals; • Stabilize & improve clinical status of persons w/serious infections or other disease manifestations. • Lack of an appropriate matched donor • Graft-vs-host disease • Graft failure • Not all affected persons are suitable candidates. • Limited availability • Different viral vectors have had varied clinical outcomes, incl risk of malignant transformation & transfection efficiency • Not all affected persons are suitable candidates. • Once the diagnosis of • HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. • Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. • The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. • Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. • Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. • Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. • Pre-transplant cytoreductive "conditioning" of the individual with • Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ • Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. • Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. • Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. ## Between 1990 and 2019, ERT for The US clinical trial that supported FDA approval of Revcovi Prior to initiation of ERT, baseline levels of ADA (i.e., ADA1) catalytic activity and total deoxyadenosine nucleotides (dAXP) in red blood cells should be determined. (Note: Prior to replacement therapy with PEGylated ADA, ADA catalytic activity in plasma is negligible in individuals with The starting dose of Revcovi Biochemical monitoring of ERT, beginning about two weeks after the first dose of Revcovi It is recommended that ERT be continued for a minimum of 12 to 24 weeks until immune reconstitution is achieved. If lymphocyte counts and in vitro function are satisfactory and clinical status is stable, the dose of Revcovi In addition to permitting immune reconstitution, ERT has been associated with resolution of hepatocellular abnormalities, pulmonary alveolar proteinosis, and skeletal dysplasia; however, to date this has not been studied systematically. Additionally, in some individuals the neurologic/behavioral abnormalities associated with ADA deficiency have improved; however, it is uncertain if ERT can reverse or prevent these complications. ERT should be provided continuously until an affected individual is able to undergo definitive therapy with HSCT or HSC-GT, ideally within two years of diagnosis. Of note, the optimal time to discontinue ERT before HSCT or HSC-GT has not been systematically studied; however, in recent years, ERT has been discontinued at the time of HSCT or up to a month after HSCT or HSC-GT. Between 1990 and 2019, when Revcovi ## Once the diagnosis of HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. Pre-transplant cytoreductive "conditioning" of the individual with Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. Note: Universal agreement regarding the best methods for performing partially mismatched HSCT/HSC-GT does not exist [ • Once the diagnosis of • HSCT can be performed without cytoreductive conditioning of the affected individual and without depletion of donor T cells. • Results vary among transplant centers, but the procedure is curative in 70% or more of affected individuals. • The main risks are graft-vs-host disease and delayed or incomplete recovery of humoral immune function that requires continued immunoglobulin replacement therapy. • Among alternative donors, HLA-matched unrelated donors historically have provided better outcomes than haploidentical HSCT. • Adult bone marrow or peripheral blood stem cells are preferred over umbilical cord blood. • Donor-derived T cells are depleted to minimize the risk of graft-vs-host disease. • Pre-transplant cytoreductive "conditioning" of the individual with • Note: Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [ • Following a T cell-depleted transplant, return of functional T cells requires three to four months. B cell reconstitution is delayed longer or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. • Sequence-based HLA typing, improved methods for graft engineering, and post-transplant cyclophosphamide for depletion of alloreactive donor T cells may improve outcomes. • Graft failures may occur, resulting in restarting ERT while a second allogeneic HSCT or HSC-GT are being considered. ## ## Surveillance Occasional monitoring of red blood cell ADA activity and dAXP levels may also be performed in individuals who have discontinued ERT to undergo HSCT or HSC-GT. This biochemical monitoring is not a substitute for evaluation of parameters of immune function. But when the results of biochemical monitoring are followed serially and compared with values prior to transplant or gene therapy, this information may provide an indication of the persistence of engraftment of donor or gene-corrected cells. Biochemical monitoring is usually initiated about six months after the transplant or gene therapy and repeated at one year, and yearly or less frequently thereafter, depending on clinical circumstances. Approximately 3%-5% of individuals receiving ERT with Adagen As Revcovi • Occasional monitoring of red blood cell ADA activity and dAXP levels may also be performed in individuals who have discontinued ERT to undergo HSCT or HSC-GT. This biochemical monitoring is not a substitute for evaluation of parameters of immune function. But when the results of biochemical monitoring are followed serially and compared with values prior to transplant or gene therapy, this information may provide an indication of the persistence of engraftment of donor or gene-corrected cells. Biochemical monitoring is usually initiated about six months after the transplant or gene therapy and repeated at one year, and yearly or less frequently thereafter, depending on clinical circumstances. • Approximately 3%-5% of individuals receiving ERT with Adagen • As Revcovi ## Agents/Circumstances to Avoid Breastfeeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection, and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant Crowded enclosed spaces due to risk of infectious exposure Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT Transfusion of non-irradiated blood products [ Areas of construction or soil manipulation, as they increase the risk for fungal exposure • Breastfeeding and breast milk, until maternal cytomegalovirus (CMV) status is established by CMV serologies. CMV is a chronic infection, and intermittent viral shedding in various bodily fluids occurs unpredictably. If maternal CMV serology is negative, breast milk may be considered safe for feeding. • Note: Use of pasteurized breast milk while the infant is being prepared for HSCT remains controversial given the severe negative effects of CMV infection in the outcome of HSCT. • Exposure to young children, sick contacts, or individuals with cold sores in order to decrease the risk of transmission of disease to the infant • Crowded enclosed spaces due to risk of infectious exposure • Live viral vaccines for the infant as well as household contacts until after immunocompetence is restored following HSCT • Transfusion of non-irradiated blood products [ • Areas of construction or soil manipulation, as they increase the risk for fungal exposure ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Looking at data on HSC-GT using either a gammaretroviral vector (see More than 100 individuals with Most of these individuals were treated with ERT for three to six months prior to HSC-GT to achieve adequate metabolic detoxification. Busulfan pre-conditioning has improved clinical outcomes [ 10%-20% of individuals receiving HSC-GT have restarted ERT or received a subsequent HSCT or HSC-GT; the other 80%-90% have normal lymphocyte subsets and are able to discontinue intravenous immunoglobulin [ In contrast to the experience with gammaretroviral gene therapy for Promising results from other lentiviral vector-based studies include: Several studies ( Lentiviral vectors are reported to have more neutral insertional sites with less risk of oncogenesis, shorter transduction time, and higher viral titers [ Search • More than 100 individuals with • Most of these individuals were treated with ERT for three to six months prior to HSC-GT to achieve adequate metabolic detoxification. • Busulfan pre-conditioning has improved clinical outcomes [ • 10%-20% of individuals receiving HSC-GT have restarted ERT or received a subsequent HSCT or HSC-GT; the other 80%-90% have normal lymphocyte subsets and are able to discontinue intravenous immunoglobulin [ • In contrast to the experience with gammaretroviral gene therapy for • Several studies ( • Lentiviral vectors are reported to have more neutral insertional sites with less risk of oncogenesis, shorter transduction time, and higher viral titers [ ## Genetic Counseling Adenosine deaminase (ADA) deficiency is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of 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 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 Although a good correlation has been established between the effect of pathogenic variants on ADA catalytic activity and both clinical and metabolic phenotype,* variability in disease manifestations may be observed among affected sibs (see * In individuals with compound heterozygosity for two different 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 for the reproductive partners of individuals known to be heterozygous for an Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of 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 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 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 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 • Although a good correlation has been established between the effect of pathogenic variants on ADA catalytic activity and both clinical and metabolic phenotype,* variability in disease manifestations may be observed among affected sibs (see • * In individuals with compound heterozygosity for two different • 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 individuals known to be heterozygous for an ## Mode of Inheritance Adenosine deaminase (ADA) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of 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 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 Although a good correlation has been established between the effect of pathogenic variants on ADA catalytic activity and both clinical and metabolic phenotype,* variability in disease manifestations may be observed among affected sibs (see * In individuals with compound heterozygosity for two different Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of 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 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 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 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 • Although a good correlation has been established between the effect of pathogenic variants on ADA catalytic activity and both clinical and metabolic phenotype,* variability in disease manifestations may be observed among affected sibs (see • * In individuals with compound heterozygosity for two different • 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 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 young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for the reproductive partners of individuals known to be heterozygous for an ## 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 United Kingdom Health Resources & Services Administration • • • • Canada • • • United Kingdom • • • • • • • • • Health Resources & Services Administration • • • • • • • ## Molecular Genetics Adenosine Deaminase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Adenosine Deaminase Deficiency ( Adenosine deaminase (ADA; also referred to as ADA1), the protein encoded by Prior to initiation of enzyme replacement therapy (ERT), it is highly recommended to send whole blood in ethylenediaminetetraacetic acid (EDTA) for measuring baseline red blood cell ADA catalytic activity and the concentration of total red blood cell deoxyadenosine nucleotides (dAXP). Levels of red blood cell dAXP correlate with When sending samples for testing of red blood cell ADA catalytic activity and dAXP, it is important to specify whether or not the individual being tested has received a blood transfusion, hematopoietic stem cell transplantation, or gene therapy, since this will confound the interpretation of the test result. Novel Variants listed in the table have been provided by the authors. • Prior to initiation of enzyme replacement therapy (ERT), it is highly recommended to send whole blood in ethylenediaminetetraacetic acid (EDTA) for measuring baseline red blood cell ADA catalytic activity and the concentration of total red blood cell deoxyadenosine nucleotides (dAXP). Levels of red blood cell dAXP correlate with • When sending samples for testing of red blood cell ADA catalytic activity and dAXP, it is important to specify whether or not the individual being tested has received a blood transfusion, hematopoietic stem cell transplantation, or gene therapy, since this will confound the interpretation of the test result. • Novel ## Molecular Pathogenesis Adenosine deaminase (ADA; also referred to as ADA1), the protein encoded by Prior to initiation of enzyme replacement therapy (ERT), it is highly recommended to send whole blood in ethylenediaminetetraacetic acid (EDTA) for measuring baseline red blood cell ADA catalytic activity and the concentration of total red blood cell deoxyadenosine nucleotides (dAXP). Levels of red blood cell dAXP correlate with When sending samples for testing of red blood cell ADA catalytic activity and dAXP, it is important to specify whether or not the individual being tested has received a blood transfusion, hematopoietic stem cell transplantation, or gene therapy, since this will confound the interpretation of the test result. Novel Variants listed in the table have been provided by the authors. • Prior to initiation of enzyme replacement therapy (ERT), it is highly recommended to send whole blood in ethylenediaminetetraacetic acid (EDTA) for measuring baseline red blood cell ADA catalytic activity and the concentration of total red blood cell deoxyadenosine nucleotides (dAXP). Levels of red blood cell dAXP correlate with • When sending samples for testing of red blood cell ADA catalytic activity and dAXP, it is important to specify whether or not the individual being tested has received a blood transfusion, hematopoietic stem cell transplantation, or gene therapy, since this will confound the interpretation of the test result. • Novel ## Chapter Notes Purine Metabolic and Immunodeficiency Lab Michael Hershfield Teresa Tarrant The authors would like to acknowledge the individuals with ADA deficiency and their families who have participated in research and clinical studies; the many clinicians who have cared for individuals with ADA deficiency and have collaborated in studies of the disorder; and the advocacy work of the Immune Deficiency Foundation. Funding support has been from Lediant, Chiesi, and the National Institutes of Health. 7 March 2024 (bp) Comprehensive update posted live 16 March 2017 (ma) Comprehensive update posted live 19 June 2014 (me) Comprehensive update posted live 22 December 2011 (me) Comprehensive update posted live 28 April 2009 (et) Comprehensive update posted live 3 October 2006 (me) Review posted live 24 April 2006 (mh) Original submission • 7 March 2024 (bp) Comprehensive update posted live • 16 March 2017 (ma) Comprehensive update posted live • 19 June 2014 (me) Comprehensive update posted live • 22 December 2011 (me) Comprehensive update posted live • 28 April 2009 (et) Comprehensive update posted live • 3 October 2006 (me) Review posted live • 24 April 2006 (mh) Original submission ## Author Notes Purine Metabolic and Immunodeficiency Lab Michael Hershfield Teresa Tarrant ## Acknowledgments The authors would like to acknowledge the individuals with ADA deficiency and their families who have participated in research and clinical studies; the many clinicians who have cared for individuals with ADA deficiency and have collaborated in studies of the disorder; and the advocacy work of the Immune Deficiency Foundation. Funding support has been from Lediant, Chiesi, and the National Institutes of Health. ## Revision History 7 March 2024 (bp) Comprehensive update posted live 16 March 2017 (ma) Comprehensive update posted live 19 June 2014 (me) Comprehensive update posted live 22 December 2011 (me) Comprehensive update posted live 28 April 2009 (et) Comprehensive update posted live 3 October 2006 (me) Review posted live 24 April 2006 (mh) Original submission • 7 March 2024 (bp) Comprehensive update posted live • 16 March 2017 (ma) Comprehensive update posted live • 19 June 2014 (me) Comprehensive update posted live • 22 December 2011 (me) Comprehensive update posted live • 28 April 2009 (et) Comprehensive update posted live • 3 October 2006 (me) Review posted live • 24 April 2006 (mh) Original submission ## Key Sections in this ## References Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114:3524-32. Grunebaum E, Booth C, Cuvelier GDE, Loves R, Aiuti A, Kohn DB. Updated management guidelines for adenosine deaminase deficiency. J Allergy Clin Immunol Pract. 2023;11:1665-75. Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019;143:852-63. • Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114:3524-32. • Grunebaum E, Booth C, Cuvelier GDE, Loves R, Aiuti A, Kohn DB. Updated management guidelines for adenosine deaminase deficiency. J Allergy Clin Immunol Pract. 2023;11:1665-75. • Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019;143:852-63. ## Published Guidelines / Consensus Statements Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114:3524-32. Grunebaum E, Booth C, Cuvelier GDE, Loves R, Aiuti A, Kohn DB. Updated management guidelines for adenosine deaminase deficiency. J Allergy Clin Immunol Pract. 2023;11:1665-75. Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019;143:852-63. • Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114:3524-32. • Grunebaum E, Booth C, Cuvelier GDE, Loves R, Aiuti A, Kohn DB. Updated management guidelines for adenosine deaminase deficiency. J Allergy Clin Immunol Pract. 2023;11:1665-75. • Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019;143:852-63. ## Literature Cited	[]	3/10/2006	7/3/2024	14/7/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ada2-def	ada2-def	[ "ADA2 Deficiency", "Deficiency of Adenosine Deaminase 2 (DADA2)", "ADA2 Deficiency", "Deficiency of Adenosine Deaminase 2 (DADA2)", "Adenosine deaminase 2", "ADA2", "Adenosine Deaminase 2 Deficiency" ]	Adenosine Deaminase 2 Deficiency	Ivona Aksentijevich, Natalia Sampaio Moura, Karyl Barron	Summary Adenosine deaminase 2 deficiency (DADA2) is a complex systemic autoinflammatory disorder in which vasculopathy/vasculitis, dysregulated immune function, and/or hematologic abnormalities may predominate. Inflammatory features include intermittent fevers, rash (often livedo racemosa/reticularis), and musculoskeletal involvement (myalgia/arthralgia, arthritis, myositis). Vasculitis, which usually begins before age ten years, may manifest as early-onset ischemic (lacunar) and/or hemorrhagic strokes, or as cutaneous or systemic polyarteritis nodosa. Hypertension and hepatosplenomegaly are often found. More severe involvement may lead to progressive central neurologic deficits (dysarthria, ataxia, cranial nerve palsies, cognitive impairment) or to ischemic injury to the kidney, intestine, and/or digits. Dysregulation of immune function can lead to immunodeficiency or autoimmunity of varying severity; lymphadenopathy may be present and some affected individuals have had lymphoproliferative disease. Hematologic disorders may begin early in life or in late adulthood, and can include lymphopenia, neutropenia, pure red cell aplasia, thrombocytopenia, or pancytopenia. Of note, both interfamilial and intrafamilial phenotypic variability (e.g., in age of onset, frequency and severity of manifestations) can be observed; also, individuals with biallelic The diagnosis of DADA2 is established in a proband with suggestive clinical and laboratory findings and biallelic loss-of-function DADA2 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 (heterozygote), and a 25% chance of being unaffected and not a carrier. Once the	## Diagnosis Formal diagnostic criteria for adenosine deaminase 2 deficiency (DADA2) have not been established. Adenosine deaminase 2 deficiency (DADA2) Intermittent fevers Hepatosplenomegaly (can be evidence of portal hypertension) Systemic hypertension Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate during flare episodes Elevated transaminases Onset. Usually in early childhood (i.e., age <10 years) Skin. Livedo racemosa/reticularis and/or polyarteritis nodosa and/or undifferentiated skin rash Neurologic. Early-onset lacunar and/or hemorrhagic strokes MRI Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter Hemorrhagic stroke and intracranial bleeding Angiography. Aneurysm or stenosis in medium-sized arteries Immunodeficiency Lymphoproliferative disease including lymphadenopathy Hypogammaglobulinemia, with low levels of IgM, IgG, and/or IgA. Low serum immunoglobulin levels may correlate with inflammatory disease activity [ Impaired production of transitional and switched memory B cells Low vaccine responses noted in some cases Although T cells are largely not affected, defective T-cell proliferation, mild-to-profound CD4+ lymphopenia, and low NK counts have been reported [ Positive lupus anticoagulant (present in 41% of the Authors' cohort of 41 patients who were tested – in which ascertainment could be skewed in favor of individuals with inflammatory findings) [Author, unpublished data] Hematologic disorders typically occur early in life; however, in rare instances bone marrow failure may initially appear as late as adulthood (i.e., 5th and 6th decades): Lymphopenia Neutropenia Pure red cell aplasia Thrombocytopenia Pancytopenia Bone marrow biopsy may reveal hypo/hypercellularity, grade I myelofibrosis, lymphocyte infiltrate (predominantly CD8+), and mild reticulin fibrosis, further suggesting a defect in cell differentiation. In one individual the bone marrow showed a reduced number of CD138+ plasma cells [ The diagnosis of DADA2 is established in a proband with Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DADA2 is broad, individuals with some of the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of DADA2 molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of DADA2 has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adenosine Deaminase 2 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. Note: (1) An ELISA-based assay for ADA2 activity is commonly used in research laboratories but may not be available in clinical laboratories; (2) although deficiency of immuno-precipitable ADA2 enzyme has been demonstrated in persons with DADA2 [ • Intermittent fevers • Hepatosplenomegaly (can be evidence of portal hypertension) • Systemic hypertension • Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate during flare episodes • Elevated transaminases • Onset. Usually in early childhood (i.e., age <10 years) • Skin. Livedo racemosa/reticularis and/or polyarteritis nodosa and/or undifferentiated skin rash • Neurologic. Early-onset lacunar and/or hemorrhagic strokes • MRI • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Angiography. Aneurysm or stenosis in medium-sized arteries • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Immunodeficiency • Lymphoproliferative disease including lymphadenopathy • Hypogammaglobulinemia, with low levels of IgM, IgG, and/or IgA. Low serum immunoglobulin levels may correlate with inflammatory disease activity [ • Impaired production of transitional and switched memory B cells • Low vaccine responses noted in some cases • Although T cells are largely not affected, defective T-cell proliferation, mild-to-profound CD4+ lymphopenia, and low NK counts have been reported [ • Positive lupus anticoagulant (present in 41% of the Authors' cohort of 41 patients who were tested – in which ascertainment could be skewed in favor of individuals with inflammatory findings) [Author, unpublished data] • Lymphopenia • Neutropenia • Pure red cell aplasia • Thrombocytopenia • Pancytopenia ## Suggestive Findings Adenosine deaminase 2 deficiency (DADA2) Intermittent fevers Hepatosplenomegaly (can be evidence of portal hypertension) Systemic hypertension Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate during flare episodes Elevated transaminases Onset. Usually in early childhood (i.e., age <10 years) Skin. Livedo racemosa/reticularis and/or polyarteritis nodosa and/or undifferentiated skin rash Neurologic. Early-onset lacunar and/or hemorrhagic strokes MRI Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter Hemorrhagic stroke and intracranial bleeding Angiography. Aneurysm or stenosis in medium-sized arteries Immunodeficiency Lymphoproliferative disease including lymphadenopathy Hypogammaglobulinemia, with low levels of IgM, IgG, and/or IgA. Low serum immunoglobulin levels may correlate with inflammatory disease activity [ Impaired production of transitional and switched memory B cells Low vaccine responses noted in some cases Although T cells are largely not affected, defective T-cell proliferation, mild-to-profound CD4+ lymphopenia, and low NK counts have been reported [ Positive lupus anticoagulant (present in 41% of the Authors' cohort of 41 patients who were tested – in which ascertainment could be skewed in favor of individuals with inflammatory findings) [Author, unpublished data] Hematologic disorders typically occur early in life; however, in rare instances bone marrow failure may initially appear as late as adulthood (i.e., 5th and 6th decades): Lymphopenia Neutropenia Pure red cell aplasia Thrombocytopenia Pancytopenia Bone marrow biopsy may reveal hypo/hypercellularity, grade I myelofibrosis, lymphocyte infiltrate (predominantly CD8+), and mild reticulin fibrosis, further suggesting a defect in cell differentiation. In one individual the bone marrow showed a reduced number of CD138+ plasma cells [ • Intermittent fevers • Hepatosplenomegaly (can be evidence of portal hypertension) • Systemic hypertension • Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate during flare episodes • Elevated transaminases • Onset. Usually in early childhood (i.e., age <10 years) • Skin. Livedo racemosa/reticularis and/or polyarteritis nodosa and/or undifferentiated skin rash • Neurologic. Early-onset lacunar and/or hemorrhagic strokes • MRI • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Angiography. Aneurysm or stenosis in medium-sized arteries • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Immunodeficiency • Lymphoproliferative disease including lymphadenopathy • Hypogammaglobulinemia, with low levels of IgM, IgG, and/or IgA. Low serum immunoglobulin levels may correlate with inflammatory disease activity [ • Impaired production of transitional and switched memory B cells • Low vaccine responses noted in some cases • Although T cells are largely not affected, defective T-cell proliferation, mild-to-profound CD4+ lymphopenia, and low NK counts have been reported [ • Positive lupus anticoagulant (present in 41% of the Authors' cohort of 41 patients who were tested – in which ascertainment could be skewed in favor of individuals with inflammatory findings) [Author, unpublished data] • Lymphopenia • Neutropenia • Pure red cell aplasia • Thrombocytopenia • Pancytopenia ## Systemic Autoinflammatory Disease Intermittent fevers Hepatosplenomegaly (can be evidence of portal hypertension) Systemic hypertension Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate during flare episodes Elevated transaminases • Intermittent fevers • Hepatosplenomegaly (can be evidence of portal hypertension) • Systemic hypertension • Elevated C-reactive protein (CRP) and erythrocyte sedimentation rate during flare episodes • Elevated transaminases ## Vasculitis Onset. Usually in early childhood (i.e., age <10 years) Skin. Livedo racemosa/reticularis and/or polyarteritis nodosa and/or undifferentiated skin rash Neurologic. Early-onset lacunar and/or hemorrhagic strokes MRI Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter Hemorrhagic stroke and intracranial bleeding Angiography. Aneurysm or stenosis in medium-sized arteries • Onset. Usually in early childhood (i.e., age <10 years) • Skin. Livedo racemosa/reticularis and/or polyarteritis nodosa and/or undifferentiated skin rash • Neurologic. Early-onset lacunar and/or hemorrhagic strokes • MRI • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding • Angiography. Aneurysm or stenosis in medium-sized arteries • Acute or chronic lacunar ischemic infarcts located in the deep-brain nuclei and/or the brain stem and sparing the subcortical white matter • Hemorrhagic stroke and intracranial bleeding ## Dysregulation of Immune Function Immunodeficiency Lymphoproliferative disease including lymphadenopathy Hypogammaglobulinemia, with low levels of IgM, IgG, and/or IgA. Low serum immunoglobulin levels may correlate with inflammatory disease activity [ Impaired production of transitional and switched memory B cells Low vaccine responses noted in some cases Although T cells are largely not affected, defective T-cell proliferation, mild-to-profound CD4+ lymphopenia, and low NK counts have been reported [ Positive lupus anticoagulant (present in 41% of the Authors' cohort of 41 patients who were tested – in which ascertainment could be skewed in favor of individuals with inflammatory findings) [Author, unpublished data] • Immunodeficiency • Lymphoproliferative disease including lymphadenopathy • Hypogammaglobulinemia, with low levels of IgM, IgG, and/or IgA. Low serum immunoglobulin levels may correlate with inflammatory disease activity [ • Impaired production of transitional and switched memory B cells • Low vaccine responses noted in some cases • Although T cells are largely not affected, defective T-cell proliferation, mild-to-profound CD4+ lymphopenia, and low NK counts have been reported [ • Positive lupus anticoagulant (present in 41% of the Authors' cohort of 41 patients who were tested – in which ascertainment could be skewed in favor of individuals with inflammatory findings) [Author, unpublished data] ## Hematologic Abnormalities Hematologic disorders typically occur early in life; however, in rare instances bone marrow failure may initially appear as late as adulthood (i.e., 5th and 6th decades): Lymphopenia Neutropenia Pure red cell aplasia Thrombocytopenia Pancytopenia Bone marrow biopsy may reveal hypo/hypercellularity, grade I myelofibrosis, lymphocyte infiltrate (predominantly CD8+), and mild reticulin fibrosis, further suggesting a defect in cell differentiation. In one individual the bone marrow showed a reduced number of CD138+ plasma cells [ • Lymphopenia • Neutropenia • Pure red cell aplasia • Thrombocytopenia • Pancytopenia ## Other ## Establishing the Diagnosis The diagnosis of DADA2 is established in a proband with Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of DADA2 is broad, individuals with some of the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of DADA2 molecular genetic testing approaches can include For an introduction to multigene panels click When the diagnosis of DADA2 has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adenosine Deaminase 2 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. Note: (1) An ELISA-based assay for ADA2 activity is commonly used in research laboratories but may not be available in clinical laboratories; (2) although deficiency of immuno-precipitable ADA2 enzyme has been demonstrated in persons with DADA2 [ ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of DADA2 molecular genetic testing approaches can include For an introduction to multigene panels click ## Option 2 When the diagnosis of DADA2 has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adenosine Deaminase 2 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. Note: (1) An ELISA-based assay for ADA2 activity is commonly used in research laboratories but may not be available in clinical laboratories; (2) although deficiency of immuno-precipitable ADA2 enzyme has been demonstrated in persons with DADA2 [ ## Clinical Characteristics Deficiency of adenosine deaminase 2 (DADA2) is a systemic autoinflammatory disorder in which the three major manifestations are vasculitis, dysregulation of immune function, and hematologic disease [ Phenotypic variability that cannot be fully explained by the effect of pathogenic variants on protein function can be observed in the same family; for example, one sib may have have early-childhood onset of manifestations whereas another may have later-childhood onset. Affected individuals homozygous for the same founder variant have variability in age of onset and in frequency and severity of manifestations [ The most frequent manifestations of DADA2 are related to arterial vasculopathy which often manifests as cutaneous lesions. Cutaneous manifestations, reported in more than 75% of affected individuals, include livedo racemosa/reticularis, polyarteritis nodosa (PAN), subcutaneous nodules, cutaneous ulcers, or lupus-like rash [ Histopathologic findings of DADA2-associated PAN and PAN of unknown cause are the same: non-granulomatous, necrotizing vasculitis of small and medium-sized vessels. Sometimes less specific findings are interpreted as leukocytoclastic vasculitis. In younger individuals with livedoid rash, skin biopsy shows interstitial neutrophil and macrophage infiltration without overt vasculitis. In one study, nine (15%) of 60 children with PAN, cutaneous PAN, unclassifiable vasculitis (UCV), young-onset chronic vasculitis, or history of stroke were found to have biallleic Ischemic strokes are often observed in (but not limited to) the brain stem, thalamus, basal ganglia, and internal capsule [ Over time accumulation of the effects of these small initially undetectable strokes can lead to severe neurologic impairments such as persistent dysarthria, ataxia, palsy of one or more cranial nerves, and cognitive impairment [ Other neurologic manifestations can include the following: Small, deep intracerebral hemorrhage. Specifically, hemorrhagic strokes were observed on MRI and/or CT in the ventricular system and right frontal insula in different individuals. Most often they occur in the setting of concomitant use of antiplatelet or anticoagulant therapy; however, on rare occasion they may occur spontaneously [ Cerebral vessel aneurysm (1 patient) [ Seizures resulting from strokes. Manifestations are related to the location of the stroke. Central and peripheral neuropathy. The diverse manifestations reported include cranial nerve palsies, sensorineural hearing loss, and ophthalmologic complications [ Other effects of distal artery occlusion include peripheral vascular insufficiency, digital necrosis, and Raynaud phenomena [ Other organs with dense vascularization such as the kidney can be affected. Multiple aneurysmal dilatations and variation in the caliber of medium-small intrarenal arteries have been reported as well as renal artery stenosis and infarcts [ General dysregulation of immune function can include immunodeficiency, lymphoproliferative disease, and autoimmune manifestations of varying severity. About 20% of individuals with DADA2 experience bacterial and/or viral infections resulting from immunodeficiency. Bacterial infections typicaly involve the upper- and lower-respiratory tract, gastrointestinal tract, and urinary tract. Viral infections have included recurrent herpes simplex infections, skin warts (caused by the human papilloma virus) [ Although fungal and mycobacterial infections are unusual, they were observed in one individual with severe monocytopenia [ Features mimicking the following disorders: GATA2 deficiency [ Multicentric Castleman disease [ CD3+ CD8+ T-cell large granular lymphocytic (T-LGL) infiltration of the bone marrow (in 2 individuals) [ Adolescent-onset Hodgkin's lymphoma (HL) was initialy reported in one individual (however, definitive supporting evidence for HL was not available) [ Hematopoietic complications include variably decreased numbers of leukocytes, platelets, and erythrocytes (including pure red cell aplasia [PRCA] similar to The initial clinical presentation in five children from four unrelated consanguineous families was PRCA and hemolytic anemia without manifestations of inflammation or vasculitis [ Neutropenia was severe (i.e., low or absent absolute neutrophil counts) in two affected individuals [ About 40% of affected individuals have the following musculoskeletal manifestations: myalgia/arthralgia (22%), arthritis (14%), and myositis (1%) [ To date no genotype-phenotype correlations associating ADA2 pathogenic variants with the clinical presentation of DADA2 have been identified. Studies of affected individuals in the two major founder populations in the Middle East and northern Europe could possibly offer insight into some genotype-phenotype correlations. See The The In a large family of Iraqi descent two affected and four unaffected members homozygous for the pathogenic missense variant DADA2 is considered a rare disease; however, since its initial description in 2014, more than 170 affected individuals have been reported in the literature. Based on allele frequencies of in silico-predicted DADA2 prevalence is higher in populations with a high degree of consanguinity or in populations with founder variants. See Most affected individuals from the Middle East are homozygous for the p.Gly47Arg founder variant. The highest carrier frequency for this variant is reported in the Georgian-Jewish population (1:10); the estimated carrier frequency of this variant in the Turkish population is about 1:500. The p.Arg169Gln founder variant has an estimated carrier frequency of 1:500 in northern European populations (Finnish, Dutch). The allele frequency is significantly lower in African, Latino, and Asian populations. • Small, deep intracerebral hemorrhage. Specifically, hemorrhagic strokes were observed on MRI and/or CT in the ventricular system and right frontal insula in different individuals. Most often they occur in the setting of concomitant use of antiplatelet or anticoagulant therapy; however, on rare occasion they may occur spontaneously [ • Cerebral vessel aneurysm (1 patient) [ • Seizures resulting from strokes. Manifestations are related to the location of the stroke. • Central and peripheral neuropathy. The diverse manifestations reported include cranial nerve palsies, sensorineural hearing loss, and ophthalmologic complications [ • Features mimicking the following disorders: • GATA2 deficiency [ • Multicentric Castleman disease [ • GATA2 deficiency [ • Multicentric Castleman disease [ • CD3+ CD8+ T-cell large granular lymphocytic (T-LGL) infiltration of the bone marrow (in 2 individuals) [ • Adolescent-onset Hodgkin's lymphoma (HL) was initialy reported in one individual (however, definitive supporting evidence for HL was not available) [ • GATA2 deficiency [ • Multicentric Castleman disease [ • The • The • In a large family of Iraqi descent two affected and four unaffected members homozygous for the pathogenic missense variant • Most affected individuals from the Middle East are homozygous for the p.Gly47Arg founder variant. The highest carrier frequency for this variant is reported in the Georgian-Jewish population (1:10); the estimated carrier frequency of this variant in the Turkish population is about 1:500. • The p.Arg169Gln founder variant has an estimated carrier frequency of 1:500 in northern European populations (Finnish, Dutch). The allele frequency is significantly lower in African, Latino, and Asian populations. ## Clinical Description Deficiency of adenosine deaminase 2 (DADA2) is a systemic autoinflammatory disorder in which the three major manifestations are vasculitis, dysregulation of immune function, and hematologic disease [ Phenotypic variability that cannot be fully explained by the effect of pathogenic variants on protein function can be observed in the same family; for example, one sib may have have early-childhood onset of manifestations whereas another may have later-childhood onset. Affected individuals homozygous for the same founder variant have variability in age of onset and in frequency and severity of manifestations [ The most frequent manifestations of DADA2 are related to arterial vasculopathy which often manifests as cutaneous lesions. Cutaneous manifestations, reported in more than 75% of affected individuals, include livedo racemosa/reticularis, polyarteritis nodosa (PAN), subcutaneous nodules, cutaneous ulcers, or lupus-like rash [ Histopathologic findings of DADA2-associated PAN and PAN of unknown cause are the same: non-granulomatous, necrotizing vasculitis of small and medium-sized vessels. Sometimes less specific findings are interpreted as leukocytoclastic vasculitis. In younger individuals with livedoid rash, skin biopsy shows interstitial neutrophil and macrophage infiltration without overt vasculitis. In one study, nine (15%) of 60 children with PAN, cutaneous PAN, unclassifiable vasculitis (UCV), young-onset chronic vasculitis, or history of stroke were found to have biallleic Ischemic strokes are often observed in (but not limited to) the brain stem, thalamus, basal ganglia, and internal capsule [ Over time accumulation of the effects of these small initially undetectable strokes can lead to severe neurologic impairments such as persistent dysarthria, ataxia, palsy of one or more cranial nerves, and cognitive impairment [ Other neurologic manifestations can include the following: Small, deep intracerebral hemorrhage. Specifically, hemorrhagic strokes were observed on MRI and/or CT in the ventricular system and right frontal insula in different individuals. Most often they occur in the setting of concomitant use of antiplatelet or anticoagulant therapy; however, on rare occasion they may occur spontaneously [ Cerebral vessel aneurysm (1 patient) [ Seizures resulting from strokes. Manifestations are related to the location of the stroke. Central and peripheral neuropathy. The diverse manifestations reported include cranial nerve palsies, sensorineural hearing loss, and ophthalmologic complications [ Other effects of distal artery occlusion include peripheral vascular insufficiency, digital necrosis, and Raynaud phenomena [ Other organs with dense vascularization such as the kidney can be affected. Multiple aneurysmal dilatations and variation in the caliber of medium-small intrarenal arteries have been reported as well as renal artery stenosis and infarcts [ General dysregulation of immune function can include immunodeficiency, lymphoproliferative disease, and autoimmune manifestations of varying severity. About 20% of individuals with DADA2 experience bacterial and/or viral infections resulting from immunodeficiency. Bacterial infections typicaly involve the upper- and lower-respiratory tract, gastrointestinal tract, and urinary tract. Viral infections have included recurrent herpes simplex infections, skin warts (caused by the human papilloma virus) [ Although fungal and mycobacterial infections are unusual, they were observed in one individual with severe monocytopenia [ Features mimicking the following disorders: GATA2 deficiency [ Multicentric Castleman disease [ CD3+ CD8+ T-cell large granular lymphocytic (T-LGL) infiltration of the bone marrow (in 2 individuals) [ Adolescent-onset Hodgkin's lymphoma (HL) was initialy reported in one individual (however, definitive supporting evidence for HL was not available) [ Hematopoietic complications include variably decreased numbers of leukocytes, platelets, and erythrocytes (including pure red cell aplasia [PRCA] similar to The initial clinical presentation in five children from four unrelated consanguineous families was PRCA and hemolytic anemia without manifestations of inflammation or vasculitis [ Neutropenia was severe (i.e., low or absent absolute neutrophil counts) in two affected individuals [ About 40% of affected individuals have the following musculoskeletal manifestations: myalgia/arthralgia (22%), arthritis (14%), and myositis (1%) [ • Small, deep intracerebral hemorrhage. Specifically, hemorrhagic strokes were observed on MRI and/or CT in the ventricular system and right frontal insula in different individuals. Most often they occur in the setting of concomitant use of antiplatelet or anticoagulant therapy; however, on rare occasion they may occur spontaneously [ • Cerebral vessel aneurysm (1 patient) [ • Seizures resulting from strokes. Manifestations are related to the location of the stroke. • Central and peripheral neuropathy. The diverse manifestations reported include cranial nerve palsies, sensorineural hearing loss, and ophthalmologic complications [ • Features mimicking the following disorders: • GATA2 deficiency [ • Multicentric Castleman disease [ • GATA2 deficiency [ • Multicentric Castleman disease [ • CD3+ CD8+ T-cell large granular lymphocytic (T-LGL) infiltration of the bone marrow (in 2 individuals) [ • Adolescent-onset Hodgkin's lymphoma (HL) was initialy reported in one individual (however, definitive supporting evidence for HL was not available) [ • GATA2 deficiency [ • Multicentric Castleman disease [ ## Vasculitis The most frequent manifestations of DADA2 are related to arterial vasculopathy which often manifests as cutaneous lesions. Cutaneous manifestations, reported in more than 75% of affected individuals, include livedo racemosa/reticularis, polyarteritis nodosa (PAN), subcutaneous nodules, cutaneous ulcers, or lupus-like rash [ Histopathologic findings of DADA2-associated PAN and PAN of unknown cause are the same: non-granulomatous, necrotizing vasculitis of small and medium-sized vessels. Sometimes less specific findings are interpreted as leukocytoclastic vasculitis. In younger individuals with livedoid rash, skin biopsy shows interstitial neutrophil and macrophage infiltration without overt vasculitis. In one study, nine (15%) of 60 children with PAN, cutaneous PAN, unclassifiable vasculitis (UCV), young-onset chronic vasculitis, or history of stroke were found to have biallleic Ischemic strokes are often observed in (but not limited to) the brain stem, thalamus, basal ganglia, and internal capsule [ Over time accumulation of the effects of these small initially undetectable strokes can lead to severe neurologic impairments such as persistent dysarthria, ataxia, palsy of one or more cranial nerves, and cognitive impairment [ Other neurologic manifestations can include the following: Small, deep intracerebral hemorrhage. Specifically, hemorrhagic strokes were observed on MRI and/or CT in the ventricular system and right frontal insula in different individuals. Most often they occur in the setting of concomitant use of antiplatelet or anticoagulant therapy; however, on rare occasion they may occur spontaneously [ Cerebral vessel aneurysm (1 patient) [ Seizures resulting from strokes. Manifestations are related to the location of the stroke. Central and peripheral neuropathy. The diverse manifestations reported include cranial nerve palsies, sensorineural hearing loss, and ophthalmologic complications [ Other effects of distal artery occlusion include peripheral vascular insufficiency, digital necrosis, and Raynaud phenomena [ Other organs with dense vascularization such as the kidney can be affected. Multiple aneurysmal dilatations and variation in the caliber of medium-small intrarenal arteries have been reported as well as renal artery stenosis and infarcts [ • Small, deep intracerebral hemorrhage. Specifically, hemorrhagic strokes were observed on MRI and/or CT in the ventricular system and right frontal insula in different individuals. Most often they occur in the setting of concomitant use of antiplatelet or anticoagulant therapy; however, on rare occasion they may occur spontaneously [ • Cerebral vessel aneurysm (1 patient) [ • Seizures resulting from strokes. Manifestations are related to the location of the stroke. • Central and peripheral neuropathy. The diverse manifestations reported include cranial nerve palsies, sensorineural hearing loss, and ophthalmologic complications [ ## Dysregulation of Immune Function General dysregulation of immune function can include immunodeficiency, lymphoproliferative disease, and autoimmune manifestations of varying severity. About 20% of individuals with DADA2 experience bacterial and/or viral infections resulting from immunodeficiency. Bacterial infections typicaly involve the upper- and lower-respiratory tract, gastrointestinal tract, and urinary tract. Viral infections have included recurrent herpes simplex infections, skin warts (caused by the human papilloma virus) [ Although fungal and mycobacterial infections are unusual, they were observed in one individual with severe monocytopenia [ Features mimicking the following disorders: GATA2 deficiency [ Multicentric Castleman disease [ CD3+ CD8+ T-cell large granular lymphocytic (T-LGL) infiltration of the bone marrow (in 2 individuals) [ Adolescent-onset Hodgkin's lymphoma (HL) was initialy reported in one individual (however, definitive supporting evidence for HL was not available) [ • Features mimicking the following disorders: • GATA2 deficiency [ • Multicentric Castleman disease [ • GATA2 deficiency [ • Multicentric Castleman disease [ • CD3+ CD8+ T-cell large granular lymphocytic (T-LGL) infiltration of the bone marrow (in 2 individuals) [ • Adolescent-onset Hodgkin's lymphoma (HL) was initialy reported in one individual (however, definitive supporting evidence for HL was not available) [ • GATA2 deficiency [ • Multicentric Castleman disease [ ## Hematologic Disease Hematopoietic complications include variably decreased numbers of leukocytes, platelets, and erythrocytes (including pure red cell aplasia [PRCA] similar to The initial clinical presentation in five children from four unrelated consanguineous families was PRCA and hemolytic anemia without manifestations of inflammation or vasculitis [ Neutropenia was severe (i.e., low or absent absolute neutrophil counts) in two affected individuals [ ## Musculoskeletal Manifestations About 40% of affected individuals have the following musculoskeletal manifestations: myalgia/arthralgia (22%), arthritis (14%), and myositis (1%) [ ## Genotype-Phenotype Correlations To date no genotype-phenotype correlations associating ADA2 pathogenic variants with the clinical presentation of DADA2 have been identified. Studies of affected individuals in the two major founder populations in the Middle East and northern Europe could possibly offer insight into some genotype-phenotype correlations. See The The In a large family of Iraqi descent two affected and four unaffected members homozygous for the pathogenic missense variant • The • The • In a large family of Iraqi descent two affected and four unaffected members homozygous for the pathogenic missense variant ## Prevalence DADA2 is considered a rare disease; however, since its initial description in 2014, more than 170 affected individuals have been reported in the literature. Based on allele frequencies of in silico-predicted DADA2 prevalence is higher in populations with a high degree of consanguinity or in populations with founder variants. See Most affected individuals from the Middle East are homozygous for the p.Gly47Arg founder variant. The highest carrier frequency for this variant is reported in the Georgian-Jewish population (1:10); the estimated carrier frequency of this variant in the Turkish population is about 1:500. The p.Arg169Gln founder variant has an estimated carrier frequency of 1:500 in northern European populations (Finnish, Dutch). The allele frequency is significantly lower in African, Latino, and Asian populations. • Most affected individuals from the Middle East are homozygous for the p.Gly47Arg founder variant. The highest carrier frequency for this variant is reported in the Georgian-Jewish population (1:10); the estimated carrier frequency of this variant in the Turkish population is about 1:500. • The p.Arg169Gln founder variant has an estimated carrier frequency of 1:500 in northern European populations (Finnish, Dutch). The allele frequency is significantly lower in African, Latino, and Asian populations. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Inherited disorders to consider in the differential diagnosis of DADA2 are included in Inherited Disorders with Normal ADA2 Enzyme Activity to Consider in the Differential Diagnosis of Adenosine Deaminase 2 Deficiency (DADA2) Immune deficiency is much more severe. Depletion of T, B, & NK cells Low levels of ADA Lack cerebrovascular disease & cutaneous manifestations Infections are often invasive. Vasculitic complications are rare. AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance ADA-SCID = severe combined immune deficiency caused by Approximately 20%-25% of individuals with ALPS lack a genetic diagnosis (see Disorders with normal ADA2 enzyme activity and without a known genetic component include the following: • Immune deficiency is much more severe. • Depletion of T, B, & NK cells • Low levels of ADA • Lack cerebrovascular disease & cutaneous manifestations • Infections are often invasive. • Vasculitic complications are rare. ## Management To establish the extent of disease and needs in an individual diagnosed with adenosine deaminase 2 deficiency (DADA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Blood pressure and other vital signs, as systemic hypertension and/or fever are common. Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. Assessment for lymphadenopathy and hepatosplenomegaly. Neurologic examination for evidence of prior or recent strokes. Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity Kidney and liver function tests Quantitative serum immunoglobulins PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. Antibody response to vaccines. Inadequate response suggests immune deficiency. Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent Magnetic resonance angiography (MRA): When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. FibroScan When clinically indicated: Skin biopsy in order to document vasculitis, or to investigate an atypical rash Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. Some individuals with low serum immunoglobulins and frequent infections may require treatment with intravenous immunoglobulin as well as antibiotics and antivirals in conjunction with anti-TNF agents [ Methotrexate is added when administering adalimumab or infliximab to prevent development of drug-related antibodies. Currently there are no predictors of which individual with biallelic Suggested follow-up evaluations include the following: Complete physical examination (performed yearly or sooner if clinically indicated): Blood pressure and other vital signs Skin examination Assessment for presence of lymphadenopathy and hepatosplenomegaly Neurologic examination for evidence of prior or recent strokes Ophthalmologic examination for ptosis, abnormal eye movements, retinal infarcts, optic nerve damage ECG (if abnormal in the past). Note: Arterial hypertension, reported in 20% of patients, can lead to myocardial dysfunction. Laboratory assessment (performed yearly or sooner if clinically indicated): CBC and differential ESR and CRP Kidney and liver function Quantitative serum immunoglobulins Lymphocyte phenotyping for evidence of a B-cell maturation defect Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations Imaging assessment (yearly or if clinically indicated): Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow FibroScan Liver biopsy (if clinically indicated) is the most reliable way to diagnose diffuse hepatic disease (e.g., in the presence of portal hypertension). Avoid the following: Antiplatelet medications including aspirin Anticoagulation medications (except in the presence of atrial fibrillation) Smoking, which may exacerbate peripheral arterial disease 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 with biallelic See Information regarding the safety of use of anti-TNF agents during pregnancy is limited. One study evaluating use of anti-TNF agents in pregnant women with inflammatory bowel disease determined that these drugs can cross the placenta from the latter part of the second trimester of gestation, though they are low risk in the short term [ Search • Blood pressure and other vital signs, as systemic hypertension and/or fever are common. • Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. • Assessment for lymphadenopathy and hepatosplenomegaly. • Neurologic examination for evidence of prior or recent strokes. • Blood pressure and other vital signs, as systemic hypertension and/or fever are common. • Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. • Assessment for lymphadenopathy and hepatosplenomegaly. • Neurologic examination for evidence of prior or recent strokes. • • Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity • Kidney and liver function tests • Quantitative serum immunoglobulins • PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke • Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. • Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. • Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. • Antibody response to vaccines. Inadequate response suggests immune deficiency. • Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity • Kidney and liver function tests • Quantitative serum immunoglobulins • PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke • Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. • Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. • Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. • Antibody response to vaccines. Inadequate response suggests immune deficiency. • • Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent • Magnetic resonance angiography (MRA): • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. • Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. • FibroScan • Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent • Magnetic resonance angiography (MRA): • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. • Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. • FibroScan • • When clinically indicated: • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. • When clinically indicated: • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. • • Blood pressure and other vital signs, as systemic hypertension and/or fever are common. • Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. • Assessment for lymphadenopathy and hepatosplenomegaly. • Neurologic examination for evidence of prior or recent strokes. • Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity • Kidney and liver function tests • Quantitative serum immunoglobulins • PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke • Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. • Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. • Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. • Antibody response to vaccines. Inadequate response suggests immune deficiency. • Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent • Magnetic resonance angiography (MRA): • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. • Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. • FibroScan • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • When clinically indicated: • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Complete physical examination (performed yearly or sooner if clinically indicated): • Blood pressure and other vital signs • Skin examination • Assessment for presence of lymphadenopathy and hepatosplenomegaly • Neurologic examination for evidence of prior or recent strokes • Blood pressure and other vital signs • Skin examination • Assessment for presence of lymphadenopathy and hepatosplenomegaly • Neurologic examination for evidence of prior or recent strokes • Ophthalmologic examination for ptosis, abnormal eye movements, retinal infarcts, optic nerve damage • ECG (if abnormal in the past). Note: Arterial hypertension, reported in 20% of patients, can lead to myocardial dysfunction. • Laboratory assessment (performed yearly or sooner if clinically indicated): • CBC and differential • ESR and CRP • Kidney and liver function • Quantitative serum immunoglobulins • Lymphocyte phenotyping for evidence of a B-cell maturation defect • Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations • CBC and differential • ESR and CRP • Kidney and liver function • Quantitative serum immunoglobulins • Lymphocyte phenotyping for evidence of a B-cell maturation defect • Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations • Imaging assessment (yearly or if clinically indicated): • Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement • Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction • Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow • FibroScan • Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement • Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction • Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow • FibroScan • Liver biopsy (if clinically indicated) is the most reliable way to diagnose diffuse hepatic disease (e.g., in the presence of portal hypertension). • Blood pressure and other vital signs • Skin examination • Assessment for presence of lymphadenopathy and hepatosplenomegaly • Neurologic examination for evidence of prior or recent strokes • CBC and differential • ESR and CRP • Kidney and liver function • Quantitative serum immunoglobulins • Lymphocyte phenotyping for evidence of a B-cell maturation defect • Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations • Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement • Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction • Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow • FibroScan • Antiplatelet medications including aspirin • Anticoagulation medications (except in the presence of atrial fibrillation) • Smoking, which may exacerbate peripheral arterial disease ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with adenosine deaminase 2 deficiency (DADA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended. Blood pressure and other vital signs, as systemic hypertension and/or fever are common. Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. Assessment for lymphadenopathy and hepatosplenomegaly. Neurologic examination for evidence of prior or recent strokes. Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity Kidney and liver function tests Quantitative serum immunoglobulins PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. Antibody response to vaccines. Inadequate response suggests immune deficiency. Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent Magnetic resonance angiography (MRA): When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. FibroScan When clinically indicated: Skin biopsy in order to document vasculitis, or to investigate an atypical rash Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. • Blood pressure and other vital signs, as systemic hypertension and/or fever are common. • Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. • Assessment for lymphadenopathy and hepatosplenomegaly. • Neurologic examination for evidence of prior or recent strokes. • Blood pressure and other vital signs, as systemic hypertension and/or fever are common. • Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. • Assessment for lymphadenopathy and hepatosplenomegaly. • Neurologic examination for evidence of prior or recent strokes. • • Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity • Kidney and liver function tests • Quantitative serum immunoglobulins • PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke • Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. • Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. • Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. • Antibody response to vaccines. Inadequate response suggests immune deficiency. • Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity • Kidney and liver function tests • Quantitative serum immunoglobulins • PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke • Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. • Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. • Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. • Antibody response to vaccines. Inadequate response suggests immune deficiency. • • Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent • Magnetic resonance angiography (MRA): • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. • Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. • FibroScan • Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent • Magnetic resonance angiography (MRA): • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. • Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. • FibroScan • • When clinically indicated: • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. • When clinically indicated: • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. • • Blood pressure and other vital signs, as systemic hypertension and/or fever are common. • Skin examination for evidence of livedo reticularis/racemosa, nodules, and Raynaud phenomenon. Severe involvement can include digital infarcts/gangrene or skin ulcerations. • Assessment for lymphadenopathy and hepatosplenomegaly. • Neurologic examination for evidence of prior or recent strokes. • Complete blood count (CBC) with differential to detect anemia, lymphopenia, neutropenia, and/or thrombocytopenia • Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) as elevated levels may correlate with disease activity • Kidney and liver function tests • Quantitative serum immunoglobulins • PT/PTT to assess the risk of stroke in a patient who has not had a stroke OR to assess the risk of subsequent strokes in those who have had a stroke • Autoantibodies including antinuclear antibodies and lupus anticoagulant. Low titers are reported in 10% of patients, whereas high titers suggest other autoimmune diseases, such as systemic lupus erythematous. • Antineutrophilic cytoplasmic antibodies (ANCA) are usually absent; their presence suggests ANCA-related vasculitis. • Lymphocyte phenotyping. Failure to develop memory B-cells, a common finding, is evidence of a B-cell maturation defect that warrants further evaluation of the immune system (quantitative serum immunoglobulins, antibody response to vaccines, and history of severe and/or multiple infections). Failure to develop memory T-cells may be seen but is uncommon. • Antibody response to vaccines. Inadequate response suggests immune deficiency. • Brain MRI in all patients, even those without overt neurologic manifestations, as a baseline given that small strokes can be clinically silent • Magnetic resonance angiography (MRA): • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • Renal ultrasound examination to assess kidney size (which can be smaller due to poor vascularization and/or infarcts), function, and blood flow. Reported abnormalities that merit documentation before intiation of treatment include renal artery aneurysm and stenosis, renal infarcts (which may be silent), renal inflammation with dense lymphocytic infiltration, and glomerular scarring. • Abdominal ultrasound examination to provide baseline assessment of liver and spleen size and hepatic blood flow. Splenomegaly occurs in up to 30% of affected individuals, hepatomegaly in 20%. • FibroScan • When brain MRI is abnormal, brain MRA (which is expected to be normal in persons with DADA2) can help differentiate the cause of stroke. • Abnormal peripheral MRA may suggest additional treatment options to improve vascular flow for cutaneous lesions (e.g., vascular insufficiency, infarcts, gangrene) or neurologic dysfunction, such as peripheral neuropathy). • When clinically indicated: • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis • Evaluation for manifestations of portal hypertension. If present, perform endoscopy to assess its extent. • Skin biopsy in order to document vasculitis, or to investigate an atypical rash • Liver biopsy to assess cause of hepatomegaly and presence of hepatic steatosis and/or nodular regenerative sclerosis ## Treatment of Manifestations Some individuals with low serum immunoglobulins and frequent infections may require treatment with intravenous immunoglobulin as well as antibiotics and antivirals in conjunction with anti-TNF agents [ Methotrexate is added when administering adalimumab or infliximab to prevent development of drug-related antibodies. Currently there are no predictors of which individual with biallelic ## Current Treatment for Persons with Symptomatic DADA2 Some individuals with low serum immunoglobulins and frequent infections may require treatment with intravenous immunoglobulin as well as antibiotics and antivirals in conjunction with anti-TNF agents [ Methotrexate is added when administering adalimumab or infliximab to prevent development of drug-related antibodies. ## Current Treatment for Asymptomatic Persons with Biallelic DADA2-Causing Variants in Currently there are no predictors of which individual with biallelic ## Surveillance Suggested follow-up evaluations include the following: Complete physical examination (performed yearly or sooner if clinically indicated): Blood pressure and other vital signs Skin examination Assessment for presence of lymphadenopathy and hepatosplenomegaly Neurologic examination for evidence of prior or recent strokes Ophthalmologic examination for ptosis, abnormal eye movements, retinal infarcts, optic nerve damage ECG (if abnormal in the past). Note: Arterial hypertension, reported in 20% of patients, can lead to myocardial dysfunction. Laboratory assessment (performed yearly or sooner if clinically indicated): CBC and differential ESR and CRP Kidney and liver function Quantitative serum immunoglobulins Lymphocyte phenotyping for evidence of a B-cell maturation defect Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations Imaging assessment (yearly or if clinically indicated): Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow FibroScan Liver biopsy (if clinically indicated) is the most reliable way to diagnose diffuse hepatic disease (e.g., in the presence of portal hypertension). • Complete physical examination (performed yearly or sooner if clinically indicated): • Blood pressure and other vital signs • Skin examination • Assessment for presence of lymphadenopathy and hepatosplenomegaly • Neurologic examination for evidence of prior or recent strokes • Blood pressure and other vital signs • Skin examination • Assessment for presence of lymphadenopathy and hepatosplenomegaly • Neurologic examination for evidence of prior or recent strokes • Ophthalmologic examination for ptosis, abnormal eye movements, retinal infarcts, optic nerve damage • ECG (if abnormal in the past). Note: Arterial hypertension, reported in 20% of patients, can lead to myocardial dysfunction. • Laboratory assessment (performed yearly or sooner if clinically indicated): • CBC and differential • ESR and CRP • Kidney and liver function • Quantitative serum immunoglobulins • Lymphocyte phenotyping for evidence of a B-cell maturation defect • Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations • CBC and differential • ESR and CRP • Kidney and liver function • Quantitative serum immunoglobulins • Lymphocyte phenotyping for evidence of a B-cell maturation defect • Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations • Imaging assessment (yearly or if clinically indicated): • Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement • Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction • Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow • FibroScan • Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement • Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction • Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow • FibroScan • Liver biopsy (if clinically indicated) is the most reliable way to diagnose diffuse hepatic disease (e.g., in the presence of portal hypertension). • Blood pressure and other vital signs • Skin examination • Assessment for presence of lymphadenopathy and hepatosplenomegaly • Neurologic examination for evidence of prior or recent strokes • CBC and differential • ESR and CRP • Kidney and liver function • Quantitative serum immunoglobulins • Lymphocyte phenotyping for evidence of a B-cell maturation defect • Additionally, follow-up evaluation of abnormal laboratory studies identified at earlier evaluations • Brain MRI if abnormal in the past or new symptoms or manifestations suggest brain involvement • Peripheral MRA if symptoms of peripheral arterial disease and/or neurologic dysfunction • Abdominal ultrasound examination to assess liver, spleen, and kidney size and hepatic blood flow • FibroScan ## Agents/Circumstances to Avoid Avoid the following: Antiplatelet medications including aspirin Anticoagulation medications (except in the presence of atrial fibrillation) Smoking, which may exacerbate peripheral arterial disease • Antiplatelet medications including aspirin • Anticoagulation medications (except in the presence of atrial fibrillation) • Smoking, which may exacerbate peripheral arterial disease ## 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 with biallelic See ## Pregnancy Management Information regarding the safety of use of anti-TNF agents during pregnancy is limited. One study evaluating use of anti-TNF agents in pregnant women with inflammatory bowel disease determined that these drugs can cross the placenta from the latter part of the second trimester of gestation, though they are low risk in the short term [ ## Therapies Under Investigation Search ## Genetic Counseling Adenosine deaminase 2 deficiency (DADA2) 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 thought to be 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 thought to be 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., carriers of one • Heterozygotes (carriers) are asymptomatic and are not thought to be 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 thought to be 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 Adenosine deaminase 2 deficiency (DADA2) 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 thought to be 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 thought to be 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 thought to be 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 thought to be at risk of developing the disorder. ## 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 Canada United Kingdom PO Box 28660 Kansas City 64188 • • • • • • Canada • • • United Kingdom • • • • • PO Box 28660 • Kansas City 64188 • • • • • • • • • ## Molecular Genetics Adenosine Deaminase 2 Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Adenosine Deaminase 2 Deficiency ( Humans express two enzymes, ADA1 (also referred to as ADA) (see ADA1 is a largely intracellular protein, whereas ADA2 is a secreted protein. It has been postulated that ADA2 may control the level of extracellular adenosine (generated by stepwise dephosphorylation of extracellular ATP and AMP) and regulate a variety of biologic processes (through 4 distinct adenosine receptors expressed on many cells in the brain and immune and cardiovascular systems). See Notable Variants listed in the table have been provided by the authors. Dimerization Catalytic Putative receptor binding Substrate binding ADA2 forms a homodimer and localizes to the extracellular space where it may reduce the extracellular adenosine concentration. ADA2 has four aspargine glycosylation sites at p.Asn127, p.Asn174, p.Asn185, and p.Asn378 [ ADA2 is predominately expressed in myeloid cells such as monocytes, macrophages, and dendritic cells. ADA2 is secreted by activated myeloid cells. Although it has been postulated that ADA2 decreases extracellular adenosine concentration at the sites of inflamed or tumor tissues, this has not been shown either in vitro or in vivo. Where measured, adenosine has not been elevated in the plasma of individuals with DADA2 [ ADA2 has homology to so-called adenosine deaminase growth factors (ADGFs) identified in several insect species, fish, and frogs. Although ADA2 is found in many species, mice lack an The role of ADA2 in multilineage hematopoiesis remains unclear. It is unknown if ADA2 plays additional roles in the development of bone marrow precursors or if the bone marrow failure in DADA2 may be related to inflammatory cell infiltration [ In ADA2 deficiency an imbalance between anti-inflammatory M2 and proinflammatory M1 macrophages may create a hyper-inflammatory environment that is damaging to blood vessels [ • Dimerization • Catalytic • Putative receptor binding • Substrate binding ## Molecular Pathogenesis Humans express two enzymes, ADA1 (also referred to as ADA) (see ADA1 is a largely intracellular protein, whereas ADA2 is a secreted protein. It has been postulated that ADA2 may control the level of extracellular adenosine (generated by stepwise dephosphorylation of extracellular ATP and AMP) and regulate a variety of biologic processes (through 4 distinct adenosine receptors expressed on many cells in the brain and immune and cardiovascular systems). See Notable Variants listed in the table have been provided by the authors. Dimerization Catalytic Putative receptor binding Substrate binding ADA2 forms a homodimer and localizes to the extracellular space where it may reduce the extracellular adenosine concentration. ADA2 has four aspargine glycosylation sites at p.Asn127, p.Asn174, p.Asn185, and p.Asn378 [ ADA2 is predominately expressed in myeloid cells such as monocytes, macrophages, and dendritic cells. ADA2 is secreted by activated myeloid cells. Although it has been postulated that ADA2 decreases extracellular adenosine concentration at the sites of inflamed or tumor tissues, this has not been shown either in vitro or in vivo. Where measured, adenosine has not been elevated in the plasma of individuals with DADA2 [ ADA2 has homology to so-called adenosine deaminase growth factors (ADGFs) identified in several insect species, fish, and frogs. Although ADA2 is found in many species, mice lack an The role of ADA2 in multilineage hematopoiesis remains unclear. It is unknown if ADA2 plays additional roles in the development of bone marrow precursors or if the bone marrow failure in DADA2 may be related to inflammatory cell infiltration [ In ADA2 deficiency an imbalance between anti-inflammatory M2 and proinflammatory M1 macrophages may create a hyper-inflammatory environment that is damaging to blood vessels [ • Dimerization • Catalytic • Putative receptor binding • Substrate binding ## References ## Literature Cited ## Chapter Notes Natalia Sampaio Moura was a post-baccalaureate research fellow at the National Human Genome Research Institute, National Institutes of Health. Her work involves conducting genetic research studies and diagnostic sequencing of patients with autoinflammatory disorders including many patients with DADA2. She earned a Bachelor of Science degree with High Honors in the Cell Biology and Molecular Genetics department at the University of Maryland, College Park. Natalia is looking forward to starting medical school this year. Dr Karyl Barron, a pediatric rheumatologist and immunologist, is the Deputy Director of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. She sees patients with autoinflammatory diseases at the National Institutes of Health where she has a large cohort of patients. Dr Ivona Aksentijevich is an Associate Investigator in the National Human Genome Research Institute (NHGRI), National Institutes of Health. The laboratory focuses on identifying genes responsible for mediating inherited human disorders of inflammation. In addition to DADA2, autoinflammatory disorders identified by the laboratory include familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), neonatal-onset multisystem inflammatory disease (NOMID), autoinflammation PLCγ2-associated antibody deficiency (APLAID), deficiency of IL-1RN (DIRA), haploinsufficiency of A20 (HA20), and Otulin deficiency (otulipenia). The laboratory works to elucidate the mechanism of these genetic disorders in order to develop insights into possible targeted treatments. Dr Aksentijevich also runs a CLIA-certified diagnostic sequencing laboratory within the NHGRI. We would like to acknowledge the 8 August 2019 (bp) Review posted live 18 April 2019 (ia) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 8 August 2019 (bp) Review posted live • 18 April 2019 (ia) Original submission ## Author Notes Natalia Sampaio Moura was a post-baccalaureate research fellow at the National Human Genome Research Institute, National Institutes of Health. Her work involves conducting genetic research studies and diagnostic sequencing of patients with autoinflammatory disorders including many patients with DADA2. She earned a Bachelor of Science degree with High Honors in the Cell Biology and Molecular Genetics department at the University of Maryland, College Park. Natalia is looking forward to starting medical school this year. Dr Karyl Barron, a pediatric rheumatologist and immunologist, is the Deputy Director of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health. She sees patients with autoinflammatory diseases at the National Institutes of Health where she has a large cohort of patients. Dr Ivona Aksentijevich is an Associate Investigator in the National Human Genome Research Institute (NHGRI), National Institutes of Health. The laboratory focuses on identifying genes responsible for mediating inherited human disorders of inflammation. In addition to DADA2, autoinflammatory disorders identified by the laboratory include familial mediterranean fever (FMF), TNF receptor-associated periodic syndrome (TRAPS), neonatal-onset multisystem inflammatory disease (NOMID), autoinflammation PLCγ2-associated antibody deficiency (APLAID), deficiency of IL-1RN (DIRA), haploinsufficiency of A20 (HA20), and Otulin deficiency (otulipenia). The laboratory works to elucidate the mechanism of these genetic disorders in order to develop insights into possible targeted treatments. Dr Aksentijevich also runs a CLIA-certified diagnostic sequencing laboratory within the NHGRI. ## Acknowledgments We would like to acknowledge the ## Revision History 8 August 2019 (bp) Review posted live 18 April 2019 (ia) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 8 August 2019 (bp) Review posted live • 18 April 2019 (ia) Original submission	[ "F Alabbas, G Elyamany, O Alsharif, M Hershfield, I. Meyts. Childhood Hodgkin lymphoma: Think DADA2.. J Clin Immunol. 2019;39:26-9", "A Alsultan, E Basher, J Alqanatish, R Mohammed, M. Alfadhel. Deficiency of ADA2 mimicking autoimmune lymphoproliferative syndrome in the absence of livedo reticularis and vasculitis.. 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J Leukoc Biol. 2010a;88:279-90", "AV Zavialov, X Yu, D Spillmann, G Lauvau, AV Zavialov. Structural basis for the growth factor activity of human adenosine deaminase ADA2.. J Biol Chem. 2010b;285:12367-77", "Q Zhou, D Yang, AK Ombrello, AV Zavialov, C Toro, AV Zavialov, DL Stone, JJ Chae, SD Rosenzweig, K Bishop, KS Barron, HS Kuehn, P Hoffmann, A Negro, WL Tsai, EW Cowen, W Pei, JD Milner, C Silvin, T Heller, DT Chin, NJ Patronas, JS Barber, CC Lee, GM Wood, A Ling, SJ Kelly, DE Kleiner, JC Mullikin, NJ Ganson, HH Kong, S Hambleton, F Candotti, MM Quezado, KR Calvo, H Alao, BK Barham, A Jones, JF Meschia, BB Worrall, SE Kasner, SS Rich, R Goldbach-Mansky, M Abinun, E Chalom, AC Gotte, M Punaro, V Pascual, JW Verbsky, TR Torgerson, NG Singer, TR Gershon, S Ozen, O Karadag, TA Fleisher, EF Remmers, SM Burgess, SL Moir, M Gadina, R Sood, MS Hershfield, M Boehm, DL Kastner, I Aksentijevich. Early-onset stroke and vasculopathy associated with mutations in ADA2.. N Engl J Med. 2014;370:911-20", "M Zurovec, T Dolezal, M Gazi, E Pavlova, PJ Bryant. Adenosine deaminase-related growth factors stimulate cell proliferation in Drosophila by depleting extracellular adenosine.. Proc Natl Acad Sci USA. 2002;99:4403-08" ]	8/8/2019			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
adams-oliver	adams-oliver	[ "Aplasia Cutis Congenita with Terminal Transverse Limb Defects", "Aplasia Cutis Congenita with Terminal Transverse Limb Defects", "Dedicator of cytokinesis protein 6", "Delta-like protein 4", "EGF domain-specific O-linked N-acetylglucosamine transferase", "Neurogenic locus notch homolog protein 1", "Recombining binding protein suppressor of hairless", "Rho GTPase-activating protein 31", "ARHGAP31", "DLL4", "DOCK6", "EOGT", "NOTCH1", "RBPJ", "Adams-Oliver Syndrome" ]	Adams-Oliver Syndrome – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Anna Lehman, Wim Wuyts, Millan S Patel	Summary Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. The diagnosis of AOS can be established in a proband with one of the following: Clinical findings of ACC of the scalp and TTLD ACC or TTLD and a first-degree relative with findings consistent with AOS ACC or TTLD and either a pathogenic variant in an autosomal dominant AOS-related gene ( ACC. Care by a pediatric dermatologist and/or plastic surgeon depending on severity. Goals of non-operative therapy are to prevent infection and promote healing. Large and/or deep lesions with calvarial involvement require acute care and may eventually also require reconstruction by a neurosurgeon. Limb. Many AOS limb anomalies are not severe enough to require surgical or prosthetic intervention. Occupational therapy and/or physical therapy are used as needed to assist with limb functioning. Rarely, surgical intervention for hand malformations is indicated. Cardiovascular. Echocardiography annually until age three years for signs of pulmonary hypertension. Neurologic. Annual pediatric care, including neurologic examination and ongoing assessment of psychomotor development. Ocular. Annual assessment by pediatric ophthalmologist until age three years for evidence of abnormal retinal vascular development. Once the	## Diagnosis Adams-Oliver syndrome (AOS) Of note, when a scalp lesion is not obviously cutis aplasia (e.g., a simple hairless lesion may appear similar to nevus psiloliparus or nevus sebaceous), a skin biopsy can confirm the characteristic features of absent epidermis, dermal atrophy, and lack of adnexal structures and elastic fibers. Generally, a skin biopsy is not necessary because a nevus sebaceous has a yellowish waxy appearance versus the eroded or scarred appearance of ACC. Almost any type of heart malformation can occur in AOS. Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. Widespread cutis marmorata telangiectatica congenita is common (19%). The diagnosis of Adams-Oliver syndrome (AOS) The clinical findings of both aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD) Either ACC or TTLD and a first-degree relative with findings consistent with AOS Either ACC or TTLD and either a pathogenic (or likely pathogenic) variant in an autosomal dominant AOS-related gene or biallelic pathogenic (or likely pathogenic) variants in an autosomal recessive AOS-related gene identified on 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 [ Molecular testing approaches can include Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found; however, it is unknown at present what proportion of individuals with AOS have intragenic deletions or duplications that cannot be detected by sequence analysis. For autosomal dominant or simplex (i.e., a single occurrence in a family) AOS: For autosomal recessive AOS with neurologic and ocular abnormalities: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adams-Oliver Syndrome (AOS) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance 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 this gene using gene-targeted deletion/duplication analysis are available. No data on detection rate of Wim Wuyts, unpublished data No data on detection rate of The genetic cause has not been found in individuals with AOS and severe or lethal pulmonary hypertension [Author, personal observation; including in 2 such individuals in whom testing of the 6 known genes revealed no pathogenic variants]. • Of note, when a scalp lesion is not obviously cutis aplasia (e.g., a simple hairless lesion may appear similar to nevus psiloliparus or nevus sebaceous), a skin biopsy can confirm the characteristic features of absent epidermis, dermal atrophy, and lack of adnexal structures and elastic fibers. Generally, a skin biopsy is not necessary because a nevus sebaceous has a yellowish waxy appearance versus the eroded or scarred appearance of ACC. • Almost any type of heart malformation can occur in AOS. • Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. • Widespread cutis marmorata telangiectatica congenita is common (19%). • Almost any type of heart malformation can occur in AOS. • Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. • Widespread cutis marmorata telangiectatica congenita is common (19%). • Almost any type of heart malformation can occur in AOS. • Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. • Widespread cutis marmorata telangiectatica congenita is common (19%). • The clinical findings of both aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD) • Either ACC or TTLD and a first-degree relative with findings consistent with AOS • Either ACC or TTLD and either a pathogenic (or likely pathogenic) variant in an autosomal dominant AOS-related gene or biallelic pathogenic (or likely pathogenic) variants in an autosomal recessive AOS-related gene identified on molecular genetic testing ( • For autosomal dominant or simplex (i.e., a single occurrence in a family) AOS: • For autosomal recessive AOS with neurologic and ocular abnormalities: ## Suggestive Findings Adams-Oliver syndrome (AOS) Of note, when a scalp lesion is not obviously cutis aplasia (e.g., a simple hairless lesion may appear similar to nevus psiloliparus or nevus sebaceous), a skin biopsy can confirm the characteristic features of absent epidermis, dermal atrophy, and lack of adnexal structures and elastic fibers. Generally, a skin biopsy is not necessary because a nevus sebaceous has a yellowish waxy appearance versus the eroded or scarred appearance of ACC. Almost any type of heart malformation can occur in AOS. Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. Widespread cutis marmorata telangiectatica congenita is common (19%). • Of note, when a scalp lesion is not obviously cutis aplasia (e.g., a simple hairless lesion may appear similar to nevus psiloliparus or nevus sebaceous), a skin biopsy can confirm the characteristic features of absent epidermis, dermal atrophy, and lack of adnexal structures and elastic fibers. Generally, a skin biopsy is not necessary because a nevus sebaceous has a yellowish waxy appearance versus the eroded or scarred appearance of ACC. • Almost any type of heart malformation can occur in AOS. • Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. • Widespread cutis marmorata telangiectatica congenita is common (19%). • Almost any type of heart malformation can occur in AOS. • Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. • Widespread cutis marmorata telangiectatica congenita is common (19%). • Almost any type of heart malformation can occur in AOS. • Vascular defects include incomplete retinal vascularization, CNS microbleeds that on imaging may mimic – and later result in – intracranial calcifications, hepatoportal sclerosis (i.e., non-cirrhotic or idiopathic portal hypertension), pulmonary vein stenosis, deficient gut vasculature, and aberrant vessels of placental chorionic villi. • Widespread cutis marmorata telangiectatica congenita is common (19%). ## Establishing the Diagnosis The diagnosis of Adams-Oliver syndrome (AOS) The clinical findings of both aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD) Either ACC or TTLD and a first-degree relative with findings consistent with AOS Either ACC or TTLD and either a pathogenic (or likely pathogenic) variant in an autosomal dominant AOS-related gene or biallelic pathogenic (or likely pathogenic) variants in an autosomal recessive AOS-related gene identified on 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 [ Molecular testing approaches can include Sequence analysis of the gene of interest is performed first, followed by gene-targeted deletion/duplication analysis if no pathogenic variant is found; however, it is unknown at present what proportion of individuals with AOS have intragenic deletions or duplications that cannot be detected by sequence analysis. For autosomal dominant or simplex (i.e., a single occurrence in a family) AOS: For autosomal recessive AOS with neurologic and ocular abnormalities: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Adams-Oliver Syndrome (AOS) AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance 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 this gene using gene-targeted deletion/duplication analysis are available. No data on detection rate of Wim Wuyts, unpublished data No data on detection rate of The genetic cause has not been found in individuals with AOS and severe or lethal pulmonary hypertension [Author, personal observation; including in 2 such individuals in whom testing of the 6 known genes revealed no pathogenic variants]. • The clinical findings of both aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD) • Either ACC or TTLD and a first-degree relative with findings consistent with AOS • Either ACC or TTLD and either a pathogenic (or likely pathogenic) variant in an autosomal dominant AOS-related gene or biallelic pathogenic (or likely pathogenic) variants in an autosomal recessive AOS-related gene identified on molecular genetic testing ( • For autosomal dominant or simplex (i.e., a single occurrence in a family) AOS: • For autosomal recessive AOS with neurologic and ocular abnormalities: ## Clinical Characteristics Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). Additional major features frequently include cardiovascular malformations/dysfunction and less frequently, renal and brain anomalies ( Frequency of Clinical Features Associated with Adams-Oliver Syndrome in Probands and Family Members Adapted from As reported in the literature The severity of malformations ranges from subtle to disabling or life threatening; variability among family members is common. Although rare, severe morbidity and mortality in AOS usually results from hemorrhage or infection involving large and deep calvarial lesions, or from cardiovascular anomalies including severe heart malformations. At least five children with AOS have died from refractory pulmonary hypertension (~1% risk), all in the first three years of life. Cutis aplasia lesions less than 5 cm often involve only the skin and almost always heal over a period of months into hairless, fibrotic patches with wound care measures only [ Larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage or thrombosis (especially of the sagittal sinus), brain herniation, CSF leakage, and seizures, and can result in death [ AOS-related ACC lesions – of the scalp and elsewhere – are generally non-membranous. Membranous ACC (appearing like a bulla) is hypothesized to arise from a different mechanism and may be associated with ectopic neural tissue and other findings such as a hair collar [ Cutis aplasia lesions histologically show variable absence of epidermis, dermis, subcutaneous tissue, muscle, or bone. CMTC typically includes areas of phlebectasia, skin atrophy, or ulceration; when severe, CMTC is often associated with hypoplasia of the underlying structures (e.g., a smaller limb). Despite its name, telangiectasiae are only found in a minority of those with CMTC. Cutis marmorata (CM), a milder vascular skin marbling phenomenon, is a normal physiologic finding in infants that shows marked enhancement with cold exposure or strong emotions and usually fades by age four months. Children with AOS may have more prominent CM than usual, but not have CMTC. A key distinction between CM and CMTC is that the vascular dilatation of CMTC does not fade markedly with local warming. The term transverse terminal limb defect (TTLD), which is used to describe the types of anomalies seen in AOS, indicates involvement of all elements distal to a certain point. (In contrast, longitudinal defects [e.g., isolated radial or fibular aplasia] are not observed in AOS.) Although a few individuals with AOS have strictly transverse limb reduction defects, most have mild medial to lateral gradients in severity (or less commonly, the reverse) and others have a medial ray defect in the form of ectrodactyly. The limb defects of AOS range from mild to severe. The mild end of the spectrum is unilateral or bilateral short distal phalanges, which may or may not affect all fingers or toes. Toes are almost always more severely affected than fingers. The nails may be dystrophic, shortened, or absent. Rarely, the distal phalanx may be present when the middle phalanx is absent [ Cutaneous or osseous syndactyly is often present. Occasionally, oligodactyly (entirely missing fingers or toes) or camptodactyly (fixed contracture of phalangeal joints) is observed. The severe end of the spectrum can involve complete absence of all toes or fingers, feet or hands, or more. The appearance of a TTLD can often resemble an amputation. Constriction rings and necrotic lesions have been observed [ Most individuals with AOS retain prehension of the thumb and fingers. Milder involvement, with fully preserved function, is much more common than severe involvement [Authors, personal observation]. Poland syndrome, the combination of unilateral aplasia of part of the pectoralis muscle and ipsilateral upper limb anomalies, has been reported convincingly in one family [ Radiographs can be helpful in delineating which bones are short; one would expect distal phalanges to be more severely affected than proximal phalanges, which in turn would be more affected than metacarpals. Twenty-three percent of individuals with AOS have a major congenital cardiac malformation which can include left-sided obstructive lesions (bicuspid aortic valve, hypoplastic left ventricle, Shone's complex), septal defects, and conotruncal defects (tetralogy of Fallot, truncus arteriosus) [ Non-cirrhotic or idiopathic portal hypertension (also known as hepatoportal sclerosis), which is likely secondary to hepatic venulopathy or thrombosis, occurs in fewer than 10% of affected individuals [ Pulmonary hypertension occurs in fewer than 5% of individuals with AOS, but when present is associated with high mortality [ Other cardiovascular problems that may be present: Pulmonary vein stenosis, hypoplastic pulmonary and cerebral arteries [ Pulmonary or intracranial arteriovenous and hemangiomatous malformations [ Cerebral microbleeds that can mimic intracerebral calcifications on neuroimaging studies [ Dilated, tortuous scalp veins (common) Absent intrahepatic portal vein [ Abnormal hepatic microvasculature Abnormal renal microvasculature [ Vascular anomalies of the limbs (such as femoral artery duplication) [ Small bowel infarction [ Dilated, tortuous placental blood vessels [ Although the majority of individuals with AOS have no neurologic deficits, a significant minority have a range of clinical and neuroimaging findings including the following [ Possible clinical findings: Cognitive disability, dyslexia, autism spectrum disorders Spastic hemiplegia or diplegia Seizures Possible imaging findings: Brain malformations and migration defects: microcephaly, cortical dysplasia, polymicrogyria, pachygyria, dysgenetic corpus callosum Cortical atrophy with ventriculomegaly, cerebral hemorrhage, intracranial calcifications (often periventricular) Delayed myelination Brain involvement appears to associate with more severe vascular phenotypes, suggesting that impaired vascular supply to the developing brain may be a key component of pathogenesis for neurologic findings. Although most individuals with brain involvement do not have an affected parent (suggesting either autosomal recessive inheritance or a The severity of neurologic impairment can be such that central respiratory insufficiency can cause early death [ One individual has been reported with Tourette syndrome, which was not noted in two other sibs with AOS [ Renal anomalies are rare and usually consist of small kidneys, hydronephrosis, or renal cortical vascular anomalies. The ophthalmologic complications of AOS can include the following [ Microphthalmos Peters anomaly-like findings Cataracts Retinal folds Incomplete or abnormal retinal vasculature (including persistent fetal vasculature) Esotropia Optic nerve hypoplasia / optic atrophy Rod dystrophy Incomplete vascularization and fibrovascular proliferative ischemic retinopathy can appear similar to retinopathy of prematurity or certain cases of Other rarely reported, not necessarily associated findings include: Midline frontonasal cysts (a single family only [ Cleft lip/palate Supernumerary nipples Dilated cardiomyopathy (may be secondary to CHD [ Gastroschisis Umbilical hernia Diastasis recti Cryptorchidism Prenatal growth restriction or postnatal impaired growth in severe forms of AOS While subtypes of AOS have not been established, emerging data suggest: High risk for severe brain involvement in Increased risk for cardiac defects in For the genes known to be associated with Adams-Oliver syndrome, no genotype-phenotype correlations (either with a class of pathogenic variants or with any specific pathogenic variants) have been identified. Familial autosomal dominant AOS typically shows decreased penetrance. A sporadic co-occurrence of ACC and TTLD was first reported by An estimate of the incidence for AOS is 0.44 per 100,000 live births [ The authors' experience in a tertiary pediatric care center supports a somewhat higher incidence, and further recognition of milder phenotypes within the spectrum of AOS may yet reveal a significantly higher incidence. • Pulmonary vein stenosis, hypoplastic pulmonary and cerebral arteries [ • Pulmonary or intracranial arteriovenous and hemangiomatous malformations [ • Cerebral microbleeds that can mimic intracerebral calcifications on neuroimaging studies [ • Dilated, tortuous scalp veins (common) • Absent intrahepatic portal vein [ • Abnormal hepatic microvasculature • Abnormal renal microvasculature [ • Vascular anomalies of the limbs (such as femoral artery duplication) [ • Small bowel infarction [ • Dilated, tortuous placental blood vessels [ • Cognitive disability, dyslexia, autism spectrum disorders • Spastic hemiplegia or diplegia • Seizures • Brain malformations and migration defects: microcephaly, cortical dysplasia, polymicrogyria, pachygyria, dysgenetic corpus callosum • Cortical atrophy with ventriculomegaly, cerebral hemorrhage, intracranial calcifications (often periventricular) • Delayed myelination • Microphthalmos • Peters anomaly-like findings • Cataracts • Retinal folds • Incomplete or abnormal retinal vasculature (including persistent fetal vasculature) • Esotropia • Optic nerve hypoplasia / optic atrophy • Rod dystrophy • Midline frontonasal cysts (a single family only [ • Cleft lip/palate • Supernumerary nipples • Dilated cardiomyopathy (may be secondary to CHD [ • Gastroschisis • Umbilical hernia • Diastasis recti • Cryptorchidism • Prenatal growth restriction or postnatal impaired growth in severe forms of AOS • High risk for severe brain involvement in • Increased risk for cardiac defects in ## Clinical Description Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). Additional major features frequently include cardiovascular malformations/dysfunction and less frequently, renal and brain anomalies ( Frequency of Clinical Features Associated with Adams-Oliver Syndrome in Probands and Family Members Adapted from As reported in the literature The severity of malformations ranges from subtle to disabling or life threatening; variability among family members is common. Although rare, severe morbidity and mortality in AOS usually results from hemorrhage or infection involving large and deep calvarial lesions, or from cardiovascular anomalies including severe heart malformations. At least five children with AOS have died from refractory pulmonary hypertension (~1% risk), all in the first three years of life. Cutis aplasia lesions less than 5 cm often involve only the skin and almost always heal over a period of months into hairless, fibrotic patches with wound care measures only [ Larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage or thrombosis (especially of the sagittal sinus), brain herniation, CSF leakage, and seizures, and can result in death [ AOS-related ACC lesions – of the scalp and elsewhere – are generally non-membranous. Membranous ACC (appearing like a bulla) is hypothesized to arise from a different mechanism and may be associated with ectopic neural tissue and other findings such as a hair collar [ Cutis aplasia lesions histologically show variable absence of epidermis, dermis, subcutaneous tissue, muscle, or bone. CMTC typically includes areas of phlebectasia, skin atrophy, or ulceration; when severe, CMTC is often associated with hypoplasia of the underlying structures (e.g., a smaller limb). Despite its name, telangiectasiae are only found in a minority of those with CMTC. Cutis marmorata (CM), a milder vascular skin marbling phenomenon, is a normal physiologic finding in infants that shows marked enhancement with cold exposure or strong emotions and usually fades by age four months. Children with AOS may have more prominent CM than usual, but not have CMTC. A key distinction between CM and CMTC is that the vascular dilatation of CMTC does not fade markedly with local warming. The term transverse terminal limb defect (TTLD), which is used to describe the types of anomalies seen in AOS, indicates involvement of all elements distal to a certain point. (In contrast, longitudinal defects [e.g., isolated radial or fibular aplasia] are not observed in AOS.) Although a few individuals with AOS have strictly transverse limb reduction defects, most have mild medial to lateral gradients in severity (or less commonly, the reverse) and others have a medial ray defect in the form of ectrodactyly. The limb defects of AOS range from mild to severe. The mild end of the spectrum is unilateral or bilateral short distal phalanges, which may or may not affect all fingers or toes. Toes are almost always more severely affected than fingers. The nails may be dystrophic, shortened, or absent. Rarely, the distal phalanx may be present when the middle phalanx is absent [ Cutaneous or osseous syndactyly is often present. Occasionally, oligodactyly (entirely missing fingers or toes) or camptodactyly (fixed contracture of phalangeal joints) is observed. The severe end of the spectrum can involve complete absence of all toes or fingers, feet or hands, or more. The appearance of a TTLD can often resemble an amputation. Constriction rings and necrotic lesions have been observed [ Most individuals with AOS retain prehension of the thumb and fingers. Milder involvement, with fully preserved function, is much more common than severe involvement [Authors, personal observation]. Poland syndrome, the combination of unilateral aplasia of part of the pectoralis muscle and ipsilateral upper limb anomalies, has been reported convincingly in one family [ Radiographs can be helpful in delineating which bones are short; one would expect distal phalanges to be more severely affected than proximal phalanges, which in turn would be more affected than metacarpals. Twenty-three percent of individuals with AOS have a major congenital cardiac malformation which can include left-sided obstructive lesions (bicuspid aortic valve, hypoplastic left ventricle, Shone's complex), septal defects, and conotruncal defects (tetralogy of Fallot, truncus arteriosus) [ Non-cirrhotic or idiopathic portal hypertension (also known as hepatoportal sclerosis), which is likely secondary to hepatic venulopathy or thrombosis, occurs in fewer than 10% of affected individuals [ Pulmonary hypertension occurs in fewer than 5% of individuals with AOS, but when present is associated with high mortality [ Other cardiovascular problems that may be present: Pulmonary vein stenosis, hypoplastic pulmonary and cerebral arteries [ Pulmonary or intracranial arteriovenous and hemangiomatous malformations [ Cerebral microbleeds that can mimic intracerebral calcifications on neuroimaging studies [ Dilated, tortuous scalp veins (common) Absent intrahepatic portal vein [ Abnormal hepatic microvasculature Abnormal renal microvasculature [ Vascular anomalies of the limbs (such as femoral artery duplication) [ Small bowel infarction [ Dilated, tortuous placental blood vessels [ Although the majority of individuals with AOS have no neurologic deficits, a significant minority have a range of clinical and neuroimaging findings including the following [ Possible clinical findings: Cognitive disability, dyslexia, autism spectrum disorders Spastic hemiplegia or diplegia Seizures Possible imaging findings: Brain malformations and migration defects: microcephaly, cortical dysplasia, polymicrogyria, pachygyria, dysgenetic corpus callosum Cortical atrophy with ventriculomegaly, cerebral hemorrhage, intracranial calcifications (often periventricular) Delayed myelination Brain involvement appears to associate with more severe vascular phenotypes, suggesting that impaired vascular supply to the developing brain may be a key component of pathogenesis for neurologic findings. Although most individuals with brain involvement do not have an affected parent (suggesting either autosomal recessive inheritance or a The severity of neurologic impairment can be such that central respiratory insufficiency can cause early death [ One individual has been reported with Tourette syndrome, which was not noted in two other sibs with AOS [ Renal anomalies are rare and usually consist of small kidneys, hydronephrosis, or renal cortical vascular anomalies. The ophthalmologic complications of AOS can include the following [ Microphthalmos Peters anomaly-like findings Cataracts Retinal folds Incomplete or abnormal retinal vasculature (including persistent fetal vasculature) Esotropia Optic nerve hypoplasia / optic atrophy Rod dystrophy Incomplete vascularization and fibrovascular proliferative ischemic retinopathy can appear similar to retinopathy of prematurity or certain cases of Other rarely reported, not necessarily associated findings include: Midline frontonasal cysts (a single family only [ Cleft lip/palate Supernumerary nipples Dilated cardiomyopathy (may be secondary to CHD [ Gastroschisis Umbilical hernia Diastasis recti Cryptorchidism Prenatal growth restriction or postnatal impaired growth in severe forms of AOS • Pulmonary vein stenosis, hypoplastic pulmonary and cerebral arteries [ • Pulmonary or intracranial arteriovenous and hemangiomatous malformations [ • Cerebral microbleeds that can mimic intracerebral calcifications on neuroimaging studies [ • Dilated, tortuous scalp veins (common) • Absent intrahepatic portal vein [ • Abnormal hepatic microvasculature • Abnormal renal microvasculature [ • Vascular anomalies of the limbs (such as femoral artery duplication) [ • Small bowel infarction [ • Dilated, tortuous placental blood vessels [ • Cognitive disability, dyslexia, autism spectrum disorders • Spastic hemiplegia or diplegia • Seizures • Brain malformations and migration defects: microcephaly, cortical dysplasia, polymicrogyria, pachygyria, dysgenetic corpus callosum • Cortical atrophy with ventriculomegaly, cerebral hemorrhage, intracranial calcifications (often periventricular) • Delayed myelination • Microphthalmos • Peters anomaly-like findings • Cataracts • Retinal folds • Incomplete or abnormal retinal vasculature (including persistent fetal vasculature) • Esotropia • Optic nerve hypoplasia / optic atrophy • Rod dystrophy • Midline frontonasal cysts (a single family only [ • Cleft lip/palate • Supernumerary nipples • Dilated cardiomyopathy (may be secondary to CHD [ • Gastroschisis • Umbilical hernia • Diastasis recti • Cryptorchidism • Prenatal growth restriction or postnatal impaired growth in severe forms of AOS ## Cutaneous/Cranial Cutis aplasia lesions less than 5 cm often involve only the skin and almost always heal over a period of months into hairless, fibrotic patches with wound care measures only [ Larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage or thrombosis (especially of the sagittal sinus), brain herniation, CSF leakage, and seizures, and can result in death [ AOS-related ACC lesions – of the scalp and elsewhere – are generally non-membranous. Membranous ACC (appearing like a bulla) is hypothesized to arise from a different mechanism and may be associated with ectopic neural tissue and other findings such as a hair collar [ Cutis aplasia lesions histologically show variable absence of epidermis, dermis, subcutaneous tissue, muscle, or bone. CMTC typically includes areas of phlebectasia, skin atrophy, or ulceration; when severe, CMTC is often associated with hypoplasia of the underlying structures (e.g., a smaller limb). Despite its name, telangiectasiae are only found in a minority of those with CMTC. Cutis marmorata (CM), a milder vascular skin marbling phenomenon, is a normal physiologic finding in infants that shows marked enhancement with cold exposure or strong emotions and usually fades by age four months. Children with AOS may have more prominent CM than usual, but not have CMTC. A key distinction between CM and CMTC is that the vascular dilatation of CMTC does not fade markedly with local warming. ## Limb The term transverse terminal limb defect (TTLD), which is used to describe the types of anomalies seen in AOS, indicates involvement of all elements distal to a certain point. (In contrast, longitudinal defects [e.g., isolated radial or fibular aplasia] are not observed in AOS.) Although a few individuals with AOS have strictly transverse limb reduction defects, most have mild medial to lateral gradients in severity (or less commonly, the reverse) and others have a medial ray defect in the form of ectrodactyly. The limb defects of AOS range from mild to severe. The mild end of the spectrum is unilateral or bilateral short distal phalanges, which may or may not affect all fingers or toes. Toes are almost always more severely affected than fingers. The nails may be dystrophic, shortened, or absent. Rarely, the distal phalanx may be present when the middle phalanx is absent [ Cutaneous or osseous syndactyly is often present. Occasionally, oligodactyly (entirely missing fingers or toes) or camptodactyly (fixed contracture of phalangeal joints) is observed. The severe end of the spectrum can involve complete absence of all toes or fingers, feet or hands, or more. The appearance of a TTLD can often resemble an amputation. Constriction rings and necrotic lesions have been observed [ Most individuals with AOS retain prehension of the thumb and fingers. Milder involvement, with fully preserved function, is much more common than severe involvement [Authors, personal observation]. Poland syndrome, the combination of unilateral aplasia of part of the pectoralis muscle and ipsilateral upper limb anomalies, has been reported convincingly in one family [ Radiographs can be helpful in delineating which bones are short; one would expect distal phalanges to be more severely affected than proximal phalanges, which in turn would be more affected than metacarpals. ## Cardiovascular Twenty-three percent of individuals with AOS have a major congenital cardiac malformation which can include left-sided obstructive lesions (bicuspid aortic valve, hypoplastic left ventricle, Shone's complex), septal defects, and conotruncal defects (tetralogy of Fallot, truncus arteriosus) [ Non-cirrhotic or idiopathic portal hypertension (also known as hepatoportal sclerosis), which is likely secondary to hepatic venulopathy or thrombosis, occurs in fewer than 10% of affected individuals [ Pulmonary hypertension occurs in fewer than 5% of individuals with AOS, but when present is associated with high mortality [ Other cardiovascular problems that may be present: Pulmonary vein stenosis, hypoplastic pulmonary and cerebral arteries [ Pulmonary or intracranial arteriovenous and hemangiomatous malformations [ Cerebral microbleeds that can mimic intracerebral calcifications on neuroimaging studies [ Dilated, tortuous scalp veins (common) Absent intrahepatic portal vein [ Abnormal hepatic microvasculature Abnormal renal microvasculature [ Vascular anomalies of the limbs (such as femoral artery duplication) [ Small bowel infarction [ Dilated, tortuous placental blood vessels [ • Pulmonary vein stenosis, hypoplastic pulmonary and cerebral arteries [ • Pulmonary or intracranial arteriovenous and hemangiomatous malformations [ • Cerebral microbleeds that can mimic intracerebral calcifications on neuroimaging studies [ • Dilated, tortuous scalp veins (common) • Absent intrahepatic portal vein [ • Abnormal hepatic microvasculature • Abnormal renal microvasculature [ • Vascular anomalies of the limbs (such as femoral artery duplication) [ • Small bowel infarction [ • Dilated, tortuous placental blood vessels [ ## Neurologic Although the majority of individuals with AOS have no neurologic deficits, a significant minority have a range of clinical and neuroimaging findings including the following [ Possible clinical findings: Cognitive disability, dyslexia, autism spectrum disorders Spastic hemiplegia or diplegia Seizures Possible imaging findings: Brain malformations and migration defects: microcephaly, cortical dysplasia, polymicrogyria, pachygyria, dysgenetic corpus callosum Cortical atrophy with ventriculomegaly, cerebral hemorrhage, intracranial calcifications (often periventricular) Delayed myelination Brain involvement appears to associate with more severe vascular phenotypes, suggesting that impaired vascular supply to the developing brain may be a key component of pathogenesis for neurologic findings. Although most individuals with brain involvement do not have an affected parent (suggesting either autosomal recessive inheritance or a The severity of neurologic impairment can be such that central respiratory insufficiency can cause early death [ One individual has been reported with Tourette syndrome, which was not noted in two other sibs with AOS [ • Cognitive disability, dyslexia, autism spectrum disorders • Spastic hemiplegia or diplegia • Seizures • Brain malformations and migration defects: microcephaly, cortical dysplasia, polymicrogyria, pachygyria, dysgenetic corpus callosum • Cortical atrophy with ventriculomegaly, cerebral hemorrhage, intracranial calcifications (often periventricular) • Delayed myelination ## Renal Renal anomalies are rare and usually consist of small kidneys, hydronephrosis, or renal cortical vascular anomalies. ## Ocular The ophthalmologic complications of AOS can include the following [ Microphthalmos Peters anomaly-like findings Cataracts Retinal folds Incomplete or abnormal retinal vasculature (including persistent fetal vasculature) Esotropia Optic nerve hypoplasia / optic atrophy Rod dystrophy Incomplete vascularization and fibrovascular proliferative ischemic retinopathy can appear similar to retinopathy of prematurity or certain cases of • Microphthalmos • Peters anomaly-like findings • Cataracts • Retinal folds • Incomplete or abnormal retinal vasculature (including persistent fetal vasculature) • Esotropia • Optic nerve hypoplasia / optic atrophy • Rod dystrophy ## Other Other rarely reported, not necessarily associated findings include: Midline frontonasal cysts (a single family only [ Cleft lip/palate Supernumerary nipples Dilated cardiomyopathy (may be secondary to CHD [ Gastroschisis Umbilical hernia Diastasis recti Cryptorchidism Prenatal growth restriction or postnatal impaired growth in severe forms of AOS • Midline frontonasal cysts (a single family only [ • Cleft lip/palate • Supernumerary nipples • Dilated cardiomyopathy (may be secondary to CHD [ • Gastroschisis • Umbilical hernia • Diastasis recti • Cryptorchidism • Prenatal growth restriction or postnatal impaired growth in severe forms of AOS ## Possible Phenotype Correlations by Gene While subtypes of AOS have not been established, emerging data suggest: High risk for severe brain involvement in Increased risk for cardiac defects in • High risk for severe brain involvement in • Increased risk for cardiac defects in ## Genotype-Phenotype Correlations For the genes known to be associated with Adams-Oliver syndrome, no genotype-phenotype correlations (either with a class of pathogenic variants or with any specific pathogenic variants) have been identified. ## Penetrance Familial autosomal dominant AOS typically shows decreased penetrance. ## Nomenclature A sporadic co-occurrence of ACC and TTLD was first reported by ## Prevalence An estimate of the incidence for AOS is 0.44 per 100,000 live births [ The authors' experience in a tertiary pediatric care center supports a somewhat higher incidence, and further recognition of milder phenotypes within the spectrum of AOS may yet reveal a significantly higher incidence. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Other phenotypes observed in Several variants have been associated with autosomal dominant congenital heart defects affecting the left ventricular outflow tract (LVOT), most commonly bicuspid aortic valve (BAV), with an additional frequent feature of adult-onset precocious aortic valve calcification [ Rare • Several variants have been associated with autosomal dominant congenital heart defects affecting the left ventricular outflow tract (LVOT), most commonly bicuspid aortic valve (BAV), with an additional frequent feature of adult-onset precocious aortic valve calcification [ • Rare ## Differential Diagnosis Variable combinations of ACC of the scalp (usually in the vertex or occipital region), hypothelia/athelia, mammary hypoplasia, ear anomalies (either cupped, overfolded, or hypoplastic) Variable digital anomalies including distal hypoplasia, syndactyly and camptodactyly Occasional hypodontia, renal hypoplasia/malformations or ocular anomalies (colobomata or cataracts) Normal intellectual development; however, affected sibs in one family presented with severe hypotonia and developmental delay, and a severe autosomal recessive form of the condition was suspected [ SEN syndrome is caused by mutation of Multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face Can feature both cutis aplasia and limb anomalies (syndactyly, polydactyly, camptodactyly or oligodactyly). A distinguishing feature from AOS is that the dermal hypoplasia usually follows lines of Blaschko. Other distinguishing features include ectodermal dysplasia, subepidermal deposits of subcutaneous fat, metaphyseal striations, and papillomas of the skin and mucous membranes. Focal dermal hypoplasia is inherited in an X-linked manner. Females (90% of affected individuals) are heterozygous or mosaic for a Typically, ACC lesions are restricted to the limbs and the clinical diagnosis is clear from persistent skin fragility and blistering postnatally. Limb anomalies are generally limited to absence of the nails. DDEB is caused by mutation of Chromosome disorders Trisomy 13 (Patau syndrome) Wolf-Hirschhorn syndrome (4p- syndrome; OMIM Setleis syndrome (focal facial dermal dysplasia 3; OMIM Johanson-Blizzard syndrome (See Oculocerebrocutaneous (Delleman) syndrome (OMIM Limb body wall complex Knobloch syndrome (OMIM Various ectodermal dysplasias Estimated to occur in one in 3,000 live births, most often as an isolated, sporadic malformation [ Familial recurrence is rarely observed, and can be caused by a heterozygous pathogenic variant in Hypoproliferation and/or impaired differentiation at a location of rapid growth (the cranium) have been hypothesized as part of the pathogenesis for this condition [ Birth trauma (e.g., scalp electrode avulsion) Amniotic bands Intrauterine vascular disruption (e.g., secondary to embolism from co-twin loss) Teratogens (misoprostol, cocaine, methotrexate, angiotensin-converting enzyme inhibitors, methimazole, benzodiazepines, valproic acid) [ Toes and fingers show limb reductions with absent or hypoplastic nails, often involving partial syndactyly. Duplicated metacarpals or metatarsals may be seen. Other features are mild to moderate macrocytic anemia and evidence of ineffective erythropoiesis on bone marrow aspirates. Jaundice, early onset gallstone formation, and splenomegaly may also be seen. CBC with blood smear should be performed in individuals with TTLD to assess for the macrocytic anemia of congenital dyserythropoietic anemia. Congenital dyserythropoietic anemia type I is caused by mutation of One individual with retinopathy of prematurity, small toes, VSD, but no cutis aplasia, was diagnosed initially with Another individual was suspected to have a variant of AOS on the basis of cutis marmorata, arterial hypertension, dilated aorta, cerebral calcifications, mild hypotrichosis, and dystrophic nails [ • Variable combinations of ACC of the scalp (usually in the vertex or occipital region), hypothelia/athelia, mammary hypoplasia, ear anomalies (either cupped, overfolded, or hypoplastic) • Variable digital anomalies including distal hypoplasia, syndactyly and camptodactyly • Occasional hypodontia, renal hypoplasia/malformations or ocular anomalies (colobomata or cataracts) • Normal intellectual development; however, affected sibs in one family presented with severe hypotonia and developmental delay, and a severe autosomal recessive form of the condition was suspected [ • Multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face • Can feature both cutis aplasia and limb anomalies (syndactyly, polydactyly, camptodactyly or oligodactyly). • A distinguishing feature from AOS is that the dermal hypoplasia usually follows lines of Blaschko. • Other distinguishing features include ectodermal dysplasia, subepidermal deposits of subcutaneous fat, metaphyseal striations, and papillomas of the skin and mucous membranes. • Typically, ACC lesions are restricted to the limbs and the clinical diagnosis is clear from persistent skin fragility and blistering postnatally. • Limb anomalies are generally limited to absence of the nails. • DDEB is caused by mutation of • Chromosome disorders • Trisomy 13 (Patau syndrome) • Wolf-Hirschhorn syndrome (4p- syndrome; OMIM • Trisomy 13 (Patau syndrome) • Wolf-Hirschhorn syndrome (4p- syndrome; OMIM • Setleis syndrome (focal facial dermal dysplasia 3; OMIM • Johanson-Blizzard syndrome (See • Oculocerebrocutaneous (Delleman) syndrome (OMIM • • Limb body wall complex • Knobloch syndrome (OMIM • Various ectodermal dysplasias • Trisomy 13 (Patau syndrome) • Wolf-Hirschhorn syndrome (4p- syndrome; OMIM • Estimated to occur in one in 3,000 live births, most often as an isolated, sporadic malformation [ • Familial recurrence is rarely observed, and can be caused by a heterozygous pathogenic variant in • Hypoproliferation and/or impaired differentiation at a location of rapid growth (the cranium) have been hypothesized as part of the pathogenesis for this condition [ • Birth trauma (e.g., scalp electrode avulsion) • Amniotic bands • Intrauterine vascular disruption (e.g., secondary to embolism from co-twin loss) • Teratogens (misoprostol, cocaine, methotrexate, angiotensin-converting enzyme inhibitors, methimazole, benzodiazepines, valproic acid) [ • Toes and fingers show limb reductions with absent or hypoplastic nails, often involving partial syndactyly. • Duplicated metacarpals or metatarsals may be seen. • Other features are mild to moderate macrocytic anemia and evidence of ineffective erythropoiesis on bone marrow aspirates. • Jaundice, early onset gallstone formation, and splenomegaly may also be seen. • CBC with blood smear should be performed in individuals with TTLD to assess for the macrocytic anemia of congenital dyserythropoietic anemia. • Congenital dyserythropoietic anemia type I is caused by mutation of ## Syndromic Aplasia Cutis Congenita (ACC) Variable combinations of ACC of the scalp (usually in the vertex or occipital region), hypothelia/athelia, mammary hypoplasia, ear anomalies (either cupped, overfolded, or hypoplastic) Variable digital anomalies including distal hypoplasia, syndactyly and camptodactyly Occasional hypodontia, renal hypoplasia/malformations or ocular anomalies (colobomata or cataracts) Normal intellectual development; however, affected sibs in one family presented with severe hypotonia and developmental delay, and a severe autosomal recessive form of the condition was suspected [ SEN syndrome is caused by mutation of Multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face Can feature both cutis aplasia and limb anomalies (syndactyly, polydactyly, camptodactyly or oligodactyly). A distinguishing feature from AOS is that the dermal hypoplasia usually follows lines of Blaschko. Other distinguishing features include ectodermal dysplasia, subepidermal deposits of subcutaneous fat, metaphyseal striations, and papillomas of the skin and mucous membranes. Focal dermal hypoplasia is inherited in an X-linked manner. Females (90% of affected individuals) are heterozygous or mosaic for a Typically, ACC lesions are restricted to the limbs and the clinical diagnosis is clear from persistent skin fragility and blistering postnatally. Limb anomalies are generally limited to absence of the nails. DDEB is caused by mutation of Chromosome disorders Trisomy 13 (Patau syndrome) Wolf-Hirschhorn syndrome (4p- syndrome; OMIM Setleis syndrome (focal facial dermal dysplasia 3; OMIM Johanson-Blizzard syndrome (See Oculocerebrocutaneous (Delleman) syndrome (OMIM Limb body wall complex Knobloch syndrome (OMIM Various ectodermal dysplasias Estimated to occur in one in 3,000 live births, most often as an isolated, sporadic malformation [ Familial recurrence is rarely observed, and can be caused by a heterozygous pathogenic variant in Hypoproliferation and/or impaired differentiation at a location of rapid growth (the cranium) have been hypothesized as part of the pathogenesis for this condition [ Birth trauma (e.g., scalp electrode avulsion) Amniotic bands Intrauterine vascular disruption (e.g., secondary to embolism from co-twin loss) Teratogens (misoprostol, cocaine, methotrexate, angiotensin-converting enzyme inhibitors, methimazole, benzodiazepines, valproic acid) [ • Variable combinations of ACC of the scalp (usually in the vertex or occipital region), hypothelia/athelia, mammary hypoplasia, ear anomalies (either cupped, overfolded, or hypoplastic) • Variable digital anomalies including distal hypoplasia, syndactyly and camptodactyly • Occasional hypodontia, renal hypoplasia/malformations or ocular anomalies (colobomata or cataracts) • Normal intellectual development; however, affected sibs in one family presented with severe hypotonia and developmental delay, and a severe autosomal recessive form of the condition was suspected [ • Multisystem disorder characterized primarily by involvement of the skin, skeletal system, eyes, and face • Can feature both cutis aplasia and limb anomalies (syndactyly, polydactyly, camptodactyly or oligodactyly). • A distinguishing feature from AOS is that the dermal hypoplasia usually follows lines of Blaschko. • Other distinguishing features include ectodermal dysplasia, subepidermal deposits of subcutaneous fat, metaphyseal striations, and papillomas of the skin and mucous membranes. • Typically, ACC lesions are restricted to the limbs and the clinical diagnosis is clear from persistent skin fragility and blistering postnatally. • Limb anomalies are generally limited to absence of the nails. • DDEB is caused by mutation of • Chromosome disorders • Trisomy 13 (Patau syndrome) • Wolf-Hirschhorn syndrome (4p- syndrome; OMIM • Trisomy 13 (Patau syndrome) • Wolf-Hirschhorn syndrome (4p- syndrome; OMIM • Setleis syndrome (focal facial dermal dysplasia 3; OMIM • Johanson-Blizzard syndrome (See • Oculocerebrocutaneous (Delleman) syndrome (OMIM • • Limb body wall complex • Knobloch syndrome (OMIM • Various ectodermal dysplasias • Trisomy 13 (Patau syndrome) • Wolf-Hirschhorn syndrome (4p- syndrome; OMIM • Estimated to occur in one in 3,000 live births, most often as an isolated, sporadic malformation [ • Familial recurrence is rarely observed, and can be caused by a heterozygous pathogenic variant in • Hypoproliferation and/or impaired differentiation at a location of rapid growth (the cranium) have been hypothesized as part of the pathogenesis for this condition [ • Birth trauma (e.g., scalp electrode avulsion) • Amniotic bands • Intrauterine vascular disruption (e.g., secondary to embolism from co-twin loss) • Teratogens (misoprostol, cocaine, methotrexate, angiotensin-converting enzyme inhibitors, methimazole, benzodiazepines, valproic acid) [ ## Terminal Transverse Limb Defects (TTLD) Toes and fingers show limb reductions with absent or hypoplastic nails, often involving partial syndactyly. Duplicated metacarpals or metatarsals may be seen. Other features are mild to moderate macrocytic anemia and evidence of ineffective erythropoiesis on bone marrow aspirates. Jaundice, early onset gallstone formation, and splenomegaly may also be seen. CBC with blood smear should be performed in individuals with TTLD to assess for the macrocytic anemia of congenital dyserythropoietic anemia. Congenital dyserythropoietic anemia type I is caused by mutation of • Toes and fingers show limb reductions with absent or hypoplastic nails, often involving partial syndactyly. • Duplicated metacarpals or metatarsals may be seen. • Other features are mild to moderate macrocytic anemia and evidence of ineffective erythropoiesis on bone marrow aspirates. • Jaundice, early onset gallstone formation, and splenomegaly may also be seen. • CBC with blood smear should be performed in individuals with TTLD to assess for the macrocytic anemia of congenital dyserythropoietic anemia. • Congenital dyserythropoietic anemia type I is caused by mutation of ## Other One individual with retinopathy of prematurity, small toes, VSD, but no cutis aplasia, was diagnosed initially with Another individual was suspected to have a variant of AOS on the basis of cutis marmorata, arterial hypertension, dilated aorta, cerebral calcifications, mild hypotrichosis, and dystrophic nails [ ## Management To establish the extent of disease and needs in an individual diagnosed with Adams-Oliver syndrome (AOS), the following evaluations are recommended. Consultation with a plastic surgeon regarding aplasia cutis congenita (ACC) or any significant cutis aplasia on the body Consultation with a dermatologist, which may be especially useful in those with extensive cutis marmorata telangiectatica congenita (CMTC) Consideration of skull x-ray; on occasion a bony defect may be present even in the absence of ACC, which may require use of a protective helmet. Ultrasonography and CT can also help assess skull involvement. Consultation with a neurosurgeon in children with a significant calvarial defect Consultation with a pediatric cardiologist. Echocardiography should be performed even when clinical signs of congenital heart disease are absent. Any evidence for pulmonary hypertension should be sought. Systemic blood pressure should be checked. Abdominal ultrasound examination should be performed to check for splenomegaly and patency of the portal vein. Brain MRI to delineate any brain malformations and identify lesions suggestive of micro-hemorrhage or ischemia. Infants with brain anomalies are at increased risk for seizures, developmental delay, or motor deficits and warrant evaluation and close follow up by developmental specialists. MR angiography and venography to show the vascular anatomy. Surgical procedures may result in unexpected complications if anomalous vasculature is unrecognized. MRI and MRV are also important to guide wound care when the ACC lesion is large and to determine whether protection of the superior sagittal sinus is sufficient. Abdominal ultrasound to look for liver or renal anomalies Consultation with a clinical geneticist and/or genetic counselor Consultation with a pediatric dermatologist or plastic surgeon provides individualized management. The goals of non-operative therapy are to prevent infection and promote healing. Other less preferred, less costly dressings are: Sterile saline-soaked gauze/compresses (wet-to-wet), which should be changed every four hours. Although this labor-intensive option is effective, it is not frequently used anymore. Silver sulfadiazine dressings changed twice daily work well in older children, but these cannot be used in infants younger than age two months (corrected for prematurity) because of the risk of accompanying electrolyte disturbance. It is critically important to avoid drying of the wound and eschar separation, which can lead to catastrophic, terminal hemorrhage from the sagittal sinus or from a dilated vein. One option is a dermal regeneration plate (a porous matrix of bovine tendon collagen and glycosaminoglycan) and a semipermeable silicone layer (which provides a framework for cell migration) which is applied in the operating room to a meticulously debrided wound and then monitored for infection [ In one child with a CSF leak, a biocellulose membrane provided a barrier and supported eventual healing [ It has been suggested that debridement over the midline be avoided (if possible) to decrease the risk of fatal hemorrhage from the sagittal sinus [ A surgical procedure may be necessary for more severe defects (e.g., large areas of aplasia cutis congenita on the scalp or skull abnormalities) or wounds complicated by hemorrhage, infection, or CSF leakage. Although some infants have received skin grafts [ Use of abdominal muscle fascia to cover exposed dura has been reported [ Cranioplasty, if needed, is usually considered around age three to four years [ Bone grafting in the neonatal period using unaffected skull, with coverage of the sampled site with vascularized peri-osteum, has been reported [ Use of a split rib graft with a latissimus dorsi muscle flap has also been reported. After healing is complete, scar revision with tissue expansion for cosmesis can be discussed. When the defect is severe the hair-bearing scalp may not be able to completely restore hair to the entire scalp even with tissue expansion. Limb malformations may warrant consultation with specialists in orthopedics, plastic surgery, and/or rehabilitation medicine. X-rays of limbs are often performed immediately after birth but are most informative, in terms of delineating the extent of involvement, after age one year. Many AOS limb anomalies are not severe enough to require surgical or prosthetic intervention. Occupational therapy and/or physical therapy is used as needed to assist with limb functioning, such as to improve walking and running stability in those with abnormal toes. Analysis in a gait laboratory may help identify those who would benefit from prosthetic rehabilitation. Distraction lengthening is problematic at the phalangeal level because of limited covering soft tissue, skeletal stock, and vascularity, but could be an option for metacarpals or the forearm bones in certain circumstances [ "On-top" plasty is another, quite complex, surgical strategy to achieve prehension when necessary; a digital tip can be transposed onto a proximal phalanx and neurovascular pedicle. Many congenital heart malformations and certain vascular malformations can be ameliorated with a range of standard surgical procedures. Treatment of pulmonary hypertension with a variety of standard therapies is often found to be ineffective. If developmental delays or disabilities are suspected, a full assessment with recommendations for supportive therapies should be obtained. Routine pediatric care should include periodic neurologic examination for signs of spasticity, particularly if neonatal brain imaging showed evidence of periventricular calcifications. Early physiotherapy can maximize motor function and range of motion. The risk for epilepsy is increased, particularly when neuroimaging and/or neurologic examination are abnormal. Management of seizures is per routine. Early prophylactic laser photocoagulation may help preserve vision of those with retinal vasculopathy [ Retinal detachments should be treated promptly with appropriate interventions, such as bilateral lensectomies, pars plana vitrectomies, or silicone oil tamponade. Echocardiography annually until age three years for signs of pulmonary hypertension Consideration of abdominal ultrasound examination for signs of portal hypertension in those with failure to thrive, persistent nausea, abdominal swelling, or black stools It is appropriate to evaluate apparently asymptomatic relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and/or surveillance for cardiovascular and/or neurologic manifestations. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Examination by a clinical geneticist if the pathogenic variant(s) in the family are not known. See Search • Consultation with a plastic surgeon regarding aplasia cutis congenita (ACC) or any significant cutis aplasia on the body • Consultation with a dermatologist, which may be especially useful in those with extensive cutis marmorata telangiectatica congenita (CMTC) • Consideration of skull x-ray; on occasion a bony defect may be present even in the absence of ACC, which may require use of a protective helmet. Ultrasonography and CT can also help assess skull involvement. • Consultation with a neurosurgeon in children with a significant calvarial defect • Consultation with a pediatric cardiologist. Echocardiography should be performed even when clinical signs of congenital heart disease are absent. • Any evidence for pulmonary hypertension should be sought. • Systemic blood pressure should be checked. • Abdominal ultrasound examination should be performed to check for splenomegaly and patency of the portal vein. • Brain MRI to delineate any brain malformations and identify lesions suggestive of micro-hemorrhage or ischemia. Infants with brain anomalies are at increased risk for seizures, developmental delay, or motor deficits and warrant evaluation and close follow up by developmental specialists. • MR angiography and venography to show the vascular anatomy. Surgical procedures may result in unexpected complications if anomalous vasculature is unrecognized. MRI and MRV are also important to guide wound care when the ACC lesion is large and to determine whether protection of the superior sagittal sinus is sufficient. • Abdominal ultrasound to look for liver or renal anomalies • Consultation with a clinical geneticist and/or genetic counselor • Sterile saline-soaked gauze/compresses (wet-to-wet), which should be changed every four hours. Although this labor-intensive option is effective, it is not frequently used anymore. • Silver sulfadiazine dressings changed twice daily work well in older children, but these cannot be used in infants younger than age two months (corrected for prematurity) because of the risk of accompanying electrolyte disturbance. • Although some infants have received skin grafts [ • Use of abdominal muscle fascia to cover exposed dura has been reported [ • Bone grafting in the neonatal period using unaffected skull, with coverage of the sampled site with vascularized peri-osteum, has been reported [ • Use of a split rib graft with a latissimus dorsi muscle flap has also been reported. • Echocardiography annually until age three years for signs of pulmonary hypertension • Consideration of abdominal ultrasound examination for signs of portal hypertension in those with failure to thrive, persistent nausea, abdominal swelling, or black stools • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Examination by a clinical geneticist if the pathogenic variant(s) in the family are not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Adams-Oliver syndrome (AOS), the following evaluations are recommended. Consultation with a plastic surgeon regarding aplasia cutis congenita (ACC) or any significant cutis aplasia on the body Consultation with a dermatologist, which may be especially useful in those with extensive cutis marmorata telangiectatica congenita (CMTC) Consideration of skull x-ray; on occasion a bony defect may be present even in the absence of ACC, which may require use of a protective helmet. Ultrasonography and CT can also help assess skull involvement. Consultation with a neurosurgeon in children with a significant calvarial defect Consultation with a pediatric cardiologist. Echocardiography should be performed even when clinical signs of congenital heart disease are absent. Any evidence for pulmonary hypertension should be sought. Systemic blood pressure should be checked. Abdominal ultrasound examination should be performed to check for splenomegaly and patency of the portal vein. Brain MRI to delineate any brain malformations and identify lesions suggestive of micro-hemorrhage or ischemia. Infants with brain anomalies are at increased risk for seizures, developmental delay, or motor deficits and warrant evaluation and close follow up by developmental specialists. MR angiography and venography to show the vascular anatomy. Surgical procedures may result in unexpected complications if anomalous vasculature is unrecognized. MRI and MRV are also important to guide wound care when the ACC lesion is large and to determine whether protection of the superior sagittal sinus is sufficient. Abdominal ultrasound to look for liver or renal anomalies Consultation with a clinical geneticist and/or genetic counselor • Consultation with a plastic surgeon regarding aplasia cutis congenita (ACC) or any significant cutis aplasia on the body • Consultation with a dermatologist, which may be especially useful in those with extensive cutis marmorata telangiectatica congenita (CMTC) • Consideration of skull x-ray; on occasion a bony defect may be present even in the absence of ACC, which may require use of a protective helmet. Ultrasonography and CT can also help assess skull involvement. • Consultation with a neurosurgeon in children with a significant calvarial defect • Consultation with a pediatric cardiologist. Echocardiography should be performed even when clinical signs of congenital heart disease are absent. • Any evidence for pulmonary hypertension should be sought. • Systemic blood pressure should be checked. • Abdominal ultrasound examination should be performed to check for splenomegaly and patency of the portal vein. • Brain MRI to delineate any brain malformations and identify lesions suggestive of micro-hemorrhage or ischemia. Infants with brain anomalies are at increased risk for seizures, developmental delay, or motor deficits and warrant evaluation and close follow up by developmental specialists. • MR angiography and venography to show the vascular anatomy. Surgical procedures may result in unexpected complications if anomalous vasculature is unrecognized. MRI and MRV are also important to guide wound care when the ACC lesion is large and to determine whether protection of the superior sagittal sinus is sufficient. • Abdominal ultrasound to look for liver or renal anomalies • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Consultation with a pediatric dermatologist or plastic surgeon provides individualized management. The goals of non-operative therapy are to prevent infection and promote healing. Other less preferred, less costly dressings are: Sterile saline-soaked gauze/compresses (wet-to-wet), which should be changed every four hours. Although this labor-intensive option is effective, it is not frequently used anymore. Silver sulfadiazine dressings changed twice daily work well in older children, but these cannot be used in infants younger than age two months (corrected for prematurity) because of the risk of accompanying electrolyte disturbance. It is critically important to avoid drying of the wound and eschar separation, which can lead to catastrophic, terminal hemorrhage from the sagittal sinus or from a dilated vein. One option is a dermal regeneration plate (a porous matrix of bovine tendon collagen and glycosaminoglycan) and a semipermeable silicone layer (which provides a framework for cell migration) which is applied in the operating room to a meticulously debrided wound and then monitored for infection [ In one child with a CSF leak, a biocellulose membrane provided a barrier and supported eventual healing [ It has been suggested that debridement over the midline be avoided (if possible) to decrease the risk of fatal hemorrhage from the sagittal sinus [ A surgical procedure may be necessary for more severe defects (e.g., large areas of aplasia cutis congenita on the scalp or skull abnormalities) or wounds complicated by hemorrhage, infection, or CSF leakage. Although some infants have received skin grafts [ Use of abdominal muscle fascia to cover exposed dura has been reported [ Cranioplasty, if needed, is usually considered around age three to four years [ Bone grafting in the neonatal period using unaffected skull, with coverage of the sampled site with vascularized peri-osteum, has been reported [ Use of a split rib graft with a latissimus dorsi muscle flap has also been reported. After healing is complete, scar revision with tissue expansion for cosmesis can be discussed. When the defect is severe the hair-bearing scalp may not be able to completely restore hair to the entire scalp even with tissue expansion. Limb malformations may warrant consultation with specialists in orthopedics, plastic surgery, and/or rehabilitation medicine. X-rays of limbs are often performed immediately after birth but are most informative, in terms of delineating the extent of involvement, after age one year. Many AOS limb anomalies are not severe enough to require surgical or prosthetic intervention. Occupational therapy and/or physical therapy is used as needed to assist with limb functioning, such as to improve walking and running stability in those with abnormal toes. Analysis in a gait laboratory may help identify those who would benefit from prosthetic rehabilitation. Distraction lengthening is problematic at the phalangeal level because of limited covering soft tissue, skeletal stock, and vascularity, but could be an option for metacarpals or the forearm bones in certain circumstances [ "On-top" plasty is another, quite complex, surgical strategy to achieve prehension when necessary; a digital tip can be transposed onto a proximal phalanx and neurovascular pedicle. Many congenital heart malformations and certain vascular malformations can be ameliorated with a range of standard surgical procedures. Treatment of pulmonary hypertension with a variety of standard therapies is often found to be ineffective. If developmental delays or disabilities are suspected, a full assessment with recommendations for supportive therapies should be obtained. Routine pediatric care should include periodic neurologic examination for signs of spasticity, particularly if neonatal brain imaging showed evidence of periventricular calcifications. Early physiotherapy can maximize motor function and range of motion. The risk for epilepsy is increased, particularly when neuroimaging and/or neurologic examination are abnormal. Management of seizures is per routine. Early prophylactic laser photocoagulation may help preserve vision of those with retinal vasculopathy [ Retinal detachments should be treated promptly with appropriate interventions, such as bilateral lensectomies, pars plana vitrectomies, or silicone oil tamponade. • Sterile saline-soaked gauze/compresses (wet-to-wet), which should be changed every four hours. Although this labor-intensive option is effective, it is not frequently used anymore. • Silver sulfadiazine dressings changed twice daily work well in older children, but these cannot be used in infants younger than age two months (corrected for prematurity) because of the risk of accompanying electrolyte disturbance. • Although some infants have received skin grafts [ • Use of abdominal muscle fascia to cover exposed dura has been reported [ • Bone grafting in the neonatal period using unaffected skull, with coverage of the sampled site with vascularized peri-osteum, has been reported [ • Use of a split rib graft with a latissimus dorsi muscle flap has also been reported. ## Cutaneous/Cranial Consultation with a pediatric dermatologist or plastic surgeon provides individualized management. The goals of non-operative therapy are to prevent infection and promote healing. Other less preferred, less costly dressings are: Sterile saline-soaked gauze/compresses (wet-to-wet), which should be changed every four hours. Although this labor-intensive option is effective, it is not frequently used anymore. Silver sulfadiazine dressings changed twice daily work well in older children, but these cannot be used in infants younger than age two months (corrected for prematurity) because of the risk of accompanying electrolyte disturbance. It is critically important to avoid drying of the wound and eschar separation, which can lead to catastrophic, terminal hemorrhage from the sagittal sinus or from a dilated vein. One option is a dermal regeneration plate (a porous matrix of bovine tendon collagen and glycosaminoglycan) and a semipermeable silicone layer (which provides a framework for cell migration) which is applied in the operating room to a meticulously debrided wound and then monitored for infection [ In one child with a CSF leak, a biocellulose membrane provided a barrier and supported eventual healing [ It has been suggested that debridement over the midline be avoided (if possible) to decrease the risk of fatal hemorrhage from the sagittal sinus [ A surgical procedure may be necessary for more severe defects (e.g., large areas of aplasia cutis congenita on the scalp or skull abnormalities) or wounds complicated by hemorrhage, infection, or CSF leakage. Although some infants have received skin grafts [ Use of abdominal muscle fascia to cover exposed dura has been reported [ Cranioplasty, if needed, is usually considered around age three to four years [ Bone grafting in the neonatal period using unaffected skull, with coverage of the sampled site with vascularized peri-osteum, has been reported [ Use of a split rib graft with a latissimus dorsi muscle flap has also been reported. After healing is complete, scar revision with tissue expansion for cosmesis can be discussed. When the defect is severe the hair-bearing scalp may not be able to completely restore hair to the entire scalp even with tissue expansion. • Sterile saline-soaked gauze/compresses (wet-to-wet), which should be changed every four hours. Although this labor-intensive option is effective, it is not frequently used anymore. • Silver sulfadiazine dressings changed twice daily work well in older children, but these cannot be used in infants younger than age two months (corrected for prematurity) because of the risk of accompanying electrolyte disturbance. • Although some infants have received skin grafts [ • Use of abdominal muscle fascia to cover exposed dura has been reported [ • Bone grafting in the neonatal period using unaffected skull, with coverage of the sampled site with vascularized peri-osteum, has been reported [ • Use of a split rib graft with a latissimus dorsi muscle flap has also been reported. ## Limb Limb malformations may warrant consultation with specialists in orthopedics, plastic surgery, and/or rehabilitation medicine. X-rays of limbs are often performed immediately after birth but are most informative, in terms of delineating the extent of involvement, after age one year. Many AOS limb anomalies are not severe enough to require surgical or prosthetic intervention. Occupational therapy and/or physical therapy is used as needed to assist with limb functioning, such as to improve walking and running stability in those with abnormal toes. Analysis in a gait laboratory may help identify those who would benefit from prosthetic rehabilitation. Distraction lengthening is problematic at the phalangeal level because of limited covering soft tissue, skeletal stock, and vascularity, but could be an option for metacarpals or the forearm bones in certain circumstances [ "On-top" plasty is another, quite complex, surgical strategy to achieve prehension when necessary; a digital tip can be transposed onto a proximal phalanx and neurovascular pedicle. ## Cardiovascular Many congenital heart malformations and certain vascular malformations can be ameliorated with a range of standard surgical procedures. Treatment of pulmonary hypertension with a variety of standard therapies is often found to be ineffective. ## Neurologic If developmental delays or disabilities are suspected, a full assessment with recommendations for supportive therapies should be obtained. Routine pediatric care should include periodic neurologic examination for signs of spasticity, particularly if neonatal brain imaging showed evidence of periventricular calcifications. Early physiotherapy can maximize motor function and range of motion. The risk for epilepsy is increased, particularly when neuroimaging and/or neurologic examination are abnormal. Management of seizures is per routine. ## Ocular Early prophylactic laser photocoagulation may help preserve vision of those with retinal vasculopathy [ Retinal detachments should be treated promptly with appropriate interventions, such as bilateral lensectomies, pars plana vitrectomies, or silicone oil tamponade. ## Surveillance Echocardiography annually until age three years for signs of pulmonary hypertension Consideration of abdominal ultrasound examination for signs of portal hypertension in those with failure to thrive, persistent nausea, abdominal swelling, or black stools • Echocardiography annually until age three years for signs of pulmonary hypertension • Consideration of abdominal ultrasound examination for signs of portal hypertension in those with failure to thrive, persistent nausea, abdominal swelling, or black stools ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic relatives of an affected individual in order to identify as early as possible those who would benefit from initiation of treatment and/or surveillance for cardiovascular and/or neurologic manifestations. Evaluations can include: Molecular genetic testing if the pathogenic variant(s) in the family are known; Examination by a clinical geneticist if the pathogenic variant(s) in the family are not known. See • Molecular genetic testing if the pathogenic variant(s) in the family are known; • Examination by a clinical geneticist if the pathogenic variant(s) in the family are not known. ## Therapies Under Investigation Search ## Genetic Counseling Some individuals diagnosed with autosomal dominant AOS have an affected parent. Intrafamilial variability in the extent and severity of cutaneous and limb defects is often striking. A proband with autosomal dominant AOS may have the disorder as the result of a If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations are (1) a The family history of individuals may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, even when there is an apparently negative family history, focused clinical evaluation of the scalp and limbs of the parents of a proband (possibly including hand and foot x-rays) and/or molecular genetic testing should be performed. Note: If the parent is the individual in whom the If a parent of the proband is affected, the risk to the sibs is 50%. The sibs of a proband with clinically unaffected parents are still at increased risk for AOS because of the possibility of reduced penetrance in a parent. If the Each child of an individual with autosomal dominant AOS has a 50% chance of inheriting the pathogenic variant. Clinical outcome in offspring who inherit a pathogenic variant cannot be accurately predicted because of reduced penetrance and variable expressivity. The parents of a child diagnosed with autosomal recessive AOS 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. 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 Other issues: Routine prenatal ultrasound examination frequently misses minor limb anomalies, but directed assessment may be able to identify and estimate the extent of any defects. Intrauterine growth restriction, while not at all specific, may be present in a minority of severely affected infants. While there is very little literature on the detection of scalp or calvarial defects with targeted 3D ultrasound or fetal MRI, it is certainly theoretically possible. Calvarial defects may lead to elevated maternal serum α-fetoprotein level and positive amniotic fluid acetylcholinesterase [ 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. • Some individuals diagnosed with autosomal dominant AOS have an affected parent. Intrafamilial variability in the extent and severity of cutaneous and limb defects is often striking. • A proband with autosomal dominant AOS may have the disorder as the result of a • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations are (1) a • The family history of individuals may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, even when there is an apparently negative family history, focused clinical evaluation of the scalp and limbs of the parents of a proband (possibly including hand and foot x-rays) and/or molecular genetic testing should be performed. • Note: If the parent is the individual in whom the • If a parent of the proband is affected, the risk to the sibs is 50%. • The sibs of a proband with clinically unaffected parents are still at increased risk for AOS because of the possibility of reduced penetrance in a parent. • If the • Each child of an individual with autosomal dominant AOS has a 50% chance of inheriting the pathogenic variant. • Clinical outcome in offspring who inherit a pathogenic variant cannot be accurately predicted because of reduced penetrance and variable expressivity. • The parents of a child diagnosed with autosomal recessive AOS 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 and discussion of the availability of prenatal/preimplantation genetic testing is before 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. • Routine prenatal ultrasound examination frequently misses minor limb anomalies, but directed assessment may be able to identify and estimate the extent of any defects. • Intrauterine growth restriction, while not at all specific, may be present in a minority of severely affected infants. • While there is very little literature on the detection of scalp or calvarial defects with targeted 3D ultrasound or fetal MRI, it is certainly theoretically possible. • Calvarial defects may lead to elevated maternal serum α-fetoprotein level and positive amniotic fluid acetylcholinesterase [ ## Mode of Inheritance ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with autosomal dominant AOS have an affected parent. Intrafamilial variability in the extent and severity of cutaneous and limb defects is often striking. A proband with autosomal dominant AOS may have the disorder as the result of a If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations are (1) a The family history of individuals may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, even when there is an apparently negative family history, focused clinical evaluation of the scalp and limbs of the parents of a proband (possibly including hand and foot x-rays) and/or molecular genetic testing should be performed. Note: If the parent is the individual in whom the If a parent of the proband is affected, the risk to the sibs is 50%. The sibs of a proband with clinically unaffected parents are still at increased risk for AOS because of the possibility of reduced penetrance in a parent. If the Each child of an individual with autosomal dominant AOS has a 50% chance of inheriting the pathogenic variant. Clinical outcome in offspring who inherit a pathogenic variant cannot be accurately predicted because of reduced penetrance and variable expressivity. • Some individuals diagnosed with autosomal dominant AOS have an affected parent. Intrafamilial variability in the extent and severity of cutaneous and limb defects is often striking. • A proband with autosomal dominant AOS may have the disorder as the result of a • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, possible explanations are (1) a • The family history of individuals may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, even when there is an apparently negative family history, focused clinical evaluation of the scalp and limbs of the parents of a proband (possibly including hand and foot x-rays) and/or molecular genetic testing should be performed. • Note: If the parent is the individual in whom the • If a parent of the proband is affected, the risk to the sibs is 50%. • The sibs of a proband with clinically unaffected parents are still at increased risk for AOS because of the possibility of reduced penetrance in a parent. • If the • Each child of an individual with autosomal dominant AOS has a 50% chance of inheriting the pathogenic variant. • Clinical outcome in offspring who inherit a pathogenic variant cannot be accurately predicted because of reduced penetrance and variable expressivity. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child diagnosed with autosomal recessive AOS 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 a child diagnosed with autosomal recessive AOS 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. ## 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 Other issues: Routine prenatal ultrasound examination frequently misses minor limb anomalies, but directed assessment may be able to identify and estimate the extent of any defects. Intrauterine growth restriction, while not at all specific, may be present in a minority of severely affected infants. While there is very little literature on the detection of scalp or calvarial defects with targeted 3D ultrasound or fetal MRI, it is certainly theoretically possible. Calvarial defects may lead to elevated maternal serum α-fetoprotein level and positive amniotic fluid acetylcholinesterase [ 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. • Routine prenatal ultrasound examination frequently misses minor limb anomalies, but directed assessment may be able to identify and estimate the extent of any defects. • Intrauterine growth restriction, while not at all specific, may be present in a minority of severely affected infants. • While there is very little literature on the detection of scalp or calvarial defects with targeted 3D ultrasound or fetal MRI, it is certainly theoretically possible. • Calvarial defects may lead to elevated maternal serum α-fetoprotein level and positive amniotic fluid acetylcholinesterase [ ## Resources United Kingdom • • • • • • • United Kingdom • ## Molecular Genetics Adams-Oliver Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Adams-Oliver Syndrome ( Adams-Oliver syndrome (AOS) results from disturbance of the Notch signaling pathway or genes that regulate GTPases involved in actin cytoskeleton organization: EOGT glycosylates NOTCH1; DLL4 is a ligand for NOTCH1; and RBPJ is a binding partner for activated NOTCH1. DOCK6 and ARHGAP31 are known regulators of CDC42, a focal point for regulation of the actin cytoskeleton. Although AOS is currently thought of as a multi-pathway disorder, the several known points of linkage between Notch signaling and CDC42 suggest that the pathogenic mechanisms may be unified in the future. For a detailed summary of gene and protein information for the genes listed below, see Binding of NOTCH ligands initiates internalization of the ligand by the presenting cell, which is thought to stretch the extracellular domain of the NOTCH receptor, removing the inhibition of the NRR and allowing ADAM10/17 protease cleavage to liberate the extracellular domain. This exposes a gamma-secretase cleavage site, with cleavage catalyzing release of the NOTCH intracellular domain (NICD). NICD translocates to the nucleus where it acts as a co-activator within a transcription factor complex to regulate gene expression [ Conversely, pathogenic variants of • EOGT glycosylates NOTCH1; DLL4 is a ligand for NOTCH1; and RBPJ is a binding partner for activated NOTCH1. • DOCK6 and ARHGAP31 are known regulators of CDC42, a focal point for regulation of the actin cytoskeleton. ## Molecular Pathogenesis Adams-Oliver syndrome (AOS) results from disturbance of the Notch signaling pathway or genes that regulate GTPases involved in actin cytoskeleton organization: EOGT glycosylates NOTCH1; DLL4 is a ligand for NOTCH1; and RBPJ is a binding partner for activated NOTCH1. DOCK6 and ARHGAP31 are known regulators of CDC42, a focal point for regulation of the actin cytoskeleton. Although AOS is currently thought of as a multi-pathway disorder, the several known points of linkage between Notch signaling and CDC42 suggest that the pathogenic mechanisms may be unified in the future. For a detailed summary of gene and protein information for the genes listed below, see Binding of NOTCH ligands initiates internalization of the ligand by the presenting cell, which is thought to stretch the extracellular domain of the NOTCH receptor, removing the inhibition of the NRR and allowing ADAM10/17 protease cleavage to liberate the extracellular domain. This exposes a gamma-secretase cleavage site, with cleavage catalyzing release of the NOTCH intracellular domain (NICD). NICD translocates to the nucleus where it acts as a co-activator within a transcription factor complex to regulate gene expression [ Conversely, pathogenic variants of • EOGT glycosylates NOTCH1; DLL4 is a ligand for NOTCH1; and RBPJ is a binding partner for activated NOTCH1. • DOCK6 and ARHGAP31 are known regulators of CDC42, a focal point for regulation of the actin cytoskeleton. ## ## ## ## ## Binding of NOTCH ligands initiates internalization of the ligand by the presenting cell, which is thought to stretch the extracellular domain of the NOTCH receptor, removing the inhibition of the NRR and allowing ADAM10/17 protease cleavage to liberate the extracellular domain. This exposes a gamma-secretase cleavage site, with cleavage catalyzing release of the NOTCH intracellular domain (NICD). NICD translocates to the nucleus where it acts as a co-activator within a transcription factor complex to regulate gene expression [ Conversely, pathogenic variants of ## ## Chapter Notes The authors are grateful to Ms S Ray and Drs M van Allen, D Courtemanche, and D Pugash for their input. 17 August 2023 (ma) Chapter retired: outdated 14 April 2016 (bp) Review posted live 13 October 2015 (mp) Original submission • 17 August 2023 (ma) Chapter retired: outdated • 14 April 2016 (bp) Review posted live • 13 October 2015 (mp) Original submission ## Acknowledgments The authors are grateful to Ms S Ray and Drs M van Allen, D Courtemanche, and D Pugash for their input. ## Revision History 17 August 2023 (ma) Chapter retired: outdated 14 April 2016 (bp) Review posted live 13 October 2015 (mp) Original submission • 17 August 2023 (ma) Chapter retired: outdated • 14 April 2016 (bp) Review posted live • 13 October 2015 (mp) Original submission ## References ## Literature Cited	[]	14/4/2016			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
adamtsl4-eyes	adamtsl4-eyes	[ "Autosomal Recessive Isolated Ectopia Lentis", "Ectopia Lentis et Pupillae", "ADAMTS-like protein 4", "ADAMTSL4", "ADAMTSL4-Related Eye Disorders" ]		Eyvind Rødahl, Anne Elisabeth Christensen Mellgren, Nils-Erik Boonstra, Per Morten Knappskog	Summary The spectrum of The diagnosis is established in individuals with characteristic eye findings by the identification of biallelic pathogenic (or likely pathogenic) variants in	Autosomal recessive isolated ectopia lentis Ectopia lentis et pupillae For other genetic causes of these phenotypes see • Autosomal recessive isolated ectopia lentis • Ectopia lentis et pupillae ## Diagnosis The spectrum of Mild-to-severe dislocation of the lens due to loss of zonular fibers without any preceding trauma. The lens may be displaced in any direction. Spherophakia, lens coloboma, and iridodonesis may be present. Mild-to-severe displacement of the pupil; in some instances the pupils are normal. If the pupil is displaced, the lens is usually displaced in the opposite direction. Enlarged iris processes; seen in most affected individuals, causing an anomalous iridocorneal angle A deep anterior chamber and a thin and flat iris with loss of iris crypts accompanied by iris transillumination; seen in individuals with prominent displacement of the pupil Fibrosis of iris tissue surrounding the pupil resulting in poor dilation of the pupil in response to mydriatics Presence of a pupillary membrane, with small strands extending from the pupillary margin visible after dilation of the pupil. A fibrous membrane, visible on ultrasound biomicroscopy, may cover the posterior part of the iris. Family history consistent with autosomal recessive inheritance The diagnosis of an 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 an When the phenotypic findings suggest the diagnosis of an For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by ectopia lentis and/or pupillary displacement or if the diagnosis of an 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. • Mild-to-severe dislocation of the lens due to loss of zonular fibers without any preceding trauma. The lens may be displaced in any direction. Spherophakia, lens coloboma, and iridodonesis may be present. • Mild-to-severe displacement of the pupil; in some instances the pupils are normal. If the pupil is displaced, the lens is usually displaced in the opposite direction. • Enlarged iris processes; seen in most affected individuals, causing an anomalous iridocorneal angle • A deep anterior chamber and a thin and flat iris with loss of iris crypts accompanied by iris transillumination; seen in individuals with prominent displacement of the pupil • Fibrosis of iris tissue surrounding the pupil resulting in poor dilation of the pupil in response to mydriatics • Presence of a pupillary membrane, with small strands extending from the pupillary margin visible after dilation of the pupil. A fibrous membrane, visible on ultrasound biomicroscopy, may cover the posterior part of the iris. • Family history consistent with autosomal recessive inheritance • For an introduction to multigene panels click ## Suggestive Findings Mild-to-severe dislocation of the lens due to loss of zonular fibers without any preceding trauma. The lens may be displaced in any direction. Spherophakia, lens coloboma, and iridodonesis may be present. Mild-to-severe displacement of the pupil; in some instances the pupils are normal. If the pupil is displaced, the lens is usually displaced in the opposite direction. Enlarged iris processes; seen in most affected individuals, causing an anomalous iridocorneal angle A deep anterior chamber and a thin and flat iris with loss of iris crypts accompanied by iris transillumination; seen in individuals with prominent displacement of the pupil Fibrosis of iris tissue surrounding the pupil resulting in poor dilation of the pupil in response to mydriatics Presence of a pupillary membrane, with small strands extending from the pupillary margin visible after dilation of the pupil. A fibrous membrane, visible on ultrasound biomicroscopy, may cover the posterior part of the iris. Family history consistent with autosomal recessive inheritance • Mild-to-severe dislocation of the lens due to loss of zonular fibers without any preceding trauma. The lens may be displaced in any direction. Spherophakia, lens coloboma, and iridodonesis may be present. • Mild-to-severe displacement of the pupil; in some instances the pupils are normal. If the pupil is displaced, the lens is usually displaced in the opposite direction. • Enlarged iris processes; seen in most affected individuals, causing an anomalous iridocorneal angle • A deep anterior chamber and a thin and flat iris with loss of iris crypts accompanied by iris transillumination; seen in individuals with prominent displacement of the pupil • Fibrosis of iris tissue surrounding the pupil resulting in poor dilation of the pupil in response to mydriatics • Presence of a pupillary membrane, with small strands extending from the pupillary margin visible after dilation of the pupil. A fibrous membrane, visible on ultrasound biomicroscopy, may cover the posterior part of the iris. • Family history consistent with autosomal recessive inheritance ## Establishing the Diagnosis The diagnosis of an 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 an When the phenotypic findings suggest the diagnosis of an For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by ectopia lentis and/or pupillary displacement or if the diagnosis of an 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. • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of an 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 ectopia lentis and/or pupillary displacement or if the diagnosis of an 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 spectrum of Hyperopia (+5 D to +15 D) occurs when the lens is dislocated out of the visual axis resulting in a functionally aphakic eye. Myopia (-5 D to >-15 D) may result from increased axial growth of the eye, or because of abnormalities like spherophakia and lens coloboma. Various degrees of astigmatism, sometimes quite large, are frequently observed. In children, uncorrected refractive errors and anisometropia (unequal refractive errors between the two eyes) may lead to amblyopia. One study found that the risk for amblyopia was highest when the lens was still covering the visual axis and the edge of the lens was within 0.3-2.3 mm of the center of the pupil [ No genotype-phenotype correlations have been noted. The phenotype may vary significantly from one individual to another within a family. The phenotype may vary significantly between eyes in the same individual. The same pathogenic variant can be associated with ectopia lentis and ectopia lentis et pupillae. In studies of individuals with nonsyndromic ectopia lentis, the proportion of those having a pathogenic variant in Pathogenic variants frequently associated with In a German study, two of 360 ethnically matched anonymous individuals were heterozygous for this pathogenic variant [ In Polynesians (Maori) the • Hyperopia (+5 D to +15 D) occurs when the lens is dislocated out of the visual axis resulting in a functionally aphakic eye. • Myopia (-5 D to >-15 D) may result from increased axial growth of the eye, or because of abnormalities like spherophakia and lens coloboma. • Various degrees of astigmatism, sometimes quite large, are frequently observed. • The phenotype may vary significantly from one individual to another within a family. • The phenotype may vary significantly between eyes in the same individual. • The same pathogenic variant can be associated with ectopia lentis and ectopia lentis et pupillae. ## Clinical Description The spectrum of Hyperopia (+5 D to +15 D) occurs when the lens is dislocated out of the visual axis resulting in a functionally aphakic eye. Myopia (-5 D to >-15 D) may result from increased axial growth of the eye, or because of abnormalities like spherophakia and lens coloboma. Various degrees of astigmatism, sometimes quite large, are frequently observed. In children, uncorrected refractive errors and anisometropia (unequal refractive errors between the two eyes) may lead to amblyopia. One study found that the risk for amblyopia was highest when the lens was still covering the visual axis and the edge of the lens was within 0.3-2.3 mm of the center of the pupil [ • Hyperopia (+5 D to +15 D) occurs when the lens is dislocated out of the visual axis resulting in a functionally aphakic eye. • Myopia (-5 D to >-15 D) may result from increased axial growth of the eye, or because of abnormalities like spherophakia and lens coloboma. • Various degrees of astigmatism, sometimes quite large, are frequently observed. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been noted. The phenotype may vary significantly from one individual to another within a family. The phenotype may vary significantly between eyes in the same individual. The same pathogenic variant can be associated with ectopia lentis and ectopia lentis et pupillae. • The phenotype may vary significantly from one individual to another within a family. • The phenotype may vary significantly between eyes in the same individual. • The same pathogenic variant can be associated with ectopia lentis and ectopia lentis et pupillae. ## Prevalence In studies of individuals with nonsyndromic ectopia lentis, the proportion of those having a pathogenic variant in Pathogenic variants frequently associated with In a German study, two of 360 ethnically matched anonymous individuals were heterozygous for this pathogenic variant [ In Polynesians (Maori) the ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Disorders with Ectopia Lentis and/or Iris Anomalies to Consider in the Differential Diagnosis of Tall, thin stature High-arched feet Chest anomalies Intellectual disability Seizures Arterial atheroma formation Seizures Ataxia Dystonia Choreoathetotic movements Proportionate short stature Brachydactyly Joint stiffness Megalocornea Glaucoma Microspherophakia Axial myopia Marfanoid features Iris hypoplasia Foveal dysplasia Optic nerve hypoplasia Nystagmus Embryotoxon posterior Iridocorneal adhesions Iris anomalies Corneal edema Corneal endothelial irregularities Polycoria Iris nevus Microphthalmia Embryotoxon posterior Corneal opacities Sclerocornea Iris hypoplasia Iridocorneal adhesions Glaucoma Posterior corneal opacities Iridocorneal adhesions Glaucoma AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MSPKA = microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucoma; XL= X-linked Ectopia lentis most frequently occurs as an autosomal dominant disorder in association with pathogenic variants in Pathogenic variants in This is an acquired disorder and rarely seen in children. There are many genes associated with iris coloboma, and accompanying features can be quite complex. • Tall, thin stature • High-arched feet • Chest anomalies • Intellectual disability • Seizures • Arterial atheroma formation • Seizures • Ataxia • Dystonia • Choreoathetotic movements • Proportionate short stature • Brachydactyly • Joint stiffness • Megalocornea • Glaucoma • Microspherophakia • Axial myopia • Marfanoid features • Iris hypoplasia • Foveal dysplasia • Optic nerve hypoplasia • Nystagmus • Embryotoxon posterior • Iridocorneal adhesions • Iris anomalies • Corneal edema • Corneal endothelial irregularities • Polycoria • Iris nevus • Microphthalmia • Embryotoxon posterior • Corneal opacities • Sclerocornea • Iris hypoplasia • Iridocorneal adhesions • Glaucoma • Posterior corneal opacities • Iridocorneal adhesions • Glaucoma ## Management To establish the extent of disease and the needs of an individual diagnosed with an Determination of visual acuity and refractive error Measurement of intraocular pressure Note: Affected individuals may have increased central corneal thickness that could explain, to some extent, why some individuals have moderately elevated intraocular pressure, but few have glaucomatous damage of the optic nerve head. Slit lamp examination Dilated fundus examination The following may also provide important information: Orthoptic examination, particularly in children Measurement of axial length Anterior segment examination with optical coherence tomography and in selected individuals ultrasound biomicroscopy Corneal topography including measurement of corneal diameter and central corneal thickness Gonioscopy Consultation with a clinical geneticist and/or genetic counselor is also recommended. In the past, lensectomy with anterior vitrectomy and correction of the aphakia with contact lenses or secondary intraocular lens (IOL) replacement has been the usual procedure. More recently, capsule-sparing lens surgery has been introduced. "Bag in the lens" (BIL) IOL implantation combined with capsular rings or lasso suture is an efficient procedure for the treatment of lens dislocation [ Surgical treatment must be weighed against loss of accommodation and the risk for secondary glaucoma and retinal detachment. Aphakia correction in children imposes challenges with respect to the use of contact lenses and IOL implantation, particularly in individuals with unilateral involvement. Special care should be taken in the youngest children (age <2 years) as the growth of the eye will give a myopic shift. All surgical procedures should therefore be planned individually by an experienced ophthalmic surgeon [ Assess visual acuity, refractive error, and intraocular pressure one to three times per year: adults who are stable may be examined yearly, whereas children require more frequent examinations. Ultrasonography may be necessary to evaluate for retinal detachment if the view of the fundus is limited. Care must be taken during contact sports to avoid blunt trauma to the eye and head. Affected individuals should not participate in activities like boxing or martial arts. Sibs of a proband with an If the pathogenic variants in a family are known, molecular genetic testing is likely to be more helpful than clinical examination in clarifying the genetic status of at-risk sibs, given the wide phenotypic variability even within the same family. See Search • Determination of visual acuity and refractive error • Measurement of intraocular pressure • Note: Affected individuals may have increased central corneal thickness that could explain, to some extent, why some individuals have moderately elevated intraocular pressure, but few have glaucomatous damage of the optic nerve head. • Slit lamp examination • Dilated fundus examination • Orthoptic examination, particularly in children • Measurement of axial length • Anterior segment examination with optical coherence tomography and in selected individuals ultrasound biomicroscopy • Corneal topography including measurement of corneal diameter and central corneal thickness • Gonioscopy ## Evaluations Following Initial Diagnosis To establish the extent of disease and the needs of an individual diagnosed with an Determination of visual acuity and refractive error Measurement of intraocular pressure Note: Affected individuals may have increased central corneal thickness that could explain, to some extent, why some individuals have moderately elevated intraocular pressure, but few have glaucomatous damage of the optic nerve head. Slit lamp examination Dilated fundus examination The following may also provide important information: Orthoptic examination, particularly in children Measurement of axial length Anterior segment examination with optical coherence tomography and in selected individuals ultrasound biomicroscopy Corneal topography including measurement of corneal diameter and central corneal thickness Gonioscopy Consultation with a clinical geneticist and/or genetic counselor is also recommended. • Determination of visual acuity and refractive error • Measurement of intraocular pressure • Note: Affected individuals may have increased central corneal thickness that could explain, to some extent, why some individuals have moderately elevated intraocular pressure, but few have glaucomatous damage of the optic nerve head. • Slit lamp examination • Dilated fundus examination • Orthoptic examination, particularly in children • Measurement of axial length • Anterior segment examination with optical coherence tomography and in selected individuals ultrasound biomicroscopy • Corneal topography including measurement of corneal diameter and central corneal thickness • Gonioscopy ## Treatment of Manifestations In the past, lensectomy with anterior vitrectomy and correction of the aphakia with contact lenses or secondary intraocular lens (IOL) replacement has been the usual procedure. More recently, capsule-sparing lens surgery has been introduced. "Bag in the lens" (BIL) IOL implantation combined with capsular rings or lasso suture is an efficient procedure for the treatment of lens dislocation [ Surgical treatment must be weighed against loss of accommodation and the risk for secondary glaucoma and retinal detachment. Aphakia correction in children imposes challenges with respect to the use of contact lenses and IOL implantation, particularly in individuals with unilateral involvement. Special care should be taken in the youngest children (age <2 years) as the growth of the eye will give a myopic shift. All surgical procedures should therefore be planned individually by an experienced ophthalmic surgeon [ ## Surveillance Assess visual acuity, refractive error, and intraocular pressure one to three times per year: adults who are stable may be examined yearly, whereas children require more frequent examinations. Ultrasonography may be necessary to evaluate for retinal detachment if the view of the fundus is limited. ## Agents/Circumstances to Avoid Care must be taken during contact sports to avoid blunt trauma to the eye and head. Affected individuals should not participate in activities like boxing or martial arts. ## Evaluation of Relatives at Risk Sibs of a proband with an If the pathogenic variants in a family are known, molecular genetic testing is likely to be more helpful than clinical examination in clarifying the genetic status of at-risk sibs, given the wide phenotypic variability even within the same family. See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • 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 (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 ADAMTSL4-Related Eye Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ADAMTSL4-Related Eye Disorders ( Variants listed in the table have been provided by the authors. Seven predicted thrombospondin type 1 repeats. Proteins with this domain have diverse biologic functions including cell adhesion, angiogenesis, and patterning of the central nervous system. Within each repeat are several protein binding sites that may anchor the protein to components of the extracellular matrix. Cysteine-rich module ADAMTS-spacer 1 domain PLAC ( Several splice variants encoding different isoforms have been described [ ADAMTSL4 is a secreted glycoprotein that is both N- and O-glycosylated [ • Seven predicted thrombospondin type 1 repeats. Proteins with this domain have diverse biologic functions including cell adhesion, angiogenesis, and patterning of the central nervous system. Within each repeat are several protein binding sites that may anchor the protein to components of the extracellular matrix. • Cysteine-rich module • ADAMTS-spacer 1 domain • PLAC ( ## Chapter Notes The contributions of the late Torunn Fiskerstrand and Helge Boman in the preparation of earlier versions of this Helge Boman, MD, PhD; University of Bergen (2012-2020)Nils-Erik Boonstra, MD (2020-present)Torunn Fiskerstrand, MD, PhD; University of Bergen (2012-2020)Per Morten Knappskog, PhD (2012-present)Anne Elisabeth Christensen Mellgren, MD, PhD (2012-present)Eyvind Rødahl, MD, PhD (2012-present) 9 July 2020 (er) Revision: treatment of lens dislocation 5 July 2018 (ha) Comprehensive update posted live 16 February 2012 (me) Review posted live 16 September 2011 (er) Original submission • 9 July 2020 (er) Revision: treatment of lens dislocation • 5 July 2018 (ha) Comprehensive update posted live • 16 February 2012 (me) Review posted live • 16 September 2011 (er) Original submission ## Acknowledgements The contributions of the late Torunn Fiskerstrand and Helge Boman in the preparation of earlier versions of this ## Author History Helge Boman, MD, PhD; University of Bergen (2012-2020)Nils-Erik Boonstra, MD (2020-present)Torunn Fiskerstrand, MD, PhD; University of Bergen (2012-2020)Per Morten Knappskog, PhD (2012-present)Anne Elisabeth Christensen Mellgren, MD, PhD (2012-present)Eyvind Rødahl, MD, PhD (2012-present) ## Revision History 9 July 2020 (er) Revision: treatment of lens dislocation 5 July 2018 (ha) Comprehensive update posted live 16 February 2012 (me) Review posted live 16 September 2011 (er) Original submission • 9 July 2020 (er) Revision: treatment of lens dislocation • 5 July 2018 (ha) Comprehensive update posted live • 16 February 2012 (me) Review posted live • 16 September 2011 (er) Original submission ## References ## Literature Cited	[ "I Anteby, M Isaac, D BenEzra. 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adcy5-dysk	adcy5-dysk	[ "Adenylate cyclase type 5", "ADCY5", "ADCY5-Related Movement Disorder" ]		Kathryn Yang, Darius Ebrahimi-Fakhari	Summary The diagnosis of Once the	## Diagnosis No consensus clinical diagnostic criteria for Axial hypotonia and weakness (severe in some individuals) Complex and often mixed hyperkinetic movement disorder of variable severity, including generalized chorea, generalized dystonia, and/or segmental or generalized myoclonus with: Paroxysmal exacerbations Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis Perioral/facial chorea and myoclonus that may be distinguishing features Lower-limb spasticity with pyramidal signs Mild-to-moderate dysarthria Delayed motor and speech development Global developmental delay / intellectual disability Neurobehavioral/psychiatric manifestations (including anxiety, obsessive-compulsive behavior, depression, and psychosis) Dilated cardiomyopathy Normal brain MRI Normal EEG The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: (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 and small 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, some pathogenic variants in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Axial hypotonia and weakness (severe in some individuals) • Complex and often mixed hyperkinetic movement disorder of variable severity, including generalized chorea, generalized dystonia, and/or segmental or generalized myoclonus with: • Paroxysmal exacerbations • Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis • Perioral/facial chorea and myoclonus that may be distinguishing features • Paroxysmal exacerbations • Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis • Perioral/facial chorea and myoclonus that may be distinguishing features • Lower-limb spasticity with pyramidal signs • Mild-to-moderate dysarthria • Delayed motor and speech development • Paroxysmal exacerbations • Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis • Perioral/facial chorea and myoclonus that may be distinguishing features • Global developmental delay / intellectual disability • Neurobehavioral/psychiatric manifestations (including anxiety, obsessive-compulsive behavior, depression, and psychosis) • Dilated cardiomyopathy • Normal brain MRI • Normal EEG • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click ## Suggestive Findings Axial hypotonia and weakness (severe in some individuals) Complex and often mixed hyperkinetic movement disorder of variable severity, including generalized chorea, generalized dystonia, and/or segmental or generalized myoclonus with: Paroxysmal exacerbations Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis Perioral/facial chorea and myoclonus that may be distinguishing features Lower-limb spasticity with pyramidal signs Mild-to-moderate dysarthria Delayed motor and speech development Global developmental delay / intellectual disability Neurobehavioral/psychiatric manifestations (including anxiety, obsessive-compulsive behavior, depression, and psychosis) Dilated cardiomyopathy Normal brain MRI Normal EEG • Axial hypotonia and weakness (severe in some individuals) • Complex and often mixed hyperkinetic movement disorder of variable severity, including generalized chorea, generalized dystonia, and/or segmental or generalized myoclonus with: • Paroxysmal exacerbations • Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis • Perioral/facial chorea and myoclonus that may be distinguishing features • Paroxysmal exacerbations • Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis • Perioral/facial chorea and myoclonus that may be distinguishing features • Lower-limb spasticity with pyramidal signs • Mild-to-moderate dysarthria • Delayed motor and speech development • Paroxysmal exacerbations • Persistence of dyskinesia during sleep, with exacerbations during sleep-wake transitions that are highly suggestive of the diagnosis • Perioral/facial chorea and myoclonus that may be distinguishing features • Global developmental delay / intellectual disability • Neurobehavioral/psychiatric manifestations (including anxiety, obsessive-compulsive behavior, depression, and psychosis) • Dilated cardiomyopathy • Normal brain MRI • Normal EEG ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: (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 and small 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, some pathogenic variants in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click ## Clinical Characteristics Chorea or dystonia that affects the face, neck, trunk, or limbs is common, and is typically uncomfortable. Frequently observed distinctive findings are facial involvement (particularly perioral and periorbital chorea or myoclonus), nocturnal paroxysmal dyskinesias, and dyskinesia that persists during sleep or worsens at sleep-wake transitions that can cause significant sleep disturbance. Although Somatic mosaicism is an important contributor to phenotypic variability, as individuals with somatic mosaicism typically have a milder phenotype [ An individual mosaic for the recurrent An individual with somatic mosaicism had predominantly paroxysmal nocturnal dyskinesias (with near-normal daytime motor function) and showed a dramatic therapeutic response to caffeine [ In two families, the mosaic parent had at disease onset a mild phenotype in contrast to the more severe phenotype in the heterozygous offspring [ The following genotype-phenotype correlations for To date, the pathogenic missense variant Pathogenic variants in the C1a and C2a domains cause moderate-to-severe disease with infantile- to childhood-onset hyperkinetic movement disorders (chorea, dystonia, myoclonus) and frequent paroxysmal exacerbations. Pathogenic variants involving the arginine residue (amino acid position 418) in the C1a domain, and especially the Pathogenic variants in the M1 and M2 domains have been associated with a spastic paraparesis phenotype [ To date, penetrance in autosomal dominant A variant of familial essential ("benign") chorea. Although the term "benign" was used to distinguish the movement disorder from progressive, neurodegenerative forms of chorea such as "Familial dyskinesia facial myokymia" because the prominent facial twitching was originally thought to be myokymia [ Prevalence is not known. To date, about 100 individuals have been reported [ • An individual mosaic for the recurrent • An individual with somatic mosaicism had predominantly paroxysmal nocturnal dyskinesias (with near-normal daytime motor function) and showed a dramatic therapeutic response to caffeine [ • In two families, the mosaic parent had at disease onset a mild phenotype in contrast to the more severe phenotype in the heterozygous offspring [ • To date, the pathogenic missense variant • Pathogenic variants in the C1a and C2a domains cause moderate-to-severe disease with infantile- to childhood-onset hyperkinetic movement disorders (chorea, dystonia, myoclonus) and frequent paroxysmal exacerbations. • Pathogenic variants involving the arginine residue (amino acid position 418) in the C1a domain, and especially the • Pathogenic variants in the M1 and M2 domains have been associated with a spastic paraparesis phenotype [ • A variant of familial essential ("benign") chorea. Although the term "benign" was used to distinguish the movement disorder from progressive, neurodegenerative forms of chorea such as • "Familial dyskinesia facial myokymia" because the prominent facial twitching was originally thought to be myokymia [ ## Clinical Description Chorea or dystonia that affects the face, neck, trunk, or limbs is common, and is typically uncomfortable. Frequently observed distinctive findings are facial involvement (particularly perioral and periorbital chorea or myoclonus), nocturnal paroxysmal dyskinesias, and dyskinesia that persists during sleep or worsens at sleep-wake transitions that can cause significant sleep disturbance. Although Somatic mosaicism is an important contributor to phenotypic variability, as individuals with somatic mosaicism typically have a milder phenotype [ An individual mosaic for the recurrent An individual with somatic mosaicism had predominantly paroxysmal nocturnal dyskinesias (with near-normal daytime motor function) and showed a dramatic therapeutic response to caffeine [ In two families, the mosaic parent had at disease onset a mild phenotype in contrast to the more severe phenotype in the heterozygous offspring [ • An individual mosaic for the recurrent • An individual with somatic mosaicism had predominantly paroxysmal nocturnal dyskinesias (with near-normal daytime motor function) and showed a dramatic therapeutic response to caffeine [ • In two families, the mosaic parent had at disease onset a mild phenotype in contrast to the more severe phenotype in the heterozygous offspring [ ## Genotype-Phenotype Correlations The following genotype-phenotype correlations for To date, the pathogenic missense variant Pathogenic variants in the C1a and C2a domains cause moderate-to-severe disease with infantile- to childhood-onset hyperkinetic movement disorders (chorea, dystonia, myoclonus) and frequent paroxysmal exacerbations. Pathogenic variants involving the arginine residue (amino acid position 418) in the C1a domain, and especially the Pathogenic variants in the M1 and M2 domains have been associated with a spastic paraparesis phenotype [ • To date, the pathogenic missense variant • Pathogenic variants in the C1a and C2a domains cause moderate-to-severe disease with infantile- to childhood-onset hyperkinetic movement disorders (chorea, dystonia, myoclonus) and frequent paroxysmal exacerbations. • Pathogenic variants involving the arginine residue (amino acid position 418) in the C1a domain, and especially the • Pathogenic variants in the M1 and M2 domains have been associated with a spastic paraparesis phenotype [ ## Penetrance To date, penetrance in autosomal dominant ## Nomenclature A variant of familial essential ("benign") chorea. Although the term "benign" was used to distinguish the movement disorder from progressive, neurodegenerative forms of chorea such as "Familial dyskinesia facial myokymia" because the prominent facial twitching was originally thought to be myokymia [ • A variant of familial essential ("benign") chorea. Although the term "benign" was used to distinguish the movement disorder from progressive, neurodegenerative forms of chorea such as • "Familial dyskinesia facial myokymia" because the prominent facial twitching was originally thought to be myokymia [ ## Prevalence Prevalence is not known. To date, about 100 individuals have been reported [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genetic disorders characterized by an early-onset hyperkinetic movement disorder with paroxysmal exacerbations of interest in the differential diagnosis of Genes of Interest in the Differential Diagnosis of Episodic hemiplegia that can last for minutes or days Often improves w/sleep On video-EEG: focal interictal epileptiform discharges arising from frontal lobe Seizures recorded Co-occurring epilepsy Severe DD or regression Co-occurring epilepsy Severe DD or regression Co-occurring epilepsy Significant developmental & cognitive delays Movements do not often persist in sleep. Progressively worsening dystonia w/frequent bulbar involvement Also assoc w/other findings such as short stature, endocrinopathies, & dysmorphic features Co-occurring epilepsy Severe DD or regression Manifestations often improve by late adolescence. Pulmonary dysfunction & endocrine abnormalities, most commonly hypothyroidism (Note: Non-neurologic manifestations are rare in Diurnal fluctuation Striatal lesions on brain MRI Unilateral or bilateral involuntary movements Attacks are spontaneous or precipitated; involve dystonic posturing w/choreic & ballistic movements; may be accompanied by preceding aura; occur while awake; are not assoc w/seizures. Improves w/alcohol consumption Psychiatric manifestations (e.g., anxiety & depression) are more common. Triggered by exercise or fasting May have co-occurring epilepsy or spasticity Often accompanied by DD & microcephaly AD = autosomal dominant; • Episodic hemiplegia that can last for minutes or days • Often improves w/sleep • On video-EEG: focal interictal epileptiform discharges arising from frontal lobe • Seizures recorded • Co-occurring epilepsy • Severe DD or regression • Co-occurring epilepsy • Severe DD or regression • Co-occurring epilepsy • Significant developmental & cognitive delays • Movements do not often persist in sleep. • Progressively worsening dystonia w/frequent bulbar involvement • Also assoc w/other findings such as short stature, endocrinopathies, & dysmorphic features • Co-occurring epilepsy • Severe DD or regression • Manifestations often improve by late adolescence. • Pulmonary dysfunction & endocrine abnormalities, most commonly hypothyroidism • (Note: Non-neurologic manifestations are rare in • Diurnal fluctuation • Striatal lesions on brain MRI • Unilateral or bilateral involuntary movements • Attacks are spontaneous or precipitated; involve dystonic posturing w/choreic & ballistic movements; may be accompanied by preceding aura; occur while awake; are not assoc w/seizures. • Improves w/alcohol consumption • Psychiatric manifestations (e.g., anxiety & depression) are more common. • Triggered by exercise or fasting • May have co-occurring epilepsy or spasticity • Often accompanied by DD & microcephaly ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Assess neurologic findings incl movement disorder, nocturnal dyskinesia, sleep disruption, speech impairment. Assess response or lack of response to medications. Refer to movement disorder specialist for consideration of treatment options. Gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Mobility, self-help skills, activities of daily living, & need for adaptive devices 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 Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) There is no cure for To help maintain mobility & function Walking aids incl canes or walkers when appropriate Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) Home adaptations for safety & function Consider disability parking placard for caregivers. Cognitive behavioral therapy Medication 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 GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy Because of the rarity of Interventions for the treatment of chorea, dyskinesia, and sleep-related movements in individuals with Monitor for anticholinergic side effects. Can worsen chorea. Improves movement disorder, particularly nocturnal dyskinesias. Caffeine, a non-selective adenosine receptor antagonist, has shown promising effects in case series, w/notable reduction in paroxysmal dyskinesias following oral administration. Improves dyskinesia but evidence is limited Istradefylline, a selective A2A receptor antagonist approved for Parkinson disease, has been trialed in at least 1 person w/ Theophylline, a long-standing bronchodilator w/adenosine antagonist properties, has garnered attention as an additional treatment option; however, data remain limited. DBS of bilateral globus pallidus internus (GPi) has been explored. Several reports describe significant improvement in chorea & dystonia following DBS, although features such as axial hypotonia may be less responsive. While still limited to case studies, DBS can provide substantial functional gains & can be considered particularly in persons w/disabling dyskinesia who do not respond to medical therapy. Given the generally non-progressive nature of Clinicians can utilize Variable dosing depending on the agent, age, and weight Wide range of dosage (25-600 mg/day) Dosage is not well established. Repeat injections every three to six months. 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. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Consider evaluation for alternative means of communication (e.g., Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in OT = occupational therapy; PT = physical therapy See Reduction in manifestations during pregnancy has been reported [ Potential teratogenic effects of medications given for treatment of See Emerging therapies for Search • Assess neurologic findings incl movement disorder, nocturnal dyskinesia, sleep disruption, speech impairment. • Assess response or lack of response to medications. • Refer to movement disorder specialist for consideration of treatment options. • Gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Mobility, self-help skills, activities of daily living, & need for adaptive devices • 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 • To help maintain mobility & function • Walking aids incl canes or walkers when appropriate • Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) • Home adaptations for safety & function • Consider disability parking placard for caregivers. • Cognitive behavioral therapy • Medication • 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 • Monitor for anticholinergic side effects. • Can worsen chorea. • Improves movement disorder, particularly nocturnal dyskinesias. • Caffeine, a non-selective adenosine receptor antagonist, has shown promising effects in case series, w/notable reduction in paroxysmal dyskinesias following oral administration. • Improves dyskinesia but evidence is limited • Istradefylline, a selective A2A receptor antagonist approved for Parkinson disease, has been trialed in at least 1 person w/ • Theophylline, a long-standing bronchodilator w/adenosine antagonist properties, has garnered attention as an additional treatment option; however, data remain limited. • DBS of bilateral globus pallidus internus (GPi) has been explored. • Several reports describe significant improvement in chorea & dystonia following DBS, although features such as axial hypotonia may be less responsive. While still limited to case studies, DBS can provide substantial functional gains & can be considered particularly in persons w/disabling dyskinesia who do not respond to medical therapy. • Given the generally non-progressive nature of • Clinicians can utilize • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 Assess neurologic findings incl movement disorder, nocturnal dyskinesia, sleep disruption, speech impairment. Assess response or lack of response to medications. Refer to movement disorder specialist for consideration of treatment options. Gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Mobility, self-help skills, activities of daily living, & need for adaptive devices 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 Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Assess neurologic findings incl movement disorder, nocturnal dyskinesia, sleep disruption, speech impairment. • Assess response or lack of response to medications. • Refer to movement disorder specialist for consideration of treatment options. • Gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Mobility, self-help skills, activities of daily living, & need for adaptive devices • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for To help maintain mobility & function Walking aids incl canes or walkers when appropriate Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) Home adaptations for safety & function Consider disability parking placard for caregivers. Cognitive behavioral therapy Medication 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 GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy Because of the rarity of Interventions for the treatment of chorea, dyskinesia, and sleep-related movements in individuals with Monitor for anticholinergic side effects. Can worsen chorea. Improves movement disorder, particularly nocturnal dyskinesias. Caffeine, a non-selective adenosine receptor antagonist, has shown promising effects in case series, w/notable reduction in paroxysmal dyskinesias following oral administration. Improves dyskinesia but evidence is limited Istradefylline, a selective A2A receptor antagonist approved for Parkinson disease, has been trialed in at least 1 person w/ Theophylline, a long-standing bronchodilator w/adenosine antagonist properties, has garnered attention as an additional treatment option; however, data remain limited. DBS of bilateral globus pallidus internus (GPi) has been explored. Several reports describe significant improvement in chorea & dystonia following DBS, although features such as axial hypotonia may be less responsive. While still limited to case studies, DBS can provide substantial functional gains & can be considered particularly in persons w/disabling dyskinesia who do not respond to medical therapy. Given the generally non-progressive nature of Clinicians can utilize Variable dosing depending on the agent, age, and weight Wide range of dosage (25-600 mg/day) Dosage is not well established. Repeat injections every three to six months. 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. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Consider evaluation for alternative means of communication (e.g., Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • To help maintain mobility & function • Walking aids incl canes or walkers when appropriate • Durable medical equipment & positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers) • Home adaptations for safety & function • Consider disability parking placard for caregivers. • Cognitive behavioral therapy • Medication • 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 • Monitor for anticholinergic side effects. • Can worsen chorea. • Improves movement disorder, particularly nocturnal dyskinesias. • Caffeine, a non-selective adenosine receptor antagonist, has shown promising effects in case series, w/notable reduction in paroxysmal dyskinesias following oral administration. • Improves dyskinesia but evidence is limited • Istradefylline, a selective A2A receptor antagonist approved for Parkinson disease, has been trialed in at least 1 person w/ • Theophylline, a long-standing bronchodilator w/adenosine antagonist properties, has garnered attention as an additional treatment option; however, data remain limited. • DBS of bilateral globus pallidus internus (GPi) has been explored. • Several reports describe significant improvement in chorea & dystonia following DBS, although features such as axial hypotonia may be less responsive. While still limited to case studies, DBS can provide substantial functional gains & can be considered particularly in persons w/disabling dyskinesia who do not respond to medical therapy. • Given the generally non-progressive nature of • Clinicians can utilize • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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., ## 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 OT = occupational therapy; PT = physical therapy ## Evaluation of Relatives at Risk See ## Pregnancy Management Reduction in manifestations during pregnancy has been reported [ Potential teratogenic effects of medications given for treatment of See ## Therapies Under Investigation Emerging therapies for Search ## Genetic Counseling The majority of individuals diagnosed with autosomal dominant 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 and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or mild/late onset of the disease in a parent with 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 gonadal (or somatic and gonadal) mosaicism* [ * A parent with somatic and gonadal mosaicism for an If a parent of the proband is affected and/or is known to have the If the Each child of an individual with a heterozygous constitutional Each child of an individual with a mosaic The parents of a child with biallelic 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. To date, the heterozygous parents of individuals with autosomal recessive If both parents are known to be heterozygous for an Heterozygous sibs of a proband with autosomal recessive The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to 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. • The majority of individuals diagnosed with autosomal dominant • 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 and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or mild/late onset of the disease in a parent with 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 gonadal (or somatic and gonadal) mosaicism* [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * A parent with somatic and gonadal mosaicism for an • If a parent of the proband is affected and/or is known to have the • If the • Each child of an individual with a heterozygous constitutional • Each child of an individual with a mosaic • The parents of a child with biallelic • 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. • To date, the heterozygous parents of individuals with autosomal recessive • 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 • Heterozygous sibs of a proband with autosomal recessive • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Autosomal Dominant Inheritance – Risk to Family Members The majority of individuals diagnosed with autosomal dominant 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 and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or mild/late onset of the disease in a parent with 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 gonadal (or somatic and gonadal) mosaicism* [ * A parent with somatic and gonadal mosaicism for an If a parent of the proband is affected and/or is known to have the If the Each child of an individual with a heterozygous constitutional Each child of an individual with a mosaic • The majority of individuals diagnosed with autosomal dominant • 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 and inform recurrence risk assessment. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in family members or mild/late onset of the disease in a parent with 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 gonadal (or somatic and gonadal) mosaicism* [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * A parent with somatic and gonadal mosaicism for an • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism* [ • * A parent with somatic and gonadal mosaicism for an • If a parent of the proband is affected and/or is known to have the • If the • Each child of an individual with a heterozygous constitutional • Each child of an individual with a mosaic ## Autosomal Recessive Inheritance – Risk to Family Members The parents of a child with biallelic 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. To date, the heterozygous parents of individuals with autosomal recessive If both parents are known to be heterozygous for an Heterozygous sibs of a proband with autosomal recessive • The parents of a child with biallelic • 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. • To date, the heterozygous parents of individuals with autosomal recessive • 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 • Heterozygous sibs of a proband with autosomal recessive ## 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 ADCY5-Related Movement Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ADCY5-Related Movement Disorder ( Variants listed in the table have been provided by the authors. See ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. See ## Chapter Notes Dr Kathryn Yang and Dr Darius Ebrahimi-Fakhari ( Active research studies include: "A Retrospective Survey-Based Multicenter Study to Delineate the Molecular and Phenotypic Spectrum of Epilepsy-Dyskinesia Syndromes." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: "Deep Brain Stimulation (DBS) MatchMaker (DBSMatchMaker)." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: The authors thank Dr Thomas D Bird, Dr Jennifer Friedman, Dr Fuki M Hisama, Dr Wendy H Raskind, and Chris Shaw for their work on earlier versions of this chapter. The authors are also grateful to their patients with Thomas D Bird, MD (2014-2025)Darius Ebrahimi-Fakhari, MD, PhD (2025-present)Jennifer Friedman, MD (2014-2025)Fuki M Hisama, MD (2014-2025)Wendy H Raskind, MD, PhD (2020-2025)Chris Shaw, BS; University of Washington (2014-2020)Kathryn Yang, MBChB, FRCPC (2025-present) 26 June 2025 (bp) Comprehensive update posted live 30 July 2020 (bp) Comprehensive update posted live 18 December 2014 (me) Review posted live 29 August 2014 (fh) Original submission • "A Retrospective Survey-Based Multicenter Study to Delineate the Molecular and Phenotypic Spectrum of Epilepsy-Dyskinesia Syndromes." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: • "Deep Brain Stimulation (DBS) MatchMaker (DBSMatchMaker)." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: • 26 June 2025 (bp) Comprehensive update posted live • 30 July 2020 (bp) Comprehensive update posted live • 18 December 2014 (me) Review posted live • 29 August 2014 (fh) Original submission ## Author Notes Dr Kathryn Yang and Dr Darius Ebrahimi-Fakhari ( Active research studies include: "A Retrospective Survey-Based Multicenter Study to Delineate the Molecular and Phenotypic Spectrum of Epilepsy-Dyskinesia Syndromes." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: "Deep Brain Stimulation (DBS) MatchMaker (DBSMatchMaker)." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: • "A Retrospective Survey-Based Multicenter Study to Delineate the Molecular and Phenotypic Spectrum of Epilepsy-Dyskinesia Syndromes." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: • "Deep Brain Stimulation (DBS) MatchMaker (DBSMatchMaker)." Sponsor: Boston Children's Hospital. ClinicalTrials.gov ID: ## Acknowledgments The authors thank Dr Thomas D Bird, Dr Jennifer Friedman, Dr Fuki M Hisama, Dr Wendy H Raskind, and Chris Shaw for their work on earlier versions of this chapter. The authors are also grateful to their patients with ## Author History Thomas D Bird, MD (2014-2025)Darius Ebrahimi-Fakhari, MD, PhD (2025-present)Jennifer Friedman, MD (2014-2025)Fuki M Hisama, MD (2014-2025)Wendy H Raskind, MD, PhD (2020-2025)Chris Shaw, BS; University of Washington (2014-2020)Kathryn Yang, MBChB, FRCPC (2025-present) ## Revision History 26 June 2025 (bp) Comprehensive update posted live 30 July 2020 (bp) Comprehensive update posted live 18 December 2014 (me) Review posted live 29 August 2014 (fh) Original submission • 26 June 2025 (bp) Comprehensive update posted live • 30 July 2020 (bp) Comprehensive update posted live • 18 December 2014 (me) Review posted live • 29 August 2014 (fh) Original submission ## References ## Literature Cited	[]	18/12/2014	26/6/2025	17/12/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
adnfle	adnfle	[ "Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), ADSHE", "Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE)", "ADSHE", "Calcium-binding protein 4", "Corticoliberin", "GATOR complex protein NPRL2", "GATOR complex protein NPRL3", "GATOR1 complex protein DEPDC5", "Neuronal acetylcholine receptor subunit alpha-2", "Neuronal acetylcholine receptor subunit alpha-4", "Neuronal acetylcholine receptor subunit beta-2", "Potassium channel subfamily T member 1", "Syntaxin-1B", "CABP4", "CHRNA2", "CHRNA4", "CHRNB2", "CRH", "DEPDC5", "KCNT1", "NPRL2", "NPRL3", "STX1B", "Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy" ]	Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy	Hirokazu Kurahashi, Shinichi Hirose	Summary Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is a seizure disorder characterized by clusters of nocturnal motor seizures that are often stereotyped and brief (<2 minutes). They vary from simple arousals from sleep to dramatic, often hyperkinetic events with tonic or dystonic features. Affected individuals may experience an aura. Retained awareness during seizures is common. A minority of individuals experience daytime seizures. Age of onset ranges from infancy to adulthood. About 80% of individuals develop ADSHE in the first two decades of life; mean age of onset is ten years. Clinical neurologic examination is normal and intellect is usually preserved, but reduced intellect, psychiatric comorbidities, or cognitive deficits may occur. Within a family, the manifestations of the disorder may vary considerably. ADSHE is lifelong but not progressive. As an individual reaches middle age, seizures may become milder and less frequent. The diagnosis of ADSHE is established in a proband who has suggestive clinical findings and a family history consistent with autosomal dominant inheritance and/or a heterozygous pathogenic variant in ADSHE, by definition, is inherited in an autosomal dominant manner. Most individuals diagnosed with ADSHE have an affected parent. Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant; the chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%. If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.	## Diagnosis The International League Against Epilepsy (ILAE) has proposed diagnostic criteria for sleep-related hypermotor (hyperkinetic) epilepsy (SHE) [ Seizures predominantly from the awake state Frequent epileptiform abnormality outside of the frontal regions Generalized epileptiform abnormality by EEG Age at onset younger than ten or older than 20 years Moderate-to-severe intellectual disability, or focal neurologic abnormalities on examination Seizures occur only during wakefulness Generalized-onset seizures Age at onset younger than two months or older than 64 years Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) Clusters of brief (<2 minutes) motor seizures during sleep that are often stereotyped with abrupt onset and offset. Seizures may include the following: Nightmares Verbalizations Sudden limb movements Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidities may occur Normal clinical neurologic examination Note: The clinical features of ADSHE are indistinguishable from those of nonfamilial SHE (i.e., SHE diagnosed in an individual with a negative family history), the causes of which are unknown but may include Interictal EEG may be normal or show infrequent epileptiform discharges. Ictal scalp EEG may be normal or obscured by movement artifact. Intracranial recordings demonstrate that ictal discharge may arise from various frontal as well as extrafrontal areas. Usually normal in individuals with ADSHE Focal cortical dysplasia may be present in some individuals with drug-resistant SHE, especially in individuals with pathogenic variants in GATOR complex genes (e.g., A clinical diagnosis of ADSHE is 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 clinical findings described in When the phenotypic and EEG findings suggest the diagnosis of ADSHE, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the phenotype is indistinguishable from many other epilepsy phenotypes, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Reported in two families [ 10%-15% of individuals with a family history have pathogenic variants in subunits of the nicotinic acetylcholine receptor [ • Seizures predominantly from the awake state • Frequent epileptiform abnormality outside of the frontal regions • Generalized epileptiform abnormality by EEG • Age at onset younger than ten or older than 20 years • Moderate-to-severe intellectual disability, or focal neurologic abnormalities on examination • Seizures occur only during wakefulness • Generalized-onset seizures • Age at onset younger than two months or older than 64 years • Clusters of brief (<2 minutes) motor seizures during sleep that are often stereotyped with abrupt onset and offset. Seizures may include the following: • Nightmares • Verbalizations • Sudden limb movements • Nightmares • Verbalizations • Sudden limb movements • Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidities may occur • Normal clinical neurologic examination • Nightmares • Verbalizations • Sudden limb movements • Interictal EEG may be normal or show infrequent epileptiform discharges. • Ictal scalp EEG may be normal or obscured by movement artifact. • Intracranial recordings demonstrate that ictal discharge may arise from various frontal as well as extrafrontal areas. • Usually normal in individuals with ADSHE • Focal cortical dysplasia may be present in some individuals with drug-resistant SHE, especially in individuals with pathogenic variants in GATOR complex genes (e.g., ## Suggestive Findings Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) Clusters of brief (<2 minutes) motor seizures during sleep that are often stereotyped with abrupt onset and offset. Seizures may include the following: Nightmares Verbalizations Sudden limb movements Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidities may occur Normal clinical neurologic examination Note: The clinical features of ADSHE are indistinguishable from those of nonfamilial SHE (i.e., SHE diagnosed in an individual with a negative family history), the causes of which are unknown but may include Interictal EEG may be normal or show infrequent epileptiform discharges. Ictal scalp EEG may be normal or obscured by movement artifact. Intracranial recordings demonstrate that ictal discharge may arise from various frontal as well as extrafrontal areas. Usually normal in individuals with ADSHE Focal cortical dysplasia may be present in some individuals with drug-resistant SHE, especially in individuals with pathogenic variants in GATOR complex genes (e.g., • Clusters of brief (<2 minutes) motor seizures during sleep that are often stereotyped with abrupt onset and offset. Seizures may include the following: • Nightmares • Verbalizations • Sudden limb movements • Nightmares • Verbalizations • Sudden limb movements • Preserved intellect, although reduced intellect, cognitive deficits, or psychiatric comorbidities may occur • Normal clinical neurologic examination • Nightmares • Verbalizations • Sudden limb movements • Interictal EEG may be normal or show infrequent epileptiform discharges. • Ictal scalp EEG may be normal or obscured by movement artifact. • Intracranial recordings demonstrate that ictal discharge may arise from various frontal as well as extrafrontal areas. • Usually normal in individuals with ADSHE • Focal cortical dysplasia may be present in some individuals with drug-resistant SHE, especially in individuals with pathogenic variants in GATOR complex genes (e.g., ## Establishing the Diagnosis A clinical diagnosis of ADSHE is 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 clinical findings described in When the phenotypic and EEG findings suggest the diagnosis of ADSHE, molecular genetic testing approaches can include use of a For an introduction to multigene panels click When the phenotype is indistinguishable from many other epilepsy phenotypes, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Reported in two families [ 10%-15% of individuals with a family history have pathogenic variants in subunits of the nicotinic acetylcholine receptor [ ## Option 1 When the phenotypic and EEG findings suggest the diagnosis of ADSHE, molecular genetic testing approaches can include use of a For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other epilepsy phenotypes, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Reported in two families [ 10%-15% of individuals with a family history have pathogenic variants in subunits of the nicotinic acetylcholine receptor [ ## Clinical Characteristics Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is characterized by clusters of nocturnal motor seizures with a range of manifestations. Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Frequency of Select Features Focal motor seizures w/vigorous hyperkinetic or asymmetric tonic/dystonic features May occur at any stage during sleep, but typically cluster in non-REM sleep Some persons experience daytime seizures. 10%-50% while awake 50% during sleep Interictal epileptiform abnormalities over the frontal areas during sleep. Ictal EEG may show evolving sharp- or spike-and-wave, rhythmic slow activity, or diffuse flattening. Seizures may occur during any stage of sleep, although typically they cluster in non-REM (NREM) sleep, most commonly in stage 2 sleep [ Seizures in ADSHE are often stereotyped and brief (<2 minutes); they vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. Subtle and stereotypic motor seizures are accompanied by abrupt recurrent arousals from NREM sleep ("paroxysmal arousals"). The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling, and a wide range of movements including flinging, throwing the arms, jumping, and pelvic thrusting. Seizures may have greater complexities ("epileptic wandering"). Reported seizure frequency ranges from one to 20 attacks each night, with a mean of 20 seizures per month; about 60% of affected individuals reported more than 15 seizures per month. Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. Autonomic signs such as tachycardia, tachypnea, and irregular respiratory rhythm are also seen. Focal aware sensory or cognitive seizures, for example, or a sense of difficulty breathing and hyperventilation may precede the motor signs. Focal seizures evolving to bilateral tonic-clonic seizures can also occur. Some individuals experience an aura preceding the seizure during sleep and are aware of the onset of a seizure. Auras may be nonspecific or may consist of numbness in one limb, fear, a shiver, vertigo, or a feeling of falling or being pushed. Note: A minority of individuals experience daytime seizures, typically during a period of poor seizure control. Some of the reported seizures are paroxysmal dystonia similar to those during sleep, and others are generalized tonic-clonic seizures, generalized atonic seizures, and focal impaired awareness seizures. Ictal EEG recordings may not show definitive ictal patterns, or ictal patterns may be obscured by movement artifact. If present, ictal rhythms may show evolving sharp waves or a spike-and-wave pattern, rhythmic slow activity, or diffuse flattening [ Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals. Interictal sleep EEG shows epileptiform abnormalities over the frontal areas in approximately 50% of affected individuals [ A high incidence of true parasomnias has been reported in relatives of individuals with ADSHE [ Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Phenotype Correlations by Gene There are no known phenotype correlations for the other ADSHE-associated genes: Individuals with heterozygous pathogenic variants in Individuals with the The Marked intrafamilial variation in severity is seen in ADSHE; the reasons for this are not well understood. The penetrance of ADSHE is estimated to be 70%. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is now referred to as autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) [ The term "nocturnal" implies a chronobiological pattern of seizure occurrence, whereas occurrence in sleep (rather than at night) is the most important characteristic of the epilepsy in ADSHE. The characteristic seizures that consist of hypermotor manifestations can arise from other cerebral regions in addition to the frontal lobe [ The number of families with ADSHE reported to date exceeds 100 [ • Focal motor seizures w/vigorous hyperkinetic or asymmetric tonic/dystonic features • May occur at any stage during sleep, but typically cluster in non-REM sleep • Some persons experience daytime seizures. • 10%-50% while awake • 50% during sleep • Interictal epileptiform abnormalities over the frontal areas during sleep. • Ictal EEG may show evolving sharp- or spike-and-wave, rhythmic slow activity, or diffuse flattening. • Ictal EEG recordings may not show definitive ictal patterns, or ictal patterns may be obscured by movement artifact. If present, ictal rhythms may show evolving sharp waves or a spike-and-wave pattern, rhythmic slow activity, or diffuse flattening [ • Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals. • Interictal sleep EEG shows epileptiform abnormalities over the frontal areas in approximately 50% of affected individuals [ ## Clinical Description Autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is characterized by clusters of nocturnal motor seizures with a range of manifestations. Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Frequency of Select Features Focal motor seizures w/vigorous hyperkinetic or asymmetric tonic/dystonic features May occur at any stage during sleep, but typically cluster in non-REM sleep Some persons experience daytime seizures. 10%-50% while awake 50% during sleep Interictal epileptiform abnormalities over the frontal areas during sleep. Ictal EEG may show evolving sharp- or spike-and-wave, rhythmic slow activity, or diffuse flattening. Seizures may occur during any stage of sleep, although typically they cluster in non-REM (NREM) sleep, most commonly in stage 2 sleep [ Seizures in ADSHE are often stereotyped and brief (<2 minutes); they vary from simple arousals from sleep to dramatic hyperkinetic events with tonic or dystonic features. Subtle and stereotypic motor seizures are accompanied by abrupt recurrent arousals from NREM sleep ("paroxysmal arousals"). The hyperkinetic manifestations may appear bizarre, sometimes with ambulation, bicycling, and a wide range of movements including flinging, throwing the arms, jumping, and pelvic thrusting. Seizures may have greater complexities ("epileptic wandering"). Reported seizure frequency ranges from one to 20 attacks each night, with a mean of 20 seizures per month; about 60% of affected individuals reported more than 15 seizures per month. Retained awareness during seizures is common and may cause affected individuals to fear falling asleep. Autonomic signs such as tachycardia, tachypnea, and irregular respiratory rhythm are also seen. Focal aware sensory or cognitive seizures, for example, or a sense of difficulty breathing and hyperventilation may precede the motor signs. Focal seizures evolving to bilateral tonic-clonic seizures can also occur. Some individuals experience an aura preceding the seizure during sleep and are aware of the onset of a seizure. Auras may be nonspecific or may consist of numbness in one limb, fear, a shiver, vertigo, or a feeling of falling or being pushed. Note: A minority of individuals experience daytime seizures, typically during a period of poor seizure control. Some of the reported seizures are paroxysmal dystonia similar to those during sleep, and others are generalized tonic-clonic seizures, generalized atonic seizures, and focal impaired awareness seizures. Ictal EEG recordings may not show definitive ictal patterns, or ictal patterns may be obscured by movement artifact. If present, ictal rhythms may show evolving sharp waves or a spike-and-wave pattern, rhythmic slow activity, or diffuse flattening [ Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals. Interictal sleep EEG shows epileptiform abnormalities over the frontal areas in approximately 50% of affected individuals [ A high incidence of true parasomnias has been reported in relatives of individuals with ADSHE [ • Focal motor seizures w/vigorous hyperkinetic or asymmetric tonic/dystonic features • May occur at any stage during sleep, but typically cluster in non-REM sleep • Some persons experience daytime seizures. • 10%-50% while awake • 50% during sleep • Interictal epileptiform abnormalities over the frontal areas during sleep. • Ictal EEG may show evolving sharp- or spike-and-wave, rhythmic slow activity, or diffuse flattening. • Ictal EEG recordings may not show definitive ictal patterns, or ictal patterns may be obscured by movement artifact. If present, ictal rhythms may show evolving sharp waves or a spike-and-wave pattern, rhythmic slow activity, or diffuse flattening [ • Interictal waking EEG shows anterior quadrant epileptiform activity in very few affected individuals. • Interictal sleep EEG shows epileptiform abnormalities over the frontal areas in approximately 50% of affected individuals [ ## Phenotype Correlations by Gene Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Phenotype Correlations by Gene There are no known phenotype correlations for the other ADSHE-associated genes: Individuals with heterozygous pathogenic variants in ## Genotype-Phenotype Correlations Individuals with the The Marked intrafamilial variation in severity is seen in ADSHE; the reasons for this are not well understood. ## Penetrance The penetrance of ADSHE is estimated to be 70%. ## Nomenclature Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is now referred to as autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) [ The term "nocturnal" implies a chronobiological pattern of seizure occurrence, whereas occurrence in sleep (rather than at night) is the most important characteristic of the epilepsy in ADSHE. The characteristic seizures that consist of hypermotor manifestations can arise from other cerebral regions in addition to the frontal lobe [ ## Prevalence The number of families with ADSHE reported to date exceeds 100 [ ## Genetically Related (Allelic) Disorders No mendelian phenotypes other than those discussed in this Other phenotypes associated with pathogenic variants in Allelic Disorders Cone rod dystrophy Retinitis pigmentosa Leber congenital amaurosis Familial focal epilepsies incl familial temporal lobe epilepsy & familial focal epilepsy w/variable foci Rolandic epilepsy, unclassified focal childhood epilepsy, & focal epilepsy w/cortical dysplasia Epilepsy of infancy w/migrating focal seizures Less common seizure phenotypes incl infantile spasms, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy &/or leukoencephalopathy, focal epilepsy, & multifocal epilepsy Familial focal epilepsy w/variable foci Infantile spasms Biallelic variants are associated with retinal disease. • Cone rod dystrophy • Retinitis pigmentosa • Leber congenital amaurosis • Familial focal epilepsies incl familial temporal lobe epilepsy & familial focal epilepsy w/variable foci • Rolandic epilepsy, unclassified focal childhood epilepsy, & focal epilepsy w/cortical dysplasia • Epilepsy of infancy w/migrating focal seizures • Less common seizure phenotypes incl infantile spasms, Ohtahara syndrome, early myoclonic encephalopathy, leukodystrophy &/or leukoencephalopathy, focal epilepsy, & multifocal epilepsy • Familial focal epilepsy w/variable foci • Infantile spasms ## Differential Diagnosis The differential diagnosis of autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) includes autosomal recessive SHE caused by biallelic pathogenic variants in ## Management No clinical practice guidelines regarding the management for autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) have been published. To establish the extent of disease and needs in an individual diagnosed with ADSHE, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy 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. ADSHE = autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment of Manifestations in Individuals with Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy Many ASM may be effective; In about 70% of persons w/ADSHE, carbamazepine is assoc w/remission of seizures, often w/relatively low doses. However, persons w/ADSHE assoc w/ Resistance to ASM occurs in ~30% of affected persons. Intrafamilial variation in pharmacoresponsiveness occurs; therefore, all appropriate ASMs should be tried. Adjunctive therapy w/fenofibrate ↓ seizure frequency in persons w/pharmacoresistant ADSHE in 1 study. Surgical treatment is effective in persons w/FCD-assoc SHE. Education of parents/caregivers is recommended. 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 support ADSHE = autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy; ASM = anti-seizure medication; EIMFS = epilepsy of infancy with migrating focal seizures; FCD = focal cortical dysplasia Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. For information on nonmedical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see 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 Autosomal Dominant Sleep-related Hypermotor Epilepsy (ADSHE) Monitor those w/seizures as clinically indicated. Assess for new manifestations such as new seizure types, changes in tone, & movement disorders. It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment. Evaluations can include one of the following: If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, a medical history to seek evidence of affected status should be elicited from relatives at risk. See 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 ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy during which the 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 • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASM may be effective; In about 70% of persons w/ADSHE, carbamazepine is assoc w/remission of seizures, often w/relatively low doses. However, persons w/ADSHE assoc w/ • Resistance to ASM occurs in ~30% of affected persons. Intrafamilial variation in pharmacoresponsiveness occurs; therefore, all appropriate ASMs should be tried. • Adjunctive therapy w/fenofibrate ↓ seizure frequency in persons w/pharmacoresistant ADSHE in 1 study. • Surgical treatment is effective in persons w/FCD-assoc SHE. • Education of parents/caregivers is recommended. • 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 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. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as new seizure types, changes in tone, & movement disorders. • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, a medical history to seek evidence of affected status should be elicited from relatives at risk. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ADSHE, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy 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. ADSHE = autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy; MOI = mode of inheritance 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 • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy Many ASM may be effective; In about 70% of persons w/ADSHE, carbamazepine is assoc w/remission of seizures, often w/relatively low doses. However, persons w/ADSHE assoc w/ Resistance to ASM occurs in ~30% of affected persons. Intrafamilial variation in pharmacoresponsiveness occurs; therefore, all appropriate ASMs should be tried. Adjunctive therapy w/fenofibrate ↓ seizure frequency in persons w/pharmacoresistant ADSHE in 1 study. Surgical treatment is effective in persons w/FCD-assoc SHE. Education of parents/caregivers is recommended. 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 support ADSHE = autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy; ASM = anti-seizure medication; EIMFS = epilepsy of infancy with migrating focal seizures; FCD = focal cortical dysplasia Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. For information on nonmedical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see • Many ASM may be effective; In about 70% of persons w/ADSHE, carbamazepine is assoc w/remission of seizures, often w/relatively low doses. However, persons w/ADSHE assoc w/ • Resistance to ASM occurs in ~30% of affected persons. Intrafamilial variation in pharmacoresponsiveness occurs; therefore, all appropriate ASMs should be tried. • Adjunctive therapy w/fenofibrate ↓ seizure frequency in persons w/pharmacoresistant ADSHE in 1 study. • Surgical treatment is effective in persons w/FCD-assoc SHE. • Education of parents/caregivers is recommended. • 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 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. ## 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. ## Caregivers For information on nonmedical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see ## 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 Autosomal Dominant Sleep-related Hypermotor Epilepsy (ADSHE) Monitor those w/seizures as clinically indicated. Assess for new manifestations such as new seizure types, changes in tone, & movement disorders. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as new seizure types, changes in tone, & movement disorders. ## Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk in order to identify as early as possible those who would benefit from initiation of treatment. Evaluations can include one of the following: If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. If the pathogenic variant in the family is not known, a medical history to seek evidence of affected status should be elicited from relatives at risk. See • If the pathogenic variant in the family is known, molecular genetic testing can be used to clarify the genetic status of at-risk relatives. • If the pathogenic variant in the family is not known, a medical history to seek evidence of affected status should be elicited from relatives at risk. ## Pregnancy Management 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 ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy during which the 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 By definition, autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is inherited in an autosomal dominant manner. Most individuals diagnosed with ADSHE have an affected parent. A proband may have the disorder as the result of a Recommendations for the evaluation of parents of a child with SHE and no known family history of SHE include: A detailed clinical and family history; Molecular genetic testing (if a molecular diagnosis has been established in the proband). If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with ADSHE may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluations of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the ADSHE-related pathogenic variant identified in the proband). If one parent has phenotypic features of ADSHE and/or is known to have an ADSHE-related pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADSHE is (50% x 70% =) 35%, assuming an estimated Within a family, the manifestations of ADSHE in affected individuals may vary considerably. If the proband has a known ADSHE-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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant. The chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%. 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. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before pregnancy (see If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Because ADSHE is associated with intrafamilial clinical variability and reduced penetrance, the prenatal identification of an ADSHE-related pathogenic variant cannot be used to reliably predict future clinical manifestations. 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 ADSHE have an affected parent. • A proband may have the disorder as the result of a • Recommendations for the evaluation of parents of a child with SHE and no known family history of SHE include: • A detailed clinical and family history; • Molecular genetic testing (if a molecular diagnosis has been established in the proband). • A detailed clinical and family history; • Molecular genetic testing (if a molecular diagnosis has been established in the proband). • If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with ADSHE may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluations of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the ADSHE-related pathogenic variant identified in the proband). • A detailed clinical and family history; • Molecular genetic testing (if a molecular diagnosis has been established 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 one parent has phenotypic features of ADSHE and/or is known to have an ADSHE-related pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADSHE is (50% x 70% =) 35%, assuming an estimated • Within a family, the manifestations of ADSHE in affected individuals may vary considerably. • If the proband has a known ADSHE-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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant. • The chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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. • Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before pregnancy (see ## Mode of Inheritance By definition, autosomal dominant sleep-related hypermotor (hyperkinetic) epilepsy (ADSHE) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with ADSHE have an affected parent. A proband may have the disorder as the result of a Recommendations for the evaluation of parents of a child with SHE and no known family history of SHE include: A detailed clinical and family history; Molecular genetic testing (if a molecular diagnosis has been established in the proband). If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with ADSHE may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluations of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the ADSHE-related pathogenic variant identified in the proband). If one parent has phenotypic features of ADSHE and/or is known to have an ADSHE-related pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADSHE is (50% x 70% =) 35%, assuming an estimated Within a family, the manifestations of ADSHE in affected individuals may vary considerably. If the proband has a known ADSHE-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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant. The chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%. • Most individuals diagnosed with ADSHE have an affected parent. • A proband may have the disorder as the result of a • Recommendations for the evaluation of parents of a child with SHE and no known family history of SHE include: • A detailed clinical and family history; • Molecular genetic testing (if a molecular diagnosis has been established in the proband). • A detailed clinical and family history; • Molecular genetic testing (if a molecular diagnosis has been established in the proband). • If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with ADSHE may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluations of the parents and/or molecular genetic testing (to establish that neither parent is heterozygous for the ADSHE-related pathogenic variant identified in the proband). • A detailed clinical and family history; • Molecular genetic testing (if a molecular diagnosis has been established 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 one parent has phenotypic features of ADSHE and/or is known to have an ADSHE-related pathogenic variant, the risk to each sib of inheriting the pathogenic variant is 50%. The chance that the sib will manifest ADSHE is (50% x 70% =) 35%, assuming an estimated • Within a family, the manifestations of ADSHE in affected individuals may vary considerably. • If the proband has a known ADSHE-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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the theoretic possibility of parental germline mosaicism. • Each child of an individual with ADSHE has a 50% chance of inheriting the ADSHE-related pathogenic variant. • The chance that the offspring will manifest ADSHE is (50% x 70% =) 35%, assuming penetrance of 70%. ## 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. Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before 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 or at risk. • Discussion of the risks and benefits of using a given anti-seizure medication during pregnancy should ideally take place before pregnancy (see ## Prenatal Testing and Preimplantation Genetic Testing If the ADSHE-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Note: Because ADSHE is associated with intrafamilial clinical variability and reduced penetrance, the prenatal identification of an ADSHE-related pathogenic variant cannot be used to reliably predict future clinical manifestations. 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 • • • • • ## Molecular Genetics Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy ( Pathogenic variants in (1) genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR) ( The nAChR is a heterologous pentamer comprising various combinations of alpha and beta subunits, encoded by Each nAChR subunit has a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region [ Pathogenic variants in DEPDC5 is a component of GATOR1 (GTPase-activating protein [GAP] Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Gene-Specific Laboratory Considerations Genes from See Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from ## Molecular Pathogenesis Pathogenic variants in (1) genes encoding subunits of the neuronal nicotinic acetylcholine receptor (nAChR) ( The nAChR is a heterologous pentamer comprising various combinations of alpha and beta subunits, encoded by Each nAChR subunit has a conserved N-terminal extracellular domain followed by three conserved transmembrane domains, a variable cytoplasmic loop, a fourth conserved transmembrane domain, and a short C-terminal extracellular region [ Pathogenic variants in DEPDC5 is a component of GATOR1 (GTPase-activating protein [GAP] Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Gene-Specific Laboratory Considerations Genes from See Autosomal Dominant Sleep-Related Hypermotor (Hyperkinetic) Epilepsy: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from ## Chapter Notes Judith Adams, MBBS, FRACP; University of Melbourne (2002-2004) Samuel F Berkovic, MD, FRACP; Epilepsy Research Institute (2002-2010) Shinichi Hirose, MD, PhD (2010-present)Hirokazu Kurahashi, MD, PhD (2010-present)Ingrid E Scheffer, MBBS, FRACP, PhD; Austin and Repatriation Medical Centre (2002-2010) 23 March 2023 (gm) Comprehensive update posted live 15 March 2018 (ma) Comprehensive update posted live 19 February 2015 (me) Comprehensive update posted live 20 September 2012 (me) Comprehensive update posted live 5 April 2010 (me) Comprehensive update posted live 24 June 2004 (me) Comprehensive update posted live 16 May 2002 (me) Review posted live 22 January 2002 (ja) Original submission • 23 March 2023 (gm) Comprehensive update posted live • 15 March 2018 (ma) Comprehensive update posted live • 19 February 2015 (me) Comprehensive update posted live • 20 September 2012 (me) Comprehensive update posted live • 5 April 2010 (me) Comprehensive update posted live • 24 June 2004 (me) Comprehensive update posted live • 16 May 2002 (me) Review posted live • 22 January 2002 (ja) Original submission ## Author History Judith Adams, MBBS, FRACP; University of Melbourne (2002-2004) Samuel F Berkovic, MD, FRACP; Epilepsy Research Institute (2002-2010) Shinichi Hirose, MD, PhD (2010-present)Hirokazu Kurahashi, MD, PhD (2010-present)Ingrid E Scheffer, MBBS, FRACP, PhD; Austin and Repatriation Medical Centre (2002-2010) ## Revision History 23 March 2023 (gm) Comprehensive update posted live 15 March 2018 (ma) Comprehensive update posted live 19 February 2015 (me) Comprehensive update posted live 20 September 2012 (me) Comprehensive update posted live 5 April 2010 (me) Comprehensive update posted live 24 June 2004 (me) Comprehensive update posted live 16 May 2002 (me) Review posted live 22 January 2002 (ja) Original submission • 23 March 2023 (gm) Comprehensive update posted live • 15 March 2018 (ma) Comprehensive update posted live • 19 February 2015 (me) Comprehensive update posted live • 20 September 2012 (me) Comprehensive update posted live • 5 April 2010 (me) Comprehensive update posted live • 24 June 2004 (me) Comprehensive update posted live • 16 May 2002 (me) Review posted live • 22 January 2002 (ja) Original submission ## References ## Literature Cited	[]	16/5/2002	23/3/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
adnp-dis	adnp-dis	[ "ADNP-Related Intellectual Disability and Autism Spectrum Disorder (ADNP-Related ID/ASD)", "ADNP Syndrome", "Helsmoortel-Van der Aa Syndrome (HVDAS)", "ADNP-Related ID/ASD", "Helsmoortel-Van der Aa Syndrome", "Activity-dependent neuroprotector homeobox protein", "ADNP", "ADNP-Related Disorder" ]		Lusine Harutyunyan, Frank R Kooy, Claudio Peter D'Incal, Anke Van Dijck	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Speech and motor delay Mild-to-severe intellectual disability Autism spectrum disorder, additional behavioral problems, and sleep disturbance Characteristic facial appearance including prominent forehead, high anterior hairline, downslanted palpebral fissures, prominent eyelashes, ear malformations, wide and depressed nasal bridge, short nose with full, upturned nasal tip, long philtrum, thin vermilion of the upper lip, pointed chin, and widely spaced teeth (See Feeding difficulties and gastrointestinal problems (e.g., gastroesophageal reflux disease, lack of satiation, frequent vomiting, constipation) Vision issues (e.g., strabismus, cortical visual impairment, hypermetropia) and various ophthalmologic defects Musculoskeletal anomalies (e.g., hand and foot anomalies, joint laxity, scoliosis, hip problems, pectus deformities, skull deformities) Other features including recurrent infections, endocrine manifestations, cardiac and kidney anomalies, hearing loss, and seizures The diagnosis of Note: (1) Per American College of Medical Genetics and Genomics (AMCG) / 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 [ For an introduction to comprehensive genomic testing click For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including One individual with a heterozygous 20q13.13 deletion that encompassed Genome-wide CpG methylation analysis (e.g., EpiSign One individual with a • Speech and motor delay • Mild-to-severe intellectual disability • Autism spectrum disorder, additional behavioral problems, and sleep disturbance • Characteristic facial appearance including prominent forehead, high anterior hairline, downslanted palpebral fissures, prominent eyelashes, ear malformations, wide and depressed nasal bridge, short nose with full, upturned nasal tip, long philtrum, thin vermilion of the upper lip, pointed chin, and widely spaced teeth (See • Feeding difficulties and gastrointestinal problems (e.g., gastroesophageal reflux disease, lack of satiation, frequent vomiting, constipation) • Vision issues (e.g., strabismus, cortical visual impairment, hypermetropia) and various ophthalmologic defects • Musculoskeletal anomalies (e.g., hand and foot anomalies, joint laxity, scoliosis, hip problems, pectus deformities, skull deformities) • Other features including recurrent infections, endocrine manifestations, cardiac and kidney anomalies, hearing loss, and seizures • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click ## Suggestive Findings Speech and motor delay Mild-to-severe intellectual disability Autism spectrum disorder, additional behavioral problems, and sleep disturbance Characteristic facial appearance including prominent forehead, high anterior hairline, downslanted palpebral fissures, prominent eyelashes, ear malformations, wide and depressed nasal bridge, short nose with full, upturned nasal tip, long philtrum, thin vermilion of the upper lip, pointed chin, and widely spaced teeth (See Feeding difficulties and gastrointestinal problems (e.g., gastroesophageal reflux disease, lack of satiation, frequent vomiting, constipation) Vision issues (e.g., strabismus, cortical visual impairment, hypermetropia) and various ophthalmologic defects Musculoskeletal anomalies (e.g., hand and foot anomalies, joint laxity, scoliosis, hip problems, pectus deformities, skull deformities) Other features including recurrent infections, endocrine manifestations, cardiac and kidney anomalies, hearing loss, and seizures • Speech and motor delay • Mild-to-severe intellectual disability • Autism spectrum disorder, additional behavioral problems, and sleep disturbance • Characteristic facial appearance including prominent forehead, high anterior hairline, downslanted palpebral fissures, prominent eyelashes, ear malformations, wide and depressed nasal bridge, short nose with full, upturned nasal tip, long philtrum, thin vermilion of the upper lip, pointed chin, and widely spaced teeth (See • Feeding difficulties and gastrointestinal problems (e.g., gastroesophageal reflux disease, lack of satiation, frequent vomiting, constipation) • Vision issues (e.g., strabismus, cortical visual impairment, hypermetropia) and various ophthalmologic defects • Musculoskeletal anomalies (e.g., hand and foot anomalies, joint laxity, scoliosis, hip problems, pectus deformities, skull deformities) • Other features including recurrent infections, endocrine manifestations, cardiac and kidney anomalies, hearing loss, and seizures ## Establishing the Diagnosis The diagnosis of Note: (1) Per American College of Medical Genetics and Genomics (AMCG) / 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 [ For an introduction to comprehensive genomic testing click For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including One individual with a heterozygous 20q13.13 deletion that encompassed Genome-wide CpG methylation analysis (e.g., EpiSign One individual with a • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click ## Clinical Characteristics ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; PE = pressure equalization; SD = standard deviation(s) All affected individuals have mild-to-severe intellectual disability. Additional behavior problems may include anxiety, obsessive-compulsive disorder, aggressive behavior, temper tantrums, attention-deficient/hyperactivity disorder, and sleep problems. Pathogenic variants result in two distinct DNA methylation patterns, depending on the location of the variant within A class 2 methylation signature appears to correlate with a generally more severe phenotypic presentation. These individuals were found to experience recurrent infections, gastrointestinal problems (including reflux, constipation, and feeding difficulties) and short stature two to three times more often than individuals with a class 1 signature. Neurodevelopmental problems are more common in individuals with a class 1 signature [ Penetrance is less than 100%. In two families reported to date, probands diagnosed with The prevalence of pathogenic variants in ## Clinical Description ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; PE = pressure equalization; SD = standard deviation(s) All affected individuals have mild-to-severe intellectual disability. Additional behavior problems may include anxiety, obsessive-compulsive disorder, aggressive behavior, temper tantrums, attention-deficient/hyperactivity disorder, and sleep problems. ## Genotype-Phenotype Correlations Pathogenic variants result in two distinct DNA methylation patterns, depending on the location of the variant within A class 2 methylation signature appears to correlate with a generally more severe phenotypic presentation. These individuals were found to experience recurrent infections, gastrointestinal problems (including reflux, constipation, and feeding difficulties) and short stature two to three times more often than individuals with a class 1 signature. Neurodevelopmental problems are more common in individuals with a class 1 signature [ ## Penetrance Penetrance is less than 100%. In two families reported to date, probands diagnosed with ## Prevalence The prevalence of pathogenic variants in ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis SWI/SNF-Related Neurodevelopmental Syndromes (BAFopathies) of Interest in the Differential Diagnosis of ID, speech & motor delays, & distinct craniofacial features Note: AD = autosomal dominant; AR = autosomal recessive; HVDAS = Helsmoortel-Van der Aa syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Typically caused by a See also OMIM Phenotypic Series for genes associated with: • ID, speech & motor delays, & distinct craniofacial features • Note: ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Motor, adaptive, cognitive, & speech-language eval Testing for ASD & ID Eval for early intervention / special education Nutrition / swallowing / feeding team eval Referral to gastroenterologist/ENT To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Joint hypermobility Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Measure growth parameters. Assess for thyroid problems. Assess for growth hormone deficiency in those w/short stature. To evaluate for growth deficiency & obesity Referral to endocrinologist if indicated Bone age if indicated Referral to neurologist if indicated Consider EEG if seizures are a concern. To incl brain MRI to detect brain abnormalities given atypical clinical signs (new-onset focal neurologic deficits, unexplained rapid neurologic deterioration), seizures Community or Social work involvement for parental support Home nursing referral Psychologist ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ENT = ear, nose, and throat specialist; HVDAS = Helsmoortel-Van der Aa syndrome; ID = intellectual disability; MOI = mode of inheritance; OCD = obsessive-compulsive disorder; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Treatment is symptomatic; no specific therapy is available. Routine medical care by a pediatrician or primary care physician is recommended. Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Growth hormone therapy in those w/deficiency per endocrinologist 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 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 Measurement of growth parameters Eval of nutritional status & safety of oral intake Assess for constipation & signs/symptoms of gastrointestinal reflux. Thyroid problems; Growth hormone deficiency in those w/short stature. Audiologic eval Referral to ENT if indicated Monitor those w/seizures as clinically indicated. Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). EEG if seizures are a concern. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ENT = ear, nose, and throat specialist; OCD = obsessive-compulsive disorder; OT = occupational therapy/theapist; PT = physical therapy/therapist See Ketamine treatment has been proposed as a potential therapy for Search • Motor, adaptive, cognitive, & speech-language eval • Testing for ASD & ID • Eval for early intervention / special education • Nutrition / swallowing / feeding team eval • Referral to gastroenterologist/ENT • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Joint hypermobility • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Measure growth parameters. • Assess for thyroid problems. • Assess for growth hormone deficiency in those w/short stature. • To evaluate for growth deficiency & obesity • Referral to endocrinologist if indicated • Bone age if indicated • Referral to neurologist if indicated • Consider EEG if seizures are a concern. • To incl brain MRI to detect brain abnormalities given atypical clinical signs (new-onset focal neurologic deficits, unexplained rapid neurologic deterioration), seizures • Community or • Social work involvement for parental support • Home nursing referral • Psychologist • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Growth hormone therapy in those w/deficiency per endocrinologist • 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 and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 • Assess for constipation & signs/symptoms of gastrointestinal reflux. • Thyroid problems; • Growth hormone deficiency in those w/short stature. • Audiologic eval • Referral to ENT if indicated • Monitor those w/seizures as clinically indicated. • Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). • EEG if seizures are a concern. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Motor, adaptive, cognitive, & speech-language eval Testing for ASD & ID Eval for early intervention / special education Nutrition / swallowing / feeding team eval Referral to gastroenterologist/ENT To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. Joint hypermobility Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Measure growth parameters. Assess for thyroid problems. Assess for growth hormone deficiency in those w/short stature. To evaluate for growth deficiency & obesity Referral to endocrinologist if indicated Bone age if indicated Referral to neurologist if indicated Consider EEG if seizures are a concern. To incl brain MRI to detect brain abnormalities given atypical clinical signs (new-onset focal neurologic deficits, unexplained rapid neurologic deterioration), seizures Community or Social work involvement for parental support Home nursing referral Psychologist ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; ENT = ear, nose, and throat specialist; HVDAS = Helsmoortel-Van der Aa syndrome; ID = intellectual disability; MOI = mode of inheritance; OCD = obsessive-compulsive disorder; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Motor, adaptive, cognitive, & speech-language eval • Testing for ASD & ID • Eval for early intervention / special education • Nutrition / swallowing / feeding team eval • Referral to gastroenterologist/ENT • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk. • Joint hypermobility • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Measure growth parameters. • Assess for thyroid problems. • Assess for growth hormone deficiency in those w/short stature. • To evaluate for growth deficiency & obesity • Referral to endocrinologist if indicated • Bone age if indicated • Referral to neurologist if indicated • Consider EEG if seizures are a concern. • To incl brain MRI to detect brain abnormalities given atypical clinical signs (new-onset focal neurologic deficits, unexplained rapid neurologic deterioration), seizures • Community or • Social work involvement for parental support • Home nursing referral • Psychologist ## Treatment of Manifestations Treatment is symptomatic; no specific therapy is available. Routine medical care by a pediatrician or primary care physician is recommended. Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Growth hormone therapy in those w/deficiency per endocrinologist 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 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. • Growth hormone therapy in those w/deficiency per endocrinologist • 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 and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 Measurement of growth parameters Eval of nutritional status & safety of oral intake Assess for constipation & signs/symptoms of gastrointestinal reflux. Thyroid problems; Growth hormone deficiency in those w/short stature. Audiologic eval Referral to ENT if indicated Monitor those w/seizures as clinically indicated. Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). EEG if seizures are a concern. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; ENT = ear, nose, and throat specialist; OCD = obsessive-compulsive disorder; OT = occupational therapy/theapist; PT = physical therapy/therapist • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Assess for constipation & signs/symptoms of gastrointestinal reflux. • Thyroid problems; • Growth hormone deficiency in those w/short stature. • Audiologic eval • Referral to ENT if indicated • Monitor those w/seizures as clinically indicated. • Assess for new manifestations (e.g., seizures, changes in tone, movement disorders). • EEG if seizures are a concern. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Ketamine treatment has been proposed as a potential therapy for Search ## Genetic Counseling Most probands reported to date with In two families reported to date, probands diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Sib recurrence of If the If the parents have not been tested for the The risk to other family members depends on the genetic status of the proband's parents: if a parent has the Given that most probands 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 the parents of an affected individual. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Most probands reported to date with • In two families reported to date, probands diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Sib recurrence of • If the • If the parents have not been tested for the • The risk to other family members depends on the genetic status of the proband's parents: if a parent has the • Given that most probands 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 the parents of an affected individual. ## Mode of Inheritance ## Risk to Family Members Most probands reported to date with In two families reported to date, probands diagnosed with Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Sib recurrence of If the If the parents have not been tested for the The risk to other family members depends on the genetic status of the proband's parents: if a parent has the Given that most probands with • Most probands reported to date with • In two families reported to date, probands diagnosed with • Molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with 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 known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Sib recurrence of • If the • If the parents have not been tested for the • The risk to other family members depends on the genetic status of the proband's parents: if a parent has the • Given that most probands with ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected individual. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 individual. ## 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 Czech Republic Italy Belgium France Netherlands • • Czech Republic • • • Italy • • • • • Belgium • • • France • • • Netherlands • • • • • • • • ## Molecular Genetics ADNP-Related Helsmoortel-Van der Aa Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ADNP-Related Helsmoortel-Van der Aa Syndrome ( 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 The Medical Genetics of the Faculty of Pharmaceutical, Biomedical, and Veterinary Sciences of the University of Antwerp research group's mission is to identify genetic causes of cognitive disorders and study the molecular defects in order to eventually develop rational therapy. Dr Anke Van Dijck ( Contact Dr Van Dijck to inquire about review of We thank the families with individuals affected by an Claudio Peter D'Incal, PhD (2025-present)Lusine Harutyunyan (2025-present)Céline Helsmoortel, MSc; University of Antwerp (2016-2021)Frank Kooy, PhD (2016-present)Anke Van Dijck, MD, PhD (2016-present)Geert Vandeweyer, PhD (2016-2025) 21 August 2025 (sw) Comprehensive update posted live 15 April 2021 (sw) Comprehensive update posted live 7 April 2016 (bp) Review posted live 18 December 2015 (avd) Original submission • 21 August 2025 (sw) Comprehensive update posted live • 15 April 2021 (sw) Comprehensive update posted live • 7 April 2016 (bp) Review posted live • 18 December 2015 (avd) Original submission ## Author Notes The Medical Genetics of the Faculty of Pharmaceutical, Biomedical, and Veterinary Sciences of the University of Antwerp research group's mission is to identify genetic causes of cognitive disorders and study the molecular defects in order to eventually develop rational therapy. Dr Anke Van Dijck ( Contact Dr Van Dijck to inquire about review of ## Acknowledgments We thank the families with individuals affected by an ## Author History Claudio Peter D'Incal, PhD (2025-present)Lusine Harutyunyan (2025-present)Céline Helsmoortel, MSc; University of Antwerp (2016-2021)Frank Kooy, PhD (2016-present)Anke Van Dijck, MD, PhD (2016-present)Geert Vandeweyer, PhD (2016-2025) ## Revision History 21 August 2025 (sw) Comprehensive update posted live 15 April 2021 (sw) Comprehensive update posted live 7 April 2016 (bp) Review posted live 18 December 2015 (avd) Original submission • 21 August 2025 (sw) Comprehensive update posted live • 15 April 2021 (sw) Comprehensive update posted live • 7 April 2016 (bp) Review posted live • 18 December 2015 (avd) Original submission ## References ## Literature Cited Facial features of individuals with Reproduced with permission from	[]	7/4/2016	21/8/2025	6/10/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aec	aec	[ "Ectrodactyly, Ectodermal Dysplasia, Cleft Lip/Palate Syndrome 3 (EEC3)", "Split-Hand/Foot Malformation Type 4 (SHFM4)", "Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome (AEC Syndrome)", "Limb-Mammary Syndrome", "Acro-Dermo-Ungual-Lacrimal-Tooth Syndrome (ADULT Syndrome)", "Isolated Cleft Lip/Cleft Palate (Orofacial Cleft 8)", "Tumor protein 63", "TP63", "TP63-Related Disorders" ]		V Reid Sutton, Hans van Bokhoven	Summary The Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome (which includes Rapp-Hodgkin syndrome) Acro-dermo-ungual-lacrimal-tooth (ADULT) syndrome Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) Limb-mammary syndrome Split-hand/foot malformation type 4 (SHFM4) Isolated cleft lip/cleft palate (orofacial cleft 8) Individuals typically have varying combinations of ectodermal dysplasia (hypohidrosis, nail dysplasia, sparse hair, tooth abnormalities), cleft lip/palate, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypopigmentation, hypoplastic breasts and/or nipples, and hypospadias. Findings associated with a single phenotype include ankyloblepharon filiforme adnatum (tissue strands that completely or partially fuse the upper and lower eyelids), skin erosions especially on the scalp associated with areas of scarring, and alopecia, trismus, and excessive freckling. The diagnosis of a The	Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome) Rapp-Hodgkin syndrome Acro-dermo-ungual-lacrimal-tooth syndrome (ADULT syndrome) Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) Limb-mammary syndrome Split-hand/foot malformation type 4 (SHFM4) Isolated cleft lip/cleft palate (orofacial cleft 8) For synonyms and outdated names see For other genetic causes of these phenotypes, see • Ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (AEC syndrome) • Rapp-Hodgkin syndrome • Rapp-Hodgkin syndrome • Acro-dermo-ungual-lacrimal-tooth syndrome (ADULT syndrome) • Ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) • Limb-mammary syndrome • Split-hand/foot malformation type 4 (SHFM4) • Isolated cleft lip/cleft palate (orofacial cleft 8) • Rapp-Hodgkin syndrome ## Diagnosis A Ankyloblepharon filiforme adnatum Dermal erosions Signs of ectodermal dysplasia Hypohidrosis Nail dysplasia Sparse hair Tooth abnormalities Freckles in sun-exposed areas Cleft lip/palate Split-hand/foot malformation and/or syndactyly Lacrimal duct obstruction Hypopigmentation Hypospadias Hypoplastic nipples/breasts Note: The The diagnosis of a Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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 single case report of a four-exon deletion of • Ankyloblepharon filiforme adnatum • Dermal erosions • Signs of ectodermal dysplasia • Hypohidrosis • Nail dysplasia • Sparse hair • Tooth abnormalities • Hypohidrosis • Nail dysplasia • Sparse hair • Tooth abnormalities • Freckles in sun-exposed areas • Cleft lip/palate • Split-hand/foot malformation and/or syndactyly • Lacrimal duct obstruction • Hypopigmentation • Hypospadias • Hypoplastic nipples/breasts • Hypohidrosis • Nail dysplasia • Sparse hair • Tooth abnormalities ## Suggestive Findings A Ankyloblepharon filiforme adnatum Dermal erosions Signs of ectodermal dysplasia Hypohidrosis Nail dysplasia Sparse hair Tooth abnormalities Freckles in sun-exposed areas Cleft lip/palate Split-hand/foot malformation and/or syndactyly Lacrimal duct obstruction Hypopigmentation Hypospadias Hypoplastic nipples/breasts Note: The • Ankyloblepharon filiforme adnatum • Dermal erosions • Signs of ectodermal dysplasia • Hypohidrosis • Nail dysplasia • Sparse hair • Tooth abnormalities • Hypohidrosis • Nail dysplasia • Sparse hair • Tooth abnormalities • Freckles in sun-exposed areas • Cleft lip/palate • Split-hand/foot malformation and/or syndactyly • Lacrimal duct obstruction • Hypopigmentation • Hypospadias • Hypoplastic nipples/breasts • Hypohidrosis • Nail dysplasia • Sparse hair • Tooth abnormalities ## Establishing the Diagnosis The diagnosis of a Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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 single case report of a four-exon deletion of ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include 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 single case report of a four-exon deletion of ## Clinical Characteristics The ADULT = acro-dermato-ungual-lacrimal-tooth; AEC = ankyloblepharon-ectodermal defects-cleft lip/palate; EEC3 = ectrodactyly (split-hand/foot malformation), ectodermal dysplasia, cleft lip/palate syndrome 3; SHFM4 = split-hand/foot malformation type 4 Mostly subjective The manifestations of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome are typically present at birth. Lacrimal puncta are frequently absent, often leading to chronic conjunctivitis and blepharitis, which is often not recognized in infancy but seen in early childhood [ The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. Congenital erythroderma (i.e., diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [ Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions that may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribriform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [ Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [ The manifestations of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome are typically present at birth (although they may become more prominent with age), with the exception of skin freckling. The manifestations of ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) are typically present at birth. The manifestations of limb-mammary syndrome are typically present at birth. Note: Skin and hair abnormalities are NOT typically seen, in contrast to other The manifestations of split-hand/foot malformation-4 (SHFM4) are typically present at birth. Identification of a Note: Pathogenic variants have been described on two Reduced penetrance or possible germline mosaicism has been documented in a small number of individuals and families. Reduced penetrance for SHFM4 [ A few individuals who do not appear to be clinically affected have had more than one child with AEC syndrome. These occurrences may be the result of reduced penetrance, but are more likely the result of somatic and germline mosaicism in one parent. In one family, the Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is also known as Hay-Wells syndrome, after the physicians who first described the condition in 1976. Rapp-Hodgkin syndrome (RHS), once considered a separate entity, is now considered to be part of the spectrum of the AEC syndrome because of the overlap of clinical manifestations and EEC3 is thought to be genetically unrelated to EEC1 (which has been mapped to chromosome 7q11q21). An entity called EEC2 was initially mapped to chromosome 19 [ • The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. • Congenital erythroderma (i.e., diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [ • Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions that may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribriform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. • Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [ • Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [ • Reduced penetrance for SHFM4 [ • A few individuals who do not appear to be clinically affected have had more than one child with AEC syndrome. These occurrences may be the result of reduced penetrance, but are more likely the result of somatic and germline mosaicism in one parent. • In one family, the ## Clinical Description The ADULT = acro-dermato-ungual-lacrimal-tooth; AEC = ankyloblepharon-ectodermal defects-cleft lip/palate; EEC3 = ectrodactyly (split-hand/foot malformation), ectodermal dysplasia, cleft lip/palate syndrome 3; SHFM4 = split-hand/foot malformation type 4 Mostly subjective The manifestations of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome are typically present at birth. Lacrimal puncta are frequently absent, often leading to chronic conjunctivitis and blepharitis, which is often not recognized in infancy but seen in early childhood [ The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. Congenital erythroderma (i.e., diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [ Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions that may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribriform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [ Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [ The manifestations of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome are typically present at birth (although they may become more prominent with age), with the exception of skin freckling. The manifestations of ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) are typically present at birth. The manifestations of limb-mammary syndrome are typically present at birth. Note: Skin and hair abnormalities are NOT typically seen, in contrast to other The manifestations of split-hand/foot malformation-4 (SHFM4) are typically present at birth. Identification of a • The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. • Congenital erythroderma (i.e., diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [ • Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions that may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribriform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. • Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [ • Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [ ## AEC Syndrome The manifestations of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome are typically present at birth. Lacrimal puncta are frequently absent, often leading to chronic conjunctivitis and blepharitis, which is often not recognized in infancy but seen in early childhood [ The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. Congenital erythroderma (i.e., diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [ Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions that may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribriform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [ Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [ • The skin erosions tend to be recurrent and intermittent throughout childhood and into adulthood with frequent involvement of the head and neck, palms, soles, and skin folds. • Congenital erythroderma (i.e., diffuse erythema with associated erosions) is observed in 70%-90% of infants. The skin can also appear shiny with a collodion membrane (red, shiny, membranous skin changes) [ • Children typically manifest cutaneous depigmentation and scarring, most likely due to postinflammatory pigmentary changes related to previous erythroderma and associated underlying erosions that may or may not be appreciated clinically. African American infants can have facial hypopigmentation in a mask pattern that improves with age. Affected individuals with fair skin typically have a reticulated hyperpigmentation on the neck and intertriginous areas that progresses with age to cribriform, reticulate, stellate, or punctate scarring most commonly on the shoulders, upper back, and chest. • Histopathologic features of skin biopsies may reveal epidermal atrophy, pigment incontinence, and a prominent superficial perivascular plexus with limited lymphocytic infiltrate [ • Linear growth abnormalities are observed in early childhood with a significantly lower height for age compared to the reference population. The growth pattern in AEC is similar to that reported for hypohidrotic ectodermal dysplasia [ ## ADULT Syndrome The manifestations of acro-dermato-ungual-lacrimal-tooth (ADULT) syndrome are typically present at birth (although they may become more prominent with age), with the exception of skin freckling. ## EEC3 The manifestations of ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome 3 (EEC3) are typically present at birth. ## Limb-Mammary Syndrome The manifestations of limb-mammary syndrome are typically present at birth. Note: Skin and hair abnormalities are NOT typically seen, in contrast to other ## SHFM4 The manifestations of split-hand/foot malformation-4 (SHFM4) are typically present at birth. ## Isolated Cleft Lip/Palate (Orofacial Cleft 8) Identification of a ## Genotype-Phenotype Correlations Note: Pathogenic variants have been described on two ## Penetrance Reduced penetrance or possible germline mosaicism has been documented in a small number of individuals and families. Reduced penetrance for SHFM4 [ A few individuals who do not appear to be clinically affected have had more than one child with AEC syndrome. These occurrences may be the result of reduced penetrance, but are more likely the result of somatic and germline mosaicism in one parent. In one family, the • Reduced penetrance for SHFM4 [ • A few individuals who do not appear to be clinically affected have had more than one child with AEC syndrome. These occurrences may be the result of reduced penetrance, but are more likely the result of somatic and germline mosaicism in one parent. • In one family, the ## Nomenclature Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome is also known as Hay-Wells syndrome, after the physicians who first described the condition in 1976. Rapp-Hodgkin syndrome (RHS), once considered a separate entity, is now considered to be part of the spectrum of the AEC syndrome because of the overlap of clinical manifestations and EEC3 is thought to be genetically unrelated to EEC1 (which has been mapped to chromosome 7q11q21). An entity called EEC2 was initially mapped to chromosome 19 [ ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Erosions in AEC syndrome are typically more superficial & not assoc w/formation of bullae. Nondermatologic features & dermatopathology also distinguish EBS from AEC syndrome. SHFM1 is assoc w/high incidence of hearing loss. Findings are largely restricted to limbs. Dental & lacrimal duct abnormalities are seen in <10% of persons. Hypohidrosis in HED is severe enough to impair body temperature regulation, a problem not seen in Orofacial clefting, universal in AEC syndrome, is not typically seen in HED. AEC = ankyloblepharon-ectodermal defects-cleft lip/palate; AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SHFM = split-hand/foot malformation; XL = X-linked Interestingly, all but one of the affected individuals in the initial pedigree also had promoter polymorphism in • Erosions in AEC syndrome are typically more superficial & not assoc w/formation of bullae. • Nondermatologic features & dermatopathology also distinguish EBS from AEC syndrome. • SHFM1 is assoc w/high incidence of hearing loss. • Findings are largely restricted to limbs. • Dental & lacrimal duct abnormalities are seen in <10% of persons. • Hypohidrosis in HED is severe enough to impair body temperature regulation, a problem not seen in • Orofacial clefting, universal in AEC syndrome, is not typically seen in HED. ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a Recommended Evaluations Following Initial Diagnosis in Individuals with a OT/PT evals Hand surgery eval Use of community or Need for social work involvement for parental support; Impact of phenotype on normal life & need for counseling. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management by multidisciplinary specialists, including clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, nutrition/gastroenterology, and psychology, is recommended. Treatment of Manifestations in Individuals with a Childhood: consider dentures. Teen or early-adult: consider dental implants. OT = occupational therapy Recommended Surveillance for Individuals with a Prolonged exposure to sunlight should be avoided to: Prevent sunburn of hypopigmented areas and increase in contrast between the patchy areas of hyper- and hypopigmentation seen in AEC syndrome; Minimize freckling of skin in individuals with ADULT syndrome. It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from regular evaluation for disease manifestations with attention to dental needs and possible hearing loss. See Search • OT/PT evals • Hand surgery eval • Use of community or • Need for social work involvement for parental support; • Impact of phenotype on normal life & need for counseling. • Childhood: consider dentures. • Teen or early-adult: consider dental implants. • Prevent sunburn of hypopigmented areas and increase in contrast between the patchy areas of hyper- and hypopigmentation seen in AEC syndrome; • Minimize freckling of skin in individuals with ADULT syndrome. ## 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 OT/PT evals Hand surgery eval Use of community or Need for social work involvement for parental support; Impact of phenotype on normal life & need for counseling. MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • OT/PT evals • Hand surgery eval • Use of community or • Need for social work involvement for parental support; • Impact of phenotype on normal life & need for counseling. ## Treatment of Manifestations Management by multidisciplinary specialists, including clinical genetics, dermatology, ophthalmology, otolaryngology, audiology, dentistry and prosthodontics, plastic surgery, nutrition/gastroenterology, and psychology, is recommended. Treatment of Manifestations in Individuals with a Childhood: consider dentures. Teen or early-adult: consider dental implants. OT = occupational therapy • Childhood: consider dentures. • Teen or early-adult: consider dental implants. ## Surveillance Recommended Surveillance for Individuals with a ## Agents/Circumstances to Avoid Prolonged exposure to sunlight should be avoided to: Prevent sunburn of hypopigmented areas and increase in contrast between the patchy areas of hyper- and hypopigmentation seen in AEC syndrome; Minimize freckling of skin in individuals with ADULT syndrome. • Prevent sunburn of hypopigmented areas and increase in contrast between the patchy areas of hyper- and hypopigmentation seen in AEC syndrome; • Minimize freckling of skin in individuals with ADULT syndrome. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives in order to identify as early as possible those who would benefit from regular evaluation for disease manifestations with attention to dental needs and possible hearing loss. See ## Therapies Under Investigation Search ## Genetic Counseling Approximately 30% of individuals diagnosed with AEC have an affected parent. This appears to be true for the other The proportion of individuals with AEC caused by a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, 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 * [ * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with 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%. There can be a significant range of clinical variability in affected family members. 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Approximately 30% of individuals diagnosed with AEC have an affected parent. This appears to be true for the other • The proportion of individuals with AEC caused by a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, 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 * [ • * 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 * [ • * A parent with somatic and germline mosaicism for a • 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 * [ • * A parent with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. There can be a significant range of clinical variability in affected family members. • 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 ## Risk to Family Members Approximately 30% of individuals diagnosed with AEC have an affected parent. This appears to be true for the other The proportion of individuals with AEC caused by a If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent, 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 * [ * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with 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%. There can be a significant range of clinical variability in affected family members. If the If the parents have not been tested for the • Approximately 30% of individuals diagnosed with AEC have an affected parent. This appears to be true for the other • The proportion of individuals with AEC caused by a • If the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent, 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 * [ • * 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 * [ • * A parent with somatic and germline mosaicism for a • 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 * [ • * A parent with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. There can be a significant range of clinical variability in affected family members. • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 Germany • • • • • • • • United Kingdom • • • United Kingdom • • • • • • Germany • • • ## Molecular Genetics TP63-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for TP63-Related Disorders ( Transcription factor p63 encoded by A broad spectrum of different heterozygous variants has been reported in ## Molecular Pathogenesis Transcription factor p63 encoded by A broad spectrum of different heterozygous variants has been reported in ## Chapter Notes The authors would like to thank the National Foundation for Ectodermal Dysplasias and Executive Director Mary Fete, who organized the International Research Symposium on AEC syndrome, and all the individuals and families who participated in the research that contributed to this review. Additionally, we would like to express our gratitude to Dr John Carey and the Alanna F Bree, MD; Dermatology Specialists of Houston (2010-2015)V Reid Sutton, MD (2010-present)Hans van Bokhoven, PhD (2010-present) 1 April 2021 (ha) Comprehensive update posted live 5 December 2019 (vrs) Revision: correction to SHFM4 6 August 2015 (me) Comprehensive update posted live 8 June 2010 (me) Review posted live 2 February 2010 (vrs) Original submission • 1 April 2021 (ha) Comprehensive update posted live • 5 December 2019 (vrs) Revision: correction to SHFM4 • 6 August 2015 (me) Comprehensive update posted live • 8 June 2010 (me) Review posted live • 2 February 2010 (vrs) Original submission ## Author Notes ## Acknowledgments The authors would like to thank the National Foundation for Ectodermal Dysplasias and Executive Director Mary Fete, who organized the International Research Symposium on AEC syndrome, and all the individuals and families who participated in the research that contributed to this review. Additionally, we would like to express our gratitude to Dr John Carey and the ## Author History Alanna F Bree, MD; Dermatology Specialists of Houston (2010-2015)V Reid Sutton, MD (2010-present)Hans van Bokhoven, PhD (2010-present) ## Revision History 1 April 2021 (ha) Comprehensive update posted live 5 December 2019 (vrs) Revision: correction to SHFM4 6 August 2015 (me) Comprehensive update posted live 8 June 2010 (me) Review posted live 2 February 2010 (vrs) Original submission • 1 April 2021 (ha) Comprehensive update posted live • 5 December 2019 (vrs) Revision: correction to SHFM4 • 6 August 2015 (me) Comprehensive update posted live • 8 June 2010 (me) Review posted live • 2 February 2010 (vrs) Original submission ## References ## Literature Cited Typical and common EEC = ectrodactyly, ectodermal dysplasia, cleft lip/palate syndrome LMS = limb-mammary syndrome ADULT = acro-dermo-ungual-lacrimal-tooth syndrome AEC = ankyloblepharon-ectodermal defects-cleft lip/palate syndrome SHFM4 = split-hand/foot malformation type 4 NSCL = nonsyndromic cleft lip	[ "J Amiel, G Bougeard, C Francannet, V Raclin, A Munnich, S Lyonnet, T. Frebourg. TP63 gene mutation in ADULT syndrome.. Eur J Hum Genet. 2001;9:642-5", "S Aradhya, R Lewis, T Bonaga, N Nwokekeh, A Stafford, B Boggs, K Hruska, N Smaoul, JG Compton, G Richard, S Suchy. Exon-level array CGH in a large clinical cohort demonstrates increased sensitivity of diagnostic testing for Mendelian disorders.. Genet Med 2012;14:594-603", "LL Barrow, H van Bokhoven, S Daack-Hirsch, T Andersen, SE van Beersum, R Gorlin, JC Murray. Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts.. J Med Genet. 2002;39:559-66", "M Basha, B Demeer, N Revencu, R Helaers, S Theys, S Bou Saba, O Boute, B Devauchelle, G Francois, B Bayet, M Vikkula. Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes.. J Med Genet. 2018;55:449-58", "PW Buss, HE Hughes, A Clarke. Twenty-four cases of the EEC syndrome: clinical presentation and management.. J Med Genet. 1995;32:716-23", "M Cadieux-Dion, NP Safina, K Engleman, C Saunders, E Repnikova, N Raje, K Canty, E Farrow, N Miller, L Zellmer, I Thiffault. Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion syndrome: a case report.. BMC Med Genet. 2018;19:41", "S Cambiaghi, G Tadini, M Barbareschi, S Menni, R Caputo. Rapp-Hodgkin syndrome and AEC syndrome: Are they the same entity?. Br J Dermatol 1994;130:97-101", "S Cefalù, AM Lena, B Vojtesek, A Musarò, A Rossi, G Melino, E Candi. Tap63gamma is required for the late stages of myogenesis.. Cell Cycle. 2015;14:894-901", "J Celli, P Duijf, BC Hamel, M Bamshad, B Kramer, AP Smits, R Newbury-Ecob, RC Hennekam, G Van Buggenhout, A van Haeringen, CG Woods, AJ van Essen, R de Waal, G Vriend, DA Haber, A Yang, F McKeon, HG Brunner, H van Bokhoven. Heterozygous germline mutations in the p53 homolog p63 are the cause of EEC syndrome.. Cell. 1999;99:143-53", "P Cole, DA Hatef, Y Kaufman, A Magruder, A Bree, E Friedman, R Sindwani, LH Hollier. Facial clefting and oroauditory pathway manifestations in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome.. Am J Med Genet 2009;149A:1910-5", "XJ de Mollerat, F Gurrieri, CT Morgan, E Sangiorgi, DB Everman, P Gaspari, J Amiel, MJ Bamshad, R Lyle, JL Blouin, JE Allanson, B Le Marec, M Wilson, NE Braverman, U Radhakrishna, C Delozier-Blanchet, A Abbott, V Elghouzzi, S Antonarakis, RE Stevenson, A Munnich, G Neri, CE Schwartz. A genomic rearrangement resulting in a tandem duplication is associated with split hand-split foot malformation 3 (SHFM3) at 10q24.. Hum Mol Genet. 2003;12:1959-71", "GB Deutsch, EM Zielonka, D Coutandin, TA Weber, B Schäfer, J Hannewald, LM Luh, FG Durst, M Ibrahim, J Hoffmann, FH Niesen, A Sentürk, H Kunkel, B Brutschy, E Schleiff, S Knapp, A Acker-Palmer, M Grez, F McKeon, V Dötsch. DNA damage in oocytes induces a switch of the quality control factor TAp63α from dimer to tetramer.. Cell. 2011;144:566-76", "MK Dishop, AF Bree, MJ Hicks. Pathologic changes of skin and hair in ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.. Am J Med Genet 2009;149A:1935-41", "AM Elliott, JA Evans. Genotype-phenotype correlations in mapped split hand foot malformation (SHFM) patients.. Am J Med Genet A. 2006;140:1419-27", "A Enriquez, M Krivanek, R Flöttmann, H Peters, M Wilson. Recurrence of split hand/foot malformation, cleft lip/palate, and severe urogenital abnormalities due to germline mosaicism for TP63 mutation.. Am J Med Genet A. 2016;170:2372-6", "F Farrington, L Lausten. Oral findings in ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) syndrome.. Am J Med Genet 2009;149A:1907-9", "P Ferstl, S Wohlfart, H Schneider. Sweating ability of patients with P63-associated syndromes.. Eur J Pediatr 2018;177:1727-31", "MR Julapalli, RK Scher, VP Sybert, EC Siegfried, AF Bree. Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome.. Am J Med Genet A. 2009;149A:1900-6", "KD Khandelwal, MH van den Boogaard, SL Mehrem, J Gebel, C Fagerberg, E van Beusekom, E van Binsbergen, O Topaloglu, M Steehouwer, C Gilissen, N Ishorst, IALM van Rooij, N Roeleveld, K Christensen, J Schoenaers, S Bergé, JC Murray, G Hens, K Devriendt, KU Ludwig, E Mangold, A Hoischen, H Zhou, V Dötsch, CEL Carels, H van Bokhoven. Deletions and loss-of-function variants in TP63 associated with orofacial clefting.. Eur J Hum Genet. 2019;27:1101-12", "MM Lane, WT Dalton, SA Sherman, AF Bree, DI Czyzewski. Psychosocial functioning and quality of life in children and families affected by AEC syndrome.. Am J Med Genet A. 2009;149A:1926-34", "P Leoyklang, P Siriwan, V Shotelersuk. A mutation of the p63 gene in non-syndromic cleft lip.. J Med Genet 2006;43", "JA McGrath, PH Duijf, V Doetsch, AD Irvine, R de Waal, KR Vanmolkot, V Wessagowit, A Kelly, DJ Atherton, WA Griffiths, SJ Orlow, A van Haeringen, MG Ausems, A Yang, F McKeon, MA Bamshad, HG Brunner, BC Hamel, H van Bokhoven. Hay-Wells syndrome is caused by heterozygous missense mutations in the SAM domain of TP63.. Hum Mol Genet 2001;10:221-9", "P Monti, D Russo, R Bocciardi, G Foggetti, P Menichini, MT Divizia, M Lerone, C Graziano, A Wischmeijer, H Viadiu, R Ravazzolo, A Inga, G Fronza. EEC- and ADULT-associated TP63 mutations exhibit functional heterogeneity toward P63 responsive sequences.. Hum Mutat. 2013;34:894-904", "KJ Motil, TJ Fete. Growth, nutritional, and gastrointestinal aspects of ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) syndrome.. Am J Med Genet A. 2009;149A:1922-5", "JR O'Quinn, RC Hennekam, LB Jorde, M Bamshad. Syndromic ectrodactyly with severe limb, ectodermal, urogenital, and palatal defects maps to chromosome 19.. Am J Hum Genet. 1998;62:130-5", "HM Pashayan, S Pruzansky, L Solomon. The EEC syndrome. Report of six patients.. Birth Defects Orig Artic Ser. 1974;10:105-27", "M Restelli, T Lopardo, N Lo Iacono, G Garaffo, D Conte, A Rustighi, M Napoli, G Del Sal, D Perez-Morga, A Costanzo, GR Merlo, L Guerrini. DLX5, FGF8 and Pin1 isomerase control ΔNp63α protein stability during limb development: a regulatory loop at the basis of the SHFM and EEC congenital malformations.. Hum Mol Genet 2014;23:3830-42", "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 Rinne, HG Brunner, H van Bokhoven. p63-associated disorders.. Cell Cycle 2007;6:262-8", "T Rinne, SE Clements, E Lamme, PH Duijf, E Bolat, R Meijer, H Scheffer, E Rosser, TY Tan, JA McGrath, J Schalkwijk, HG Brunner, H Zhou, H van Bokhoven. A novel translation re-initiation mechanism for the p63 gene revealed by amino-terminal truncating mutations in Rapp-Hodgkin/Hay-Wells-like syndromes.. Hum Mol Genet 2008;17:1968-77", "T Rinne, B Hamel, H van Bokhoven, HG Brunner. Pattern of p63 mutations and their phenotypes--update.. Am J Med Genet A. 2006a;140:1396-406", "T Rinne, E Spadoni, KW Kjaer, C Danesino, D Larizza, M Kock, K Huoponen, M-L Savontaus, M Aaltonen, P Duijf, HG Brunner, M Penttinen, H van Bokhoven. Delineation of the ADULT syndrome phenotype due to arginine 298 mutgations of the p63 gene.. Eur J Hum Genet 2006b;14:904-10", "M Rouleau, A Medawar, L Hamon, S Shivtiel, Z Wolchinsky, H Zhou, L De Rosa, E Candi, S de la Forest Divonne, ML Mikkola, H van Bokhoven, C Missero, G Melino, M Pucéat, D Aberdam. TAp63 is important for cardiac differentiation of embryonic stem cells and heart development.. Stem Cells. 2011;29:1672-83", "I Sethi, R-A Romano, C Gluck, K Smalley, B Vojtesek, MJ Buck, S Sinha. A global analysis of the complex landscape of isoforms and regulatory networks of p63 in human cells and tissues.. BMC Genomics. 2015;16:584", "R Shalom-Feuerstein, L Serror, E Aberdam, FJ Müller, H van Bokhoven, KG Wiman, H Zhou, D Aberdam, I Petit. Impaired epithelial differentiation of induced pluripotent stem cells from ectodermal dysplasia-related patients is rescued by the small compound APR-246/PRIMA-1MET.. Proc Natl Acad Sci U S A. 2013;110:2152-6", "E Siegfried, A Bree, M Fete, V Sybert. Skin erosions and wound healing in ankyloblepharon-ectodermal defect – cleft lip and/or palate.. Arch Dermatol 2005;141:1591-4", "E Soares, H Zhou. Master regulatory role of p63 in epidermal development and disease.. Cell Mol Life Sci. 2018;75:1179-90", "M Spranger, J Schapera. Anomalous inheritance in a kindred with split hand, split foot malformation.. Eur J Pediatr. 1988;147:202-5", "PD Stenson, M Mort, EV Ball, K Evans, M Hayden, S Heywood, M Hussain, AD Phillips, DN Cooper. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies.. Hum Genet. 2017;136:665-77", "VR Sutton, K Plunkett, DX Dang, RA Lewis, AF Bree, CA Bacino. Craniofacial and anthropometric phenotype in ankyloblepharon-ectodermal defects-cleft lip/palate syndrome (Hay-Wells syndrome) in a cohort of 17 patients.. Am J Med Genet A 2009;149A:1916-21", "A Terrinoni, V Serra, E Bruno, A Strasser, E Valente, ER Flores, H van Bokhoven, X Lu, RA Knight, G Melino. Role of p63 and the Notch pathway in cochlea development and sensorineural deafness.. Proc Natl Acad Sci USA. 2013;110:7300-5", "SA Ugur, A Tolun. Homozygous WNT10b mutation and complex inheritance in Split-Hand/Foot Malformation.. Hum Mol Genet. 2008;17:2644-53", "H van Bokhoven, BC Hamel, M Bamshad, E Sangiorgi, F Gurrieri, PH Duijf, KR Vanmolkot, E van Beusekom, SE van Beersum, J Celli, GF Merkx, R Tenconi, JP Fryns, A Verloes, RA Newbury-Ecob, A Raas-Rotschild, F Majewski, FA Beemer, A Janecke, D Chitayat, G Crisponi, H Kayserili, JR Yates, G Neri, HG Brunner. p63 Gene mutations in eec syndrome, limb-mammary syndrome, and isolated split hand-split foot malformation suggest a genotype-phenotype correlation.. Am J Hum Genet 2001;69:481-92", "H van Bokhoven, M Jung, AP Smits, S van Beersum, F Rüschendorf, M van Steensel, M Veenstra, JH Tuerlings, EC Mariman, HG Brunner, TF Wienker, A Reis, HH Ropers, BC Hamel. Limb mammary syndrome: a new genetic disorder with mammary hypoplasia, ectrodactyly, and other Hand/Foot anomalies maps to human chromosome 3q27.. Am J Hum Genet. 1999;64:538-46", "WA van Zelst-Stams, MA van Steensel. A novel TP63 mutation in family with ADULT syndrome presenting with eczema and hypothelia.. Am J Med Genet A. 2009;149A:1558-60", "BJ Zarnegar, DE Webster, V Lopez-Pajares, B Vander Stoep Hunt, K Qu, KJ Yan, DR Berk, GL Sen, PA Khavari. Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63.. Am J Hum Genet. 2012;91:435-43" ]	8/6/2010	1/4/2021	5/12/2019	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ags	ags	[ "Deoxynucleoside triphosphate triphosphohydrolase SAMHD1", "Double-stranded RNA-specific adenosine deaminase", "Interferon-induced helicase C domain-containing protein 1", "Ribonuclease H2 subunit A", "Ribonuclease H2 subunit B", "Ribonuclease H2 subunit C", "Three prime repair exonuclease 1", "ADAR", "IFIH1", "RNASEH2A", "RNASEH2B", "RNASEH2C", "SAMHD1", "TREX1", "Aicardi-Goutieres Syndrome" ]	Aicardi-Goutières Syndrome	Yanick J Crow	Summary Most characteristically, Aicardi-Goutières syndrome (AGS) manifests as an early-onset encephalopathy that usually, but not always, results in severe intellectual and physical disability. A subgroup of infants with AGS present at birth with abnormal neurologic findings, hepatosplenomegaly, elevated liver enzymes, and thrombocytopenia, a picture highly suggestive of congenital infection. Otherwise, most affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. Typically, they demonstrate the subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. Over time, as many as 40% develop chilblain skin lesions on the fingers, toes, and ears. It is becoming apparent that atypical, sometimes milder, cases of AGS exist, and thus the true extent of the phenotype associated with pathogenic variants in the AGS-related genes is not yet known. The diagnosis of AGS is established in a proband with typical clinical findings and characteristic abnormalities on cranial CT (calcification of the basal ganglia and white matter) and MRI (leukodystrophic changes); AND/OR by identification of one of the following: Biallelic pathogenic variants in Specific heterozygous autosomal dominant pathogenic variants in A variety of heterozygous autosomal dominant pathogenic variants in AGS is most frequently inherited in an autosomal recessive manner; in a few instances the disease can result from specific	## Diagnosis In its most characteristic form, Aicardi-Goutières syndrome (AGS) can be considered an early-onset encephalopathy associated with significant intellectual and physical disability. Aicardi-Goutières syndrome (AGS) Encephalopathy and/or significant intellectual disability Acquired microcephaly during the first year of life Dystonia and spasticity Sterile pyrexias Hepatosplenomegaly Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See Exclusion criteria include the following: Evidence of prenatal/perinatal infection including, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika, and HIV Evidence of a known other metabolic disorder or neurodegenerative disorder Calcification (best visualized on CT scan) of the basal ganglia, particularly the putamen, globus pallidus and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution [ Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See On MRI, appears on T Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci Cerebellar atrophy and brain stem atrophy may also be prominent ( Bilateral striatal necrosis Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms Positive interferon signature identified using quantitative PCR analysis of RNA/cDNA [ Elevated liver enzymes Thrombocytopenia Chronic CSF leukocytosis, defined as more than five lymphocytes/mm Typical values range from five to 100 lymphocytes/mm A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ Increased interferon-alpha (IFN-α) activity in the CSF (normal: <2 IU/mL) Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ Increased concentration of neopterin in the CSF [ Levels are highest in the early stages of the disease and can normalize over time. Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. The diagnosis of AGS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular testing approaches can include If only one pathogenic variant is identified in Gene-targeted deletion/duplication analysis may also be considered if a heterozygous pathogenic variant that is not known to be associated with autosomal dominant AGS is identified in For an introduction to multigene panels click Molecular Genetic Testing Used in Aicardi-Goutières 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 Sequence analysis of the coding regions and splice sites of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 32/32 alleles were detectable by sequence analysis [ No deletions or duplications involving 90% of individuals with biallelic pathogenic variants in A deletion of The 25/26 alleles [ A recurrent deletion including exon 1 has been observed in several affected individuals of Ashkenazi Jewish ancestry and very likely represents a founder variant [ In approximately 100 individuals with • Encephalopathy and/or significant intellectual disability • Acquired microcephaly during the first year of life • Dystonia and spasticity • Sterile pyrexias • Hepatosplenomegaly • Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See • Evidence of prenatal/perinatal infection including, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika, and HIV • Evidence of a known other metabolic disorder or neurodegenerative disorder • Calcification (best visualized on CT scan) of the basal ganglia, particularly the putamen, globus pallidus and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution [ • Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. • White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See • On MRI, appears on T • Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci • Cerebellar atrophy and brain stem atrophy may also be prominent ( • Bilateral striatal necrosis • Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms • Positive interferon signature identified using quantitative PCR analysis of RNA/cDNA [ • Elevated liver enzymes • Thrombocytopenia • Chronic CSF leukocytosis, defined as more than five lymphocytes/mm • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Increased interferon-alpha (IFN-α) activity in the CSF (normal: <2 IU/mL) • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Increased concentration of neopterin in the CSF [ • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • If only one pathogenic variant is identified in • Gene-targeted deletion/duplication analysis may also be considered if a heterozygous pathogenic variant that is not known to be associated with autosomal dominant AGS is identified in ## Suggestive Findings Aicardi-Goutières syndrome (AGS) Encephalopathy and/or significant intellectual disability Acquired microcephaly during the first year of life Dystonia and spasticity Sterile pyrexias Hepatosplenomegaly Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See Exclusion criteria include the following: Evidence of prenatal/perinatal infection including, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika, and HIV Evidence of a known other metabolic disorder or neurodegenerative disorder Calcification (best visualized on CT scan) of the basal ganglia, particularly the putamen, globus pallidus and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution [ Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See On MRI, appears on T Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci Cerebellar atrophy and brain stem atrophy may also be prominent ( Bilateral striatal necrosis Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms Positive interferon signature identified using quantitative PCR analysis of RNA/cDNA [ Elevated liver enzymes Thrombocytopenia Chronic CSF leukocytosis, defined as more than five lymphocytes/mm Typical values range from five to 100 lymphocytes/mm A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ Increased interferon-alpha (IFN-α) activity in the CSF (normal: <2 IU/mL) Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ Increased concentration of neopterin in the CSF [ Levels are highest in the early stages of the disease and can normalize over time. Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Encephalopathy and/or significant intellectual disability • Acquired microcephaly during the first year of life • Dystonia and spasticity • Sterile pyrexias • Hepatosplenomegaly • Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See • Evidence of prenatal/perinatal infection including, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika, and HIV • Evidence of a known other metabolic disorder or neurodegenerative disorder • Calcification (best visualized on CT scan) of the basal ganglia, particularly the putamen, globus pallidus and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution [ • Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. • White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See • On MRI, appears on T • Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci • Cerebellar atrophy and brain stem atrophy may also be prominent ( • Bilateral striatal necrosis • Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms • Positive interferon signature identified using quantitative PCR analysis of RNA/cDNA [ • Elevated liver enzymes • Thrombocytopenia • Chronic CSF leukocytosis, defined as more than five lymphocytes/mm • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Increased interferon-alpha (IFN-α) activity in the CSF (normal: <2 IU/mL) • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Increased concentration of neopterin in the CSF [ • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. ## Clinical features Encephalopathy and/or significant intellectual disability Acquired microcephaly during the first year of life Dystonia and spasticity Sterile pyrexias Hepatosplenomegaly Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See Exclusion criteria include the following: Evidence of prenatal/perinatal infection including, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika, and HIV Evidence of a known other metabolic disorder or neurodegenerative disorder • Encephalopathy and/or significant intellectual disability • Acquired microcephaly during the first year of life • Dystonia and spasticity • Sterile pyrexias • Hepatosplenomegaly • Chilblain lesions on the feet, hands, ears, and sometimes more generalized mottling of the skin. See • Evidence of prenatal/perinatal infection including, but not limited to, CMV, toxoplasmosis, rubella, herpes simplex, Zika, and HIV • Evidence of a known other metabolic disorder or neurodegenerative disorder ## Neuroimaging Calcification (best visualized on CT scan) of the basal ganglia, particularly the putamen, globus pallidus and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution [ Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See On MRI, appears on T Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci Cerebellar atrophy and brain stem atrophy may also be prominent ( Bilateral striatal necrosis Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms • Calcification (best visualized on CT scan) of the basal ganglia, particularly the putamen, globus pallidus and thalamus but also extending into the white matter, sometimes in a para- (rather than true peri-) ventricular distribution [ • Note: Intracranial calcification is not always recognized on MRI, the initial imaging modality employed in most units. • White matter changes, particularly affecting the frontotemporal regions with (in severe cases) temporal lobe cyst-like formation. See • On MRI, appears on T • Cerebral atrophy, which may be progressive and involve the periventricular white matter and sulci • Cerebellar atrophy and brain stem atrophy may also be prominent ( • Bilateral striatal necrosis • Intracerebral vasculopathy including intracranial stenosis, moyamoya, and aneurysms ## Supportive Laboratory Findings Positive interferon signature identified using quantitative PCR analysis of RNA/cDNA [ Elevated liver enzymes Thrombocytopenia Chronic CSF leukocytosis, defined as more than five lymphocytes/mm Typical values range from five to 100 lymphocytes/mm A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ Increased interferon-alpha (IFN-α) activity in the CSF (normal: <2 IU/mL) Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ Increased concentration of neopterin in the CSF [ Levels are highest in the early stages of the disease and can normalize over time. Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Positive interferon signature identified using quantitative PCR analysis of RNA/cDNA [ • Elevated liver enzymes • Thrombocytopenia • Chronic CSF leukocytosis, defined as more than five lymphocytes/mm • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Increased interferon-alpha (IFN-α) activity in the CSF (normal: <2 IU/mL) • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Increased concentration of neopterin in the CSF [ • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. • Typical values range from five to 100 lymphocytes/mm • A decrease in the number of lymphocytes occurs with time, although high cell counts may persist for several years. • A normal cell count can be observed in the presence of elevated concentrations of IFN-α in the CSF even at an early stage of the disease [ • Recorded IFN-α activity is usually highest in the early stages of the disease. The IFN-α CSF activity can normalize over the first three to four years of life [ • Recorded IFN-α activity is usually higher in CSF than in blood, where it may be normal. • High IFN-α activity has been identified in fetal blood at 26 weeks' gestation [ • Levels are highest in the early stages of the disease and can normalize over time. • Levels of the neurotransmitter metabolites 5HIAA, HVA, and 5MTHF are normal. ## Establishing the Diagnosis The diagnosis of AGS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular testing approaches can include If only one pathogenic variant is identified in Gene-targeted deletion/duplication analysis may also be considered if a heterozygous pathogenic variant that is not known to be associated with autosomal dominant AGS is identified in For an introduction to multigene panels click Molecular Genetic Testing Used in Aicardi-Goutières 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 Sequence analysis of the coding regions and splice sites of Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 32/32 alleles were detectable by sequence analysis [ No deletions or duplications involving 90% of individuals with biallelic pathogenic variants in A deletion of The 25/26 alleles [ A recurrent deletion including exon 1 has been observed in several affected individuals of Ashkenazi Jewish ancestry and very likely represents a founder variant [ In approximately 100 individuals with • If only one pathogenic variant is identified in • Gene-targeted deletion/duplication analysis may also be considered if a heterozygous pathogenic variant that is not known to be associated with autosomal dominant AGS is identified in ## Clinical Characteristics In its most characteristic form, Aicardi-Goutières syndrome (AGS) can be considered an early-onset encephalopathy associated with significant intellectual and physical disability. All other affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. The majority of these later-presenting infants exhibit subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. The encephalopathic phase usually lasts several months. The opinion of most pediatricians caring for such children is that the disease does not progress beyond the encephalopathic period; occasionally, however, affected individuals do appear to show progression and/or episodes of regression. Death is usually considered to be secondary to the neurologic damage incurred during the initial disease episode, not to further regression. Several affected individuals older than age 30 years show no obvious signs of disease progression. Individuals can be developmentally normal at initial presentation. This phenotype can occur due to either biallelic pathogenic variants in Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in Additional infrequently observed features of AGS are summarized in Infrequent Features Seen in a Cohort of 123 Individuals with Molecularly Confirmed AGS Calcifications on neuroimaging: Are often punctate but may be dense and rock-like; When identified at diagnosis tend to remain stable, although progression can be observed [ Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ The main neuropathologic findings identified in severely affected individuals include [ Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; Calcification in the media, adventitia, and perivascular spaces of small vessels; Inflammation in the leptomeninges and areas of necrosis. In general, the early-onset neonatal form of AGS is most frequently seen in association with biallelic pathogenic variants in Mortality is correlated with genotype: 34% of individuals with A subgroup of individuals with Intracerebral vasculopathy, including intracranial stenosis and aneurysms, is observed more frequently in individuals who have biallelic pathogenic variants in Biallelic pathogenic variants in The microcephaly-intracranial calcification syndrome (MICS; also known as pseudo-TORCH syndrome or Baraitser-Reardon syndrome) was previously differentiated from AGS on the basis of congenital microcephaly and the presence of non-neurologic abnormalities including elevation of liver enzymes, hepatomegaly, and thrombocytopenia at birth [ The actual frequency of AGS is unknown. Pathogenic variants have been found in affected individuals of all ethnic origins [ • Individuals can be developmentally normal at initial presentation. • This phenotype can occur due to either biallelic pathogenic variants in • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in • Individuals can be developmentally normal at initial presentation. • This phenotype can occur due to either biallelic pathogenic variants in • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in • Individuals can be developmentally normal at initial presentation. • This phenotype can occur due to either biallelic pathogenic variants in • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in • Calcifications on neuroimaging: • Are often punctate but may be dense and rock-like; • When identified at diagnosis tend to remain stable, although progression can be observed [ • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ • Are often punctate but may be dense and rock-like; • When identified at diagnosis tend to remain stable, although progression can be observed [ • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ • The main neuropathologic findings identified in severely affected individuals include [ • Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; • Calcification in the media, adventitia, and perivascular spaces of small vessels; • Inflammation in the leptomeninges and areas of necrosis. • Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; • Calcification in the media, adventitia, and perivascular spaces of small vessels; • Inflammation in the leptomeninges and areas of necrosis. • Are often punctate but may be dense and rock-like; • When identified at diagnosis tend to remain stable, although progression can be observed [ • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ • Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; • Calcification in the media, adventitia, and perivascular spaces of small vessels; • Inflammation in the leptomeninges and areas of necrosis. • Intracerebral vasculopathy, including intracranial stenosis and aneurysms, is observed more frequently in individuals who have biallelic pathogenic variants in • Biallelic pathogenic variants in ## Clinical Description In its most characteristic form, Aicardi-Goutières syndrome (AGS) can be considered an early-onset encephalopathy associated with significant intellectual and physical disability. All other affected infants present at variable times after the first few weeks of life, frequently after a period of apparently normal development. The majority of these later-presenting infants exhibit subacute onset of a severe encephalopathy characterized by extreme irritability, intermittent sterile pyrexias, loss of skills, and slowing of head growth. The encephalopathic phase usually lasts several months. The opinion of most pediatricians caring for such children is that the disease does not progress beyond the encephalopathic period; occasionally, however, affected individuals do appear to show progression and/or episodes of regression. Death is usually considered to be secondary to the neurologic damage incurred during the initial disease episode, not to further regression. Several affected individuals older than age 30 years show no obvious signs of disease progression. Individuals can be developmentally normal at initial presentation. This phenotype can occur due to either biallelic pathogenic variants in Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in Additional infrequently observed features of AGS are summarized in Infrequent Features Seen in a Cohort of 123 Individuals with Molecularly Confirmed AGS Calcifications on neuroimaging: Are often punctate but may be dense and rock-like; When identified at diagnosis tend to remain stable, although progression can be observed [ Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ The main neuropathologic findings identified in severely affected individuals include [ Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; Calcification in the media, adventitia, and perivascular spaces of small vessels; Inflammation in the leptomeninges and areas of necrosis. • Individuals can be developmentally normal at initial presentation. • This phenotype can occur due to either biallelic pathogenic variants in • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in • Individuals can be developmentally normal at initial presentation. • This phenotype can occur due to either biallelic pathogenic variants in • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in • Individuals can be developmentally normal at initial presentation. • This phenotype can occur due to either biallelic pathogenic variants in • Like other AGS-related phenotypes, bilateral striatal necrosis due to biallelic pathogenic variants in • Calcifications on neuroimaging: • Are often punctate but may be dense and rock-like; • When identified at diagnosis tend to remain stable, although progression can be observed [ • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ • Are often punctate but may be dense and rock-like; • When identified at diagnosis tend to remain stable, although progression can be observed [ • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ • The main neuropathologic findings identified in severely affected individuals include [ • Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; • Calcification in the media, adventitia, and perivascular spaces of small vessels; • Inflammation in the leptomeninges and areas of necrosis. • Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; • Calcification in the media, adventitia, and perivascular spaces of small vessels; • Inflammation in the leptomeninges and areas of necrosis. • Are often punctate but may be dense and rock-like; • When identified at diagnosis tend to remain stable, although progression can be observed [ • Are not correlated with the severity of neurologic outcome; in rare cases, calcifications may be absent and may or may not be seen on repeat scans. Therefore, their absence does not rule out the diagnosis [ • Diffuse but nonhomogeneous demyelination with astrocytosis; absence of signs of storage or myelin breakdown; • Multiple wedge-shaped microinfarcts in the neocortex and cerebellar cortex, suggestive of a microangiopathy; • Calcific deposits in the white matter, thalami, basal ganglia, and dentate nuclei; • Calcification in the media, adventitia, and perivascular spaces of small vessels; • Inflammation in the leptomeninges and areas of necrosis. ## Phenotype Correlations by Gene In general, the early-onset neonatal form of AGS is most frequently seen in association with biallelic pathogenic variants in Mortality is correlated with genotype: 34% of individuals with A subgroup of individuals with Intracerebral vasculopathy, including intracranial stenosis and aneurysms, is observed more frequently in individuals who have biallelic pathogenic variants in Biallelic pathogenic variants in • Intracerebral vasculopathy, including intracranial stenosis and aneurysms, is observed more frequently in individuals who have biallelic pathogenic variants in • Biallelic pathogenic variants in ## Nomenclature The microcephaly-intracranial calcification syndrome (MICS; also known as pseudo-TORCH syndrome or Baraitser-Reardon syndrome) was previously differentiated from AGS on the basis of congenital microcephaly and the presence of non-neurologic abnormalities including elevation of liver enzymes, hepatomegaly, and thrombocytopenia at birth [ ## Prevalence The actual frequency of AGS is unknown. Pathogenic variants have been found in affected individuals of all ethnic origins [ ## Genetically Related (Allelic) Disorders Other phenotypes caused by pathogenic variants in Allelic Disorders Mutation of The heterozygous Linkage analysis and measurement of CSF concentration of IFN-α suggested that AGS and Cree encephalitis were allelic [ No phenotypes other than those discussed in this ## Differential Diagnosis Calcification of the basal ganglia is a nonspecific finding seen in many diseases. However, in the context of an early-onset encephalopathy, conditions to consider include the following: Note: Other congenital infections, such as those associated with Zika and HIV, should also be considered in the differential diagnosis. Superficially, at least, the MRI scan findings in AGS with frontotemporal white matter changes and cysts can be confused with • Note: Other congenital infections, such as those associated with Zika and HIV, should also be considered in the differential diagnosis. • Superficially, at least, the MRI scan findings in AGS with frontotemporal white matter changes and cysts can be confused with ## Management To establish the extent of disease and needs in an individual diagnosed with Aicardi-Goutières syndrome (AGS), the following evaluations are recommended: Developmental assessment Assessment of feeding and nutritional status Ophthalmologic examination EEG to evaluate for seizures, if suspected Consultation with a clinical geneticist and/or genetic counselor The following are appropriate: Chest physiotherapy and vigorous treatment of respiratory complications Attention to diet and method of feeding to assure adequate caloric intake Management of seizures using standard protocols Surveillance includes the following: Monitoring for signs of diabetes insipidus in the neonatal period Assessment for glaucoma at least for the first few years of life Monitoring of the spine for the development of scoliosis Monitoring for signs of insulin-dependent diabetes mellitus and hypothyroidism See Research into the role of immunosuppressive agents in the treatment of AGS is ongoing [ Search Corticosteroids can lower the CSF concentration of interferon [PG Barth 2003, personal communication]; the clinical benefit of such treatment is unproven. Note: The description of intracranial large-vessel disease in association with biallelic pathogenic variants in Given the lack of evidence, no definitive statement about these issues can be made at present. However, the potential for intervention exists, and it could be argued that some individuals (e.g., those with lesser psychomotor problems) warrant such intervention and should be actively screened for intracranial arteriopathy, if only by close inspection of the vasculature at the base of the brain seen on routine MRI. Chilblains were present in all the affected individuals described by • Developmental assessment • Assessment of feeding and nutritional status • Ophthalmologic examination • EEG to evaluate for seizures, if suspected • Consultation with a clinical geneticist and/or genetic counselor • Chest physiotherapy and vigorous treatment of respiratory complications • Attention to diet and method of feeding to assure adequate caloric intake • Management of seizures using standard protocols • Monitoring for signs of diabetes insipidus in the neonatal period • Assessment for glaucoma at least for the first few years of life • Monitoring of the spine for the development of scoliosis • Monitoring for signs of insulin-dependent diabetes mellitus and hypothyroidism ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Aicardi-Goutières syndrome (AGS), the following evaluations are recommended: Developmental assessment Assessment of feeding and nutritional status Ophthalmologic examination EEG to evaluate for seizures, if suspected Consultation with a clinical geneticist and/or genetic counselor • Developmental assessment • Assessment of feeding and nutritional status • Ophthalmologic examination • EEG to evaluate for seizures, if suspected • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations The following are appropriate: Chest physiotherapy and vigorous treatment of respiratory complications Attention to diet and method of feeding to assure adequate caloric intake Management of seizures using standard protocols • Chest physiotherapy and vigorous treatment of respiratory complications • Attention to diet and method of feeding to assure adequate caloric intake • Management of seizures using standard protocols ## Surveillance Surveillance includes the following: Monitoring for signs of diabetes insipidus in the neonatal period Assessment for glaucoma at least for the first few years of life Monitoring of the spine for the development of scoliosis Monitoring for signs of insulin-dependent diabetes mellitus and hypothyroidism • Monitoring for signs of diabetes insipidus in the neonatal period • Assessment for glaucoma at least for the first few years of life • Monitoring of the spine for the development of scoliosis • Monitoring for signs of insulin-dependent diabetes mellitus and hypothyroidism ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Research into the role of immunosuppressive agents in the treatment of AGS is ongoing [ Search ## Other Corticosteroids can lower the CSF concentration of interferon [PG Barth 2003, personal communication]; the clinical benefit of such treatment is unproven. Note: The description of intracranial large-vessel disease in association with biallelic pathogenic variants in Given the lack of evidence, no definitive statement about these issues can be made at present. However, the potential for intervention exists, and it could be argued that some individuals (e.g., those with lesser psychomotor problems) warrant such intervention and should be actively screened for intracranial arteriopathy, if only by close inspection of the vasculature at the base of the brain seen on routine MRI. Chilblains were present in all the affected individuals described by ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one AGS-related pathogenic variant). Heterozygotes (carriers) are not at risk of developing AGS; however, the findings of 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 AGS; however, heterozygotes may be at increased risk of developing later-onset systemic lupus erythematosus (SLE) or retinal vasculopathy with cerebral leukodystrophy (RVCL), depending on the specific gene and pathogenic variant involved (see To date, most probands with autosomal dominant AGS have had the disorder as a result of a Vertical transmission of pathogenic variants in Molecular genetic testing is recommended for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the proband most likely has a If a parent of the proband is affected, the risk to the sibs is 50%. If the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once the pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for AGS are possible. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one AGS-related pathogenic variant). • Heterozygotes (carriers) are not at risk of developing AGS; however, the findings of • 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 AGS; however, heterozygotes may be at increased risk of developing later-onset systemic lupus erythematosus (SLE) or retinal vasculopathy with cerebral leukodystrophy (RVCL), depending on the specific gene and pathogenic variant involved (see • To date, most probands with autosomal dominant AGS have had the disorder as a result of a • Vertical transmission of pathogenic variants in • Molecular genetic testing is recommended for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the proband most likely has a • If a parent of the proband is affected, the risk to the sibs is 50%. • If the • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., carriers of one AGS-related pathogenic variant). Heterozygotes (carriers) are not at risk of developing AGS; however, the findings of 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 AGS; however, heterozygotes may be at increased risk of developing later-onset systemic lupus erythematosus (SLE) or retinal vasculopathy with cerebral leukodystrophy (RVCL), depending on the specific gene and pathogenic variant involved (see • The parents of an affected child are obligate heterozygotes (i.e., carriers of one AGS-related pathogenic variant). • Heterozygotes (carriers) are not at risk of developing AGS; however, the findings of • 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 AGS; however, heterozygotes may be at increased risk of developing later-onset systemic lupus erythematosus (SLE) or retinal vasculopathy with cerebral leukodystrophy (RVCL), depending on the specific gene and pathogenic variant involved (see ## Autosomal Dominant Inheritance – Risk to Family Members To date, most probands with autosomal dominant AGS have had the disorder as a result of a Vertical transmission of pathogenic variants in Molecular genetic testing is recommended for the evaluation of parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the proband most likely has a If a parent of the proband is affected, the risk to the sibs is 50%. If the • To date, most probands with autosomal dominant AGS have had the disorder as a result of a • Vertical transmission of pathogenic variants in • Molecular genetic testing is recommended for the evaluation of parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the proband most likely has a • If a parent of the proband is affected, the risk to the sibs is 50%. • 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 testing is before 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 testing is before 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 pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for AGS are possible. ## Resources Italy 224 North Second Street Suite 2 DeKalb IL 60115 • • Italy • • • • • 224 North Second Street • Suite 2 • DeKalb IL 60115 • • • ## Molecular Genetics Aicardi-Goutieres Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Aicardi-Goutieres Syndrome ( Selected Variants listed in the table have been provided by the author. Selected Variants listed in the table have been provided by the author. Frequency of each allele is less than 1%. Two synonymous variants (c.69G>A and c.75C>T) in The frequency of alleles identified in affected individuals is: p.Ala177Thr (62%) p.Thr163Ile (7%) p.Val185Gly (7%) c.136+1delG (4%) Remaining alleles (<2%) [ Selected Variants listed in the table have been provided by the author. The frequency of alleles identified in affected individuals is: p.Arg69Trp (72%) Remaining alleles (seen only in single families) Selected Variants listed in the table have been provided by the author. Three large deletions plus a small deletion have also been identified. A large deletion of exon 1 is common among individuals of Ashkenazi Jewish descent [ Selected Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions Note: A great deal of confusion regarding Affected individuals are almost always homozygotes or compound heterozygotes for pathogenic variants within the same gene. However, children with clinically typical AGS had a The frequency of alleles identified in affected individuals is [ p.Arg114His (50%) c.58_59insG (1%) Remaining alleles (<1%) Selected Variants listed in the table have been provided by the author. TREX1 protein represents the major 3'→5' DNA exonuclease activity measured in mammalian cells. The protein has three conserved sequence motifs known as Exo I, II, and III. These motifs contain four conserved acidic residues that participate in coordination of divalent metal ions required for catalysis. In addition, the protein contains a C-terminal domain of about 75 amino acids, which is probably involved in subcellular localization of the protein, and a polyproline motif that may be involved in the interaction with other proteins. • p.Ala177Thr (62%) • p.Thr163Ile (7%) • p.Val185Gly (7%) • c.136+1delG (4%) • Remaining alleles (<2%) [ • p.Arg69Trp (72%) • Remaining alleles (seen only in single families) • p.Arg114His (50%) • c.58_59insG (1%) • Remaining alleles (<1%) ## Chapter Notes We would like to thank Dr Gillian Rice for her help in compiling the gene variant data. Jean Aicardi, MD, FRCP; Hospital Robert-Debré, Paris (2005-2014)Yanick J Crow, MBBS, BMedSci, MRCP, PhD (2005-present)John BP Stephenson, DM, FRCP, HonFRCPCH; Royal Hospital for Sick Children, Glasgow (2008-2014) 22 November 2016 (ma) Comprehensive update posted live 13 March 2014 (me) Comprehensive update posted live 1 March 2012 (cd) Revision: targeted mutation analysis for the c.490C>T mutation in 19 January 2012 (cd) Revision: deletion/duplication analysis available clinically for 4 November 2010 (me) Comprehensive update posted live 17 April 2008 (me) Comprehensive update posted live 29 June 2005 (me) Review posted live 1 September 2004 (ja) Original submission • 22 November 2016 (ma) Comprehensive update posted live • 13 March 2014 (me) Comprehensive update posted live • 1 March 2012 (cd) Revision: targeted mutation analysis for the c.490C>T mutation in • 19 January 2012 (cd) Revision: deletion/duplication analysis available clinically for • 4 November 2010 (me) Comprehensive update posted live • 17 April 2008 (me) Comprehensive update posted live • 29 June 2005 (me) Review posted live • 1 September 2004 (ja) Original submission ## Acknowledgments We would like to thank Dr Gillian Rice for her help in compiling the gene variant data. ## Author History Jean Aicardi, MD, FRCP; Hospital Robert-Debré, Paris (2005-2014)Yanick J Crow, MBBS, BMedSci, MRCP, PhD (2005-present)John BP Stephenson, DM, FRCP, HonFRCPCH; Royal Hospital for Sick Children, Glasgow (2008-2014) ## Revision History 22 November 2016 (ma) Comprehensive update posted live 13 March 2014 (me) Comprehensive update posted live 1 March 2012 (cd) Revision: targeted mutation analysis for the c.490C>T mutation in 19 January 2012 (cd) Revision: deletion/duplication analysis available clinically for 4 November 2010 (me) Comprehensive update posted live 17 April 2008 (me) Comprehensive update posted live 29 June 2005 (me) Review posted live 1 September 2004 (ja) Original submission • 22 November 2016 (ma) Comprehensive update posted live • 13 March 2014 (me) Comprehensive update posted live • 1 March 2012 (cd) Revision: targeted mutation analysis for the c.490C>T mutation in • 19 January 2012 (cd) Revision: deletion/duplication analysis available clinically for • 4 November 2010 (me) Comprehensive update posted live • 17 April 2008 (me) Comprehensive update posted live • 29 June 2005 (me) Review posted live • 1 September 2004 (ja) Original submission ## References ## Literature Cited Examples of chilblains seen in AGS Examples of intracranial calcification on CT scan in individuals with AGS. 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agu	agu	[ "AGA Deficiency", "Aspartylglucosaminidase Deficiency", "Aspartylglycosaminuria", "Glycoasparaginase Deficiency", "Glycosylasparaginase Deficiency", "Aspartylglycosaminuria", "Glycosylasparaginase Deficiency", "Aspartylglucosaminidase Deficiency", "AGA Deficiency", "Glycoasparaginase Deficiency", "N(4)-(beta-N-acetylglucosaminyl)-L-asparaginase", "AGA", "Aspartylglucosaminuria" ]	Aspartylglucosaminuria	Kimberly Goodspeed, Xin Chen, Michel Tchan	Summary Aspartylglucosaminuria is a lysosomal storage disorder characterized by developmental delay, intellectual disability, behavioral manifestations (hyperactivity in young children, anxiety and restlessness in adolescence, and apathy in adulthood), recurrent infections, musculoskeletal features, and characteristic craniofacial features (prominent supraorbital ridges, hypertelorism, periorbital fullness, short nose with broad nasal bridge, thick vermilion of the upper and lower lips, and macroglossia) that become more prominent with age. Additional neurologic manifestations can include seizures, poor balance and coordination, and progressive cerebral atrophy in adulthood. Macrocephaly is common. Musculoskeletal features include lordosis, scoliosis, and arthritis in adolescents and young adults; vertebral dysplasia and/or rib cage abnormalities; and progressive muscle wasting, joint contractures, bursitis, and osteoporosis in adulthood. Skin manifestations (facial seborrhea, rosacea, and angiofibromas), gastrointestinal manifestations, neutropenia, and thrombocytopenia occur in some individuals. The clinical manifestations of aspartylglucosaminuria worsen with age, and adults have progressive psychomotor decline. The diagnosis of aspartylglucosaminuria can be established in a proband with characteristic clinical and laboratory findings by identification of decreased aspartylglucosaminidase enzymatic activity in serum, leukocytes, or fibroblasts and/or biallelic pathogenic variants in Aspartylglucosaminuria is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No consensus clinical diagnostic criteria for aspartylglucosaminuria have been published. Aspartylglucosaminuria Mild-to-moderate developmental delay Mild-to-moderate intellectual disability Other neurologic manifestations (seizures, poor balance, and coordination) Behavioral manifestations (hyperactivity in young children, anxiety and restlessness in adolescence, and apathy in adulthood; disruptive sleep patterns) Recurrent infections (typically respiratory tract, ear, or skin infections) Characteristic craniofacial features (macrocephaly; coarsening of the facial features through childhood and adolescence progressing to characteristic facial features in adults, including prominent supraorbital ridges, hypertelorism, periorbital fullness, short nose with broad nasal bridge, relatively small ears, thick vermilion of the upper and lower lips, and macroglossia) (See Skin manifestations (facial seborrhea, rosacea, and angiofibromas) Musculoskeletal manifestations (lordosis, scoliosis, and arthritis in adolescents and young adults; progressive muscle wasting, joint contractures, bursitis, and osteoporosis in adulthood) Gastrointestinal manifestations (chronic diarrhea or constipation, abdominal or inguinal hernias) Neutropenia and thrombocytopenia in some individuals Elevated aspartylglucosamine and other glycoasparagines on urinary oligosaccharide analysis Vacuoles and large lysosomes in analysis of leukocytes or fibroblasts [ The diagnosis of aspartylglucosaminuria can be Reduced aspartylglucosaminidase enzymatic activity in serum, leukocytes, or fibroblasts [ AND/OR 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 Note: Targeted analysis for For an introduction to multigene panels click When the phenotype is indistinguishable from many neurodevelopmental disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aspartylglucosaminuria 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. • Mild-to-moderate developmental delay • Mild-to-moderate intellectual disability • Other neurologic manifestations (seizures, poor balance, and coordination) • Behavioral manifestations (hyperactivity in young children, anxiety and restlessness in adolescence, and apathy in adulthood; disruptive sleep patterns) • Recurrent infections (typically respiratory tract, ear, or skin infections) • Characteristic craniofacial features (macrocephaly; coarsening of the facial features through childhood and adolescence progressing to characteristic facial features in adults, including prominent supraorbital ridges, hypertelorism, periorbital fullness, short nose with broad nasal bridge, relatively small ears, thick vermilion of the upper and lower lips, and macroglossia) (See • Skin manifestations (facial seborrhea, rosacea, and angiofibromas) • Musculoskeletal manifestations (lordosis, scoliosis, and arthritis in adolescents and young adults; progressive muscle wasting, joint contractures, bursitis, and osteoporosis in adulthood) • Gastrointestinal manifestations (chronic diarrhea or constipation, abdominal or inguinal hernias) • Neutropenia and thrombocytopenia in some individuals • Elevated aspartylglucosamine and other glycoasparagines on urinary oligosaccharide analysis • Vacuoles and large lysosomes in analysis of leukocytes or fibroblasts [ • Reduced aspartylglucosaminidase enzymatic activity in serum, leukocytes, or fibroblasts [ • AND/OR • Biallelic pathogenic (or likely pathogenic) variants in ## Suggestive Findings Aspartylglucosaminuria Mild-to-moderate developmental delay Mild-to-moderate intellectual disability Other neurologic manifestations (seizures, poor balance, and coordination) Behavioral manifestations (hyperactivity in young children, anxiety and restlessness in adolescence, and apathy in adulthood; disruptive sleep patterns) Recurrent infections (typically respiratory tract, ear, or skin infections) Characteristic craniofacial features (macrocephaly; coarsening of the facial features through childhood and adolescence progressing to characteristic facial features in adults, including prominent supraorbital ridges, hypertelorism, periorbital fullness, short nose with broad nasal bridge, relatively small ears, thick vermilion of the upper and lower lips, and macroglossia) (See Skin manifestations (facial seborrhea, rosacea, and angiofibromas) Musculoskeletal manifestations (lordosis, scoliosis, and arthritis in adolescents and young adults; progressive muscle wasting, joint contractures, bursitis, and osteoporosis in adulthood) Gastrointestinal manifestations (chronic diarrhea or constipation, abdominal or inguinal hernias) Neutropenia and thrombocytopenia in some individuals Elevated aspartylglucosamine and other glycoasparagines on urinary oligosaccharide analysis Vacuoles and large lysosomes in analysis of leukocytes or fibroblasts [ • Mild-to-moderate developmental delay • Mild-to-moderate intellectual disability • Other neurologic manifestations (seizures, poor balance, and coordination) • Behavioral manifestations (hyperactivity in young children, anxiety and restlessness in adolescence, and apathy in adulthood; disruptive sleep patterns) • Recurrent infections (typically respiratory tract, ear, or skin infections) • Characteristic craniofacial features (macrocephaly; coarsening of the facial features through childhood and adolescence progressing to characteristic facial features in adults, including prominent supraorbital ridges, hypertelorism, periorbital fullness, short nose with broad nasal bridge, relatively small ears, thick vermilion of the upper and lower lips, and macroglossia) (See • Skin manifestations (facial seborrhea, rosacea, and angiofibromas) • Musculoskeletal manifestations (lordosis, scoliosis, and arthritis in adolescents and young adults; progressive muscle wasting, joint contractures, bursitis, and osteoporosis in adulthood) • Gastrointestinal manifestations (chronic diarrhea or constipation, abdominal or inguinal hernias) • Neutropenia and thrombocytopenia in some individuals • Elevated aspartylglucosamine and other glycoasparagines on urinary oligosaccharide analysis • Vacuoles and large lysosomes in analysis of leukocytes or fibroblasts [ ## Establishing the Diagnosis The diagnosis of aspartylglucosaminuria can be Reduced aspartylglucosaminidase enzymatic activity in serum, leukocytes, or fibroblasts [ AND/OR 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 Note: Targeted analysis for For an introduction to multigene panels click When the phenotype is indistinguishable from many neurodevelopmental disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aspartylglucosaminuria 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. • Reduced aspartylglucosaminidase enzymatic activity in serum, leukocytes, or fibroblasts [ • AND/OR • Biallelic pathogenic (or likely pathogenic) variants in ## Option 1 Note: Targeted analysis for For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many neurodevelopmental disorders, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aspartylglucosaminuria 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. ## Clinical Characteristics Aspartylglucosaminuria is a lysosomal storage disorder characterized by developmental delay, intellectual disability, behavioral manifestations, recurrent infections, growth deficiency, musculoskeletal features, and characteristic craniofacial features that become more prominent with age. Adults have progressive psychomotor decline and eventually lose the ability to communicate verbally and remain completely dependent as adults. To date, approximately 500 individuals have been identified with biallelic pathogenic variants in Aspartylglucosaminuria: Frequency of Select Features Based on No genotype-phenotype correlations have been identified. In a small study including both Finnish and non-Finnish individuals with aspartylglucosaminuria, there were no clear genotype-phenotype correlations identified [ In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ The vast majority of identified individuals with aspartylglucosaminuria are of Finnish descent, with a prevalence rate of 1.5-5:100,000 live births in Finland [ ## Clinical Description Aspartylglucosaminuria is a lysosomal storage disorder characterized by developmental delay, intellectual disability, behavioral manifestations, recurrent infections, growth deficiency, musculoskeletal features, and characteristic craniofacial features that become more prominent with age. Adults have progressive psychomotor decline and eventually lose the ability to communicate verbally and remain completely dependent as adults. To date, approximately 500 individuals have been identified with biallelic pathogenic variants in Aspartylglucosaminuria: Frequency of Select Features Based on ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. In a small study including both Finnish and non-Finnish individuals with aspartylglucosaminuria, there were no clear genotype-phenotype correlations identified [ ## Nomenclature In the 2023 revision of the Nosology of Genetic Skeletal Disorders [ ## Prevalence The vast majority of identified individuals with aspartylglucosaminuria are of Finnish descent, with a prevalence rate of 1.5-5:100,000 live births in Finland [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Aspartylglucosaminuria ↑ oligosaccharides & GAGs in urine ↑ lysosomal hydrolases ML II has a more severe neurodegenerative phenotype than AGU. ML III has more cardiorespiratory symptoms than AGU. Urinary testing may be similar. Emergence of joint deformities in early childhood Significant cardiorespiratory disease w/death in early adulthood Neurodevelopmental delay & challenging behaviors w/progressive mobility impairment Clinical severity can vary. Intellectual decline in some Coarse features Dysostosis multiplex Organomegaly ↑ urinary chondroitin, heparan, & dermatan sulfates Beta-glucuronidase deficiency Neurodevelopmental delay & challenging behaviors w/progressive mobility impairment in males Clinical severity can vary. Phenotypic presentation may be similar to AGU in those w/milder forms of MPS II. However, AGU will typically have earlier cognitive impairment compared to mild MPS II. Severe form has neurodegeneration from early childhood & death by adolescence. Attenuated form may have normal early development w/psychomotor decline beginning in adolescence or adulthood. Coarse features Progressive ataxia ID Hearing loss Skeletal abnormalities Recurrent infections ↑ urinary oligosaccharides Acid alpha-mannosidase deficiency Mild-to-profound DD/ID ↓ tear production Liver dysfunction Hyperkinetic movements (choreoathetosis, dystonia, myoclonus, tremor, dysmetria) Seizures Sleep disorders Neuropathy ↑ ALT & AST in early childhood that resolves spontaneously ↑ urine mucopolysaccharides Mild elevation of lactate Generalized aminoaciduria Childhood-onset neurodegenerative disorder w/varying severity Neonatal form is most severe, w/death by age 2 yrs. Infantile form has a slower progression w/variable rates of psychomotor decline beginning in early childhood. ↓ activity of at least 2 sulfatases ↑ GAGs in urine ↑ sulfatides in urine AGU = aspartylglucosaminuria; ALT = alanine transaminase; AR = autosomal recessive; AST = aspartate transaminase; DD = developmental delay; GAGs = glycosaminoglycans; ID = intellectual disability; ML = mucolipidosis; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked • ↑ oligosaccharides & GAGs in urine • ↑ lysosomal hydrolases • ML II has a more severe neurodegenerative phenotype than AGU. • ML III has more cardiorespiratory symptoms than AGU. • Urinary testing may be similar. • Emergence of joint deformities in early childhood • Significant cardiorespiratory disease w/death in early adulthood • Neurodevelopmental delay & challenging behaviors w/progressive mobility impairment • Clinical severity can vary. • Intellectual decline in some • Coarse features • Dysostosis multiplex • Organomegaly • ↑ urinary chondroitin, heparan, & dermatan sulfates • Beta-glucuronidase deficiency • Neurodevelopmental delay & challenging behaviors w/progressive mobility impairment in males • Clinical severity can vary. • Phenotypic presentation may be similar to AGU in those w/milder forms of MPS II. • However, AGU will typically have earlier cognitive impairment compared to mild MPS II. • Severe form has neurodegeneration from early childhood & death by adolescence. • Attenuated form may have normal early development w/psychomotor decline beginning in adolescence or adulthood. • Coarse features • Progressive ataxia • ID • Hearing loss • Skeletal abnormalities • Recurrent infections • ↑ urinary oligosaccharides • Acid alpha-mannosidase deficiency • Mild-to-profound DD/ID • ↓ tear production • Liver dysfunction • Hyperkinetic movements (choreoathetosis, dystonia, myoclonus, tremor, dysmetria) • Seizures • Sleep disorders • Neuropathy • ↑ ALT & AST in early childhood that resolves spontaneously • ↑ urine mucopolysaccharides • Mild elevation of lactate • Generalized aminoaciduria • Childhood-onset neurodegenerative disorder w/varying severity • Neonatal form is most severe, w/death by age 2 yrs. • Infantile form has a slower progression w/variable rates of psychomotor decline beginning in early childhood. • ↓ activity of at least 2 sulfatases • ↑ GAGs in urine • ↑ sulfatides in urine ## Management No clinical practice guidelines for aspartylglucosaminuria have been published. To establish the extent of disease and needs in an individual diagnosed with aspartylglucosaminuria, the evaluations summarized in Aspartylglucosaminuria: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Consider brain MRI. Consider EEG if seizures are a concern. 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) Gastrointestinal eval Assessment for hernias Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; AGU = aspartylglucosaminuria; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for aspartylglucosaminuria. 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 Aspartylglucosaminuria: 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; ENT = ears, nose, and throat; GI = gastrointestinal 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 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 Aspartylglucosaminuria: Recommended Surveillance Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, balance, & coordination issues. Assessment for spine issues, muscle wasting, & joint manifestations Physical medicine, OT/PT assessment of mobility, self-help skills DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of supportive treatments. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Biochemical testing, including urinary oligosaccharide analysis to identify elevated aspartylglucosamine and other glycoasparagines, if the pathogenic variants in the family are not known. See Early studies of bone marrow transplantation demonstrated no benefit in individuals with aspartylglucosaminuria. However, a case series of four children treated with hematopoietic stem cell transplant at an early age (age five months to nine years) demonstrated reduction in aspartylglucosamine and favorable neurodevelopmental outcomes [ There are also many small molecules that show promise as chaperone therapies to increase aspartylglucosaminidase activity [ Furthermore, early initiation of enzyme replacement therapy (ERT) in mice with aspartylglucosaminuria has been shown to reduce accumulation of aspartylglucosamine, but clinical development of ERT is complicated by the need to deliver high doses of recombinant aspartylglucosaminidase at an early age to improve penetration of the blood-brain barrier in individuals with aspartylglucosaminuria [ Finally, gene transfer therapy using an adeno-associated viral type 9 (AAV9) vector carrying codon-optimized human Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Consider brain MRI. • Consider EEG if seizures are a concern. • 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) • Gastrointestinal eval • Assessment for hernias • 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 • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, balance, & coordination issues. • Assessment for spine issues, muscle wasting, & joint manifestations • Physical medicine, OT/PT assessment of mobility, self-help skills • Molecular genetic testing if the pathogenic variants in the family are known; • Biochemical testing, including urinary oligosaccharide analysis to identify elevated aspartylglucosamine and other glycoasparagines, 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 aspartylglucosaminuria, the evaluations summarized in Aspartylglucosaminuria: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Consider brain MRI. Consider EEG if seizures are a concern. 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) Gastrointestinal eval Assessment for hernias Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; AGU = aspartylglucosaminuria; ASD = autism spectrum disorder; 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. • Consider EEG if seizures are a concern. • 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) • Gastrointestinal eval • Assessment for hernias • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for aspartylglucosaminuria. 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 Aspartylglucosaminuria: 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; ENT = ears, nose, and throat; GI = gastrointestinal 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 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 • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 ## 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 Aspartylglucosaminuria: Recommended Surveillance Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, balance, & coordination issues. Assessment for spine issues, muscle wasting, & joint manifestations Physical medicine, OT/PT assessment of mobility, self-help skills DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, balance, & coordination issues. • Assessment for spine issues, muscle wasting, & joint manifestations • Physical medicine, OT/PT assessment of mobility, self-help skills ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of supportive treatments. Evaluations can include: Molecular genetic testing if the pathogenic variants in the family are known; Biochemical testing, including urinary oligosaccharide analysis to identify elevated aspartylglucosamine and other glycoasparagines, if the pathogenic variants in the family are not known. See • Molecular genetic testing if the pathogenic variants in the family are known; • Biochemical testing, including urinary oligosaccharide analysis to identify elevated aspartylglucosamine and other glycoasparagines, if the pathogenic variants in the family are not known. ## Therapies Under Investigation Early studies of bone marrow transplantation demonstrated no benefit in individuals with aspartylglucosaminuria. However, a case series of four children treated with hematopoietic stem cell transplant at an early age (age five months to nine years) demonstrated reduction in aspartylglucosamine and favorable neurodevelopmental outcomes [ There are also many small molecules that show promise as chaperone therapies to increase aspartylglucosaminidase activity [ Furthermore, early initiation of enzyme replacement therapy (ERT) in mice with aspartylglucosaminuria has been shown to reduce accumulation of aspartylglucosamine, but clinical development of ERT is complicated by the need to deliver high doses of recombinant aspartylglucosaminidase at an early age to improve penetration of the blood-brain barrier in individuals with aspartylglucosaminuria [ Finally, gene transfer therapy using an adeno-associated viral type 9 (AAV9) vector carrying codon-optimized human Search ## Genetic Counseling Aspartylglucosaminuria is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (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. Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ancestry. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (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. • Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ancestry. ## Mode of Inheritance Aspartylglucosaminuria is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The parents of an affected child are presumed to be heterozygous for an • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (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. Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ancestry. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 should be considered, particularly if both partners are of the same ancestry. ## 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 • • • • • • • • United Kingdom • • • United Kingdom • • • ## Molecular Genetics Aspartylglucosaminuria: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Aspartylglucosaminuria ( Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Kimberly Goodspeed ( Dr Goodspeed ( Contact Dr Xin Chen ( We would like to thank the Rare Trait Hope Fund (USA), the UNC TraCS Institute (550KR121511), and AFM-Téléthon (France, Award 19715) for their funding support to the preclinical studies of gene transfer therapy. 18 January 2024 (sw) Review posted live 14 August 2023 (kg) Original submission • 18 January 2024 (sw) Review posted live • 14 August 2023 (kg) Original submission ## Author Notes Dr Kimberly Goodspeed ( Dr Goodspeed ( Contact Dr Xin Chen ( ## Acknowledgments We would like to thank the Rare Trait Hope Fund (USA), the UNC TraCS Institute (550KR121511), and AFM-Téléthon (France, Award 19715) for their funding support to the preclinical studies of gene transfer therapy. ## Revision History 18 January 2024 (sw) Review posted live 14 August 2023 (kg) Original submission • 18 January 2024 (sw) Review posted live • 14 August 2023 (kg) Original submission ## References ## Literature Cited Two brothers with aspartylglucosaminuria demonstrate progression of facial features with age. One sib at age two years (A), three years (B), four years (C), six years (D), and ten years (E). Second sib at age four months (F), one year (G), two years (H), five years (I), and nine years (J). Two unrelated individuals with aspartylglucosaminuria demonstrate progression of facial features with age, notably periorbital fullness, short nose, thick vermilion of the upper and lower lips, and obesity. First individual at age two years (A), four years (B), five years (C), nine years (D), 14 years (E), and 17 years (F). Second individual at age three years (G), four years (H), five years (I), eight years (J), ten years (K), and 13 years (L).	[]	18/1/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ahc	ahc	[ "Adrenal Hypoplasia Congenita", "Congenital Adrenal Hypoplasia", "X-Linked AHC", "X-Linked Adrenal Hypoplasia Congenita", "Xp21 Deletion (Complex Glycerol Kinase Deficiency)", "Dystrophin", "Glycerol kinase", "Interleukin-1 receptor accessory protein-like 1", "Nuclear receptor subfamily 0 group B member 1", "DMD", "GK", "IL1RAPL1", "NR0B1", "NR0B1-Related Adrenal Hypoplasia Congenita" ]		John C Achermann, Eric J Vilain	Summary Xp21 deletion includes deletion of The diagnosis of If puberty has not started by age 14 years, monitoring of serum concentrations of LH, FSH, testosterone, and inhibin B to evaluate for the possibility of HH is necessary. If puberty has started spontaneously, it is likely to arrest; thus, yearly routine monitoring of levels of LH, FSH, and testosterone is necessary. Once the	X-linked adrenal hypoplasia congenita Xp21 deletion (complex glycerol kinase deficiency) For synonyms and outdated names see • X-linked adrenal hypoplasia congenita • Xp21 deletion (complex glycerol kinase deficiency) ## Diagnosis Acute primary adrenal insufficiency in the first (or second) month of life Primary adrenal insufficiency later in childhood Primary adrenal insufficiency and/or hypogonadotropic hypogonadism in young adulthood Xp21 deletion. Developmental delay and seizures, strabismus Glycerol kinase deficiency. Metabolic acidosis, hypoglycemia Duchenne muscular dystrophy. See Primary adrenal insufficiency A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. Hypogonadotropic hypogonadism Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test Low inhibin B Glycerol kinase deficiency, diagnosed by either of the following: Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) Duchenne muscular dystrophy (See Note: (1) While ultrasound imaging is less specific than CT or MRI, it avoids the radiation exposure of CT and the need for sedation for MRI in a potentially sick child. (2) The apparent absence of the adrenal glands on imaging studies may also rarely be due to ectopia of normal-sized adrenal glands. The diagnosis of Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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 may not detect deletion of adjacent genes (see Footnote 7). Note that, although gene-targeted deletion/duplication assays may detect smaller events than genomic deletion/duplication assays, gene-targeted deletion/duplication assays will detect larger events but may not be able to determine the size. The majority of reported intragenic deletions and duplications, as well as Xp21 deletions, are detectable by CMA. It is possible that additional smaller deletions and duplications could be detected by these methods. Deletion/duplication analysis (genomic approach) detects deletion of Xp21 deletion includes X-linked AHC (caused by deletion of • Acute primary adrenal insufficiency in the first (or second) month of life • Primary adrenal insufficiency later in childhood • Primary adrenal insufficiency and/or hypogonadotropic hypogonadism in young adulthood • Xp21 deletion. Developmental delay and seizures, strabismus • Glycerol kinase deficiency. Metabolic acidosis, hypoglycemia • Duchenne muscular dystrophy. See • Primary adrenal insufficiency • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • Hypogonadotropic hypogonadism • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • Glycerol kinase deficiency, diagnosed by either of the following: • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) • Duchenne muscular dystrophy (See • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) • For an introduction to multigene panels click ## Suggestive Findings Acute primary adrenal insufficiency in the first (or second) month of life Primary adrenal insufficiency later in childhood Primary adrenal insufficiency and/or hypogonadotropic hypogonadism in young adulthood Xp21 deletion. Developmental delay and seizures, strabismus Glycerol kinase deficiency. Metabolic acidosis, hypoglycemia Duchenne muscular dystrophy. See Primary adrenal insufficiency A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. Hypogonadotropic hypogonadism Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test Low inhibin B Glycerol kinase deficiency, diagnosed by either of the following: Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) Duchenne muscular dystrophy (See Note: (1) While ultrasound imaging is less specific than CT or MRI, it avoids the radiation exposure of CT and the need for sedation for MRI in a potentially sick child. (2) The apparent absence of the adrenal glands on imaging studies may also rarely be due to ectopia of normal-sized adrenal glands. • Acute primary adrenal insufficiency in the first (or second) month of life • Primary adrenal insufficiency later in childhood • Primary adrenal insufficiency and/or hypogonadotropic hypogonadism in young adulthood • Xp21 deletion. Developmental delay and seizures, strabismus • Glycerol kinase deficiency. Metabolic acidosis, hypoglycemia • Duchenne muscular dystrophy. See • Primary adrenal insufficiency • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • Hypogonadotropic hypogonadism • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • Glycerol kinase deficiency, diagnosed by either of the following: • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) • Duchenne muscular dystrophy (See • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) ## Clinical Findings Acute primary adrenal insufficiency in the first (or second) month of life Primary adrenal insufficiency later in childhood Primary adrenal insufficiency and/or hypogonadotropic hypogonadism in young adulthood Xp21 deletion. Developmental delay and seizures, strabismus Glycerol kinase deficiency. Metabolic acidosis, hypoglycemia Duchenne muscular dystrophy. See • Acute primary adrenal insufficiency in the first (or second) month of life • Primary adrenal insufficiency later in childhood • Primary adrenal insufficiency and/or hypogonadotropic hypogonadism in young adulthood • Xp21 deletion. Developmental delay and seizures, strabismus • Glycerol kinase deficiency. Metabolic acidosis, hypoglycemia • Duchenne muscular dystrophy. See ## Laboratory Findings Primary adrenal insufficiency A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. Hypogonadotropic hypogonadism Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test Low inhibin B Glycerol kinase deficiency, diagnosed by either of the following: Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) Duchenne muscular dystrophy (See • Primary adrenal insufficiency • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • Hypogonadotropic hypogonadism • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • A high serum ACTH concentration in the presence of a low or normal serum concentration of cortisol is diagnostic of primary adrenal insufficiency. Note: An impaired cortisol response is usually seen after an ACTH (cosyntropin) stimulation test. • Note: Basal plasma concentration of cortisol is not reliable by itself in the evaluation of an individual with suspected adrenal insufficiency, as it may be within normal limits (which is – in a sick child – inappropriately low). • In some individuals salt loss may be the presenting feature of adrenal insufficiency, and cortisol insufficiency may develop with time. • Rarely, boys may have a predominant cortisol insufficiency and normal salt balance. • Low or normal basal gonadotropins (luteinizing hormone (LH), follicle-stimulating hormone (FSH), and low testosterone in the context of absent or arrested puberty (primary hypogonadism) • Impaired LH and FSH response in an LHRH (LH-releasing hormone) stimulation test • Low inhibin B • Glycerol kinase deficiency, diagnosed by either of the following: • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) • Duchenne muscular dystrophy (See • Elevated serum concentrations of glycerol (hyperglycerolemia) and triglycerides (pseudohypertriglyceridemia) • Increased urine glycerol (measured in a urinary organic acids test prepared by solvent extraction method) ## Imaging Studies Note: (1) While ultrasound imaging is less specific than CT or MRI, it avoids the radiation exposure of CT and the need for sedation for MRI in a potentially sick child. (2) The apparent absence of the adrenal glands on imaging studies may also rarely be due to ectopia of normal-sized adrenal glands. ## Establishing the Diagnosis The diagnosis of Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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 may not detect deletion of adjacent genes (see Footnote 7). Note that, although gene-targeted deletion/duplication assays may detect smaller events than genomic deletion/duplication assays, gene-targeted deletion/duplication assays will detect larger events but may not be able to determine the size. The majority of reported intragenic deletions and duplications, as well as Xp21 deletions, are detectable by CMA. It is possible that additional smaller deletions and duplications could be detected by these methods. Deletion/duplication analysis (genomic approach) detects deletion of Xp21 deletion includes X-linked AHC (caused by deletion of • For an introduction to multigene panels click ## Clinical Characteristics X-linked adrenal hypoplasia congenita (X-linked AHC) is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency has acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40% [ HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, the initial manifestation of X-linked AHC occurs in early adulthood with a primarily reproductive phenotype (e.g., infertility) [ Intrafamilial variability in age of onset occurs [ In older children, adrenal insufficiency may be precipitated by intercurrent illness or stress. If untreated with glucocorticoids and mineralocorticoids, adrenal insufficiency is rapidly lethal as a result of hyperkalemia, acidosis, hypoglycemia, and shock. If not recognized and treated in children, acute adrenal insufficiency and its complications of hypoglycemia and shock may result in neurologic abnormalities and developmental delay. In rare instances delayed-onset adrenal insufficiency becomes evident in early adulthood [ Adrenal insufficiency is usually accompanied by varying degrees of hyperpigmentation caused by increased pituitary production of POMC (proopiomelanocortin); the original report of X-linked AHC described an affected newborn with "coal-black hyperpigmentation" of the skin sparing the palms and soles [ Typically, HH is manifest in affected males as delayed puberty (onset age >14 years). In addition, a proportion of males may experience pubertal arrest, i.e., they enter puberty normally and progress to about Tanner Stage 3 (or testicular volume of 6-8 cc) after which pubertal development ceases. Without testosterone treatment, full attainment of secondary sexual characteristics is unlikely. Males with classic X-linked AHC typically have azoospermia and are infertile despite treatment with exogenous gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH) [ Progressive high-frequency sensorineural hearing loss starting at about age 14 years was described in two individuals with X-linked AHC whose A heterozygous female with extreme pubertal delay has been described [ In one family with affected males, a female homozygous for an The phenotypes resulting from deletion of some of the genes in the Xp21 region are X-linked AHC (deletion of The clinical findings in glycerol kinase deficiency vary and can include metabolic crisis during starvation, hypoglycemia, seizures, growth restriction, and developmental delay. Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include Two girls reported with developmental delay and myopathy due to an Xp21 deletion involving In X-linked AHC caused by a single-nucleotide variant in Late-onset X-linked AHC can result from variants in the ligand-like binding region of Late-onset X-linked AHC may also occur as a result of nonsense variants at the amino-terminal region of The term "congenital adrenal hypoplasia" is used less and less because it is easily confused with the much more common disorder, Xp21 deletion is also referred to as Xp21 contiguous gene deletion or complex glycerol kinase deficiency. The incidence of No specific populations are known to be at increased or decreased risk for this disorder. • Late-onset X-linked AHC can result from variants in the ligand-like binding region of • Late-onset X-linked AHC may also occur as a result of nonsense variants at the amino-terminal region of ## Clinical Description X-linked adrenal hypoplasia congenita (X-linked AHC) is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency has acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40% [ HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, the initial manifestation of X-linked AHC occurs in early adulthood with a primarily reproductive phenotype (e.g., infertility) [ Intrafamilial variability in age of onset occurs [ In older children, adrenal insufficiency may be precipitated by intercurrent illness or stress. If untreated with glucocorticoids and mineralocorticoids, adrenal insufficiency is rapidly lethal as a result of hyperkalemia, acidosis, hypoglycemia, and shock. If not recognized and treated in children, acute adrenal insufficiency and its complications of hypoglycemia and shock may result in neurologic abnormalities and developmental delay. In rare instances delayed-onset adrenal insufficiency becomes evident in early adulthood [ Adrenal insufficiency is usually accompanied by varying degrees of hyperpigmentation caused by increased pituitary production of POMC (proopiomelanocortin); the original report of X-linked AHC described an affected newborn with "coal-black hyperpigmentation" of the skin sparing the palms and soles [ Typically, HH is manifest in affected males as delayed puberty (onset age >14 years). In addition, a proportion of males may experience pubertal arrest, i.e., they enter puberty normally and progress to about Tanner Stage 3 (or testicular volume of 6-8 cc) after which pubertal development ceases. Without testosterone treatment, full attainment of secondary sexual characteristics is unlikely. Males with classic X-linked AHC typically have azoospermia and are infertile despite treatment with exogenous gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH) [ Progressive high-frequency sensorineural hearing loss starting at about age 14 years was described in two individuals with X-linked AHC whose A heterozygous female with extreme pubertal delay has been described [ In one family with affected males, a female homozygous for an The phenotypes resulting from deletion of some of the genes in the Xp21 region are X-linked AHC (deletion of The clinical findings in glycerol kinase deficiency vary and can include metabolic crisis during starvation, hypoglycemia, seizures, growth restriction, and developmental delay. Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include Two girls reported with developmental delay and myopathy due to an Xp21 deletion involving ## X-linked Adrenal Hypoplasia Congenita X-linked adrenal hypoplasia congenita (X-linked AHC) is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency has acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40% [ HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, the initial manifestation of X-linked AHC occurs in early adulthood with a primarily reproductive phenotype (e.g., infertility) [ Intrafamilial variability in age of onset occurs [ In older children, adrenal insufficiency may be precipitated by intercurrent illness or stress. If untreated with glucocorticoids and mineralocorticoids, adrenal insufficiency is rapidly lethal as a result of hyperkalemia, acidosis, hypoglycemia, and shock. If not recognized and treated in children, acute adrenal insufficiency and its complications of hypoglycemia and shock may result in neurologic abnormalities and developmental delay. In rare instances delayed-onset adrenal insufficiency becomes evident in early adulthood [ Adrenal insufficiency is usually accompanied by varying degrees of hyperpigmentation caused by increased pituitary production of POMC (proopiomelanocortin); the original report of X-linked AHC described an affected newborn with "coal-black hyperpigmentation" of the skin sparing the palms and soles [ Typically, HH is manifest in affected males as delayed puberty (onset age >14 years). In addition, a proportion of males may experience pubertal arrest, i.e., they enter puberty normally and progress to about Tanner Stage 3 (or testicular volume of 6-8 cc) after which pubertal development ceases. Without testosterone treatment, full attainment of secondary sexual characteristics is unlikely. Males with classic X-linked AHC typically have azoospermia and are infertile despite treatment with exogenous gonadotropin therapy or pulsatile gonadotropin-releasing hormone (GnRH) [ Progressive high-frequency sensorineural hearing loss starting at about age 14 years was described in two individuals with X-linked AHC whose A heterozygous female with extreme pubertal delay has been described [ In one family with affected males, a female homozygous for an ## Xp21 Deletion The phenotypes resulting from deletion of some of the genes in the Xp21 region are X-linked AHC (deletion of The clinical findings in glycerol kinase deficiency vary and can include metabolic crisis during starvation, hypoglycemia, seizures, growth restriction, and developmental delay. Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include Two girls reported with developmental delay and myopathy due to an Xp21 deletion involving ## Genotype-Phenotype Correlations In X-linked AHC caused by a single-nucleotide variant in Late-onset X-linked AHC can result from variants in the ligand-like binding region of Late-onset X-linked AHC may also occur as a result of nonsense variants at the amino-terminal region of • Late-onset X-linked AHC can result from variants in the ligand-like binding region of • Late-onset X-linked AHC may also occur as a result of nonsense variants at the amino-terminal region of ## Nomenclature The term "congenital adrenal hypoplasia" is used less and less because it is easily confused with the much more common disorder, Xp21 deletion is also referred to as Xp21 contiguous gene deletion or complex glycerol kinase deficiency. ## Prevalence The incidence of No specific populations are known to be at increased or decreased risk for this disorder. ## Genetically Related Disorders No phenotypes other than those discussed in this Duplication of ## Differential Diagnosis In males with salt-losing primary adrenal insufficiency and either a family history of X-linked adrenal insufficiency or other features of The differential diagnosis of The salt-losing form of Deficiency in 11-hydroxylase (OMIM The following disorders may present with findings similar to those seen in ACTH deficiency presents with glucocorticoid (but not mineralocorticoid) insufficiency and low or unmeasurable serum concentration of ACTH (with and without corticotropin-releasing hormone stimulation). Isolated ACTH deficiency can result from alterations in Congenital adrenal lipoid hyperplasia may present with salt-losing adrenal failure in a manner similar to X-linked AHC. Congenital adrenal lipoid hyperplasia is caused either by biallelic pathogenic variants in Adrenal hypoplasia congenita, autosomal recessive form (OMIM Familial glucocorticoid deficiency and ACTH resistance (OMIM Syndromes with AHC or AHC-like manifestations as a feature include the following: Pena-Shokeir syndrome, type 1 (fetal akinesia deformation sequence) (OMIM Meckel syndrome (OMIM SeRKAL (46,XX Triple A ( Natural killer cell and glucocorticoid deficiency with DNA repair defect (NKGCD) caused by biallelic pathogenic variants in Primary adrenal insufficiency and steroid-resistant nephrotic syndrome caused by biallelic pathogenic variants in Chromosomal abnormalities with AHC or AHC-like manifestations as a feature: Tetraploidy Triploidy Trisomy 19 Trisomy 21 5p duplication 11q- syndrome (OMIM Other forms of primary adrenal failure may need to be considered in boys presenting with primary adrenal failure: The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years. Adrenomyeloneuropathy (AMN) manifests most commonly in the late 20s as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops later. Approximately 20% of females who are carriers develop neurologic manifestations that resemble AMN but have later onset (age ≥35 years) and milder disease than do affected males. Other metabolic causes; for example, Wolman disease (see Autoimmune syndromes (e.g., polyglandular endocrine disease caused by mutation of Extrinsic (e.g., mechanical, infective, or drug-related) causes • The salt-losing form of • Deficiency in 11-hydroxylase (OMIM • ACTH deficiency presents with glucocorticoid (but not mineralocorticoid) insufficiency and low or unmeasurable serum concentration of ACTH (with and without corticotropin-releasing hormone stimulation). Isolated ACTH deficiency can result from alterations in • Congenital adrenal lipoid hyperplasia may present with salt-losing adrenal failure in a manner similar to X-linked AHC. Congenital adrenal lipoid hyperplasia is caused either by biallelic pathogenic variants in • Adrenal hypoplasia congenita, autosomal recessive form (OMIM • Familial glucocorticoid deficiency and ACTH resistance (OMIM • Pena-Shokeir syndrome, type 1 (fetal akinesia deformation sequence) (OMIM • Meckel syndrome (OMIM • SeRKAL (46,XX • Triple A ( • Natural killer cell and glucocorticoid deficiency with DNA repair defect (NKGCD) caused by biallelic pathogenic variants in • Primary adrenal insufficiency and steroid-resistant nephrotic syndrome caused by biallelic pathogenic variants in • Tetraploidy • Triploidy • Trisomy 19 • Trisomy 21 • 5p duplication • 11q- syndrome (OMIM • The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years. • Adrenomyeloneuropathy (AMN) manifests most commonly in the late 20s as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. • "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops later. • Approximately 20% of females who are carriers develop neurologic manifestations that resemble AMN but have later onset (age ≥35 years) and milder disease than do affected males. • The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years. • Adrenomyeloneuropathy (AMN) manifests most commonly in the late 20s as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. • "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops later. • Other metabolic causes; for example, Wolman disease (see • Autoimmune syndromes (e.g., polyglandular endocrine disease caused by mutation of • Extrinsic (e.g., mechanical, infective, or drug-related) causes • The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within two years. • Adrenomyeloneuropathy (AMN) manifests most commonly in the late 20s as progressive paraparesis, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. • "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops later. ## Management To assess the extent of disease and needs in an individual diagnosed with Assessment of adrenal function: If the presentation is predominantly mineralocorticoid insufficiency (salt loss), assess adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test). If function is reduced, appropriate glucocorticoid replacement is needed (see If the presentation is predominantly glucocorticoid insufficiency, assess adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity). If function is reduced, fludrocortisone replacement is required as well as adequate salt supplementation in young children (age <1 year) (see Assessment for early puberty or hypogonadotropic hypogonadism: When the initial diagnosis is in infancy or childhood, assess for signs of When the initial diagnosis is after the usual time of puberty and if testosterone production has been adequate, consider discussion of the options of semen analysis for sperm count and sperm banking. Other: Consultation with a clinical geneticist and/or genetic counselor for the affected person and family are advised. Psychological support should be offered. In addition to the evaluations for adrenal function and hypogonadotropic hypogonadism discussed Serum creatine kinase to evaluate for Plasma glycerol, triglycerides, and urinary glycerol to evaluate for glycerol kinase deficiency Developmental assessment regarding possible global developmental delays Some guidance on the treatment of adrenal insufficiency in children and adults is provided by recent Endocrine Society clinical practice guidelines [ Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist. Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Correction of hypoglycemia may also be needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear. Children should carry appropriate documentation indicating that they are steroid deficient. Death from acute adrenal insufficiency in individuals known to have The wearing of a Medic Alert Ongoing education and support, as well as access to appropriate resources, is important for families and young people. Testosterone supplementation is also needed to support growth and bone mineralization. If mineralocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity) is necessary. Monitoring should be fairly intense in the first two years of life (e.g., every 4 months) or at times of clinical concern. With age, mineralocorticoid sensitivity improves, but annual reviews would be appropriate and care needed during times of limited salt intake, fluid restriction, fluid loss (e.g., vomiting, diarrhea), or extreme heat. Clinical concern in the older child (e.g., postural hypotension or dizziness) needs investigation. If glucocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test) is necessary. Basal ACTH is a useful marker of impaired glucocorticoid function and should be measured together with cortisol during the first two years of life. If there are any concerns, a cosyntropin stimulation test should be performed, looking for an impaired cortisol response, not just an inadequate basal cortisol level. Annual reviews of basal ACTH/cortisol and possibly cosyntropin stimulation should be considered in a boy with a genuine X-linked AHC if glucocorticoid insufficiency has not yet developed. Any clinical concerns (e.g., tiredness, symptoms of hypoglycemia, poor weight gain, hyperpigmentation) need urgent investigation with measurement of ACTH concentration and a cosyntropin stimulation test. If puberty has not started by age 14 years, serum concentrations of LH and FSH (basal concentration and GnRH-stimulated concentration), testosterone, and inhibin B are monitored to evaluate for the possibility of HH. If the results of this laboratory testing indicate that HH is likely to occur, the young person may want to start puberty induction earlier in keeping with his peer group. If puberty has started spontaneously, it is likely to arrest; thus, yearly routine monitoring of levels of testosterone, LH, and FSH is needed. See Search • If the presentation is predominantly mineralocorticoid insufficiency (salt loss), assess adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test). If function is reduced, appropriate glucocorticoid replacement is needed (see • If the presentation is predominantly glucocorticoid insufficiency, assess adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity). If function is reduced, fludrocortisone replacement is required as well as adequate salt supplementation in young children (age <1 year) (see • When the initial diagnosis is in infancy or childhood, assess for signs of • When the initial diagnosis is after the usual time of puberty and if testosterone production has been adequate, consider discussion of the options of semen analysis for sperm count and sperm banking. • Consultation with a clinical geneticist and/or genetic counselor for the affected person and family are advised. • Psychological support should be offered. • Serum creatine kinase to evaluate for • Plasma glycerol, triglycerides, and urinary glycerol to evaluate for glycerol kinase deficiency • Developmental assessment regarding possible global developmental delays • Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. • Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist. • Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Correction of hypoglycemia may also be needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear. • Children should carry appropriate documentation indicating that they are steroid deficient. Death from acute adrenal insufficiency in individuals known to have ## Evaluations Following Initial Diagnosis To assess the extent of disease and needs in an individual diagnosed with Assessment of adrenal function: If the presentation is predominantly mineralocorticoid insufficiency (salt loss), assess adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test). If function is reduced, appropriate glucocorticoid replacement is needed (see If the presentation is predominantly glucocorticoid insufficiency, assess adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity). If function is reduced, fludrocortisone replacement is required as well as adequate salt supplementation in young children (age <1 year) (see Assessment for early puberty or hypogonadotropic hypogonadism: When the initial diagnosis is in infancy or childhood, assess for signs of When the initial diagnosis is after the usual time of puberty and if testosterone production has been adequate, consider discussion of the options of semen analysis for sperm count and sperm banking. Other: Consultation with a clinical geneticist and/or genetic counselor for the affected person and family are advised. Psychological support should be offered. In addition to the evaluations for adrenal function and hypogonadotropic hypogonadism discussed Serum creatine kinase to evaluate for Plasma glycerol, triglycerides, and urinary glycerol to evaluate for glycerol kinase deficiency Developmental assessment regarding possible global developmental delays • If the presentation is predominantly mineralocorticoid insufficiency (salt loss), assess adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test). If function is reduced, appropriate glucocorticoid replacement is needed (see • If the presentation is predominantly glucocorticoid insufficiency, assess adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity). If function is reduced, fludrocortisone replacement is required as well as adequate salt supplementation in young children (age <1 year) (see • When the initial diagnosis is in infancy or childhood, assess for signs of • When the initial diagnosis is after the usual time of puberty and if testosterone production has been adequate, consider discussion of the options of semen analysis for sperm count and sperm banking. • Consultation with a clinical geneticist and/or genetic counselor for the affected person and family are advised. • Psychological support should be offered. • Serum creatine kinase to evaluate for • Plasma glycerol, triglycerides, and urinary glycerol to evaluate for glycerol kinase deficiency • Developmental assessment regarding possible global developmental delays ## All Individuals with Assessment of adrenal function: If the presentation is predominantly mineralocorticoid insufficiency (salt loss), assess adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test). If function is reduced, appropriate glucocorticoid replacement is needed (see If the presentation is predominantly glucocorticoid insufficiency, assess adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity). If function is reduced, fludrocortisone replacement is required as well as adequate salt supplementation in young children (age <1 year) (see Assessment for early puberty or hypogonadotropic hypogonadism: When the initial diagnosis is in infancy or childhood, assess for signs of When the initial diagnosis is after the usual time of puberty and if testosterone production has been adequate, consider discussion of the options of semen analysis for sperm count and sperm banking. Other: Consultation with a clinical geneticist and/or genetic counselor for the affected person and family are advised. Psychological support should be offered. • If the presentation is predominantly mineralocorticoid insufficiency (salt loss), assess adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test). If function is reduced, appropriate glucocorticoid replacement is needed (see • If the presentation is predominantly glucocorticoid insufficiency, assess adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity). If function is reduced, fludrocortisone replacement is required as well as adequate salt supplementation in young children (age <1 year) (see • When the initial diagnosis is in infancy or childhood, assess for signs of • When the initial diagnosis is after the usual time of puberty and if testosterone production has been adequate, consider discussion of the options of semen analysis for sperm count and sperm banking. • Consultation with a clinical geneticist and/or genetic counselor for the affected person and family are advised. • Psychological support should be offered. ## Xp21 Deletion In addition to the evaluations for adrenal function and hypogonadotropic hypogonadism discussed Serum creatine kinase to evaluate for Plasma glycerol, triglycerides, and urinary glycerol to evaluate for glycerol kinase deficiency Developmental assessment regarding possible global developmental delays • Serum creatine kinase to evaluate for • Plasma glycerol, triglycerides, and urinary glycerol to evaluate for glycerol kinase deficiency • Developmental assessment regarding possible global developmental delays ## Treatment of Manifestations Some guidance on the treatment of adrenal insufficiency in children and adults is provided by recent Endocrine Society clinical practice guidelines [ Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist. Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Correction of hypoglycemia may also be needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear. Children should carry appropriate documentation indicating that they are steroid deficient. Death from acute adrenal insufficiency in individuals known to have The wearing of a Medic Alert Ongoing education and support, as well as access to appropriate resources, is important for families and young people. Testosterone supplementation is also needed to support growth and bone mineralization. • Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. • Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist. • Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Correction of hypoglycemia may also be needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear. • Children should carry appropriate documentation indicating that they are steroid deficient. Death from acute adrenal insufficiency in individuals known to have ## Adrenal Insufficiency Some guidance on the treatment of adrenal insufficiency in children and adults is provided by recent Endocrine Society clinical practice guidelines [ Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist. Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Correction of hypoglycemia may also be needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear. Children should carry appropriate documentation indicating that they are steroid deficient. Death from acute adrenal insufficiency in individuals known to have The wearing of a Medic Alert Ongoing education and support, as well as access to appropriate resources, is important for families and young people. • Steroid doses need to be adjusted to allow normal linear growth without risking an adrenal crisis. • Maintenance hormone treatment is best managed in growing children by a pediatric endocrinologist. • Local hospitals should provide parents with a plan for emergency treatment and instruction regarding when extra oral or injected hydrocortisone is needed. Correction of hypoglycemia may also be needed. Parents should have access to rapid medical advice; guidelines for hospital admission should be clear. • Children should carry appropriate documentation indicating that they are steroid deficient. Death from acute adrenal insufficiency in individuals known to have ## Hypogonadotropic Hypogonadism Testosterone supplementation is also needed to support growth and bone mineralization. ## Surveillance If mineralocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity) is necessary. Monitoring should be fairly intense in the first two years of life (e.g., every 4 months) or at times of clinical concern. With age, mineralocorticoid sensitivity improves, but annual reviews would be appropriate and care needed during times of limited salt intake, fluid restriction, fluid loss (e.g., vomiting, diarrhea), or extreme heat. Clinical concern in the older child (e.g., postural hypotension or dizziness) needs investigation. If glucocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test) is necessary. Basal ACTH is a useful marker of impaired glucocorticoid function and should be measured together with cortisol during the first two years of life. If there are any concerns, a cosyntropin stimulation test should be performed, looking for an impaired cortisol response, not just an inadequate basal cortisol level. Annual reviews of basal ACTH/cortisol and possibly cosyntropin stimulation should be considered in a boy with a genuine X-linked AHC if glucocorticoid insufficiency has not yet developed. Any clinical concerns (e.g., tiredness, symptoms of hypoglycemia, poor weight gain, hyperpigmentation) need urgent investigation with measurement of ACTH concentration and a cosyntropin stimulation test. If puberty has not started by age 14 years, serum concentrations of LH and FSH (basal concentration and GnRH-stimulated concentration), testosterone, and inhibin B are monitored to evaluate for the possibility of HH. If the results of this laboratory testing indicate that HH is likely to occur, the young person may want to start puberty induction earlier in keeping with his peer group. If puberty has started spontaneously, it is likely to arrest; thus, yearly routine monitoring of levels of testosterone, LH, and FSH is needed. ## Primary Adrenal Insufficiency If mineralocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal mineralocorticoid function (sodium, potassium, aldosterone, plasma renin activity) is necessary. Monitoring should be fairly intense in the first two years of life (e.g., every 4 months) or at times of clinical concern. With age, mineralocorticoid sensitivity improves, but annual reviews would be appropriate and care needed during times of limited salt intake, fluid restriction, fluid loss (e.g., vomiting, diarrhea), or extreme heat. Clinical concern in the older child (e.g., postural hypotension or dizziness) needs investigation. If glucocorticoid production is sufficient at the time of initial diagnosis, long-term follow up of adrenal glucocorticoid function (basal ACTH, cortisol, cosyntropin test) is necessary. Basal ACTH is a useful marker of impaired glucocorticoid function and should be measured together with cortisol during the first two years of life. If there are any concerns, a cosyntropin stimulation test should be performed, looking for an impaired cortisol response, not just an inadequate basal cortisol level. Annual reviews of basal ACTH/cortisol and possibly cosyntropin stimulation should be considered in a boy with a genuine X-linked AHC if glucocorticoid insufficiency has not yet developed. Any clinical concerns (e.g., tiredness, symptoms of hypoglycemia, poor weight gain, hyperpigmentation) need urgent investigation with measurement of ACTH concentration and a cosyntropin stimulation test. ## Hypogonadotropic Hypogonadism If puberty has not started by age 14 years, serum concentrations of LH and FSH (basal concentration and GnRH-stimulated concentration), testosterone, and inhibin B are monitored to evaluate for the possibility of HH. If the results of this laboratory testing indicate that HH is likely to occur, the young person may want to start puberty induction earlier in keeping with his peer group. If puberty has started spontaneously, it is likely to arrest; thus, yearly routine monitoring of levels of testosterone, LH, and FSH is needed. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The father of an affected male will not have In a family with more than one affected male, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one son and no other affected relatives and if the If a male is the only affected family member, the mother may be a carrier or the affected male may have a The risk to sibs depends on the genetic status of the mother. If the mother of the proband is heterozygous for an Germline mosaicism is possible but uncommon. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Most males with AHC are infertile. If an affected male conceives through assisted reproductive technologies: All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, No son will inherit the The specific Xp21 deletion in a family generally affects all members similarly. Some families have a deletion that includes Most mothers of individuals diagnosed with an Xp21 deletion are carriers; however, a proband may have the disorder as the result of a The proportion of cases caused by a Evaluation of the mother of a child with an Xp21 deletion and no known family history of an Xp21 deletion should include chromosomal microarray analysis (CMA) (see The risk to the sibs of the proband depends on the genetic status of the mother. If the mother is heterozygous for the Xp21 deletion, the chance of transmitting the deletion in each pregnancy is 50%. Males who inherit the deletion will be affected; females who inherit the deletion will be heterozygotes and, in rare instances, have clinical manifestations (see Clinical Description, If the mother does not have the Xp21 deletion, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism [ Genetic testing of at-risk female relatives to determine their genetic status is most informative if the Note: (1) In rare instances, heterozygotes for this X-linked disorder may develop clinical findings related to the disorder, for example as a result of skewed X-chromosome inactivation [ 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 carriers, are at risk of being carriers, or are affected. Once the • The father of an affected male will not have • In a family with more than one affected male, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one son and no other affected relatives and if the • If a male is the only affected family member, the mother may be a carrier or the affected male may have a • The risk to sibs depends on the genetic status of the mother. • If the mother of the proband is heterozygous for an • Germline mosaicism is possible but uncommon. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Most males with AHC are infertile. • If an affected male conceives through assisted reproductive technologies: • All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, • No son will inherit the • All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, • No son will inherit the • All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, • No son will inherit the • Most mothers of individuals diagnosed with an Xp21 deletion are carriers; however, a proband may have the disorder as the result of a • The proportion of cases caused by a • Evaluation of the mother of a child with an Xp21 deletion and no known family history of an Xp21 deletion should include chromosomal microarray analysis (CMA) (see • The risk to the sibs of the proband depends on the genetic status of the mother. • If the mother is heterozygous for the Xp21 deletion, the chance of transmitting the deletion in each pregnancy is 50%. Males who inherit the deletion will be affected; females who inherit the deletion will be heterozygotes and, in rare instances, have clinical manifestations (see Clinical Description, • If the mother does not have the Xp21 deletion, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism [ • 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, are at risk of being carriers, or are affected. ## Mode of Inheritance ## X-Linked Adrenal Hypoplasia ‒ Risk to Family Members The father of an affected male will not have In a family with more than one affected male, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one son and no other affected relatives and if the If a male is the only affected family member, the mother may be a carrier or the affected male may have a The risk to sibs depends on the genetic status of the mother. If the mother of the proband is heterozygous for an Germline mosaicism is possible but uncommon. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Most males with AHC are infertile. If an affected male conceives through assisted reproductive technologies: All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, No son will inherit the • The father of an affected male will not have • In a family with more than one affected male, the mother of an affected male is an obligate heterozygote (carrier). Note: If a woman has more than one son and no other affected relatives and if the • If a male is the only affected family member, the mother may be a carrier or the affected male may have a • The risk to sibs depends on the genetic status of the mother. • If the mother of the proband is heterozygous for an • Germline mosaicism is possible but uncommon. If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Most males with AHC are infertile. • If an affected male conceives through assisted reproductive technologies: • All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, • No son will inherit the • All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, • No son will inherit the • All daughters will be heterozygotes and may, in rare instances, have manifestations of adrenal insufficiency and/or hypogonadotropic hypogonadism (see Clinical Description, • No son will inherit the ## Xp21 Deletion – Risk to Family Members The specific Xp21 deletion in a family generally affects all members similarly. Some families have a deletion that includes Most mothers of individuals diagnosed with an Xp21 deletion are carriers; however, a proband may have the disorder as the result of a The proportion of cases caused by a Evaluation of the mother of a child with an Xp21 deletion and no known family history of an Xp21 deletion should include chromosomal microarray analysis (CMA) (see The risk to the sibs of the proband depends on the genetic status of the mother. If the mother is heterozygous for the Xp21 deletion, the chance of transmitting the deletion in each pregnancy is 50%. Males who inherit the deletion will be affected; females who inherit the deletion will be heterozygotes and, in rare instances, have clinical manifestations (see Clinical Description, If the mother does not have the Xp21 deletion, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism [ • Most mothers of individuals diagnosed with an Xp21 deletion are carriers; however, a proband may have the disorder as the result of a • The proportion of cases caused by a • Evaluation of the mother of a child with an Xp21 deletion and no known family history of an Xp21 deletion should include chromosomal microarray analysis (CMA) (see • The risk to the sibs of the proband depends on the genetic status of the mother. • If the mother is heterozygous for the Xp21 deletion, the chance of transmitting the deletion in each pregnancy is 50%. Males who inherit the deletion will be affected; females who inherit the deletion will be heterozygotes and, in rare instances, have clinical manifestations (see Clinical Description, • If the mother does not have the Xp21 deletion, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism [ ## Heterozygote Detection Genetic testing of at-risk female relatives to determine their genetic status is most informative if the Note: (1) In rare instances, heterozygotes for this X-linked disorder may develop clinical findings related to the disorder, for example as a result of skewed X-chromosome inactivation [ ## 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 carriers, are at risk of being carriers, or are affected. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers, are at risk of being carriers, or are affected. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources 505 Northern Boulevard Great Neck NY 11021 • • • • 505 Northern Boulevard • Great Neck NY 11021 • ## Molecular Genetics NR0B1-Related Adrenal Hypoplasia Congenita: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for NR0B1-Related Adrenal Hypoplasia Congenita ( In the late 1980s and early 1990s these reports focused on individuals and families with an Xp21 deletion [ Sequence analysis detects a pathogenic variant in the remaining approximately 75% of probands [ Two missense variants in the amino-terminal repeat region of Late-onset X-linked AHC is associated with nonsense variants in the amino-terminal region of Variants listed in the table have been provided by the authors. The carboxyl-terminal region of NR0B1 has a structure similar to the ligand-binding domains of nuclear receptors. The amino-terminal region of NR0B1 contains repeat motifs and lacks a typical DNA-binding domain found in other nuclear receptors. Crystal studies have shown that NR0B1 can bind to NR5A2 directly as part of a complex involving two NR0B1 transcripts [ NR0B1 plays an important role in the normal development of the adrenal glands, the hypothalamus, the pituitary, and the ovary and testis and is expressed in these tissues during development and into postnatal life. The exact biologic role of NR0B1 is unknown. Most studies have shown that NR0B1 acts as a negative regulator of other nuclear receptor-signaling pathways including transactivation mediated by steroidogenic factor 1 (SF1) [ In addition to its role in the pathogenesis of X-linked AHC, ## References ## Literature Cited ## Chapter Notes JCA is a Wellcome Trust Senior Research Fellow in Clinical Science (grant 098513/Z/12/Z) with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust, UCL, and Great Ormond Street Hospital Children's Charity. 25 January 2018 (bp) Comprehensive update posted live 17 October 2013 (me) Comprehensive update posted live 7 May 2009 (cd) Revision: deletion/duplication analysis available clinically 1 August 2006 (me) Comprehensive update posted live 10 December 2003 (me) Comprehensive update posted live 20 November 2001 (me) Review posted live March 2001 (ev) Original submission • 25 January 2018 (bp) Comprehensive update posted live • 17 October 2013 (me) Comprehensive update posted live • 7 May 2009 (cd) Revision: deletion/duplication analysis available clinically • 1 August 2006 (me) Comprehensive update posted live • 10 December 2003 (me) Comprehensive update posted live • 20 November 2001 (me) Review posted live • March 2001 (ev) Original submission ## Acknowledgments JCA is a Wellcome Trust Senior Research Fellow in Clinical Science (grant 098513/Z/12/Z) with support from the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust, UCL, and Great Ormond Street Hospital Children's Charity. ## Revision History 25 January 2018 (bp) Comprehensive update posted live 17 October 2013 (me) Comprehensive update posted live 7 May 2009 (cd) Revision: deletion/duplication analysis available clinically 1 August 2006 (me) Comprehensive update posted live 10 December 2003 (me) Comprehensive update posted live 20 November 2001 (me) Review posted live March 2001 (ev) Original submission • 25 January 2018 (bp) Comprehensive update posted live • 17 October 2013 (me) Comprehensive update posted live • 7 May 2009 (cd) Revision: deletion/duplication analysis available clinically • 1 August 2006 (me) Comprehensive update posted live • 10 December 2003 (me) Comprehensive update posted live • 20 November 2001 (me) Review posted live • March 2001 (ev) Original submission	[ "JC Achermann, M Ito, BL Silverman, RL Habiby, S Pang, A Rosler, JL Jameson. 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Minerva Pediatr 1995;47:471-6", "G Mantovani, E De Menis, G Borretta, G Radetti, S Bondioni, A Spada, L Persani, P Beck-Peccoz. DAX1 and X-linked adrenal hypoplasia congenita: clinical and molecular analysis in five patients.. Eur J Endocrinol 2006;154:685-9", "G Mantovani, G Ozisik, JC Achermann, R Romoli, G Borretta, L Persani, A Spada, JL Jameson, P Beck-Peccoz. Hypogonadotropic hypogonadism as a presenting feature of late-onset X-linked adrenal hypoplasia congenita.. J Clin Endocrinol Metab 2002;87:44-8", "E Meimaridou, J Kowalczyk, L Guasti, CR Hughes, F Wagner, P Frommolt, P Nürnberg, NP Mann, R Banerjee, HN Saka, JP Chapple, PJ King, AJ Clark, LA Metherell. Mutations in NNT encoding nicotinamide nucleotide transhydrogenase cause familial glucocorticoid deficiency.. Nat Genet 2012;44:740-2", "DP Merke, T Tajima, J Baron, GB Cutler. Hypogonadotropic hypogonadism in a female caused by an X-linked recessive mutation in the DAX1 gene.. N Engl J Med 1999;340:1248-52", "F Muscatelli, TM Strom, AP Walker, E Zanaria, D Récan, A Meindl, B Bardoni, S Guioli, G Zehetner, W Rabl. Mutations in the DAX-1 gene give rise to both X-linked adrenal hypoplasia congenita and hypogonadotropic hypogonadism.. Nature. 1994;372:672-6", "G Ozisik, G Mantovani, JC Achermann, L Persani, A Spada, J Weiss, P Beck-Peccoz, JL Jameson. An alternate translation initiation site circumvents an amino-terminal DAX1 nonsense mutation leading to a mild form of X-linked adrenal hypoplasia congenita.. J Clin Endocrinol Metab 2003;88:417-23", "M Peter, M Viemann, CJ Partsch, WG Sippell. Congenital adrenal hypoplasia: clinical spectrum, experience with hormonal diagnosis, and report on new point mutations of the DAX-1 gene.. J Clin Endocrinol Metab 1998;83:2666-74", "R Prasad, I Hadjidemetriou, A Maharaj, E Meimaridou, F Buonocore, M Saleem, J Hurcombe, A Bierzynska, E Barbagelata, I Bergadá, H Cassinelli, U Das, R Krone, B Hacihamdioglu, E Sari, E Yesilkaya, HL Storr, M Clemente, M Fernandez-Cancio, N Camats, N Ram, JC Achermann, PP Van Veldhoven, L Guasti, D Braslavsky, T Guran, LA Metherell. Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.. J Clin Invest. 2017;127:942-53", "ML Raffin-Sanson, B Oudet, S Salenave, S Brailly-Tabard, M Pehuet, S Christin-Maitre, Y Morel, J Young. A man with a DAX1/NR0B1 mutation, normal puberty, and an intact hypothalamic-pituitary-gonadal axis but deteriorating oligospermia during long-term follow up.. Eur J Endocrinol. 2013;168:K45-50", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton. UK10K Consortium, Hurles ME. Timing, rates and spectra of human germline mutation.. Nat Genet 2016;48:126-33", "AT Reutens, JC Achermann, M Ito, M Ito, WX Gu, RL Habiby, PA Donohoue, S Pang, PC Hindmarsh, JL Jameson. Clinical and functional effects of mutations in the DAX-1 gene in patients with adrenal hypoplasia congenita.. J Clin Endocrinol Metab 1999;84:504-11", "EP Sablin, A Woods, IN Krylova, P Hwang, HA Ingraham, RJ Fletterick. The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1.. Proc Natl Acad Sci U S A 2008;105:18390-5", "JO Scheys, JH Heaton, GD Hammer. Evidence of adrenal failure in aging Dax1-deficient mice.. Endocrinology 2011;152:3430-9", "SB Seminara, JC Achermann, M Genel, JL Jameson, WF Crowley. X-linked adrenal hypoplasia congenita: a mutation in DAX1 expands the phenotypic spectrum in males and females.. J Clin Endocrinol Metab 1999;84:4501-9", "MG Shaikh, L Boyes, H Kingston, R Collins, GT Besley, B Padmakumar, O Ismayl, I Hughes, CM Hall, C Hellerud, JC Achermann, PE Clayton. Skewed X inactivation is associated with phenotype in a female with adrenal hypoplasia congenita.. J Med Genet 2008;45", "H Shima, S Yatsuga, A Nakamura, S Sano, T Sasaki, N Katsumata, E Suzuki, K Hata, K Nakabayashi, Y Momozawa, M Kubo, K Okamura, S Kure, Y Matsubara, T Ogata, S Narumi, M Fukami. NR0B1 Frameshift mutation in a boy with idiopathic central precocious puberty.. Sex Dev. 2016;10:205-9", "H Sikl. Addison's disease due to congential adrenal hypoplasia of the adrenals in an infant aged 33 days.. J Pathol Bacteriol 1948;60:323-6", "JP Suntharalingham, F Buonocore, AJ Duncan, JC Achermann. DAX-1 (NR0B1) and steroidogenic factor-1 (SF-1, NR5A1) in human disease.. Best Pract Res Clin Endocrinol Metab. 2015;29:607-19", "A Tabarin, JC Achermann, D Recan, V Bex, X Bertagna, S Christin-Maitre, M Ito, JL Jameson, P Bouchard. A novel mutation in DAX1 causes delayed-onset adrenal insufficiency and incomplete hypogonadotropic hypogonadism.. J Clin Invest 2000;105:321-8", "AA Verrijn Stuart, G Ozisik, MA de Vroede, JC Giltay, RJ Sinke, TJ Peterson, RM Harris, J Weiss, JL Jameson. An amino-terminal DAX1 (NR0B1) missense mutation associated with isolated mineralocorticoid deficiency.. J Clin Endocrinol Metab 2007;92:755-61", "E Wiltshire, J Couper, C Rodda, JL Jameson, JC Achermann. Variable presentation of X-linked adrenal hypoplasia congenita.. J Pediatr Endocrinol Metab 2001;14:1093-6", "B Xu, WH Yang, I Gerin, CD Hu, GD Hammer, RJ Koenig. Dax-1 and steroid receptor RNA activator (SRA) function as transcriptional coactivators for steroidogenic factor 1 in steroidogenesis.. Mol Cell Biol 2009;29:1719-34", "M Zachmann, E Fuchs, A Prader. Progressive high frequency hearing loss: an additional feature in the syndrome of congenital adrenal hypoplasia and gonadotrophin deficiency.. Eur J Pediatr 1992;151:167-9", "E Zanaria, F Muscatelli, B Bardoni, TM Strom, S Guioli, W Guo, E Lalli, C Moser, AP Walker, ER McCabe. An unusual member of the nuclear hormone receptor superfamily responsible for X-linked adrenal hypoplasia congenita.. Nature. 1994;372:635-41", "YH Zhang, BL Huang, KK Niakan, LL McCabe, ER McCabe, KM Dipple. IL1RAPL1 is associated with mental retardation in patients with complex glycerol kinase deficiency who have deletions extending telomeric of DAX1.. Hum Mutat. 2004;24:273" ]	20/11/2001	25/1/2018	7/5/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aic	aic	[ "Aicardi Syndrome" ]	Aicardi Syndrome	V Reid Sutton, Ignatia B Van den Veyver	Summary Aicardi syndrome is a neurodevelopmental disorder that affects primarily females. Initially it was characterized by a typical triad of agenesis of the corpus callosum, central chorioretinal lacunae, and infantile spasms. As more affected individuals have been ascertained, it has become clear that not all affected girls have all three features of the classic triad and that other neurologic and systemic defects are common, including other brain malformations, optic nerve abnormalities, other seizure types, intellectual disability of varying severity, and scoliosis. The diagnosis of Aicardi syndrome is based exclusively on clinical findings. Modified diagnostic criteria include either presence of the classic triad or the presence of two of the classic triad plus at least two other major or supporting features. A gene for Aicardi syndrome has not been identified, but several observations support a hypothesis that Aicardi syndrome is caused by With the exception of affected monozygotic twin girls, all individuals with Aicardi syndrome reported to date have represented simplex cases (i.e., a single affected family member). Parent-to-child transmission of Aicardi syndrome has not been reported, and the recurrence risk to sibs is thought to be less than 1%. While prenatal ultrasound or intrauterine MRI findings of corpus callosum agenesis and neuronal migration abnormalities may be suggestive of Aicardi syndrome, no findings are diagnostic.	## Diagnosis No consensus clinical diagnostic criteria for Aicardi syndrome have been published. The diagnosis of Aicardi syndrome is based exclusively on clinical findings. Modified diagnostic criteria have been proposed [ The presence of the classic triad is diagnostic for Aicardi syndrome. The presence of two of the classic triad plus at least two other major or supporting features is strongly suggestive of the diagnosis of Aicardi syndrome. Agenesis of the corpus callosum Distinctive chorioretinal lacunae Infantile spasms Cortical malformations (mostly polymicrogyria) Periventricular and subcortical heterotopia Cysts around third cerebral ventricle and/or choroid plexus Optic disc/nerve coloboma or hypoplasia Vertebral and rib abnormalities Microphthalmia "Split-brain" EEG Gross cerebral hemispheric asymmetry Vascular malformations or vascular malignancy Note: Aicardi syndrome appears to be an X-linked dominant disorder with lethality in males; however, no gene or candidate region on the X chromosome has been identified (see • The presence of the classic triad is diagnostic for Aicardi syndrome. • The presence of two of the classic triad plus at least two other major or supporting features is strongly suggestive of the diagnosis of Aicardi syndrome. • Agenesis of the corpus callosum • Distinctive chorioretinal lacunae • Infantile spasms • Cortical malformations (mostly polymicrogyria) • Periventricular and subcortical heterotopia • Cysts around third cerebral ventricle and/or choroid plexus • Optic disc/nerve coloboma or hypoplasia • Vertebral and rib abnormalities • Microphthalmia • "Split-brain" EEG • Gross cerebral hemispheric asymmetry • Vascular malformations or vascular malignancy ## Clinical Characteristics Aicardi syndrome, first described by Select Features of Aicardi Syndrome Based on DD = developmental delay; ID = intellectual disability Many girls with Aicardi syndrome develop seizures before age three months, and most before age one year. Infantile spasms are seen early on; ongoing medically refractory epilepsy with a variety of seizure types develops over time. Common EEG findings include asynchronous multifocal epileptiform abnormalities with burst suppression and dissociation between the two hemispheres. Brain MRI reveals dysgenesis of the corpus callosum, which is most often complete but can be partial. Polymicrogyria or pachygyria, which are predominantly frontal and perisylvian and associated with underopercularization, are typical. Periventricular and intracortical gray matter heterotopia are very common. Gross cerebral asymmetry, choroid plexus papillomas, ventriculomegaly, and intracerebral cysts, often at the third ventricle and in the choroid plexus, are frequently present [ Almost all individuals have some ocular abnormalities. Coloboma (39% of eyes) Glial proliferation (19% of eyes) Severe dysplasia (17% of eyes) Pseudoadenomatous proliferation of the retinal pigment epithelium (14% of eyes) All eye findings can be unilateral or bilateral and asymmetric. Plagiocephaly and facial asymmetry, occasionally with cleft lip and palate (3%), have been reported. Pierre Robin sequence has been reported in a single case [ Note: Aicardi syndrome is NOT related to Aicardi syndrome is very rare and appears to affect all ethnicities equally. Its incidence has been estimated at between 1:105,000 and 1:167,000 in the United States and between 1:93,000 and 1:99,000 in some European countries [ The exact prevalence of Aicardi syndrome is unknown; it has been estimated to be at least 853 in the US and over 4,000 worldwide [ • Coloboma (39% of eyes) • Glial proliferation (19% of eyes) • Severe dysplasia (17% of eyes) • Pseudoadenomatous proliferation of the retinal pigment epithelium (14% of eyes) ## Clinical Description Aicardi syndrome, first described by Select Features of Aicardi Syndrome Based on DD = developmental delay; ID = intellectual disability Many girls with Aicardi syndrome develop seizures before age three months, and most before age one year. Infantile spasms are seen early on; ongoing medically refractory epilepsy with a variety of seizure types develops over time. Common EEG findings include asynchronous multifocal epileptiform abnormalities with burst suppression and dissociation between the two hemispheres. Brain MRI reveals dysgenesis of the corpus callosum, which is most often complete but can be partial. Polymicrogyria or pachygyria, which are predominantly frontal and perisylvian and associated with underopercularization, are typical. Periventricular and intracortical gray matter heterotopia are very common. Gross cerebral asymmetry, choroid plexus papillomas, ventriculomegaly, and intracerebral cysts, often at the third ventricle and in the choroid plexus, are frequently present [ Almost all individuals have some ocular abnormalities. Coloboma (39% of eyes) Glial proliferation (19% of eyes) Severe dysplasia (17% of eyes) Pseudoadenomatous proliferation of the retinal pigment epithelium (14% of eyes) All eye findings can be unilateral or bilateral and asymmetric. Plagiocephaly and facial asymmetry, occasionally with cleft lip and palate (3%), have been reported. Pierre Robin sequence has been reported in a single case [ • Coloboma (39% of eyes) • Glial proliferation (19% of eyes) • Severe dysplasia (17% of eyes) • Pseudoadenomatous proliferation of the retinal pigment epithelium (14% of eyes) ## Nomenclature Note: Aicardi syndrome is NOT related to ## Prevalence Aicardi syndrome is very rare and appears to affect all ethnicities equally. Its incidence has been estimated at between 1:105,000 and 1:167,000 in the United States and between 1:93,000 and 1:99,000 in some European countries [ The exact prevalence of Aicardi syndrome is unknown; it has been estimated to be at least 853 in the US and over 4,000 worldwide [ ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Aicardi Syndrome AD = autosomal dominant; AIC = Aicardi syndrome; AR = autosomal recessive; DiffDx = differential diagnosis; ID = intellectual disability; MCCRP = microcephaly and chorioretinopathy, autosomal recessive; MCLMR = microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability; MOI = mode of inheritance; XL = X-linked In contrast to AIC, in which chorioretinal lacunae are central & optic nerves almost always involved ## Management No clinical practice guidelines for Aicardi syndrome have been published. To establish the extent of disease and needs in an individual diagnosed with Aicardi syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Aicardi Syndrome To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To evaluate for hemivertebrae, block vertebrae, fused vertebrae; missing, malformed, fused ribs Orthopedics consultation if costovertebral abnormalities are significant Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) History of constipation, diarrhea, GERD Eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with Aicardi Syndrome Most persons require multiple medications for mgmt of seizures, & seizure types may change over time, requiring changes in medications. Education of parents/caregivers ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Consider evaluation for alternative means of communication (e.g., Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Aicardi Syndrome Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone (e.g., spasticity), movement disorders. OT = occupational therapy; PT = physical therapy See Search • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To evaluate for hemivertebrae, block vertebrae, fused vertebrae; missing, malformed, fused ribs • Orthopedics consultation if costovertebral abnormalities are significant • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • History of constipation, diarrhea, GERD • Eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support; • Home nursing referral. • Most persons require multiple medications for mgmt of seizures, & seizure types may change over time, requiring changes in medications. • 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. • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone (e.g., spasticity), movement disorders. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Aicardi syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Aicardi Syndrome To incl brain MRI Consider EEG if seizures are a concern. To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education To evaluate for hemivertebrae, block vertebrae, fused vertebrae; missing, malformed, fused ribs Orthopedics consultation if costovertebral abnormalities are significant Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) History of constipation, diarrhea, GERD Eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl brain MRI • Consider EEG if seizures are a concern. • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • To evaluate for hemivertebrae, block vertebrae, fused vertebrae; missing, malformed, fused ribs • Orthopedics consultation if costovertebral abnormalities are significant • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • History of constipation, diarrhea, GERD • Eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in affected 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 Aicardi Syndrome Most persons require multiple medications for mgmt of seizures, & seizure types may change over time, requiring changes in medications. Education of parents/caregivers ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Consider evaluation for alternative means of communication (e.g., Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Most persons require multiple medications for mgmt of seizures, & seizure types may change over time, requiring changes in medications. • 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. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Communication Issues Consider evaluation for alternative means of communication (e.g., ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Aicardi Syndrome Measure growth parameters. Evaluate nutritional status & safety of oral intake. Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone (e.g., spasticity), movement disorders. OT = occupational therapy; PT = physical therapy • Measure growth parameters. • Evaluate nutritional status & safety of oral intake. • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone (e.g., spasticity), movement disorders. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The gene(s) in which pathogenic variants are causative of Aicardi syndrome are not known. While autosomal inheritance cannot be fully excluded in the absence of a known genetic cause, several observations support a hypothesis that Aicardi syndrome is caused by a Aicardi syndrome is typically seen in females but has also been reported in males with a 47,XXY karyotype and, very rarely, in 46,XY males. No instances of mother-to-daughter transmission have been documented, despite the presence of rare adult women with Aicardi syndrome who do not have a degree of intellectual disability that would result in decreased reproductive fitness. This raises the question of whether fertility may be reduced in women with Aicardi syndrome. The hypothesis that fertility in Aicardi syndrome is reduced could also be supported by reports of precocious puberty in individuals with Aicardi syndrome [ While the genetic cause is currently unknown, theoretically, if a female with Aicardi syndrome conceives, the risk that the causative variant will be transmitted could be as high as 50%. Some features detected on prenatal ultrasound examination, such as agenesis of the corpus callosum with intracranial cysts in a female fetus, may raise suspicion for Aicardi syndrome and a number of other developmental brain abnormalities. Findings of corpus callosum agenesis and neuronal migration abnormalities on intrauterine MRI may be suggestive but not diagnostic [ Other features, such as costovertebral defects and microphthalmia, are more difficult to detect prenatally and are not present in all cases. Definitive prenatal diagnosis of Aicardi syndrome has not been reported in a low-risk pregnancy; furthermore, definitive diagnosis of Aicardi syndrome relies on neonatal confirmation of suspected findings and detection of additional features including chorioretinal lacunae and seizures. • No instances of mother-to-daughter transmission have been documented, despite the presence of rare adult women with Aicardi syndrome who do not have a degree of intellectual disability that would result in decreased reproductive fitness. This raises the question of whether fertility may be reduced in women with Aicardi syndrome. The hypothesis that fertility in Aicardi syndrome is reduced could also be supported by reports of precocious puberty in individuals with Aicardi syndrome [ • While the genetic cause is currently unknown, theoretically, if a female with Aicardi syndrome conceives, the risk that the causative variant will be transmitted could be as high as 50%. • Some features detected on prenatal ultrasound examination, such as agenesis of the corpus callosum with intracranial cysts in a female fetus, may raise suspicion for Aicardi syndrome and a number of other developmental brain abnormalities. • Findings of corpus callosum agenesis and neuronal migration abnormalities on intrauterine MRI may be suggestive but not diagnostic [ • Other features, such as costovertebral defects and microphthalmia, are more difficult to detect prenatally and are not present in all cases. • Definitive prenatal diagnosis of Aicardi syndrome has not been reported in a low-risk pregnancy; furthermore, definitive diagnosis of Aicardi syndrome relies on neonatal confirmation of suspected findings and detection of additional features including chorioretinal lacunae and seizures. ## Mode of Inheritance The gene(s) in which pathogenic variants are causative of Aicardi syndrome are not known. While autosomal inheritance cannot be fully excluded in the absence of a known genetic cause, several observations support a hypothesis that Aicardi syndrome is caused by a Aicardi syndrome is typically seen in females but has also been reported in males with a 47,XXY karyotype and, very rarely, in 46,XY males. ## Risk to Family Members No instances of mother-to-daughter transmission have been documented, despite the presence of rare adult women with Aicardi syndrome who do not have a degree of intellectual disability that would result in decreased reproductive fitness. This raises the question of whether fertility may be reduced in women with Aicardi syndrome. The hypothesis that fertility in Aicardi syndrome is reduced could also be supported by reports of precocious puberty in individuals with Aicardi syndrome [ While the genetic cause is currently unknown, theoretically, if a female with Aicardi syndrome conceives, the risk that the causative variant will be transmitted could be as high as 50%. • No instances of mother-to-daughter transmission have been documented, despite the presence of rare adult women with Aicardi syndrome who do not have a degree of intellectual disability that would result in decreased reproductive fitness. This raises the question of whether fertility may be reduced in women with Aicardi syndrome. The hypothesis that fertility in Aicardi syndrome is reduced could also be supported by reports of precocious puberty in individuals with Aicardi syndrome [ • While the genetic cause is currently unknown, theoretically, if a female with Aicardi syndrome conceives, the risk that the causative variant will be transmitted could be as high as 50%. ## Related Genetic Counseling Issues ## Prenatal Testing Some features detected on prenatal ultrasound examination, such as agenesis of the corpus callosum with intracranial cysts in a female fetus, may raise suspicion for Aicardi syndrome and a number of other developmental brain abnormalities. Findings of corpus callosum agenesis and neuronal migration abnormalities on intrauterine MRI may be suggestive but not diagnostic [ Other features, such as costovertebral defects and microphthalmia, are more difficult to detect prenatally and are not present in all cases. Definitive prenatal diagnosis of Aicardi syndrome has not been reported in a low-risk pregnancy; furthermore, definitive diagnosis of Aicardi syndrome relies on neonatal confirmation of suspected findings and detection of additional features including chorioretinal lacunae and seizures. • Some features detected on prenatal ultrasound examination, such as agenesis of the corpus callosum with intracranial cysts in a female fetus, may raise suspicion for Aicardi syndrome and a number of other developmental brain abnormalities. • Findings of corpus callosum agenesis and neuronal migration abnormalities on intrauterine MRI may be suggestive but not diagnostic [ • Other features, such as costovertebral defects and microphthalmia, are more difficult to detect prenatally and are not present in all cases. • Definitive prenatal diagnosis of Aicardi syndrome has not been reported in a low-risk pregnancy; furthermore, definitive diagnosis of Aicardi syndrome relies on neonatal confirmation of suspected findings and detection of additional features including chorioretinal lacunae and seizures. ## Resources PO Box 3202 St. Charles IL 60174 PO Box 5801 Bethesda MD 20824 • • PO Box 3202 • St. Charles IL 60174 • • • • • PO Box 5801 • Bethesda MD 20824 • • • ## Molecular Genetics OMIM Entries for Aicardi Syndrome ( A gene for Aicardi syndrome has not been identified, but several observations support a hypothesis that Aicardi syndrome is caused by Nearly all affected individuals are female and, except for one pair of sisters and a pair of concordant monozygotic twins, all reported cases are simplex (i.e., a single occurrence in a family). At least six pairs of twins who are discordant for Aicardi syndrome are known, five of whom are confirmed dizygotic, excluding the possibility that the etiology is a prenatal toxin or other disruptive event [ Rare known males with a confirmed diagnosis of Aicardi syndrome have a 47,XXY karyotype [ The variable severity and asymmetry of the Aicardi syndrome phenotype could be explained if the putative mutated gene undergoes X-chromosome inactivation. Earlier limited studies, some using older methods, had conflicting results, showing either random or skewed X-chromosome inactivation patterns. The most recent study on 35 individuals with Aicardi syndrome, the largest series examined thus far, demonstrated non-random X-chromosome inactivation in leukocyte-derived DNA in 11 of 33 informative individuals, with six (18%) having extremely skewed patterns. This is significantly increased compared to the general population [ Because a subset of the clinical findings of Aicardi syndrome (including colobomas, agenesis of the corpus callosum, microphthalmia, and seizures) overlaps with those of Until the genetic basis of Aicardi syndrome is known, the possibility remains that Aicardi syndrome is caused by a Efforts to identify the mutated gene using array comparative hybridization with genome-wide DNA microarrays [ • Nearly all affected individuals are female and, except for one pair of sisters and a pair of concordant monozygotic twins, all reported cases are simplex (i.e., a single occurrence in a family). • At least six pairs of twins who are discordant for Aicardi syndrome are known, five of whom are confirmed dizygotic, excluding the possibility that the etiology is a prenatal toxin or other disruptive event [ • Rare known males with a confirmed diagnosis of Aicardi syndrome have a 47,XXY karyotype [ • The variable severity and asymmetry of the Aicardi syndrome phenotype could be explained if the putative mutated gene undergoes X-chromosome inactivation. Earlier limited studies, some using older methods, had conflicting results, showing either random or skewed X-chromosome inactivation patterns. The most recent study on 35 individuals with Aicardi syndrome, the largest series examined thus far, demonstrated non-random X-chromosome inactivation in leukocyte-derived DNA in 11 of 33 informative individuals, with six (18%) having extremely skewed patterns. This is significantly increased compared to the general population [ • Because a subset of the clinical findings of Aicardi syndrome (including colobomas, agenesis of the corpus callosum, microphthalmia, and seizures) overlaps with those of • Until the genetic basis of Aicardi syndrome is known, the possibility remains that Aicardi syndrome is caused by a ## Molecular Pathogenesis A gene for Aicardi syndrome has not been identified, but several observations support a hypothesis that Aicardi syndrome is caused by Nearly all affected individuals are female and, except for one pair of sisters and a pair of concordant monozygotic twins, all reported cases are simplex (i.e., a single occurrence in a family). At least six pairs of twins who are discordant for Aicardi syndrome are known, five of whom are confirmed dizygotic, excluding the possibility that the etiology is a prenatal toxin or other disruptive event [ Rare known males with a confirmed diagnosis of Aicardi syndrome have a 47,XXY karyotype [ The variable severity and asymmetry of the Aicardi syndrome phenotype could be explained if the putative mutated gene undergoes X-chromosome inactivation. Earlier limited studies, some using older methods, had conflicting results, showing either random or skewed X-chromosome inactivation patterns. The most recent study on 35 individuals with Aicardi syndrome, the largest series examined thus far, demonstrated non-random X-chromosome inactivation in leukocyte-derived DNA in 11 of 33 informative individuals, with six (18%) having extremely skewed patterns. This is significantly increased compared to the general population [ Because a subset of the clinical findings of Aicardi syndrome (including colobomas, agenesis of the corpus callosum, microphthalmia, and seizures) overlaps with those of Until the genetic basis of Aicardi syndrome is known, the possibility remains that Aicardi syndrome is caused by a Efforts to identify the mutated gene using array comparative hybridization with genome-wide DNA microarrays [ • Nearly all affected individuals are female and, except for one pair of sisters and a pair of concordant monozygotic twins, all reported cases are simplex (i.e., a single occurrence in a family). • At least six pairs of twins who are discordant for Aicardi syndrome are known, five of whom are confirmed dizygotic, excluding the possibility that the etiology is a prenatal toxin or other disruptive event [ • Rare known males with a confirmed diagnosis of Aicardi syndrome have a 47,XXY karyotype [ • The variable severity and asymmetry of the Aicardi syndrome phenotype could be explained if the putative mutated gene undergoes X-chromosome inactivation. Earlier limited studies, some using older methods, had conflicting results, showing either random or skewed X-chromosome inactivation patterns. The most recent study on 35 individuals with Aicardi syndrome, the largest series examined thus far, demonstrated non-random X-chromosome inactivation in leukocyte-derived DNA in 11 of 33 informative individuals, with six (18%) having extremely skewed patterns. This is significantly increased compared to the general population [ • Because a subset of the clinical findings of Aicardi syndrome (including colobomas, agenesis of the corpus callosum, microphthalmia, and seizures) overlaps with those of • Until the genetic basis of Aicardi syndrome is known, the possibility remains that Aicardi syndrome is caused by a ## Chapter Notes Research by the authors is supported by the Aicardi Syndrome Foundation and the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center, supported by IDDRC grant number U54HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health. The retina photo and legend were provided by Dr Richard A Lewis. 12 November 2020 (bp) Comprehensive update posted live 6 November 2014 (me) Comprehensive update posted live 27 April 2010 (me) Comprehensive update posted live 30 June 2006 (ca) Review posted live 2 August 2005 (ivv) Original submission • 12 November 2020 (bp) Comprehensive update posted live • 6 November 2014 (me) Comprehensive update posted live • 27 April 2010 (me) Comprehensive update posted live • 30 June 2006 (ca) Review posted live • 2 August 2005 (ivv) Original submission ## Author Notes ## Acknowledgments Research by the authors is supported by the Aicardi Syndrome Foundation and the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center, supported by IDDRC grant number U54HD083092 from the Eunice Kennedy Shriver National Institute of Child Health & Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Eunice Kennedy Shriver National Institute of Child Health & Human Development or the National Institutes of Health. The retina photo and legend were provided by Dr Richard A Lewis. ## Revision History 12 November 2020 (bp) Comprehensive update posted live 6 November 2014 (me) Comprehensive update posted live 27 April 2010 (me) Comprehensive update posted live 30 June 2006 (ca) Review posted live 2 August 2005 (ivv) Original submission • 12 November 2020 (bp) Comprehensive update posted live • 6 November 2014 (me) Comprehensive update posted live • 27 April 2010 (me) Comprehensive update posted live • 30 June 2006 (ca) Review posted live • 2 August 2005 (ivv) Original submission ## References ## Literature Cited Classic lacunae surround the modestly dysplastic left optic disc. Note the nasal "papilla nigra" appearance and the anomalous branching patterns of the central vasculature. Image courtesy of Dr Richard A Lewis	[]	30/6/2006	12/11/2020	20/9/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aip	aip	[ "PBGD Deficiency", "Porphobilinogen Deaminase Deficiency", "Porphobilinogen Deaminase Deficiency", "PBGD Deficiency", "Porphobilinogen deaminase", "HMBS", "Acute Intermittent Porphyria (AIP)" ]	Acute Intermittent Porphyria	Eliane Sardh, Michela Barbaro	Summary An acute porphyria attack is characterized by a urine porphobilinogen (PBG)-to-creatinine ratio ≥10 times the upper limit of normal (ULN) and the presence of ≥2 porphyria manifestations (involving the visceral, peripheral, autonomic, and/or central nervous systems) persisting for >24 hours in the absence of other likely explanations. Onset of acute attacks typically occurs in the second or third decade of life. Acute attacks are more common in women than men. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, often no precipitating factor can be identified. The course of acute porphyria attacks is highly variable in an individual and between individuals. Recovery from acute porphyria attacks may occur within days; however, recovery from severe attacks that are not promptly recognized and treated may take weeks or months. The five categories of acute intermittent porphyria (AIP), caused by a heterozygous When the diagnosis of an AIP attack is suspected based on clinical findings, establishing the diagnosis begins with biochemical testing. If the urinary concentration of PBG is increased, molecular genetic testing is performed to confirm the diagnosis and/or to facilitate cascade screening of family members. When a multigene panel or genomic testing has identified an AIP is inherited in an autosomal dominant manner. The majority of individuals diagnosed with AIP inherited an	Acute Intermittent Porphyria: Clinical Designations for Individuals Heterozygous for an Sporadic AIP: 1-3 acute porphyria attacks in any 12-month period within the last 2 years Recurrent AIP: ≥4 acute porphyria attacks in a maximum period of 12 months within the last 2 years Latent at-risk individual: An asymptomatic individual with a positive family history of AIP in whom an Latent low-risk individual: An asymptomatic individual with no known family history of AIP in whom the identification of an Based on AIP = acute intermittent porphyria; PBG= porphobilinogen; ULN = upper limit of normal The quality of the PBG analysis should be within specifications set by Ipnet EQAS (or another EQA organization, such as An acute porphyria attack is defined as a urine PBG-to-creatinine ratio ≥10 times the upper limit of normal in the presence of two or more porphyria manifestations typically persisting for more than 24 hours in the absence of other likely explanations. "Incidental finding" in this context refers to the identification of a pathogenic variant in a gene that does not account for the phenotype that prompted the diagnostic testing. • Sporadic AIP: 1-3 acute porphyria attacks in any 12-month period within the last 2 years • Recurrent AIP: ≥4 acute porphyria attacks in a maximum period of 12 months within the last 2 years • Latent at-risk individual: An asymptomatic individual with a positive family history of AIP in whom an • Latent low-risk individual: An asymptomatic individual with no known family history of AIP in whom the identification of an ## Diagnosis An acute porphyria attack Presence of otherwise unexplained severe, acute abdominal pain (without physical signs) in the vast majority (90%) of acute attacks [ During attacks nausea, vomiting, constipation, tachycardia, and hypertension are common. Muscle weakness, seizures, mental changes, and hyponatremia are features that alone or in combination increase the probability of acute porphyria. The urine may be reddish brown or red; however, this should not be used as a diagnostic criterion as it is not a constant finding, especially if the sample is fresh. The color is enhanced by exposure to air and light and reflects increased urinary concentrations of porphyrins and porphobilins formed from the porphyrin precursor porphobilinogen (PBG). An increased urinary PBG concentration, using a specific quantitative assay and confirmatory biochemical testing, are essential to establish an unequivocal diagnosis of an acute porphyria attack in a symptomatic individual [ The concentration of PBG in urine is invariably increased in individuals with manifestations of AIP during an acute attack. Urine PBG-to-creatinine ratio is typically increased to more than 10 times the upper limit of normal (ULN) or significantly above the individual's baseline if baseline is more than 10 times the ULN [ Urine PBG concentration is best analyzed in a fresh random 10 mL urine sample collected without preservative and protected from prolonged exposure to bright light [ Note: Positive results on qualitative or semiquantitative urine PBG tests Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal; Plasma porphyrin fluorescence emission scan either shows a peak around 620 nm or is normal. Identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see When the phenotypic and findings on biochemical testing suggest the diagnosis of AIP, 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 Acute Intermittent Porphyria 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 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. Larger deletions/duplications/insertions and whole-gene deletions have been reported. These will not be detected by single-gene sequencing but may be identified by gene-targeted deletion/duplication analysis or next-generation sequencing. • Presence of otherwise unexplained severe, acute abdominal pain (without physical signs) in the vast majority (90%) of acute attacks [ • During attacks nausea, vomiting, constipation, tachycardia, and hypertension are common. • Muscle weakness, seizures, mental changes, and hyponatremia are features that alone or in combination increase the probability of acute porphyria. • The urine may be reddish brown or red; however, this should not be used as a diagnostic criterion as it is not a constant finding, especially if the sample is fresh. The color is enhanced by exposure to air and light and reflects increased urinary concentrations of porphyrins and porphobilins formed from the porphyrin precursor porphobilinogen (PBG). • Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal; • Plasma porphyrin fluorescence emission scan either shows a peak around 620 nm or is normal. • For an introduction to multigene panels click ## Suggestive Findings An acute porphyria attack Presence of otherwise unexplained severe, acute abdominal pain (without physical signs) in the vast majority (90%) of acute attacks [ During attacks nausea, vomiting, constipation, tachycardia, and hypertension are common. Muscle weakness, seizures, mental changes, and hyponatremia are features that alone or in combination increase the probability of acute porphyria. The urine may be reddish brown or red; however, this should not be used as a diagnostic criterion as it is not a constant finding, especially if the sample is fresh. The color is enhanced by exposure to air and light and reflects increased urinary concentrations of porphyrins and porphobilins formed from the porphyrin precursor porphobilinogen (PBG). • Presence of otherwise unexplained severe, acute abdominal pain (without physical signs) in the vast majority (90%) of acute attacks [ • During attacks nausea, vomiting, constipation, tachycardia, and hypertension are common. • Muscle weakness, seizures, mental changes, and hyponatremia are features that alone or in combination increase the probability of acute porphyria. • The urine may be reddish brown or red; however, this should not be used as a diagnostic criterion as it is not a constant finding, especially if the sample is fresh. The color is enhanced by exposure to air and light and reflects increased urinary concentrations of porphyrins and porphobilins formed from the porphyrin precursor porphobilinogen (PBG). ## Establishing the Diagnosis An increased urinary PBG concentration, using a specific quantitative assay and confirmatory biochemical testing, are essential to establish an unequivocal diagnosis of an acute porphyria attack in a symptomatic individual [ The concentration of PBG in urine is invariably increased in individuals with manifestations of AIP during an acute attack. Urine PBG-to-creatinine ratio is typically increased to more than 10 times the upper limit of normal (ULN) or significantly above the individual's baseline if baseline is more than 10 times the ULN [ Urine PBG concentration is best analyzed in a fresh random 10 mL urine sample collected without preservative and protected from prolonged exposure to bright light [ Note: Positive results on qualitative or semiquantitative urine PBG tests Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal; Plasma porphyrin fluorescence emission scan either shows a peak around 620 nm or is normal. Identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see When the phenotypic and findings on biochemical testing suggest the diagnosis of AIP, 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 Acute Intermittent Porphyria 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 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. Larger deletions/duplications/insertions and whole-gene deletions have been reported. These will not be detected by single-gene sequencing but may be identified by gene-targeted deletion/duplication analysis or next-generation sequencing. • Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal; • Plasma porphyrin fluorescence emission scan either shows a peak around 620 nm or is normal. • For an introduction to multigene panels click ## Biochemical Testing An increased urinary PBG concentration, using a specific quantitative assay and confirmatory biochemical testing, are essential to establish an unequivocal diagnosis of an acute porphyria attack in a symptomatic individual [ The concentration of PBG in urine is invariably increased in individuals with manifestations of AIP during an acute attack. Urine PBG-to-creatinine ratio is typically increased to more than 10 times the upper limit of normal (ULN) or significantly above the individual's baseline if baseline is more than 10 times the ULN [ Urine PBG concentration is best analyzed in a fresh random 10 mL urine sample collected without preservative and protected from prolonged exposure to bright light [ Note: Positive results on qualitative or semiquantitative urine PBG tests Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal; Plasma porphyrin fluorescence emission scan either shows a peak around 620 nm or is normal. • Total fecal porphyrin concentration or coproporphyrin isomer ratio is normal; • Plasma porphyrin fluorescence emission scan either shows a peak around 620 nm or is normal. ## Molecular Genetic Testing Identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see When the phenotypic and findings on biochemical testing suggest the diagnosis of AIP, 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 Acute Intermittent Porphyria 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 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. Larger deletions/duplications/insertions and whole-gene deletions have been reported. These will not be detected by single-gene sequencing but may be identified by gene-targeted deletion/duplication analysis or next-generation sequencing. • For an introduction to multigene panels click ## When the phenotypic and findings on biochemical testing suggest the diagnosis of AIP, 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 Acute Intermittent Porphyria 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 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. Larger deletions/duplications/insertions and whole-gene deletions have been reported. These will not be detected by single-gene sequencing but may be identified by gene-targeted deletion/duplication analysis or next-generation sequencing. ## Clinical Characteristics Acute intermittent porphyria (AIP), caused by a heterozygous Acute Intermittent Porphyria: Clinical Designations Sporadic AIP (individual has experienced 1 to ≤ 3 acute porphyria attacks); Recurrent AIP (individual has experienced ≥4 acute porphyria attacks in a maximum period of 12 mos within the last 2 yrs). Latent at risk (an individual who has been found to have a pathogenic variant as part of family screening); Latent low risk (an individual in whom the identification of an Based on AIP = acute intermittent porphyria; PBG = porphobilinogen; ULN = upper limit of normal The quality of the PBG analysis should be within specifications set by Ipnet EQAS (or another EQA organization, such as "Incidental finding" in this context refers to the identification of a pathogenic variant in a gene that does not account for the phenotype that prompted the diagnostic testing. Note that cutaneous manifestations of porphyria do not occur in AIP. Manifestations of AIP, which are more common in women than men, are very rare before puberty. Onset typically occurs in the second or third decade [ The visceral, peripheral, autonomic, and/or central nervous systems may be affected, leading to a range of findings that are usually intermittent and sometimes life-threatening. The course of acute porphyria attacks is highly variable in an individual and between individuals. Affected individuals may recover from acute porphyria attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified. Severe abdominal pain, which may be generalized or localized and not accompanied by muscle guarding, is the most common symptom and is often the initial sign of an acute attack. Back, buttock, or limb pain may be a feature. Gastrointestinal features including nausea, vomiting, constipation or diarrhea, and abdominal distention are common, and ileus can occur. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently. Urinary retention, incontinence, and dysuria may be present. Approximately 3%-8% of individuals with AIP, mainly women, experience recurrent AIP (defined as ≥4 attacks in one year [ Acute porphyria attacks may be precipitated by endogenous or exogenous factors [ Patchy sensory neuropathy may also occur. The condition usually occurs after an acute porphyria attack and can persist for many years [ Asymptomatic AIP (also called acute porphyria in remission) refers to a person has had one or more acute porphyria attacks in the past but has had no acute porphyria-related manifestations during the last two years and has a urine PBG-to-creatinine ratio is less than four times the upper limit of normal. Latent AIP refers to a person who is heterozygous for an The risk of becoming symptomatic depends on age, sex, and exposure to provoking agents, and is higher if the individual belongs to a family with other symptomatic individuals [ In all forms of AIP, clinical manifestations must always be evaluated in relation to the urinary PBG concentration. A Swedish national cohort study of 1,244 individuals with acute hepatic porphyria (i.e., individuals with AIP or one of the other two types of hepatic porphyria) demonstrated a 44-fold increased risk for individuals with AIP to develop PLC compared to a matched cohort. In individuals with active disease, defined as elevated urinary PBG concentration at some point in their lifetime, the risk of developing PLC was 63 times higher [ A longitudinal US study showed that 1.5% of individuals diagnosed with acute hepatic porphyria developed HCC; urine PBG concentration was not available at the time of HCC diagnosis, and three of five individuals reported having symptomatic porphyria at baseline [ Although the risk of PLC appears higher in individuals with clinically and biochemically active disease, it has also been reported in individuals with asymptomatic AIP [ No genotype-phenotype correlations have been identified. In a French cohort of 253 families including 496 individuals with active (symptomatic) AIP and 1,672 individuals with latent AIP, the estimated penetrance of AIP in heterozygous family members was 22.9% [ In a Finnish study, the average penetrance was 30% for an acute attack and 35% for acute symptoms in In Sweden and Spain, where Although there is no proven correlation between genotype and phenotype, some Individuals with latent AIP are often referred to as "carriers" in the medical literature. Active AIP, either clinically or biochemically, has also been referred to as manifest or overt AIP in the older medical literature (in which its definition varied). In most countries, AIP is the most common of the acute hepatic porphyrias [ Because the real prevalence of AIP is difficult to evaluate, in most instances it is based on estimations. The prevalence of "overt AIP" (defined as having at least one acute porphyria attack) in France is 1:132,000 inhabitants [ In Sweden the incidence and prevalence of AIP are about four times higher than in Europe due to an In Spain, the prevalence in the Murcia region is 17.7 individuals in one million inhabitants due to another • Sporadic AIP (individual has experienced 1 to ≤ 3 acute porphyria attacks); • Recurrent AIP (individual has experienced ≥4 acute porphyria attacks in a maximum period of 12 mos within the last 2 yrs). • Latent at risk (an individual who has been found to have a pathogenic variant as part of family screening); • Latent low risk (an individual in whom the identification of an • A Swedish national cohort study of 1,244 individuals with acute hepatic porphyria (i.e., individuals with AIP or one of the other two types of hepatic porphyria) demonstrated a 44-fold increased risk for individuals with AIP to develop PLC compared to a matched cohort. In individuals with active disease, defined as elevated urinary PBG concentration at some point in their lifetime, the risk of developing PLC was 63 times higher [ • A longitudinal US study showed that 1.5% of individuals diagnosed with acute hepatic porphyria developed HCC; urine PBG concentration was not available at the time of HCC diagnosis, and three of five individuals reported having symptomatic porphyria at baseline [ • Although the risk of PLC appears higher in individuals with clinically and biochemically active disease, it has also been reported in individuals with asymptomatic AIP [ • In a French cohort of 253 families including 496 individuals with active (symptomatic) AIP and 1,672 individuals with latent AIP, the estimated penetrance of AIP in heterozygous family members was 22.9% [ • In a Finnish study, the average penetrance was 30% for an acute attack and 35% for acute symptoms in • In Sweden and Spain, where • The prevalence of "overt AIP" (defined as having at least one acute porphyria attack) in France is 1:132,000 inhabitants [ • In Sweden the incidence and prevalence of AIP are about four times higher than in Europe due to an • In Spain, the prevalence in the Murcia region is 17.7 individuals in one million inhabitants due to another ## Clinical Description Acute intermittent porphyria (AIP), caused by a heterozygous Acute Intermittent Porphyria: Clinical Designations Sporadic AIP (individual has experienced 1 to ≤ 3 acute porphyria attacks); Recurrent AIP (individual has experienced ≥4 acute porphyria attacks in a maximum period of 12 mos within the last 2 yrs). Latent at risk (an individual who has been found to have a pathogenic variant as part of family screening); Latent low risk (an individual in whom the identification of an Based on AIP = acute intermittent porphyria; PBG = porphobilinogen; ULN = upper limit of normal The quality of the PBG analysis should be within specifications set by Ipnet EQAS (or another EQA organization, such as "Incidental finding" in this context refers to the identification of a pathogenic variant in a gene that does not account for the phenotype that prompted the diagnostic testing. Note that cutaneous manifestations of porphyria do not occur in AIP. Manifestations of AIP, which are more common in women than men, are very rare before puberty. Onset typically occurs in the second or third decade [ The visceral, peripheral, autonomic, and/or central nervous systems may be affected, leading to a range of findings that are usually intermittent and sometimes life-threatening. The course of acute porphyria attacks is highly variable in an individual and between individuals. Affected individuals may recover from acute porphyria attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified. Severe abdominal pain, which may be generalized or localized and not accompanied by muscle guarding, is the most common symptom and is often the initial sign of an acute attack. Back, buttock, or limb pain may be a feature. Gastrointestinal features including nausea, vomiting, constipation or diarrhea, and abdominal distention are common, and ileus can occur. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently. Urinary retention, incontinence, and dysuria may be present. Approximately 3%-8% of individuals with AIP, mainly women, experience recurrent AIP (defined as ≥4 attacks in one year [ Acute porphyria attacks may be precipitated by endogenous or exogenous factors [ Patchy sensory neuropathy may also occur. The condition usually occurs after an acute porphyria attack and can persist for many years [ Asymptomatic AIP (also called acute porphyria in remission) refers to a person has had one or more acute porphyria attacks in the past but has had no acute porphyria-related manifestations during the last two years and has a urine PBG-to-creatinine ratio is less than four times the upper limit of normal. Latent AIP refers to a person who is heterozygous for an The risk of becoming symptomatic depends on age, sex, and exposure to provoking agents, and is higher if the individual belongs to a family with other symptomatic individuals [ In all forms of AIP, clinical manifestations must always be evaluated in relation to the urinary PBG concentration. A Swedish national cohort study of 1,244 individuals with acute hepatic porphyria (i.e., individuals with AIP or one of the other two types of hepatic porphyria) demonstrated a 44-fold increased risk for individuals with AIP to develop PLC compared to a matched cohort. In individuals with active disease, defined as elevated urinary PBG concentration at some point in their lifetime, the risk of developing PLC was 63 times higher [ A longitudinal US study showed that 1.5% of individuals diagnosed with acute hepatic porphyria developed HCC; urine PBG concentration was not available at the time of HCC diagnosis, and three of five individuals reported having symptomatic porphyria at baseline [ Although the risk of PLC appears higher in individuals with clinically and biochemically active disease, it has also been reported in individuals with asymptomatic AIP [ • Sporadic AIP (individual has experienced 1 to ≤ 3 acute porphyria attacks); • Recurrent AIP (individual has experienced ≥4 acute porphyria attacks in a maximum period of 12 mos within the last 2 yrs). • Latent at risk (an individual who has been found to have a pathogenic variant as part of family screening); • Latent low risk (an individual in whom the identification of an • A Swedish national cohort study of 1,244 individuals with acute hepatic porphyria (i.e., individuals with AIP or one of the other two types of hepatic porphyria) demonstrated a 44-fold increased risk for individuals with AIP to develop PLC compared to a matched cohort. In individuals with active disease, defined as elevated urinary PBG concentration at some point in their lifetime, the risk of developing PLC was 63 times higher [ • A longitudinal US study showed that 1.5% of individuals diagnosed with acute hepatic porphyria developed HCC; urine PBG concentration was not available at the time of HCC diagnosis, and three of five individuals reported having symptomatic porphyria at baseline [ • Although the risk of PLC appears higher in individuals with clinically and biochemically active disease, it has also been reported in individuals with asymptomatic AIP [ ## Active (Symptomatic) AIP Manifestations of AIP, which are more common in women than men, are very rare before puberty. Onset typically occurs in the second or third decade [ The visceral, peripheral, autonomic, and/or central nervous systems may be affected, leading to a range of findings that are usually intermittent and sometimes life-threatening. The course of acute porphyria attacks is highly variable in an individual and between individuals. Affected individuals may recover from acute porphyria attacks within days, but recovery from severe attacks that are not promptly recognized and treated may take weeks or months. Although attacks in most individuals are typically caused by exposure to certain endogenous or exogenous factors, it is not uncommon for individuals to have acute attacks in which no precipitating factor can be identified. Severe abdominal pain, which may be generalized or localized and not accompanied by muscle guarding, is the most common symptom and is often the initial sign of an acute attack. Back, buttock, or limb pain may be a feature. Gastrointestinal features including nausea, vomiting, constipation or diarrhea, and abdominal distention are common, and ileus can occur. Tachycardia and hypertension are frequent, while fever, sweating, restlessness, and tremor are seen less frequently. Urinary retention, incontinence, and dysuria may be present. Approximately 3%-8% of individuals with AIP, mainly women, experience recurrent AIP (defined as ≥4 attacks in one year [ Acute porphyria attacks may be precipitated by endogenous or exogenous factors [ Patchy sensory neuropathy may also occur. ## High Excreter The condition usually occurs after an acute porphyria attack and can persist for many years [ ## Asymptomatic AIP Asymptomatic AIP (also called acute porphyria in remission) refers to a person has had one or more acute porphyria attacks in the past but has had no acute porphyria-related manifestations during the last two years and has a urine PBG-to-creatinine ratio is less than four times the upper limit of normal. ## Latent AIP Latent AIP refers to a person who is heterozygous for an The risk of becoming symptomatic depends on age, sex, and exposure to provoking agents, and is higher if the individual belongs to a family with other symptomatic individuals [ ## Clinical Manifestations of AIP In all forms of AIP, clinical manifestations must always be evaluated in relation to the urinary PBG concentration. A Swedish national cohort study of 1,244 individuals with acute hepatic porphyria (i.e., individuals with AIP or one of the other two types of hepatic porphyria) demonstrated a 44-fold increased risk for individuals with AIP to develop PLC compared to a matched cohort. In individuals with active disease, defined as elevated urinary PBG concentration at some point in their lifetime, the risk of developing PLC was 63 times higher [ A longitudinal US study showed that 1.5% of individuals diagnosed with acute hepatic porphyria developed HCC; urine PBG concentration was not available at the time of HCC diagnosis, and three of five individuals reported having symptomatic porphyria at baseline [ Although the risk of PLC appears higher in individuals with clinically and biochemically active disease, it has also been reported in individuals with asymptomatic AIP [ • A Swedish national cohort study of 1,244 individuals with acute hepatic porphyria (i.e., individuals with AIP or one of the other two types of hepatic porphyria) demonstrated a 44-fold increased risk for individuals with AIP to develop PLC compared to a matched cohort. In individuals with active disease, defined as elevated urinary PBG concentration at some point in their lifetime, the risk of developing PLC was 63 times higher [ • A longitudinal US study showed that 1.5% of individuals diagnosed with acute hepatic porphyria developed HCC; urine PBG concentration was not available at the time of HCC diagnosis, and three of five individuals reported having symptomatic porphyria at baseline [ • Although the risk of PLC appears higher in individuals with clinically and biochemically active disease, it has also been reported in individuals with asymptomatic AIP [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance In a French cohort of 253 families including 496 individuals with active (symptomatic) AIP and 1,672 individuals with latent AIP, the estimated penetrance of AIP in heterozygous family members was 22.9% [ In a Finnish study, the average penetrance was 30% for an acute attack and 35% for acute symptoms in In Sweden and Spain, where Although there is no proven correlation between genotype and phenotype, some • In a French cohort of 253 families including 496 individuals with active (symptomatic) AIP and 1,672 individuals with latent AIP, the estimated penetrance of AIP in heterozygous family members was 22.9% [ • In a Finnish study, the average penetrance was 30% for an acute attack and 35% for acute symptoms in • In Sweden and Spain, where ## Nomenclature Individuals with latent AIP are often referred to as "carriers" in the medical literature. Active AIP, either clinically or biochemically, has also been referred to as manifest or overt AIP in the older medical literature (in which its definition varied). ## Prevalence In most countries, AIP is the most common of the acute hepatic porphyrias [ Because the real prevalence of AIP is difficult to evaluate, in most instances it is based on estimations. The prevalence of "overt AIP" (defined as having at least one acute porphyria attack) in France is 1:132,000 inhabitants [ In Sweden the incidence and prevalence of AIP are about four times higher than in Europe due to an In Spain, the prevalence in the Murcia region is 17.7 individuals in one million inhabitants due to another • The prevalence of "overt AIP" (defined as having at least one acute porphyria attack) in France is 1:132,000 inhabitants [ • In Sweden the incidence and prevalence of AIP are about four times higher than in Europe due to an • In Spain, the prevalence in the Murcia region is 17.7 individuals in one million inhabitants due to another ## Genetically Related (Allelic) Disorders To date, six children and six adults with biallelic germline Phenotypes Described in Individuals with Biallelic CNS = central nervous system Relatives of affected individuals who are heterozygous for these variants had decreased porphobilinogen deaminase activity but no clinical manifestations of AIP. Additionally, to date no individuals heterozygous for these ## Differential Diagnosis Genetic Disorders in the Differential Diagnosis of Symptomatic Acute Intermittent Porphyria AD = autosomal dominant; ALA = 5-aminolevulinic acid; AR = autosomal recessive; MOI = mode of inheritance; PBG = porphobilinogen See Acute neurovisceral attacks are accompanied by porphyric skin lesions (bullae, fragile skin) in about 15% of persons with HCP and about 60% of persons with VP. PBG increased more than ALA; both may decrease rapidly as symptoms resolve. Uroporphyrin from in vitro polymerization of PBG and coproporphyrin; measurement is not required for diagnosis and may mislead. Plasma porphyrin concentration may occasionally be normal; fluorescence emission spectroscopy does not distinguish between HCP and AIP. Protoporphyrin is the main stool porphyrin, but a small increase in coproporphyrin III is also observed. Plasma porphyrin concentration is always increased, and fluorescence emission spectroscopy distinguishes VP from all other porphyrias. ## Management No clinical practice guidelines for acute intermittent porphyria (AIP) have been published. To establish the extent of disease and needs in an individual diagnosed with AIP who is experiencing acute manifestations, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Consider other causes of abdominal pain in addition to porphyria. Review all medications and discontinue any that can exacerbate acute porphyria [ Initial investigations should include the following: Complete blood count Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) Brain MRI when central nervous system manifestations are present Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. Assess need for family support and resources including community or online To establish the extent of disease and needs in an individual found to have an Perform full clinical history and examination, including neurologic evaluation. Review medications to assess risk versus benefit (see Measure urinary porphobilinogen (PBG) concentration to establish a baseline for comparison with future measurements taken during clinical findings suggestive of symptomatic porphyria. Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. Assess need for family support and resources including community or online Treatment of an acute porphyria attack depends on the type and severity of the attack. Treat intercurrent infections and other diseases promptly. For mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral, is recommended. When required, intravenous (IV) fluid may be used for up to 48 hours. IV fluid should contain a minimum of 5% dextrose; the recommendation in most countries is 10% glucose with added sodium (40 mmol) and potassium (20 mmol) given at a rate of 1,000 mL over 12 hours. Note that hypotonic dextrose in water solutions should be avoided because of the risk of hyponatremia. If improvement is unsatisfactory or if additional and progressive neurologic features present, intravenous administration of hemin preparations is recommended (see The recommended dose for hemin is 3-4 mg/kg by IV, given once daily for four days. Treatment may be extended, depending on the clinical course. Note: Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin. Panhematin Heme arginate (Normosang Note: (1) Phlebitis after IV injection can be minimized by reconstituting hematin in 20% human serum albumin solution and/or by using a large vein or a central catheter for infusion. Peripheral cannulas used to administer hematin should be replaced after each use. (2) An infusion set with an in-line filter is recommended to remove any undissolved particulate matter. (3) Rigorous flushing of venous catheters with boluses of saline totaling 200 mL is recommended. Recurrent acute attacks are best managed with support and advice from a porphyria specialist. See information and contact details of specialist porphyria centers at the If the criterion for recurrent attacks is met [ When available, use of this treatment has meant that older treatment alternatives such as ovulation suppression therapy and preventive hemin can be avoided. For the sporadic acute attack, hemin is still the treatment of primary choice. Note that ALA toxicity is the major hypothesis proposed for the pathogenesis of the neurologic lesions causing the clinical features of acute porphyria attacks. Support for this hypothesis are (1) the success of liver transplantation as a cure for recurrent acute attacks [ Alternative medical therapies to reduce the frequency and/or severity of acute porphyria attacks if givosiran is not available include ovulation suppression therapy and prophylactic hemin infusion. Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised diets that restrict caloric intake, particularly those that exclude carbohydrates completely. Seek timely treatment of systemic illness or infection. Advice on safe treatment of persons with porphyria in some specific clinical situations (e.g., epilepsy, HIV, malaria, tuberculosis, hyperlipidemia, and hypertension) is available on the Based on current knowledge, it is not possible to distinguish whether certain groups of individuals who are heterozygous for a pathogenic Most porphyria centers recommend PLC surveillance by annual or twice a year ultrasound examination for all individuals who are heterozygous for a pathogenic Note: Serum alpha-fetoprotein measurement is not helpful in surveillance. Individuals with AIP are advised to avoid excessive alcohol consumption. Alcohol has been shown to upregulate ALAS1, the first enzyme of hepatic heme biosynthesis [ In all the acute porphyrias, information on the safety of many drugs and other over-the-counter preparations is incomplete; however, evidence-based guidelines for assessment of drug porphyrogenicity have been published [ For a searchable drug safety database, see the See the For information on prescribing medication in the context of certain conditions (e.g., HIV, epilepsy, malaria), see Safe drug lists are available at Providing information to individuals newly identified as being heterozygous for an Note: (1) Measurement of erythrocyte HMBS activity cannot be used to detect heterozygotes if the proband has the non-erythroid variant form of acute intermittent porphyria (see Urinary PBG excretion should See Pregnancy in women with AIP is usually uncomplicated. Although urinary PBG concentration may increase during pregnancy, this does not lead to a higher frequency of clinical manifestations of porphyria [ Preconception counseling is recommended to advise women with AIP of the clinical manifestations of porphyria, self-care, and preventative measures to avoid exacerbations (i.e., adequate and regular nutrition, rest, and carbohydrate intake for treating mild-to-moderate symptoms). See also There is a higher risk for pregnancy-induced hypertensive disorder, gestational diabetes, and fetuses with intrauterine growth restriction (IUGR). In general, risk ratios are higher among women with AIP who have high lifetime urinary PBG concentrations [ Testing for urinary PBG concentration prior to pregnancy may establish the individual's risk levels. Women with biochemically active acute hepatic porphyria (AHP) (i.e., urinary PBG concentration greater than four times the upper limit of normal) or a history of active AHP should be offered specialized prenatal care. Hyperemesis, a catabolic risk for precipitating acute attacks, should be treated promptly. Blood pressure should be monitored once monthly during the first and second trimesters, and weekly during the last trimester. Additional monitoring of fetal growth during pregnancy will help identify IUGR [ When a woman with AIP experiences abdominal pain, hypertension, and tachycardia during pregnancy, urine PBG concentration should be measured, and complications of pregnancy should be excluded in consultation with an obstetrician before the findings are attributed to an acute attack. If an acute porphyria attack is suspected, a urine PBG concentration should be measured before deciding on specific treatment (see Any symptomatic treatment needed should be chosen after considering the risk of the drug triggering/aggravating an acute porphyria attack in the pregnant woman (see An obstetrician should be consulted regarding medical treatment and possible effects on the fetus. Human hemin is safe to be used during pregnancy [ No human pregnancies have been reported during or after treatment with Givlaari See Search • Consider other causes of abdominal pain in addition to porphyria. • Review all medications and discontinue any that can exacerbate acute porphyria [ • Initial investigations should include the following: • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see • Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. • Assess need for family support and resources including community or online • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Perform full clinical history and examination, including neurologic evaluation. • Review medications to assess risk versus benefit (see • Measure urinary porphobilinogen (PBG) concentration to establish a baseline for comparison with future measurements taken during clinical findings suggestive of symptomatic porphyria. • Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see • Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. • Assess need for family support and resources including community or online • Treat intercurrent infections and other diseases promptly. • For mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral, is recommended. When required, intravenous (IV) fluid may be used for up to 48 hours. IV fluid should contain a minimum of 5% dextrose; the recommendation in most countries is 10% glucose with added sodium (40 mmol) and potassium (20 mmol) given at a rate of 1,000 mL over 12 hours. Note that hypotonic dextrose in water solutions should be avoided because of the risk of hyponatremia. • If improvement is unsatisfactory or if additional and progressive neurologic features present, intravenous administration of hemin preparations is recommended (see • Panhematin • Heme arginate (Normosang • Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised diets that restrict caloric intake, particularly those that exclude carbohydrates completely. • Seek timely treatment of systemic illness or infection. • For a searchable drug safety database, see the • See the • For information on prescribing medication in the context of certain conditions (e.g., HIV, epilepsy, malaria), see • Safe drug lists are available at • If an acute porphyria attack is suspected, a urine PBG concentration should be measured before deciding on specific treatment (see • Any symptomatic treatment needed should be chosen after considering the risk of the drug triggering/aggravating an acute porphyria attack in the pregnant woman (see • An obstetrician should be consulted regarding medical treatment and possible effects on the fetus. • Human hemin is safe to be used during pregnancy [ • No human pregnancies have been reported during or after treatment with Givlaari ## Initial Evaluations To establish the extent of disease and needs in an individual diagnosed with AIP who is experiencing acute manifestations, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Consider other causes of abdominal pain in addition to porphyria. Review all medications and discontinue any that can exacerbate acute porphyria [ Initial investigations should include the following: Complete blood count Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) Brain MRI when central nervous system manifestations are present Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. Assess need for family support and resources including community or online To establish the extent of disease and needs in an individual found to have an Perform full clinical history and examination, including neurologic evaluation. Review medications to assess risk versus benefit (see Measure urinary porphobilinogen (PBG) concentration to establish a baseline for comparison with future measurements taken during clinical findings suggestive of symptomatic porphyria. Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. Assess need for family support and resources including community or online • Consider other causes of abdominal pain in addition to porphyria. • Review all medications and discontinue any that can exacerbate acute porphyria [ • Initial investigations should include the following: • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see • Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. • Assess need for family support and resources including community or online • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Perform full clinical history and examination, including neurologic evaluation. • Review medications to assess risk versus benefit (see • Measure urinary porphobilinogen (PBG) concentration to establish a baseline for comparison with future measurements taken during clinical findings suggestive of symptomatic porphyria. • Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see • Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. • Assess need for family support and resources including community or online ## Evaluations Following Initial Diagnosis of an AIP Attack To establish the extent of disease and needs in an individual diagnosed with AIP who is experiencing acute manifestations, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended: Consider other causes of abdominal pain in addition to porphyria. Review all medications and discontinue any that can exacerbate acute porphyria [ Initial investigations should include the following: Complete blood count Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) Brain MRI when central nervous system manifestations are present Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. Assess need for family support and resources including community or online • Consider other causes of abdominal pain in addition to porphyria. • Review all medications and discontinue any that can exacerbate acute porphyria [ • Initial investigations should include the following: • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present • Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see • Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. • Assess need for family support and resources including community or online • Complete blood count • Measurement of serum/plasma concentrations of urea, creatinine, and electrolytes • If there is hyponatremia, measure serum and urine osmolality, and urine sodium concentration • Other blood tests as indicated by the individual's condition and possible cause of the attack (e.g., C-reactive protein, blood cultures, serum creatine kinase, and plasma magnesium concentration) • Brain MRI when central nervous system manifestations are present ## Evaluations Following Identification of an To establish the extent of disease and needs in an individual found to have an Perform full clinical history and examination, including neurologic evaluation. Review medications to assess risk versus benefit (see Measure urinary porphobilinogen (PBG) concentration to establish a baseline for comparison with future measurements taken during clinical findings suggestive of symptomatic porphyria. Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. Assess need for family support and resources including community or online • Perform full clinical history and examination, including neurologic evaluation. • Review medications to assess risk versus benefit (see • Measure urinary porphobilinogen (PBG) concentration to establish a baseline for comparison with future measurements taken during clinical findings suggestive of symptomatic porphyria. • Refer individual to a porphyria specialist for more detailed clinical advice on AIP (see • Affected individuals should be advised to register with an organization that provides warning jewelry in case of an accident (e.g., MedicAlert • Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of AIP to facilitate medical and personal decision making. • Assess need for family support and resources including community or online ## Treatment of Manifestations Treatment of an acute porphyria attack depends on the type and severity of the attack. Treat intercurrent infections and other diseases promptly. For mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral, is recommended. When required, intravenous (IV) fluid may be used for up to 48 hours. IV fluid should contain a minimum of 5% dextrose; the recommendation in most countries is 10% glucose with added sodium (40 mmol) and potassium (20 mmol) given at a rate of 1,000 mL over 12 hours. Note that hypotonic dextrose in water solutions should be avoided because of the risk of hyponatremia. If improvement is unsatisfactory or if additional and progressive neurologic features present, intravenous administration of hemin preparations is recommended (see The recommended dose for hemin is 3-4 mg/kg by IV, given once daily for four days. Treatment may be extended, depending on the clinical course. Note: Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin. Panhematin Heme arginate (Normosang Note: (1) Phlebitis after IV injection can be minimized by reconstituting hematin in 20% human serum albumin solution and/or by using a large vein or a central catheter for infusion. Peripheral cannulas used to administer hematin should be replaced after each use. (2) An infusion set with an in-line filter is recommended to remove any undissolved particulate matter. (3) Rigorous flushing of venous catheters with boluses of saline totaling 200 mL is recommended. Recurrent acute attacks are best managed with support and advice from a porphyria specialist. See information and contact details of specialist porphyria centers at the If the criterion for recurrent attacks is met [ When available, use of this treatment has meant that older treatment alternatives such as ovulation suppression therapy and preventive hemin can be avoided. For the sporadic acute attack, hemin is still the treatment of primary choice. Note that ALA toxicity is the major hypothesis proposed for the pathogenesis of the neurologic lesions causing the clinical features of acute porphyria attacks. Support for this hypothesis are (1) the success of liver transplantation as a cure for recurrent acute attacks [ Alternative medical therapies to reduce the frequency and/or severity of acute porphyria attacks if givosiran is not available include ovulation suppression therapy and prophylactic hemin infusion. Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised diets that restrict caloric intake, particularly those that exclude carbohydrates completely. Seek timely treatment of systemic illness or infection. Advice on safe treatment of persons with porphyria in some specific clinical situations (e.g., epilepsy, HIV, malaria, tuberculosis, hyperlipidemia, and hypertension) is available on the • Treat intercurrent infections and other diseases promptly. • For mild acute neurovisceral attacks, a high carbohydrate intake, preferably oral, is recommended. When required, intravenous (IV) fluid may be used for up to 48 hours. IV fluid should contain a minimum of 5% dextrose; the recommendation in most countries is 10% glucose with added sodium (40 mmol) and potassium (20 mmol) given at a rate of 1,000 mL over 12 hours. Note that hypotonic dextrose in water solutions should be avoided because of the risk of hyponatremia. • If improvement is unsatisfactory or if additional and progressive neurologic features present, intravenous administration of hemin preparations is recommended (see • Panhematin • Heme arginate (Normosang • Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised diets that restrict caloric intake, particularly those that exclude carbohydrates completely. • Seek timely treatment of systemic illness or infection. ## Targeted Therapies The recommended dose for hemin is 3-4 mg/kg by IV, given once daily for four days. Treatment may be extended, depending on the clinical course. Note: Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin. Panhematin Heme arginate (Normosang Note: (1) Phlebitis after IV injection can be minimized by reconstituting hematin in 20% human serum albumin solution and/or by using a large vein or a central catheter for infusion. Peripheral cannulas used to administer hematin should be replaced after each use. (2) An infusion set with an in-line filter is recommended to remove any undissolved particulate matter. (3) Rigorous flushing of venous catheters with boluses of saline totaling 200 mL is recommended. Recurrent acute attacks are best managed with support and advice from a porphyria specialist. See information and contact details of specialist porphyria centers at the If the criterion for recurrent attacks is met [ When available, use of this treatment has meant that older treatment alternatives such as ovulation suppression therapy and preventive hemin can be avoided. For the sporadic acute attack, hemin is still the treatment of primary choice. Note that ALA toxicity is the major hypothesis proposed for the pathogenesis of the neurologic lesions causing the clinical features of acute porphyria attacks. Support for this hypothesis are (1) the success of liver transplantation as a cure for recurrent acute attacks [ Alternative medical therapies to reduce the frequency and/or severity of acute porphyria attacks if givosiran is not available include ovulation suppression therapy and prophylactic hemin infusion. • Panhematin • Heme arginate (Normosang ## The recommended dose for hemin is 3-4 mg/kg by IV, given once daily for four days. Treatment may be extended, depending on the clinical course. Note: Because 100 mg of hemin contains 8 mg of iron, frequent administration of hemin may increase the risk for iron overload. Periodic monitoring of serum ferritin concentration and/or transferrin saturation is therefore appropriate in individuals treated repeatedly with hemin. Panhematin Heme arginate (Normosang Note: (1) Phlebitis after IV injection can be minimized by reconstituting hematin in 20% human serum albumin solution and/or by using a large vein or a central catheter for infusion. Peripheral cannulas used to administer hematin should be replaced after each use. (2) An infusion set with an in-line filter is recommended to remove any undissolved particulate matter. (3) Rigorous flushing of venous catheters with boluses of saline totaling 200 mL is recommended. Recurrent acute attacks are best managed with support and advice from a porphyria specialist. See information and contact details of specialist porphyria centers at the If the criterion for recurrent attacks is met [ • Panhematin • Heme arginate (Normosang ## When available, use of this treatment has meant that older treatment alternatives such as ovulation suppression therapy and preventive hemin can be avoided. For the sporadic acute attack, hemin is still the treatment of primary choice. ## Note that ALA toxicity is the major hypothesis proposed for the pathogenesis of the neurologic lesions causing the clinical features of acute porphyria attacks. Support for this hypothesis are (1) the success of liver transplantation as a cure for recurrent acute attacks [ ## Alternative medical therapies to reduce the frequency and/or severity of acute porphyria attacks if givosiran is not available include ovulation suppression therapy and prophylactic hemin infusion. ## Supportive Care Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised diets that restrict caloric intake, particularly those that exclude carbohydrates completely. Seek timely treatment of systemic illness or infection. Advice on safe treatment of persons with porphyria in some specific clinical situations (e.g., epilepsy, HIV, malaria, tuberculosis, hyperlipidemia, and hypertension) is available on the • Assure that adequate nutrition is provided by a normal balanced diet. Avoid unsupervised diets that restrict caloric intake, particularly those that exclude carbohydrates completely. • Seek timely treatment of systemic illness or infection. ## Surveillance for All Based on current knowledge, it is not possible to distinguish whether certain groups of individuals who are heterozygous for a pathogenic Most porphyria centers recommend PLC surveillance by annual or twice a year ultrasound examination for all individuals who are heterozygous for a pathogenic Note: Serum alpha-fetoprotein measurement is not helpful in surveillance. ## Agents/Circumstances to Avoid Individuals with AIP are advised to avoid excessive alcohol consumption. Alcohol has been shown to upregulate ALAS1, the first enzyme of hepatic heme biosynthesis [ In all the acute porphyrias, information on the safety of many drugs and other over-the-counter preparations is incomplete; however, evidence-based guidelines for assessment of drug porphyrogenicity have been published [ For a searchable drug safety database, see the See the For information on prescribing medication in the context of certain conditions (e.g., HIV, epilepsy, malaria), see Safe drug lists are available at • For a searchable drug safety database, see the • See the • For information on prescribing medication in the context of certain conditions (e.g., HIV, epilepsy, malaria), see • Safe drug lists are available at ## Evaluation of Relatives at Risk Providing information to individuals newly identified as being heterozygous for an Note: (1) Measurement of erythrocyte HMBS activity cannot be used to detect heterozygotes if the proband has the non-erythroid variant form of acute intermittent porphyria (see Urinary PBG excretion should See ## Pregnancy Management Pregnancy in women with AIP is usually uncomplicated. Although urinary PBG concentration may increase during pregnancy, this does not lead to a higher frequency of clinical manifestations of porphyria [ Preconception counseling is recommended to advise women with AIP of the clinical manifestations of porphyria, self-care, and preventative measures to avoid exacerbations (i.e., adequate and regular nutrition, rest, and carbohydrate intake for treating mild-to-moderate symptoms). See also There is a higher risk for pregnancy-induced hypertensive disorder, gestational diabetes, and fetuses with intrauterine growth restriction (IUGR). In general, risk ratios are higher among women with AIP who have high lifetime urinary PBG concentrations [ Testing for urinary PBG concentration prior to pregnancy may establish the individual's risk levels. Women with biochemically active acute hepatic porphyria (AHP) (i.e., urinary PBG concentration greater than four times the upper limit of normal) or a history of active AHP should be offered specialized prenatal care. Hyperemesis, a catabolic risk for precipitating acute attacks, should be treated promptly. Blood pressure should be monitored once monthly during the first and second trimesters, and weekly during the last trimester. Additional monitoring of fetal growth during pregnancy will help identify IUGR [ When a woman with AIP experiences abdominal pain, hypertension, and tachycardia during pregnancy, urine PBG concentration should be measured, and complications of pregnancy should be excluded in consultation with an obstetrician before the findings are attributed to an acute attack. If an acute porphyria attack is suspected, a urine PBG concentration should be measured before deciding on specific treatment (see Any symptomatic treatment needed should be chosen after considering the risk of the drug triggering/aggravating an acute porphyria attack in the pregnant woman (see An obstetrician should be consulted regarding medical treatment and possible effects on the fetus. Human hemin is safe to be used during pregnancy [ No human pregnancies have been reported during or after treatment with Givlaari See • If an acute porphyria attack is suspected, a urine PBG concentration should be measured before deciding on specific treatment (see • Any symptomatic treatment needed should be chosen after considering the risk of the drug triggering/aggravating an acute porphyria attack in the pregnant woman (see • An obstetrician should be consulted regarding medical treatment and possible effects on the fetus. • Human hemin is safe to be used during pregnancy [ • No human pregnancies have been reported during or after treatment with Givlaari ## Therapies Under Investigation Search ## Genetic Counseling Acute intermittent porphyria (AIP) is inherited in an autosomal dominant manner. The majority of individuals diagnosed with AIP inherited an Rarely, individuals diagnosed with AIP have the disorder as the result of a Unless a parent is already known to be heterozygous for 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 of 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. Due to the low penetrance of clinical manifestations of AIP, a significant proportion of heterozygotes are asymptomatic and the family history of many probands will appear to be negative. 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 one of the parents of the proband has an If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband should be considered to be at risk for AIP (and thus at increased risk of developing acute porphyria attacks and hepatocellular carcinoma) and should be counseled about preventive measures and surveillance. (Note: Surveillance is only offered to genetically confirmed heterozygotes.) Each child of an individual with an Because clinical penetrance is low, it is not possible to predict whether offspring who inherit an See Management, The optimal time for determination of genetic risk and discussion of the availability and indications for prenatal/preimplantation genetic testing is before pregnancy. Preconception counseling is recommended to advise women with AIP of the clinical manifestations of porphyria, self-care, and preventative measures to avoid exacerbations (see 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 familial Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The majority of individuals diagnosed with AIP inherited an • Rarely, individuals diagnosed with AIP have the disorder as the result of a • Unless a parent is already known to be heterozygous for 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 of 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. • Due to the low penetrance of clinical manifestations of AIP, a significant proportion of heterozygotes are asymptomatic and the family history of many probands will appear to be negative. 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 (gonadal) cells only. • If one of the parents of the proband has an • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband should be considered to be at risk for AIP (and thus at increased risk of developing acute porphyria attacks and hepatocellular carcinoma) and should be counseled about preventive measures and surveillance. (Note: Surveillance is only offered to genetically confirmed heterozygotes.) • Each child of an individual with an • Because clinical penetrance is low, it is not possible to predict whether offspring who inherit an • The optimal time for determination of genetic risk and discussion of the availability and indications for prenatal/preimplantation genetic testing is before pregnancy. • Preconception counseling is recommended to advise women with AIP of the clinical manifestations of porphyria, self-care, and preventative measures to avoid exacerbations (see • 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 Acute intermittent porphyria (AIP) is inherited in an autosomal dominant manner. ## Risk to Family Members The majority of individuals diagnosed with AIP inherited an Rarely, individuals diagnosed with AIP have the disorder as the result of a Unless a parent is already known to be heterozygous for 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 of 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. Due to the low penetrance of clinical manifestations of AIP, a significant proportion of heterozygotes are asymptomatic and the family history of many probands will appear to be negative. 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 one of the parents of the proband has an If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband should be considered to be at risk for AIP (and thus at increased risk of developing acute porphyria attacks and hepatocellular carcinoma) and should be counseled about preventive measures and surveillance. (Note: Surveillance is only offered to genetically confirmed heterozygotes.) Each child of an individual with an Because clinical penetrance is low, it is not possible to predict whether offspring who inherit an • The majority of individuals diagnosed with AIP inherited an • Rarely, individuals diagnosed with AIP have the disorder as the result of a • Unless a parent is already known to be heterozygous for 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 of 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. • Due to the low penetrance of clinical manifestations of AIP, a significant proportion of heterozygotes are asymptomatic and the family history of many probands will appear to be negative. 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 (gonadal) cells only. • If one of the parents of the proband has an • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, sibs of a proband should be considered to be at risk for AIP (and thus at increased risk of developing acute porphyria attacks and hepatocellular carcinoma) and should be counseled about preventive measures and surveillance. (Note: Surveillance is only offered to genetically confirmed heterozygotes.) • Each child of an individual with an • Because clinical penetrance is low, it is not possible to predict whether offspring who inherit an ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability and indications for prenatal/preimplantation genetic testing is before pregnancy. Preconception counseling is recommended to advise women with AIP of the clinical manifestations of porphyria, self-care, and preventative measures to avoid exacerbations (see 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 and indications for prenatal/preimplantation genetic testing is before pregnancy. • Preconception counseling is recommended to advise women with AIP of the clinical manifestations of porphyria, self-care, and preventative measures to avoid exacerbations (see • 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 familial 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 Canada American Porphyria Foundation South Africa United Kingdom Sweden • • • • United Kingdom • • • Canada • • • American Porphyria Foundation • • • • • South Africa • • • • • • United Kingdom • • • • • • • Sweden • ## Molecular Genetics Acute Intermittent Porphyria: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Acute Intermittent Porphyria ( The gene AIP results from Exons 1 and 3-15 of Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The gene AIP results from Exons 1 and 3-15 of Variants listed in the table have been provided by the authors. ## Chapter Notes Contact Michela Barbaro, PhD, a clinical laboratory geneticist, to inquire about review of Michael Badminton, PhD, FRCPath; University Hospital of Wales Cardiff (2013-2023) Michela Barbaro, Sc, PhD (2023-present)Eliane Sardh, MD, PhD (2023-present) Shigeru Sassa, MD, PhD; The Rockefeller University (2005-2010) Stig Thunell, MD, PhD; Karolinska University Hospitall Huddinge (2010-2013)Sharon Whatley, PhD, FRCPath; University Hospital of Wales Cardiff (2013-2023) 8 February 2024 (bp) Comprehensive update posted live 5 December 2019 (bp) Comprehensive update posted live 7 February 2013 (me) Comprehensive update posted live 23 March 2010 (me) Comprehensive update posted live 27 September 2005 (me) Review posted live 3 January 2005 (ss) Original submission • 8 February 2024 (bp) Comprehensive update posted live • 5 December 2019 (bp) Comprehensive update posted live • 7 February 2013 (me) Comprehensive update posted live • 23 March 2010 (me) Comprehensive update posted live • 27 September 2005 (me) Review posted live • 3 January 2005 (ss) Original submission ## Author Notes Contact Michela Barbaro, PhD, a clinical laboratory geneticist, to inquire about review of ## Author History Michael Badminton, PhD, FRCPath; University Hospital of Wales Cardiff (2013-2023) Michela Barbaro, Sc, PhD (2023-present)Eliane Sardh, MD, PhD (2023-present) Shigeru Sassa, MD, PhD; The Rockefeller University (2005-2010) Stig Thunell, MD, PhD; Karolinska University Hospitall Huddinge (2010-2013)Sharon Whatley, PhD, FRCPath; University Hospital of Wales Cardiff (2013-2023) ## Revision History 8 February 2024 (bp) Comprehensive update posted live 5 December 2019 (bp) Comprehensive update posted live 7 February 2013 (me) Comprehensive update posted live 23 March 2010 (me) Comprehensive update posted live 27 September 2005 (me) Review posted live 3 January 2005 (ss) Original submission • 8 February 2024 (bp) Comprehensive update posted live • 5 December 2019 (bp) Comprehensive update posted live • 7 February 2013 (me) Comprehensive update posted live • 23 March 2010 (me) Comprehensive update posted live • 27 September 2005 (me) Review posted live • 3 January 2005 (ss) Original submission ## Key Sections in this ## References ## Literature Cited	[]	27/9/2005	8/2/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alagille	alagille	[ "Arteriohepatic Dysplasia", "Syndromic Bile Duct Paucity", "Arteriohepatic Dysplasia", "Syndromic Bile Duct Paucity", "Neurogenic locus notch homolog protein 2", "Protein jagged-1", "JAG1", "NOTCH2", "Alagille Syndrome" ]	Alagille Syndrome	Nancy B Spinner, Kathleen M Loomes, Ian D Krantz, Melissa A Gilbert	Summary Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability; this variability is seen even among individuals from the same family. The major clinical manifestations of ALGS are bile duct paucity on liver biopsy, cholestasis, congenital cardiac defects (primarily involving the pulmonary arteries), butterfly vertebrae, ophthalmologic abnormalities (most commonly posterior embryotoxon), and characteristic facial features. Renal abnormalities, growth failure, behavioral differences, splenomegaly, retinal changes, and vascular abnormalities may also occur. The diagnosis of ALGS is established in a proband who meets clinical diagnostic criteria and/or has a heterozygous pathogenic variant in ALGS is inherited in an autosomal dominant manner. Approximately 40% of individuals have an inherited pathogenic variant and about 60% have a	## Diagnosis Clinical diagnostic criteria for Alagille syndrome (ALGS) have been published [ ALGS Cholestasis Cardiac defect (most commonly stenosis of the peripheral pulmonary artery and its branches) Skeletal abnormalities (most commonly butterfly vertebrae identified in AP chest radiographs) Ophthalmologic abnormalities (most commonly posterior embryotoxon) Characteristic facial features (most commonly triangular-shaped face with a broad forehead and a pointed chin, bulbous tip of the nose, deep-set eyes, and hypertelorism) (See The clinical diagnosis of ALGS can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: (1) If a deletion involving the entire For an introduction to multigene panels click When the diagnosis of ALGS is not considered because an individual does not meet the clinical diagnostic criteria, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alagille Syndrome ALGS = Alagille syndrome; NA = not applicable 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 analysis detects intragenic deletions or duplications. One individual with a 5.9-kb deletion including exons 31 and 34 has been reported after genome sequencing [ Individuals with a clinical diagnosis of ALGS but without a detectable pathogenic variant in either • Cholestasis • Cardiac defect (most commonly stenosis of the peripheral pulmonary artery and its branches) • Skeletal abnormalities (most commonly butterfly vertebrae identified in AP chest radiographs) • Ophthalmologic abnormalities (most commonly posterior embryotoxon) • Characteristic facial features (most commonly triangular-shaped face with a broad forehead and a pointed chin, bulbous tip of the nose, deep-set eyes, and hypertelorism) (See ## Suggestive Findings ALGS Cholestasis Cardiac defect (most commonly stenosis of the peripheral pulmonary artery and its branches) Skeletal abnormalities (most commonly butterfly vertebrae identified in AP chest radiographs) Ophthalmologic abnormalities (most commonly posterior embryotoxon) Characteristic facial features (most commonly triangular-shaped face with a broad forehead and a pointed chin, bulbous tip of the nose, deep-set eyes, and hypertelorism) (See • Cholestasis • Cardiac defect (most commonly stenosis of the peripheral pulmonary artery and its branches) • Skeletal abnormalities (most commonly butterfly vertebrae identified in AP chest radiographs) • Ophthalmologic abnormalities (most commonly posterior embryotoxon) • Characteristic facial features (most commonly triangular-shaped face with a broad forehead and a pointed chin, bulbous tip of the nose, deep-set eyes, and hypertelorism) (See ## Establishing the Diagnosis The clinical diagnosis of ALGS can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: (1) If a deletion involving the entire For an introduction to multigene panels click When the diagnosis of ALGS is not considered because an individual does not meet the clinical diagnostic criteria, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alagille Syndrome ALGS = Alagille syndrome; NA = not applicable 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 analysis detects intragenic deletions or duplications. One individual with a 5.9-kb deletion including exons 31 and 34 has been reported after genome sequencing [ Individuals with a clinical diagnosis of ALGS but without a detectable pathogenic variant in either ## Option 1 Note: (1) If a deletion involving the entire For an introduction to multigene panels click ## Option 2 When the diagnosis of ALGS is not considered because an individual does not meet the clinical diagnostic criteria, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alagille Syndrome ALGS = Alagille syndrome; NA = not applicable 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 analysis detects intragenic deletions or duplications. One individual with a 5.9-kb deletion including exons 31 and 34 has been reported after genome sequencing [ Individuals with a clinical diagnosis of ALGS but without a detectable pathogenic variant in either ## Clinical Characteristics Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability ranging from life-threatening liver or cardiac disease to only subclinical manifestations (e.g., butterfly vertebrae, posterior embryotoxon, characteristic facial features) [ To date, more than 700 individuals with ALGS have been found to have a pathogenic variant in Alagille Syndrome: Frequency of Select Features Jaundice and conjugated hyperbilirubinemia may be present in the neonatal period. Increased serum concentrations of bile acids, alkaline phosphatase, gamma-glutamyl transpeptidase, triglycerides, and the aminotransferases are also commonly observed. Impaired bile salt secretion can lead to fat-soluble vitamin deficiencies and malnutrition. Cholestasis manifests as pruritus, increased serum concentration of bile acids, growth failure, and xanthomas. Pruritus is reported to occur in 74% of children at a median age of onset of 12 months [ Liver biopsy typically shows paucity of the intrahepatic bile ducts, which may be progressive. In infants younger than age six months, bile duct paucity is not always present, and the liver biopsy may demonstrate ductal proliferation, resulting in the possible misdiagnosis of ALGS as biliary atresia. An increased risk for hepatocellular carcinoma (HCC) has been identified in children and adults with Other defects of the anterior chamber seen in individuals with ALGS include Axenfeld anomaly and Rieger anomaly. Ocular ultrasonographic examination in 20 children with ALGS found optic disk drusen in 90%. Retinal pigmentary changes are also common (32% in one study) [ While for many individuals the visual prognosis is good, recently additional abnormalities have been recognized such as peripheral chorioretinal changes (including atrophy with accompanying loss of function in the visual field) and other retinal pigmentary changes, macular atrophy, and progressive decreases in vision in some individuals [ Other skeletal manifestations in individuals with ALGS have been reported less frequently [ Although the facial phenotype in ALGS is specific to the syndrome and is often a powerful diagnostic tool, Delayed puberty and high-pitched voice [ Splenomegaly [ Although very few individuals with No genotype-phenotype correlations for ALGS associated with pathogenic variants in either of the known causative genes ( The prevalence of ALGS is estimated at 1:30,000-50,000 live births [ • Delayed puberty and high-pitched voice [ • Splenomegaly [ ## Clinical Description Alagille syndrome (ALGS) is a multisystem disorder with a wide spectrum of clinical variability ranging from life-threatening liver or cardiac disease to only subclinical manifestations (e.g., butterfly vertebrae, posterior embryotoxon, characteristic facial features) [ To date, more than 700 individuals with ALGS have been found to have a pathogenic variant in Alagille Syndrome: Frequency of Select Features Jaundice and conjugated hyperbilirubinemia may be present in the neonatal period. Increased serum concentrations of bile acids, alkaline phosphatase, gamma-glutamyl transpeptidase, triglycerides, and the aminotransferases are also commonly observed. Impaired bile salt secretion can lead to fat-soluble vitamin deficiencies and malnutrition. Cholestasis manifests as pruritus, increased serum concentration of bile acids, growth failure, and xanthomas. Pruritus is reported to occur in 74% of children at a median age of onset of 12 months [ Liver biopsy typically shows paucity of the intrahepatic bile ducts, which may be progressive. In infants younger than age six months, bile duct paucity is not always present, and the liver biopsy may demonstrate ductal proliferation, resulting in the possible misdiagnosis of ALGS as biliary atresia. An increased risk for hepatocellular carcinoma (HCC) has been identified in children and adults with Other defects of the anterior chamber seen in individuals with ALGS include Axenfeld anomaly and Rieger anomaly. Ocular ultrasonographic examination in 20 children with ALGS found optic disk drusen in 90%. Retinal pigmentary changes are also common (32% in one study) [ While for many individuals the visual prognosis is good, recently additional abnormalities have been recognized such as peripheral chorioretinal changes (including atrophy with accompanying loss of function in the visual field) and other retinal pigmentary changes, macular atrophy, and progressive decreases in vision in some individuals [ Other skeletal manifestations in individuals with ALGS have been reported less frequently [ Although the facial phenotype in ALGS is specific to the syndrome and is often a powerful diagnostic tool, Delayed puberty and high-pitched voice [ Splenomegaly [ • Delayed puberty and high-pitched voice [ • Splenomegaly [ ## Phenotype Correlations by Gene Although very few individuals with ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Penetrance ALGS associated with pathogenic variants in either of the known causative genes ( ## Prevalence The prevalence of ALGS is estimated at 1:30,000-50,000 live births [ ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders ALGS = Alagille syndrome ## Differential Diagnosis Several of the Selected Genes of Interest in the Differential Diagnosis of Posterior Embryotoxon and Pulmonic Vascular System Abnormalities AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; WBSCR = Williams-Beuren syndrome critical region Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in ## Management No clinical practice guidelines for Alagille syndrome (ALGS) have been published. To establish the extent of disease and needs in an individual diagnosed with ALGS, the evaluations summarized in Alagille Syndrome: Recommended Evaluations Following Initial Diagnosis Total & conjugated/direct bilirubin Liver enzymes (incl GGT) Clotting studies Serum bile acids Lipid panel Fat-soluble vitamin levels Hepatic ultrasound Tc-99m DISIDA scintigraphy Liver biopsy Community or Social work involvement for parental support Home nursing referral ALGS = Alagille syndrome; GGT = gamma-glutamyl transpeptidase; MOI = mode of inheritance There is no cure for ALGS. Severe cholestasis and pruritus are often the most debilitating manifestations of ALGS and are a frequent indication for liver transplantation. Ileal bile acid transport inhibitors are a new class of medications that have recently been approved for treatment of cholestatic pruritus in ALGS. Orally administered and minimally absorbed, these drugs result in a medical interruption of the enterohepatic circulation, increasing excretion of bile acids in the stool. Maralixibat is currently FDA approved for treatment of children older than age three months and odevixibat for children older than age 12 months [ A multidisciplinary approach to the management of individuals with ALGS is often beneficial because of the multisystem involvement. Evaluation by specialists in clinical genetics, gastroenterology/hepatology, nutrition, cardiology, ophthalmology, nephrology, transplant hepatology, and child development may be indicated, depending on the age and specific difficulties of the individual [ Alagille Syndrome: Treatment of Manifestations ALGS = Alagille syndrome To date, surveillance guidelines for ALGS have not been published. In the absence of published guidelines, recommendations to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations are based on the authors' personal experience managing individuals with this disorder (see Alagille Syndrome: Recommended Surveillance Per cardiologist Note: At this time, the efficacy of presymptomatic screening for vascular anomalies in persons w/ALGS has not been formally evaluated. The possibility of a vascular accident should be considered in any symptomatic person, & MRI, magnetic resonance angiography, &/or angiography to identify aneurysms, dissections, or bleeds should be pursued aggressively as warranted. Assess developmental progress. Assess for attention & executive function impairment. Contact sports should be avoided by all individuals, especially those with chronic liver disease, splenomegaly, and vascular involvement. Individuals with liver disease should avoid alcohol consumption. Molecular genetic testing if the Measurement of liver enzymes, cardiac evaluation, eye examination, skeletal survey, and evaluation of facial features if the See Liver and cardiac features should be monitored to ensure that portal hypertension and cardiac dysfunction do not worsen during pregnancy [ Search • Total & conjugated/direct bilirubin • Liver enzymes (incl GGT) • Clotting studies • Serum bile acids • Lipid panel • Fat-soluble vitamin levels • Hepatic ultrasound • Tc-99m DISIDA scintigraphy • Liver biopsy • Community or • Social work involvement for parental support • Home nursing referral • Per cardiologist • Note: At this time, the efficacy of presymptomatic screening for vascular anomalies in persons w/ALGS has not been formally evaluated. The possibility of a vascular accident should be considered in any symptomatic person, & MRI, magnetic resonance angiography, &/or angiography to identify aneurysms, dissections, or bleeds should be pursued aggressively as warranted. • Assess developmental progress. • Assess for attention & executive function impairment. • Molecular genetic testing if the • Measurement of liver enzymes, cardiac evaluation, eye examination, skeletal survey, and evaluation of facial features if the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ALGS, the evaluations summarized in Alagille Syndrome: Recommended Evaluations Following Initial Diagnosis Total & conjugated/direct bilirubin Liver enzymes (incl GGT) Clotting studies Serum bile acids Lipid panel Fat-soluble vitamin levels Hepatic ultrasound Tc-99m DISIDA scintigraphy Liver biopsy Community or Social work involvement for parental support Home nursing referral ALGS = Alagille syndrome; GGT = gamma-glutamyl transpeptidase; MOI = mode of inheritance • Total & conjugated/direct bilirubin • Liver enzymes (incl GGT) • Clotting studies • Serum bile acids • Lipid panel • Fat-soluble vitamin levels • Hepatic ultrasound • Tc-99m DISIDA scintigraphy • Liver biopsy • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for ALGS. Severe cholestasis and pruritus are often the most debilitating manifestations of ALGS and are a frequent indication for liver transplantation. Ileal bile acid transport inhibitors are a new class of medications that have recently been approved for treatment of cholestatic pruritus in ALGS. Orally administered and minimally absorbed, these drugs result in a medical interruption of the enterohepatic circulation, increasing excretion of bile acids in the stool. Maralixibat is currently FDA approved for treatment of children older than age three months and odevixibat for children older than age 12 months [ A multidisciplinary approach to the management of individuals with ALGS is often beneficial because of the multisystem involvement. Evaluation by specialists in clinical genetics, gastroenterology/hepatology, nutrition, cardiology, ophthalmology, nephrology, transplant hepatology, and child development may be indicated, depending on the age and specific difficulties of the individual [ Alagille Syndrome: Treatment of Manifestations ALGS = Alagille syndrome ## Targeted Therapy Severe cholestasis and pruritus are often the most debilitating manifestations of ALGS and are a frequent indication for liver transplantation. Ileal bile acid transport inhibitors are a new class of medications that have recently been approved for treatment of cholestatic pruritus in ALGS. Orally administered and minimally absorbed, these drugs result in a medical interruption of the enterohepatic circulation, increasing excretion of bile acids in the stool. Maralixibat is currently FDA approved for treatment of children older than age three months and odevixibat for children older than age 12 months [ ## Supportive Care A multidisciplinary approach to the management of individuals with ALGS is often beneficial because of the multisystem involvement. Evaluation by specialists in clinical genetics, gastroenterology/hepatology, nutrition, cardiology, ophthalmology, nephrology, transplant hepatology, and child development may be indicated, depending on the age and specific difficulties of the individual [ Alagille Syndrome: Treatment of Manifestations ALGS = Alagille syndrome ## Surveillance To date, surveillance guidelines for ALGS have not been published. In the absence of published guidelines, recommendations to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations are based on the authors' personal experience managing individuals with this disorder (see Alagille Syndrome: Recommended Surveillance Per cardiologist Note: At this time, the efficacy of presymptomatic screening for vascular anomalies in persons w/ALGS has not been formally evaluated. The possibility of a vascular accident should be considered in any symptomatic person, & MRI, magnetic resonance angiography, &/or angiography to identify aneurysms, dissections, or bleeds should be pursued aggressively as warranted. Assess developmental progress. Assess for attention & executive function impairment. • Per cardiologist • Note: At this time, the efficacy of presymptomatic screening for vascular anomalies in persons w/ALGS has not been formally evaluated. The possibility of a vascular accident should be considered in any symptomatic person, & MRI, magnetic resonance angiography, &/or angiography to identify aneurysms, dissections, or bleeds should be pursued aggressively as warranted. • Assess developmental progress. • Assess for attention & executive function impairment. ## Agents/Circumstances to Avoid Contact sports should be avoided by all individuals, especially those with chronic liver disease, splenomegaly, and vascular involvement. Individuals with liver disease should avoid alcohol consumption. ## Evaluation of Relatives at Risk Molecular genetic testing if the Measurement of liver enzymes, cardiac evaluation, eye examination, skeletal survey, and evaluation of facial features if the See • Molecular genetic testing if the • Measurement of liver enzymes, cardiac evaluation, eye examination, skeletal survey, and evaluation of facial features if the ## Pregnancy Management Liver and cardiac features should be monitored to ensure that portal hypertension and cardiac dysfunction do not worsen during pregnancy [ ## Therapies Under Investigation Search ## Genetic Counseling Alagille syndrome (ALGS) is inherited in an autosomal dominant manner. Approximately 40% of individuals diagnosed with ALGS have an affected parent. Approximately 60% of affected individuals have ALGS as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the causative genetic alteration has not been identified in the proband, recommendations for the evaluation of parents include liver function testing, cardiac evaluation, radiographs of the spine, ophthalmologic examination, and evaluation of facial features by a clinical geneticist. If the The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ * Parents with somatic mosaicism for an ALGS-causing genetic alteration may be mildly/minimally affected. The family history of some individuals diagnosed with ALGS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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 the ALGS-related genetic alteration but are clinically unaffected, sibs are still presumed to be at increased risk for ALGS because of the possibility of reduced penetrance in a heterozygous parent or parental mosaicism. Offspring of an individual with ALGS have a 50% chance of inheriting the The clinical manifestations in heterozygous offspring cannot be predicted and range from mild or subclinical features to severe heart and/or liver disease. 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. 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 40% of individuals diagnosed with ALGS have an affected parent. • Approximately 60% of affected individuals have ALGS as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the causative genetic alteration has not been identified in the proband, recommendations for the evaluation of parents include liver function testing, cardiac evaluation, radiographs of the spine, ophthalmologic examination, and evaluation of facial features by a clinical geneticist. • If the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • * Parents with somatic mosaicism for an ALGS-causing genetic alteration 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 [ • * Parents with somatic mosaicism for an ALGS-causing genetic alteration may be mildly/minimally affected. • The family history of some individuals diagnosed with ALGS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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 [ • * Parents with somatic mosaicism for an ALGS-causing genetic alteration 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 the ALGS-related genetic alteration but are clinically unaffected, sibs are still presumed to be at increased risk for ALGS because of the possibility of reduced penetrance in a heterozygous parent or parental mosaicism. • Offspring of an individual with ALGS have a 50% chance of inheriting the • The clinical manifestations in heterozygous offspring cannot be predicted and range from mild or subclinical features to severe heart and/or liver disease. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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 Alagille syndrome (ALGS) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 40% of individuals diagnosed with ALGS have an affected parent. Approximately 60% of affected individuals have ALGS as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the causative genetic alteration has not been identified in the proband, recommendations for the evaluation of parents include liver function testing, cardiac evaluation, radiographs of the spine, ophthalmologic examination, and evaluation of facial features by a clinical geneticist. If the The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ * Parents with somatic mosaicism for an ALGS-causing genetic alteration may be mildly/minimally affected. The family history of some individuals diagnosed with ALGS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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 the ALGS-related genetic alteration but are clinically unaffected, sibs are still presumed to be at increased risk for ALGS because of the possibility of reduced penetrance in a heterozygous parent or parental mosaicism. Offspring of an individual with ALGS have a 50% chance of inheriting the The clinical manifestations in heterozygous offspring cannot be predicted and range from mild or subclinical features to severe heart and/or liver disease. • Approximately 40% of individuals diagnosed with ALGS have an affected parent. • Approximately 60% of affected individuals have ALGS as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the causative genetic alteration has not been identified in the proband, recommendations for the evaluation of parents include liver function testing, cardiac evaluation, radiographs of the spine, ophthalmologic examination, and evaluation of facial features by a clinical geneticist. • If the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [ • * Parents with somatic mosaicism for an ALGS-causing genetic alteration 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 [ • * Parents with somatic mosaicism for an ALGS-causing genetic alteration may be mildly/minimally affected. • The family history of some individuals diagnosed with ALGS may appear to be negative because of failure to recognize the disorder in family members or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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 [ • * Parents with somatic mosaicism for an ALGS-causing genetic alteration 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 the ALGS-related genetic alteration but are clinically unaffected, sibs are still presumed to be at increased risk for ALGS because of the possibility of reduced penetrance in a heterozygous parent or parental mosaicism. • Offspring of an individual with ALGS have a 50% chance of inheriting the • The clinical manifestations in heterozygous offspring cannot be predicted and range from mild or subclinical features to severe heart and/or liver disease. ## 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 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 • • • • • • • • Canada • • • • • United Kingdom • ## Molecular Genetics Alagille Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alagille Syndrome ( The JAG1 and NOTCH2 proteins are both single-pass, transmembrane proteins. Binding of the extracellular region of JAG1 to the extracellular region of NOTCH2 prompts cleavage of the intracellular domain of NOTCH2, which translocates to the nucleus to regulate the expression of Notch signaling target genes, including those belonging to the During cholangiocyte specification, mesenchymal cells surrounding the portal vein express JAG1, while the hepatocytes express NOTCH2. Mouse studies have demonstrated a requirement of Notch signaling for liver development. Disease-associated ## Molecular Pathogenesis The JAG1 and NOTCH2 proteins are both single-pass, transmembrane proteins. Binding of the extracellular region of JAG1 to the extracellular region of NOTCH2 prompts cleavage of the intracellular domain of NOTCH2, which translocates to the nucleus to regulate the expression of Notch signaling target genes, including those belonging to the During cholangiocyte specification, mesenchymal cells surrounding the portal vein express JAG1, while the hepatocytes express NOTCH2. Mouse studies have demonstrated a requirement of Notch signaling for liver development. Disease-associated ## Chapter Notes Melissa Gilbert ( Melissa Gilbert ( Contact Melissa Gilbert ( The authors would like to thank the Alagille Syndrome Alliance ( Lynn D Bason, MS, CGC; Children's Hospital of Philadelphia (2000-2003) Melissa A Gilbert, PhD (2019-present)Anne L Hutchinson, BS; Children's Hospital of Philadelphia (2010-2013)Binita M Kamath, MBBChir MRCP; The Hospital for Sick Children (2003-2013) Ian D Krantz, MD (2000-present) Laura D Leonard, BA; Children's Hospital of Philadelphia (2013-2019)Kathleen M Loomes, MD (2019-present)Nancy B Spinner, PhD (2000-present) 4 January 2024 (sw) Comprehensive update posted live 12 December 2019 (ha) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 11 May 2010 (me) Comprehensive update posted live 2 July 2007 (me) Comprehensive update posted live 18 February 2005 (mr) Comprehensive update posted live 4 February 2003 (me) Comprehensive update posted live 19 May 2000 (me) Review posted live January 2000 (ns) Original submission • 4 January 2024 (sw) Comprehensive update posted live • 12 December 2019 (ha) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 11 May 2010 (me) Comprehensive update posted live • 2 July 2007 (me) Comprehensive update posted live • 18 February 2005 (mr) Comprehensive update posted live • 4 February 2003 (me) Comprehensive update posted live • 19 May 2000 (me) Review posted live • January 2000 (ns) Original submission ## Author Notes Melissa Gilbert ( Melissa Gilbert ( Contact Melissa Gilbert ( ## Acknowledgments The authors would like to thank the Alagille Syndrome Alliance ( ## Author History Lynn D Bason, MS, CGC; Children's Hospital of Philadelphia (2000-2003) Melissa A Gilbert, PhD (2019-present)Anne L Hutchinson, BS; Children's Hospital of Philadelphia (2010-2013)Binita M Kamath, MBBChir MRCP; The Hospital for Sick Children (2003-2013) Ian D Krantz, MD (2000-present) Laura D Leonard, BA; Children's Hospital of Philadelphia (2013-2019)Kathleen M Loomes, MD (2019-present)Nancy B Spinner, PhD (2000-present) ## Revision History 4 January 2024 (sw) Comprehensive update posted live 12 December 2019 (ha) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 11 May 2010 (me) Comprehensive update posted live 2 July 2007 (me) Comprehensive update posted live 18 February 2005 (mr) Comprehensive update posted live 4 February 2003 (me) Comprehensive update posted live 19 May 2000 (me) Review posted live January 2000 (ns) Original submission • 4 January 2024 (sw) Comprehensive update posted live • 12 December 2019 (ha) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 11 May 2010 (me) Comprehensive update posted live • 2 July 2007 (me) Comprehensive update posted live • 18 February 2005 (mr) Comprehensive update posted live • 4 February 2003 (me) Comprehensive update posted live • 19 May 2000 (me) Review posted live • January 2000 (ns) Original submission ## Key Sections in this ## References ## Literature Cited Typical facial features of Alagille syndrome. Note broad forehead, deep-set eyes, and pointed chin.	[]	19/5/2000	4/1/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alexander	alexander	[ "Glial fibrillary acidic protein", "GFAP", "Alexander Disease" ]	Alexander Disease	Siddharth Srivastava, Amy Waldman, Sakkubai Naidu	Summary Alexander disease, a progressive disorder of cerebral white matter caused by a heterozygous The The The The The diagnosis of Alexander disease is established in a proband with suggestive clinical and neuroimaging findings and a heterozygous pathogenic variant in Alexander disease is inherited in an autosomal dominant manner. To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a	With the currently widespread use of advanced molecular genetic testing, it is apparent that heterozygous ## Diagnosis Alexander disease Weak suck, feeding difficulties, hypotonia, and myoclonus Progressive psychomotor impairment or developmental regression Megalencephaly with frontal bossing Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull. Seizures Occasional hydrocephalus secondary to aqueductal stenosis CSF protein elevation [ Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones) Seizures Megalencephaly Gradual loss of intellectual function Regression after mild head injury or seizure Dysarthria (in those children who attain speech) Failure to thrive Developmental delay Seizures Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia Failure to thrive Intractable vomiting Scoliosis Autonomic dysfunction Bulbar/pseudobulbar signs Pyramidal tract signs Cerebellar signs Dysautonomia Sleep disturbance Gait disturbance Hemiparesis/hemiplegia or quadriparesis/quadriplegia Diplopia or oculomotor abnormalities Based on a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy [ Extensive cerebral white matter abnormalities with a frontal preponderance Periventricular rim of decreased signal intensity on T Abnormalities of the basal ganglia and thalami that may include one or both of the following: Swelling and increased signal intensity on T Atrophy and increased/decreased signal intensity on T Brain stem abnormalities, particularly involving the medulla and midbrain Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem Alexander Disease: MRI Features by Age of Presentation Prominent or distinguishing features within the Severe white matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging Involvement of the basal ganglia and cerebellum Frontally predominant white matter T Brain stem abnormalities are less prominent than in other forms; typical findings may include symmetric signal abnormalities of the medulla. Significant involvement of posterior fossa structures, such as focal brain stem lesions (mimicking tumor), or T T Some individuals may lack other features described by Characteristic imaging features of this subgroup include symmetric or asymmetric lesions in the dorsal medulla that may enhance with gadolinium administration and are often initially diagnosed as tumors, especially in the absence of other imaging features of Alexander disease. The later onset and presence of prominent mass-like brain stem lesions and cerebellar abnormalities distinguish this phenotype from infantile cases. Such lesions account for the vomiting and cerebellar abnormalities seen in patients with this phenotype. While some individuals may have supratentorial and infratentorial abnormalities (an intermediate phenotype described by Abnormal signal intensity of the anterior portion of the medulla oblongata along with atrophy of the medulla and cervical spinal cord Signal abnormalities in the cerebellar white matter or hilus of the dentate nucleus [ Supratentorial white matter findings that may include [ Mild-to-moderate cerebral involvement T Cyst formation in white matter around the anterior horn of the lateral ventricles Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ The diagnosis of Alexander disease 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. Individuals with the distinctive findings described in Note: Alexander disease occurs through a gain-of-function mechanism (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alexander Disease 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 Based on a summary of prior published reports in which 293 of 299 (98%) individuals tested had a 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. Deletion of exon 5, an in-frame exon, has been reported [ • Weak suck, feeding difficulties, hypotonia, and myoclonus • Progressive psychomotor impairment or developmental regression • Megalencephaly with frontal bossing • Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull. • Seizures • Occasional hydrocephalus secondary to aqueductal stenosis • CSF protein elevation [ • Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones) • Seizures • Megalencephaly • Gradual loss of intellectual function • Regression after mild head injury or seizure • Dysarthria (in those children who attain speech) • Failure to thrive • Developmental delay • Seizures • Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia • Failure to thrive • Intractable vomiting • Scoliosis • Autonomic dysfunction • Bulbar/pseudobulbar signs • Pyramidal tract signs • Cerebellar signs • Dysautonomia • Sleep disturbance • Gait disturbance • Hemiparesis/hemiplegia or quadriparesis/quadriplegia • Diplopia or oculomotor abnormalities • Extensive cerebral white matter abnormalities with a frontal preponderance • Periventricular rim of decreased signal intensity on T • Abnormalities of the basal ganglia and thalami that may include one or both of the following: • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Brain stem abnormalities, particularly involving the medulla and midbrain • Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Severe white matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging • Involvement of the basal ganglia and cerebellum • Frontally predominant white matter T • Brain stem abnormalities are less prominent than in other forms; typical findings may include symmetric signal abnormalities of the medulla. • Significant involvement of posterior fossa structures, such as focal brain stem lesions (mimicking tumor), or T • T • Some individuals may lack other features described by • Characteristic imaging features of this subgroup include symmetric or asymmetric lesions in the dorsal medulla that may enhance with gadolinium administration and are often initially diagnosed as tumors, especially in the absence of other imaging features of Alexander disease. • The later onset and presence of prominent mass-like brain stem lesions and cerebellar abnormalities distinguish this phenotype from infantile cases. Such lesions account for the vomiting and cerebellar abnormalities seen in patients with this phenotype. While some individuals may have supratentorial and infratentorial abnormalities (an intermediate phenotype described by • Abnormal signal intensity of the anterior portion of the medulla oblongata along with atrophy of the medulla and cervical spinal cord • Signal abnormalities in the cerebellar white matter or hilus of the dentate nucleus [ • Supratentorial white matter findings that may include [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ ## Suggestive Findings Alexander disease Weak suck, feeding difficulties, hypotonia, and myoclonus Progressive psychomotor impairment or developmental regression Megalencephaly with frontal bossing Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull. Seizures Occasional hydrocephalus secondary to aqueductal stenosis CSF protein elevation [ Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones) Seizures Megalencephaly Gradual loss of intellectual function Regression after mild head injury or seizure Dysarthria (in those children who attain speech) Failure to thrive Developmental delay Seizures Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia Failure to thrive Intractable vomiting Scoliosis Autonomic dysfunction Bulbar/pseudobulbar signs Pyramidal tract signs Cerebellar signs Dysautonomia Sleep disturbance Gait disturbance Hemiparesis/hemiplegia or quadriparesis/quadriplegia Diplopia or oculomotor abnormalities Based on a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy [ Extensive cerebral white matter abnormalities with a frontal preponderance Periventricular rim of decreased signal intensity on T Abnormalities of the basal ganglia and thalami that may include one or both of the following: Swelling and increased signal intensity on T Atrophy and increased/decreased signal intensity on T Brain stem abnormalities, particularly involving the medulla and midbrain Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem Alexander Disease: MRI Features by Age of Presentation Prominent or distinguishing features within the Severe white matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging Involvement of the basal ganglia and cerebellum Frontally predominant white matter T Brain stem abnormalities are less prominent than in other forms; typical findings may include symmetric signal abnormalities of the medulla. Significant involvement of posterior fossa structures, such as focal brain stem lesions (mimicking tumor), or T T Some individuals may lack other features described by Characteristic imaging features of this subgroup include symmetric or asymmetric lesions in the dorsal medulla that may enhance with gadolinium administration and are often initially diagnosed as tumors, especially in the absence of other imaging features of Alexander disease. The later onset and presence of prominent mass-like brain stem lesions and cerebellar abnormalities distinguish this phenotype from infantile cases. Such lesions account for the vomiting and cerebellar abnormalities seen in patients with this phenotype. While some individuals may have supratentorial and infratentorial abnormalities (an intermediate phenotype described by Abnormal signal intensity of the anterior portion of the medulla oblongata along with atrophy of the medulla and cervical spinal cord Signal abnormalities in the cerebellar white matter or hilus of the dentate nucleus [ Supratentorial white matter findings that may include [ Mild-to-moderate cerebral involvement T Cyst formation in white matter around the anterior horn of the lateral ventricles Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Weak suck, feeding difficulties, hypotonia, and myoclonus • Progressive psychomotor impairment or developmental regression • Megalencephaly with frontal bossing • Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull. • Seizures • Occasional hydrocephalus secondary to aqueductal stenosis • CSF protein elevation [ • Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones) • Seizures • Megalencephaly • Gradual loss of intellectual function • Regression after mild head injury or seizure • Dysarthria (in those children who attain speech) • Failure to thrive • Developmental delay • Seizures • Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia • Failure to thrive • Intractable vomiting • Scoliosis • Autonomic dysfunction • Bulbar/pseudobulbar signs • Pyramidal tract signs • Cerebellar signs • Dysautonomia • Sleep disturbance • Gait disturbance • Hemiparesis/hemiplegia or quadriparesis/quadriplegia • Diplopia or oculomotor abnormalities • Extensive cerebral white matter abnormalities with a frontal preponderance • Periventricular rim of decreased signal intensity on T • Abnormalities of the basal ganglia and thalami that may include one or both of the following: • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Brain stem abnormalities, particularly involving the medulla and midbrain • Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Severe white matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging • Involvement of the basal ganglia and cerebellum • Frontally predominant white matter T • Brain stem abnormalities are less prominent than in other forms; typical findings may include symmetric signal abnormalities of the medulla. • Significant involvement of posterior fossa structures, such as focal brain stem lesions (mimicking tumor), or T • T • Some individuals may lack other features described by • Characteristic imaging features of this subgroup include symmetric or asymmetric lesions in the dorsal medulla that may enhance with gadolinium administration and are often initially diagnosed as tumors, especially in the absence of other imaging features of Alexander disease. • The later onset and presence of prominent mass-like brain stem lesions and cerebellar abnormalities distinguish this phenotype from infantile cases. Such lesions account for the vomiting and cerebellar abnormalities seen in patients with this phenotype. While some individuals may have supratentorial and infratentorial abnormalities (an intermediate phenotype described by • Abnormal signal intensity of the anterior portion of the medulla oblongata along with atrophy of the medulla and cervical spinal cord • Signal abnormalities in the cerebellar white matter or hilus of the dentate nucleus [ • Supratentorial white matter findings that may include [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ ## Clinical Findings Weak suck, feeding difficulties, hypotonia, and myoclonus Progressive psychomotor impairment or developmental regression Megalencephaly with frontal bossing Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull. Seizures Occasional hydrocephalus secondary to aqueductal stenosis CSF protein elevation [ Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones) Seizures Megalencephaly Gradual loss of intellectual function Regression after mild head injury or seizure Dysarthria (in those children who attain speech) Failure to thrive Developmental delay Seizures Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia Failure to thrive Intractable vomiting Scoliosis Autonomic dysfunction Bulbar/pseudobulbar signs Pyramidal tract signs Cerebellar signs Dysautonomia Sleep disturbance Gait disturbance Hemiparesis/hemiplegia or quadriparesis/quadriplegia Diplopia or oculomotor abnormalities • Weak suck, feeding difficulties, hypotonia, and myoclonus • Progressive psychomotor impairment or developmental regression • Megalencephaly with frontal bossing • Note: Though the terms megalencephaly and macrocephaly are sometimes used interchangeably, macrocephaly refers to head circumference that is more than two standard deviations above the mean adjusting for age and sex, whereas megalencephaly refers to increased volume of brain parenchyma. Macrocephaly – which reflects the size of intracranial contents as well as bone and scalp – may result from megalencephaly but also other medical issues, such as hydrocephalus or thickening of the skull. • Seizures • Occasional hydrocephalus secondary to aqueductal stenosis • CSF protein elevation [ • Developmental delay (slow attainment of developmental milestones or failure to achieve later milestones) • Seizures • Megalencephaly • Gradual loss of intellectual function • Regression after mild head injury or seizure • Dysarthria (in those children who attain speech) • Failure to thrive • Developmental delay • Seizures • Bulbar/pseudobulbar signs with nasal speech, dysphagia, dysphonia • Failure to thrive • Intractable vomiting • Scoliosis • Autonomic dysfunction • Bulbar/pseudobulbar signs • Pyramidal tract signs • Cerebellar signs • Dysautonomia • Sleep disturbance • Gait disturbance • Hemiparesis/hemiplegia or quadriparesis/quadriplegia • Diplopia or oculomotor abnormalities ## Brain MRI Findings Based on a multi-institutional retrospective survey of MRI studies of 217 individuals with leukoencephalopathy [ Extensive cerebral white matter abnormalities with a frontal preponderance Periventricular rim of decreased signal intensity on T Abnormalities of the basal ganglia and thalami that may include one or both of the following: Swelling and increased signal intensity on T Atrophy and increased/decreased signal intensity on T Brain stem abnormalities, particularly involving the medulla and midbrain Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem Alexander Disease: MRI Features by Age of Presentation Prominent or distinguishing features within the Severe white matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging Involvement of the basal ganglia and cerebellum Frontally predominant white matter T Brain stem abnormalities are less prominent than in other forms; typical findings may include symmetric signal abnormalities of the medulla. Significant involvement of posterior fossa structures, such as focal brain stem lesions (mimicking tumor), or T T Some individuals may lack other features described by Characteristic imaging features of this subgroup include symmetric or asymmetric lesions in the dorsal medulla that may enhance with gadolinium administration and are often initially diagnosed as tumors, especially in the absence of other imaging features of Alexander disease. The later onset and presence of prominent mass-like brain stem lesions and cerebellar abnormalities distinguish this phenotype from infantile cases. Such lesions account for the vomiting and cerebellar abnormalities seen in patients with this phenotype. While some individuals may have supratentorial and infratentorial abnormalities (an intermediate phenotype described by Abnormal signal intensity of the anterior portion of the medulla oblongata along with atrophy of the medulla and cervical spinal cord Signal abnormalities in the cerebellar white matter or hilus of the dentate nucleus [ Supratentorial white matter findings that may include [ Mild-to-moderate cerebral involvement T Cyst formation in white matter around the anterior horn of the lateral ventricles Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Extensive cerebral white matter abnormalities with a frontal preponderance • Periventricular rim of decreased signal intensity on T • Abnormalities of the basal ganglia and thalami that may include one or both of the following: • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Brain stem abnormalities, particularly involving the medulla and midbrain • Contrast enhancement of one or more of the following: ventricular lining, periventricular rim, frontal white matter, optic chiasm, fornix, basal ganglia, thalamus, dentate nucleus, and brain stem • Swelling and increased signal intensity on T • Atrophy and increased/decreased signal intensity on T • Severe white matter abnormalities with frontal predominance and extensive pathologic periventricular enhancement demonstrated on neuroradiologic contrast imaging • Involvement of the basal ganglia and cerebellum • Frontally predominant white matter T • Brain stem abnormalities are less prominent than in other forms; typical findings may include symmetric signal abnormalities of the medulla. • Significant involvement of posterior fossa structures, such as focal brain stem lesions (mimicking tumor), or T • T • Some individuals may lack other features described by • Characteristic imaging features of this subgroup include symmetric or asymmetric lesions in the dorsal medulla that may enhance with gadolinium administration and are often initially diagnosed as tumors, especially in the absence of other imaging features of Alexander disease. • The later onset and presence of prominent mass-like brain stem lesions and cerebellar abnormalities distinguish this phenotype from infantile cases. Such lesions account for the vomiting and cerebellar abnormalities seen in patients with this phenotype. While some individuals may have supratentorial and infratentorial abnormalities (an intermediate phenotype described by • Abnormal signal intensity of the anterior portion of the medulla oblongata along with atrophy of the medulla and cervical spinal cord • Signal abnormalities in the cerebellar white matter or hilus of the dentate nucleus [ • Supratentorial white matter findings that may include [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ • Mild-to-moderate cerebral involvement • T • Cyst formation in white matter around the anterior horn of the lateral ventricles • Appearance of garland-like structures along the ventricular wall (ventricular garlands), reported to represent blood vessels with a high density of periventricular Rosenthal fibers [ ## Establishing the Diagnosis The diagnosis of Alexander disease 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. Individuals with the distinctive findings described in Note: Alexander disease occurs through a gain-of-function mechanism (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alexander Disease 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 Based on a summary of prior published reports in which 293 of 299 (98%) individuals tested had a 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. Deletion of exon 5, an in-frame exon, has been reported [ ## Option 1 Note: Alexander disease occurs through a gain-of-function mechanism (see For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alexander Disease 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 Based on a summary of prior published reports in which 293 of 299 (98%) individuals tested had a 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. Deletion of exon 5, an in-frame exon, has been reported [ ## Clinical Characteristics Alexander disease is a progressive disorder affecting cerebral white matter. It is most readily recognized in infants and children. Adults can also be affected, but manifestations and diagnosis may be under-recognized. Life expectancy is variable. Many individuals with Alexander disease present with nonspecific neurologic manifestations. Previous classification recognized four forms: neonatal (sometimes considered a subset of the infantile form), infantile, juvenile, and adult. Based on a prior review of reports of Additional case series have suggested a two-group classification system (Type I and Type II) [ See Alexander Disease: Comparison of Forms by Select Features The forms described in Most children are referred to neurology after an initial seizure, often leading to brain MRI that reveals characteristic features (see Frontal bossing and megalencephaly are not universally present. Macrocephaly is not always noted at the time of other neurologic manifestations (e.g., seizures, developmental delay) and may be detected through serial measurement of the head circumference many years after the initial neurologic manifestations and diagnosis. While developmental regression may occur after a seizure or mild head trauma, some individuals can regain skills over time. Disease progression is also variable, with some individuals losing gross and fine motor as well as language skills in the first decade of life, while others follow a very slow disease course that spans decades. Compared to the infantile form, affected children have milder manifestations in early childhood. For example, mild language delay may be the only developmental abnormality or, with language acquisition, a change in voice (hypophonia or nasal speech) may develop, often prior to other neurologic features. Children and adolescents with this phenotype frequently have vomiting and failure to thrive as well as scoliosis and autonomic dysfunction. Some individuals with Alexander disease present with vomiting as the only manifestation of bulbar dysfunction (i.e., dysphagia and dysphonia may not be present initially) [ It is possible that this phenotype represents a spectrum of disease with other presentations. Longitudinal evaluations of individuals with Alexander disease have deidentified those with isolated brain stem lesions whose symptoms spontaneously resolved and who subsequently developed medullary and cervical cord atrophy as noted in the adult phenotype [ In contrast, in one family all three individuals with a A number of genotype-phenotype correlations have been observed for some recurrent variants, albeit with a limited number of affected individuals (see Penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms [ Reports of molecularly confirmed familial cases support the existence of asymptomatic adults with Alexander disease [ Alexander Disease: Comparison of Classification Systems The prevalence of Alexander disease is not known, but hundreds of affected individuals with heterozygous The only population-based prevalence estimate is one in 2.7 million [ The disorder is known to occur in diverse ethnic and racial groups [ ## Clinical Description Alexander disease is a progressive disorder affecting cerebral white matter. It is most readily recognized in infants and children. Adults can also be affected, but manifestations and diagnosis may be under-recognized. Life expectancy is variable. Many individuals with Alexander disease present with nonspecific neurologic manifestations. Previous classification recognized four forms: neonatal (sometimes considered a subset of the infantile form), infantile, juvenile, and adult. Based on a prior review of reports of Additional case series have suggested a two-group classification system (Type I and Type II) [ See Alexander Disease: Comparison of Forms by Select Features The forms described in Most children are referred to neurology after an initial seizure, often leading to brain MRI that reveals characteristic features (see Frontal bossing and megalencephaly are not universally present. Macrocephaly is not always noted at the time of other neurologic manifestations (e.g., seizures, developmental delay) and may be detected through serial measurement of the head circumference many years after the initial neurologic manifestations and diagnosis. While developmental regression may occur after a seizure or mild head trauma, some individuals can regain skills over time. Disease progression is also variable, with some individuals losing gross and fine motor as well as language skills in the first decade of life, while others follow a very slow disease course that spans decades. Compared to the infantile form, affected children have milder manifestations in early childhood. For example, mild language delay may be the only developmental abnormality or, with language acquisition, a change in voice (hypophonia or nasal speech) may develop, often prior to other neurologic features. Children and adolescents with this phenotype frequently have vomiting and failure to thrive as well as scoliosis and autonomic dysfunction. Some individuals with Alexander disease present with vomiting as the only manifestation of bulbar dysfunction (i.e., dysphagia and dysphonia may not be present initially) [ It is possible that this phenotype represents a spectrum of disease with other presentations. Longitudinal evaluations of individuals with Alexander disease have deidentified those with isolated brain stem lesions whose symptoms spontaneously resolved and who subsequently developed medullary and cervical cord atrophy as noted in the adult phenotype [ In contrast, in one family all three individuals with a ## Genotype-Phenotype Correlations A number of genotype-phenotype correlations have been observed for some recurrent variants, albeit with a limited number of affected individuals (see ## Penetrance Penetrance appears to be nearly 100% in individuals with the infantile and juvenile forms [ Reports of molecularly confirmed familial cases support the existence of asymptomatic adults with Alexander disease [ ## Nomenclature Alexander Disease: Comparison of Classification Systems ## Prevalence The prevalence of Alexander disease is not known, but hundreds of affected individuals with heterozygous The only population-based prevalence estimate is one in 2.7 million [ The disorder is known to occur in diverse ethnic and racial groups [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Alexander disease is usually considered in the differential diagnosis of infants who present with megalencephaly, developmental delay, spasticity, and seizures, or in older individuals who have a preponderance of brain stem signs and spasticity with or without megalencephaly or seizures. Genes of Interest in the Differential Diagnosis of the Neonatal, Infantile, and Juvenile Forms of Alexander Disease Male children present w/regression in motor & cognitive skills. Spasticity & gait abnormalities Developmental regression in early childhood Spasticity w/preserved cognitive function Hypotonia, head lag, macrocephaly, & difficulties w/suck & swallow DD ± regression MRI: involvement of subcortical WM & globus pallidus & thalami Elevation in N-acetylcysteine on MR spectroscopy MRI: diffuse WM changes w/o frontal predominance; sparing of putamen Early feeding difficulties, hypotonia, & irritability Developmental regression & seizures MRI: involvement of thalami & cerebellar WM Macrocephaly not present MRI: involvement of deep WM primarily w/sparing of subcortical WM until later in disease course; thickening/enhancement of optic nerves & peripheral nerves Macrocephaly, DD, extrapyramidal signs (often preceded by an acute encephalopathy during infancy) MRI: involvement of basal ganglia Megalencephaly during infancy, DD, seizures MRI: involvement of subcortical WM DD, seizures, dysarthria, ataxia (often w/insidious progression) MRI: involvement of subcortical, WM & basal ganglia; anterior to posterior involvement of WM Neonatal-infantile onset: hypotonia, feeding difficulties, & seizures Childhood onset: hypotonia, DD, regression, & diffuse involvement of WM incl cerebrum, brain stem, & cerebellum Adolescent-adult onset: variable ID, pyramidal signs, & ataxia May be assoc w/liver, heart, kidney, & skeletal system dysfunction; distinct facial features Neonatal-infantile onset of ZSD MRI findings: cortical dysplasia, generalized ↓ in WM volume, delayed myelination, & ventricular dilatation Childhood onset of ZSD MRI findings: involvement of parietooccipital WM progressing to entire cerebral WM CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; WM = white matter Mode of inheritance is autosomal recessive. Biallelic pathogenic variants in Hereditary disorders in the differential diagnosis of the adult form of Alexander disease are summarized in Genes of Interest in the Differential Diagnosis of the Adult Form of Alexander Disease Progressive gait disorder, spasticity or weakness, & abnormalities of sphincter control MRI: cerebellar lesions & demyelination Abnormal VLCFAs MRI: T Spastic paraplegia or progressive gait impairment Ataxia Cognitive decline MRI: abnormalities in medulla & upper cervical cord ↓ position & vibratory sensation MRI: abnormalities visualized in dorsal columns & lateral corticospinal tracts of spinal cord, splenium of CC, posterior limb of internal capsule, intraparenchymal part of trigeminal nerve, & mesencephalic trigeminal tracts Ischemic stroke & migraine w/aura MRI: T AD = autosomal dominant; AR = autosomal recessive; CACH/VWM = childhood ataxia with central nervous system hypomyelination / vanishing white matter; CC = corpus callosum; MOI = mode of inheritance; VLCFA = very long chain fatty acid; WM = white matter; XL = X-linked • Male children present w/regression in motor & cognitive skills. • Spasticity & gait abnormalities • Developmental regression in early childhood • Spasticity w/preserved cognitive function • Hypotonia, head lag, macrocephaly, & difficulties w/suck & swallow • DD ± regression • MRI: involvement of subcortical WM & globus pallidus & thalami • Elevation in N-acetylcysteine on MR spectroscopy • MRI: diffuse WM changes w/o frontal predominance; sparing of putamen • Early feeding difficulties, hypotonia, & irritability • Developmental regression & seizures • MRI: involvement of thalami & cerebellar WM • Macrocephaly not present • MRI: involvement of deep WM primarily w/sparing of subcortical WM until later in disease course; thickening/enhancement of optic nerves & peripheral nerves • Macrocephaly, DD, extrapyramidal signs (often preceded by an acute encephalopathy during infancy) • MRI: involvement of basal ganglia • Megalencephaly during infancy, DD, seizures • MRI: involvement of subcortical WM • DD, seizures, dysarthria, ataxia (often w/insidious progression) • MRI: involvement of subcortical, WM & basal ganglia; anterior to posterior involvement of WM • Neonatal-infantile onset: hypotonia, feeding difficulties, & seizures • Childhood onset: hypotonia, DD, regression, & diffuse involvement of WM incl cerebrum, brain stem, & cerebellum • Adolescent-adult onset: variable ID, pyramidal signs, & ataxia • May be assoc w/liver, heart, kidney, & skeletal system dysfunction; distinct facial features • Neonatal-infantile onset of ZSD MRI findings: cortical dysplasia, generalized ↓ in WM volume, delayed myelination, & ventricular dilatation • Childhood onset of ZSD MRI findings: involvement of parietooccipital WM progressing to entire cerebral WM • Progressive gait disorder, spasticity or weakness, & abnormalities of sphincter control • MRI: cerebellar lesions & demyelination • Abnormal VLCFAs • MRI: T • Spastic paraplegia or progressive gait impairment • Ataxia • Cognitive decline • MRI: abnormalities in medulla & upper cervical cord • ↓ position & vibratory sensation • MRI: abnormalities visualized in dorsal columns & lateral corticospinal tracts of spinal cord, splenium of CC, posterior limb of internal capsule, intraparenchymal part of trigeminal nerve, & mesencephalic trigeminal tracts • Ischemic stroke & migraine w/aura • MRI: T ## Differential Diagnosis in Neonates, Infants, and Juveniles Genes of Interest in the Differential Diagnosis of the Neonatal, Infantile, and Juvenile Forms of Alexander Disease Male children present w/regression in motor & cognitive skills. Spasticity & gait abnormalities Developmental regression in early childhood Spasticity w/preserved cognitive function Hypotonia, head lag, macrocephaly, & difficulties w/suck & swallow DD ± regression MRI: involvement of subcortical WM & globus pallidus & thalami Elevation in N-acetylcysteine on MR spectroscopy MRI: diffuse WM changes w/o frontal predominance; sparing of putamen Early feeding difficulties, hypotonia, & irritability Developmental regression & seizures MRI: involvement of thalami & cerebellar WM Macrocephaly not present MRI: involvement of deep WM primarily w/sparing of subcortical WM until later in disease course; thickening/enhancement of optic nerves & peripheral nerves Macrocephaly, DD, extrapyramidal signs (often preceded by an acute encephalopathy during infancy) MRI: involvement of basal ganglia Megalencephaly during infancy, DD, seizures MRI: involvement of subcortical WM DD, seizures, dysarthria, ataxia (often w/insidious progression) MRI: involvement of subcortical, WM & basal ganglia; anterior to posterior involvement of WM Neonatal-infantile onset: hypotonia, feeding difficulties, & seizures Childhood onset: hypotonia, DD, regression, & diffuse involvement of WM incl cerebrum, brain stem, & cerebellum Adolescent-adult onset: variable ID, pyramidal signs, & ataxia May be assoc w/liver, heart, kidney, & skeletal system dysfunction; distinct facial features Neonatal-infantile onset of ZSD MRI findings: cortical dysplasia, generalized ↓ in WM volume, delayed myelination, & ventricular dilatation Childhood onset of ZSD MRI findings: involvement of parietooccipital WM progressing to entire cerebral WM CSF = cerebrospinal fluid; DD = developmental delay; ID = intellectual disability; WM = white matter Mode of inheritance is autosomal recessive. Biallelic pathogenic variants in • Male children present w/regression in motor & cognitive skills. • Spasticity & gait abnormalities • Developmental regression in early childhood • Spasticity w/preserved cognitive function • Hypotonia, head lag, macrocephaly, & difficulties w/suck & swallow • DD ± regression • MRI: involvement of subcortical WM & globus pallidus & thalami • Elevation in N-acetylcysteine on MR spectroscopy • MRI: diffuse WM changes w/o frontal predominance; sparing of putamen • Early feeding difficulties, hypotonia, & irritability • Developmental regression & seizures • MRI: involvement of thalami & cerebellar WM • Macrocephaly not present • MRI: involvement of deep WM primarily w/sparing of subcortical WM until later in disease course; thickening/enhancement of optic nerves & peripheral nerves • Macrocephaly, DD, extrapyramidal signs (often preceded by an acute encephalopathy during infancy) • MRI: involvement of basal ganglia • Megalencephaly during infancy, DD, seizures • MRI: involvement of subcortical WM • DD, seizures, dysarthria, ataxia (often w/insidious progression) • MRI: involvement of subcortical, WM & basal ganglia; anterior to posterior involvement of WM • Neonatal-infantile onset: hypotonia, feeding difficulties, & seizures • Childhood onset: hypotonia, DD, regression, & diffuse involvement of WM incl cerebrum, brain stem, & cerebellum • Adolescent-adult onset: variable ID, pyramidal signs, & ataxia • May be assoc w/liver, heart, kidney, & skeletal system dysfunction; distinct facial features • Neonatal-infantile onset of ZSD MRI findings: cortical dysplasia, generalized ↓ in WM volume, delayed myelination, & ventricular dilatation • Childhood onset of ZSD MRI findings: involvement of parietooccipital WM progressing to entire cerebral WM ## Differential Diagnosis in Adults Hereditary disorders in the differential diagnosis of the adult form of Alexander disease are summarized in Genes of Interest in the Differential Diagnosis of the Adult Form of Alexander Disease Progressive gait disorder, spasticity or weakness, & abnormalities of sphincter control MRI: cerebellar lesions & demyelination Abnormal VLCFAs MRI: T Spastic paraplegia or progressive gait impairment Ataxia Cognitive decline MRI: abnormalities in medulla & upper cervical cord ↓ position & vibratory sensation MRI: abnormalities visualized in dorsal columns & lateral corticospinal tracts of spinal cord, splenium of CC, posterior limb of internal capsule, intraparenchymal part of trigeminal nerve, & mesencephalic trigeminal tracts Ischemic stroke & migraine w/aura MRI: T AD = autosomal dominant; AR = autosomal recessive; CACH/VWM = childhood ataxia with central nervous system hypomyelination / vanishing white matter; CC = corpus callosum; MOI = mode of inheritance; VLCFA = very long chain fatty acid; WM = white matter; XL = X-linked • Progressive gait disorder, spasticity or weakness, & abnormalities of sphincter control • MRI: cerebellar lesions & demyelination • Abnormal VLCFAs • MRI: T • Spastic paraplegia or progressive gait impairment • Ataxia • Cognitive decline • MRI: abnormalities in medulla & upper cervical cord • ↓ position & vibratory sensation • MRI: abnormalities visualized in dorsal columns & lateral corticospinal tracts of spinal cord, splenium of CC, posterior limb of internal capsule, intraparenchymal part of trigeminal nerve, & mesencephalic trigeminal tracts • Ischemic stroke & migraine w/aura • MRI: T ## Management No clinical practice guidelines for Alexander disease have been published. To establish the extent of disease and needs in an individual diagnosed with Alexander disease, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Alexander Disease Review clinical & MRI findings w/affected individual & caregivers. Perform formal, age-appropriate developmental assessment (in children). Discuss symptomatic therapy. Determine if EEG is needed. AAC = augmentative alternative communication; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse No specific therapy is currently available for Alexander disease; however, clinicians and families should routinely check Management is supportive and includes attention to general care, feeding and nutrition, anti-seizure medication (ASM) for seizure control, physical and occupational therapy, speech and language therapy, and appropriate educational services. The management by multidisciplinary specialists as outlined in Treatment of Manifestations in Individuals with Alexander Disease ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; OT = occupational therapist; UTI = urinary tract infection 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. Recommended Surveillance for Individuals with Alexander Disease GI = gastrointestinal; OT = occupational therapy; PT = physical therapy Active issues may require more frequent evaluations See Search • Review clinical & MRI findings w/affected individual & caregivers. • Perform formal, age-appropriate developmental assessment (in children). • Discuss symptomatic therapy. • Determine if EEG is needed. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Alexander disease, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Alexander Disease Review clinical & MRI findings w/affected individual & caregivers. Perform formal, age-appropriate developmental assessment (in children). Discuss symptomatic therapy. Determine if EEG is needed. AAC = augmentative alternative communication; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Review clinical & MRI findings w/affected individual & caregivers. • Perform formal, age-appropriate developmental assessment (in children). • Discuss symptomatic therapy. • Determine if EEG is needed. ## Treatment of Manifestations No specific therapy is currently available for Alexander disease; however, clinicians and families should routinely check Management is supportive and includes attention to general care, feeding and nutrition, anti-seizure medication (ASM) for seizure control, physical and occupational therapy, speech and language therapy, and appropriate educational services. The management by multidisciplinary specialists as outlined in Treatment of Manifestations in Individuals with Alexander Disease ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; OT = occupational therapist; UTI = urinary tract infection 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. ## 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. ## Surveillance Recommended Surveillance for Individuals with Alexander Disease GI = gastrointestinal; OT = occupational therapy; PT = physical therapy Active issues may require more frequent evaluations ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Alexander disease is inherited in an autosomal dominant manner. To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a A study on unrelated individuals with Alexander disease revealed that the Some individuals with slowly progressive adult Alexander disease have an affected parent [ Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ * An individual with somatic and germline mosaicism for a Some individuals with Alexander disease may appear to be the only affected family member because of failure to recognize the disorder in other family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. 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%. Variable expressivity may occur in heterozygous family members (see If the If the parents have not been tested for the Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce. Each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting 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 Alexander 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 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 reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a • A study on unrelated individuals with Alexander disease revealed that the • Some individuals with slowly progressive adult Alexander disease have an affected parent [ • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ • * An individual 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. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ • * An individual with somatic and germline mosaicism for a • Some individuals with Alexander disease may appear to be the only affected family member because of failure to recognize the disorder in other family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. • 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. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ • * An individual with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Variable expressivity may occur in heterozygous family members (see • If the • If the parents have not been tested for the • Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce. • Each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting 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 Alexander disease is inherited in an autosomal dominant manner. ## Risk to Family Members To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a A study on unrelated individuals with Alexander disease revealed that the Some individuals with slowly progressive adult Alexander disease have an affected parent [ Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ * An individual with somatic and germline mosaicism for a Some individuals with Alexander disease may appear to be the only affected family member because of failure to recognize the disorder in other family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. 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%. Variable expressivity may occur in heterozygous family members (see If the If the parents have not been tested for the Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce. Each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting the • To date, most reported individuals with molecularly confirmed Alexander disease have the disorder as the result of a • A study on unrelated individuals with Alexander disease revealed that the • Some individuals with slowly progressive adult Alexander disease have an affected parent [ • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. * Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ • * An individual 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. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ • * An individual with somatic and germline mosaicism for a • Some individuals with Alexander disease may appear to be the only affected family member because of failure to recognize the disorder in other family members, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance. • 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. Sib recurrence of neuropathologically and molecularly proven Alexander disease in families in which the parents are neurologically intact suggest the possibility of germline mosaicism in one of the parents [ • * An individual with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Variable expressivity may occur in heterozygous family members (see • If the • If the parents have not been tested for the • Individuals with Alexander disease with significant neurologic and cognitive impairment typically do not reproduce. • Each child of an adult with slowly progressing Alexander disease has a 50% chance of inheriting 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 Alexander 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 affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources MD University of Wisconsin-Madison 1500 Highland Avenue Room 277 Madison WI 53705 • • • • MD • • • • • University of Wisconsin-Madison • 1500 Highland Avenue • Room 277 • Madison WI 53705 • • • • • ## Molecular Genetics Alexander Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alexander Disease ( Consistent with a gain-of-function mechanism, the majority of disease-associated variants are missense or in-frame variants [ Most Notable Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( The most common pathogenic variants occur at the three amino acid residues p.Arg79, p.Arg88, and p.Arg239. ## Molecular Pathogenesis Consistent with a gain-of-function mechanism, the majority of disease-associated variants are missense or in-frame variants [ Most Notable Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( The most common pathogenic variants occur at the three amino acid residues p.Arg79, p.Arg88, and p.Arg239. ## Chapter Notes Website for Amy Waldman at the Children's Hospital of Philadelphia Website for Siddharth Srivastava at Boston Children's Hospital Clinical trial pertaining to outcome measures of Alexander disease at the Children's Hospital of Philadelphia J Rafael Gorospe, MD, PhD; NIH – National Center for Research Resource (2002-2015)Sakkubai Naidu, MD (2015-present)Siddharth Srivastava, MD (2015-present)Amy Waldman, MD, MSCE (2020-present) 12 November 2020 (bp) Comprehensive update posted live 8 January 2015 (me) Comprehensive update posted live 22 April 2010 (me) Comprehensive update posted live 9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available 2 October 2006 (me) Comprehensive update posted live 28 September 2004 (me) Comprehensive update posted live 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available 15 November 2002 (me) Review posted live 24 April 2002 (jrg) Original submission • 12 November 2020 (bp) Comprehensive update posted live • 8 January 2015 (me) Comprehensive update posted live • 22 April 2010 (me) Comprehensive update posted live • 9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available • 2 October 2006 (me) Comprehensive update posted live • 28 September 2004 (me) Comprehensive update posted live • 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available • 15 November 2002 (me) Review posted live • 24 April 2002 (jrg) Original submission ## Author Notes Website for Amy Waldman at the Children's Hospital of Philadelphia Website for Siddharth Srivastava at Boston Children's Hospital Clinical trial pertaining to outcome measures of Alexander disease at the Children's Hospital of Philadelphia ## Author History J Rafael Gorospe, MD, PhD; NIH – National Center for Research Resource (2002-2015)Sakkubai Naidu, MD (2015-present)Siddharth Srivastava, MD (2015-present)Amy Waldman, MD, MSCE (2020-present) ## Revision History 12 November 2020 (bp) Comprehensive update posted live 8 January 2015 (me) Comprehensive update posted live 22 April 2010 (me) Comprehensive update posted live 9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available 2 October 2006 (me) Comprehensive update posted live 28 September 2004 (me) Comprehensive update posted live 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available 15 November 2002 (me) Review posted live 24 April 2002 (jrg) Original submission • 12 November 2020 (bp) Comprehensive update posted live • 8 January 2015 (me) Comprehensive update posted live • 22 April 2010 (me) Comprehensive update posted live • 9 March 2007 (cd,jrg) Revision: sequence analysis of select exons and targeted mutation analysis no longer clinically available • 2 October 2006 (me) Comprehensive update posted live • 28 September 2004 (me) Comprehensive update posted live • 5 May 2003 (cd,jrg) Revision: molecular genetic testing clinically available • 15 November 2002 (me) Review posted live • 24 April 2002 (jrg) Original submission ## References ## Literature Cited	[ "T Ayaki, M Shinohara, S Tatsumi, M Namekawa, T. 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Autonomic dysfunction in adult-onset alexander disease: a case report and review of the literature.. Clin Auton Res. 2013;23:333-8", "E Stumpf, H Masson, A Duquette, F Berthelet, J McNabb, A Lortie, J Lesage, J Montplaisir, B Brais, P Cossette. Adult Alexander disease with autosomal dominant transmission: a distinct entity caused by mutation in the glial fibrillary acid protein gene.. Arch Neurol 2003;60:1307-12", "D Thyagarajan, T Chataway, R Li, WP Gai, M Brenner. Dominantly-inherited adult-onset leukodystrophy with palatal tremor caused by a mutation in the glial fibrillary acidic protein gene.. Mov Disord 2004;19:1244-8", "MS van der Knaap, S Naidu, SN Breiter, S Blaser, H Stroink, S Springer, JC Begeer, R van Coster, PG Barth, NH Thomas, J Valk, JM Powers. Alexander disease: diagnosis with MR imaging.. 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Familial adult-onset Alexander disease with a novel mutation (D78N) in the glial fibrillary acidic protein gene with unusual bilateral basal ganglia involvement.. J Neurol Sci. 2013;331:161-4", "T Yoshida, M Sasaki, M Yoshida, M Namekawa, Y Okamoto, S Tsujino, H Sasayama, I Mizuta, M Nakagawa. Nationwide survey of Alexander disease in Japan and proposed new guidelines for diagnosis.. J Neurol. 2011;258:1998-2008", "T Yoshida, I Mizuta, R Yasuda, M Nakagawa, T Mizuno. Characteristics of cerebral lesions in adult-onset Alexander disease.. Neurol Sci. 2020;41:225-7" ]	15/11/2002	12/11/2020	9/3/2007	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alk-nbs	alk-nbs	[ "ALK-Related Neuroblastoma", "ALK-Related Ganglioneuroblastoma", "ALK-Related Ganglioneuroma", "ALK tyrosine kinase receptor", "ALK", "ALK-Related Neuroblastic Tumor Susceptibility" ]		Emily G Greengard, Melissa R Perrino, Julie R Park	Summary	Neuroblastoma Ganglioneuroblastoma Ganglioneuroma For other genetic causes of these phenotypes see • Neuroblastoma • Ganglioneuroblastoma • Ganglioneuroma ## Diagnosis A neuroblastic tumor including neuroblastoma, ganglioneuroblastoma, or ganglioneuroma; Multiple primary neuroblastic tumors that arise either synchronously or metachronously; A family history of one or more relatives with one of these three neuroblastic tumors. Note: Both benign and malignant tumors can occur in the same family. As neuroblastoma most often occurs sporadically and is rarely attributed to germline variants in cancer-predisposing genes (1%-2% of individuals), routine germline testing for All children with documented somatic An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor * Germline An individual with a neuroblastic tumor and a family history of neuroblastic tumors that are not a manifestation of a neural crest disorder such as Hirschsprung disease or Some institutions are currently screening tumors of all children with neuroblastoma, and others are screening tumors at the time of recurrence or progression, primarily for potential for The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include Note: For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small 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 families with two or more first-degree relatives with neuroblastoma, the incidence of germline Somatic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 neuroblastic tumor including neuroblastoma, ganglioneuroblastoma, or ganglioneuroma; • Multiple primary neuroblastic tumors that arise either synchronously or metachronously; • A family history of one or more relatives with one of these three neuroblastic tumors. Note: Both benign and malignant tumors can occur in the same family. • All children with documented somatic • An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor • * Germline • An individual with a neuroblastic tumor and a family history of neuroblastic tumors that are not a manifestation of a neural crest disorder such as Hirschsprung disease or • Note: • For an introduction to multigene panels click ## Suggestive Findings A neuroblastic tumor including neuroblastoma, ganglioneuroblastoma, or ganglioneuroma; Multiple primary neuroblastic tumors that arise either synchronously or metachronously; A family history of one or more relatives with one of these three neuroblastic tumors. Note: Both benign and malignant tumors can occur in the same family. As neuroblastoma most often occurs sporadically and is rarely attributed to germline variants in cancer-predisposing genes (1%-2% of individuals), routine germline testing for All children with documented somatic An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor * Germline An individual with a neuroblastic tumor and a family history of neuroblastic tumors that are not a manifestation of a neural crest disorder such as Hirschsprung disease or Some institutions are currently screening tumors of all children with neuroblastoma, and others are screening tumors at the time of recurrence or progression, primarily for potential for • A neuroblastic tumor including neuroblastoma, ganglioneuroblastoma, or ganglioneuroma; • Multiple primary neuroblastic tumors that arise either synchronously or metachronously; • A family history of one or more relatives with one of these three neuroblastic tumors. Note: Both benign and malignant tumors can occur in the same family. • All children with documented somatic • An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor • * Germline • An individual with a neuroblastic tumor and a family history of neuroblastic tumors that are not a manifestation of a neural crest disorder such as Hirschsprung disease or ## Recommendations for Testing for Germline All children with documented somatic An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor * Germline An individual with a neuroblastic tumor and a family history of neuroblastic tumors that are not a manifestation of a neural crest disorder such as Hirschsprung disease or • All children with documented somatic • An individual with a neuroblastic tumor* who has at least one first-degree relative with a neuroblastic tumor • * Germline • An individual with a neuroblastic tumor and a family history of neuroblastic tumors that are not a manifestation of a neural crest disorder such as Hirschsprung disease or ## Considerations for Testing for Somatic Some institutions are currently screening tumors of all children with neuroblastoma, and others are screening tumors at the time of recurrence or progression, primarily for potential for ## 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: 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 In families with two or more first-degree relatives with neuroblastoma, the incidence of germline Somatic Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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: • For an introduction to multigene panels click ## Clinical Characteristics Individuals with Within this spectrum, neuroblastomas represent a more malignant tumor and ganglioneuromas a more benign tumor. The three neuroblastic tumor types are defined histologically. Depending on the histologic findings, ganglioneuroblastomas can behave in a benign fashion, like ganglioneuromas, or in a more aggressive fashion, like neuroblastomas. Since neuroblastomic tumor outcome is heavily dependent on biological characteristics and stage of the tumor, it is likely that survival from a neuroblastic tumor depends more on tumor type (neuroblastomas having the poorest outcome), tumor stage, and appropriate medical intervention than on the presence or absence of a germline Aside from the following pathogenic variants, no associations between specific germline The pathogenic variant The pathogenic variant The overall penetrance of a germline See also Familial neuroblastoma occurs in approximately 1%-2% of all individuals with neuroblastoma [ ## Clinical Description Individuals with Within this spectrum, neuroblastomas represent a more malignant tumor and ganglioneuromas a more benign tumor. The three neuroblastic tumor types are defined histologically. Depending on the histologic findings, ganglioneuroblastomas can behave in a benign fashion, like ganglioneuromas, or in a more aggressive fashion, like neuroblastomas. Since neuroblastomic tumor outcome is heavily dependent on biological characteristics and stage of the tumor, it is likely that survival from a neuroblastic tumor depends more on tumor type (neuroblastomas having the poorest outcome), tumor stage, and appropriate medical intervention than on the presence or absence of a germline ## Genotype-Phenotype Correlations Aside from the following pathogenic variants, no associations between specific germline The pathogenic variant The pathogenic variant ## Penetrance The overall penetrance of a germline See also ## Prevalence Familial neuroblastoma occurs in approximately 1%-2% of all individuals with neuroblastoma [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Germline pathogenic variants in Heterozygous germline Heterozygous germline Neuroblastoma Susceptibility Disorders to Consider in the Differential Diagnosis of Characteristic facies Short stature Congenital heart disease Developmental delay Leukemias, rhabdomyosarcoma Leukemia / non-Hodgkin lymphoma Overgrowth Characteristic facial features (broad forehead, ocular hypertelorism, long/prominent philtrum, "stuck-on" appearance of chin Characteristic facies Growth deficiency Developmental delay Characteristic hair & skin findings Cardiac disease Café au lait macules, intertriginous freckling, cutaneous neurofibromas Peripheral nerve sheath tumors Iris Lisch nodules Learning disabilities &/or behavior issues Hirschsprung disease ↓ esophageal motility Characteristic facial features (downslanted palpebral fissures, small nose, triangular mouth, low-set & posteriorly rotated ears) Macrosomia, macroglossia, visceromegaly, omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, renal abnormalities, hemihyperplasia Wilms tumor, hepatoblastoma, rhabdomyosarcoma AD = autosomal dominant; Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in Beckwith-Wiedemann syndrome (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 (see Beckwith-Wiedemann Syndrome, Neuroblastoma susceptibility candidate genes include • Heterozygous germline • Heterozygous germline • Characteristic facies • Short stature • Congenital heart disease • Developmental delay • Leukemias, rhabdomyosarcoma • Leukemia / non-Hodgkin lymphoma • Overgrowth • Characteristic facial features (broad forehead, ocular hypertelorism, long/prominent philtrum, "stuck-on" appearance of chin • Characteristic facies • Growth deficiency • Developmental delay • Characteristic hair & skin findings • Cardiac disease • Café au lait macules, intertriginous freckling, cutaneous neurofibromas • Peripheral nerve sheath tumors • Iris Lisch nodules • Learning disabilities &/or behavior issues • Hirschsprung disease • ↓ esophageal motility • Characteristic facial features (downslanted palpebral fissures, small nose, triangular mouth, low-set & posteriorly rotated ears) • Macrosomia, macroglossia, visceromegaly, omphalocele, neonatal hypoglycemia, ear creases/pits, adrenocortical cytomegaly, renal abnormalities, hemihyperplasia • Wilms tumor, hepatoblastoma, rhabdomyosarcoma ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Medical geneticist, certified genetic counselor, certified advanced genetic nurse The treatment for individuals with a neuroblastic tumor who have a germline Depending on age of affected person, tumor stage, & biologic characteristics, treatment may involve observation or surgical resection. Tumors w/risk for metastatic spread or those that have already metastasized require chemotherapy & sometimes radiation therapy, HSCT, & immunotherapy. The mgmt guidelines for neuroblastomas & ganglioneuroblastomas are complex. Clinical trials are ongoing to study efficacy of HSCT = hematopoietic stem cell transplantation Guidelines for the screening of asymptomatic children with familial neuroblastoma – including those with germline Abdominal ultrasound Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) Physical exam Chest radiograph Physical exam Abdominal ultrasound Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) There is currently no evidence that individuals with It is appropriate to test sibs younger than age ten years at the time of the proband's diagnosis as well as sibs born subsequently for the See Several early-phase clinical trials of small-molecule inhibitors targeting the ALK tyrosine kinase receptor have been completed in individuals with Search • Depending on age of affected person, tumor stage, & biologic characteristics, treatment may involve observation or surgical resection. • Tumors w/risk for metastatic spread or those that have already metastasized require chemotherapy & sometimes radiation therapy, HSCT, & immunotherapy. • The mgmt guidelines for neuroblastomas & ganglioneuroblastomas are complex. • Clinical trials are ongoing to study efficacy of • Abdominal ultrasound • Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) • Physical exam • Chest radiograph • Physical exam • Abdominal ultrasound • Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Medical geneticist, certified genetic counselor, certified advanced genetic nurse ## Treatment of Manifestations The treatment for individuals with a neuroblastic tumor who have a germline Depending on age of affected person, tumor stage, & biologic characteristics, treatment may involve observation or surgical resection. Tumors w/risk for metastatic spread or those that have already metastasized require chemotherapy & sometimes radiation therapy, HSCT, & immunotherapy. The mgmt guidelines for neuroblastomas & ganglioneuroblastomas are complex. Clinical trials are ongoing to study efficacy of HSCT = hematopoietic stem cell transplantation • Depending on age of affected person, tumor stage, & biologic characteristics, treatment may involve observation or surgical resection. • Tumors w/risk for metastatic spread or those that have already metastasized require chemotherapy & sometimes radiation therapy, HSCT, & immunotherapy. • The mgmt guidelines for neuroblastomas & ganglioneuroblastomas are complex. • Clinical trials are ongoing to study efficacy of ## Surveillance Guidelines for the screening of asymptomatic children with familial neuroblastoma – including those with germline Abdominal ultrasound Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) Physical exam Chest radiograph Physical exam Abdominal ultrasound Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) • Abdominal ultrasound • Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) • Physical exam • Chest radiograph • Physical exam • Abdominal ultrasound • Measurement of urine catecholamine metabolite levels (homovanillic acid & vanillylmandelic acid) ## Agents/Circumstances to Avoid There is currently no evidence that individuals with ## Evaluation of Relatives at Risk It is appropriate to test sibs younger than age ten years at the time of the proband's diagnosis as well as sibs born subsequently for the See ## Therapies Under Investigation Several early-phase clinical trials of small-molecule inhibitors targeting the ALK tyrosine kinase receptor have been completed in individuals with Search ## Genetic Counseling Some individuals diagnosed with Because of reduced penetrance, a parent may have a germline As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline Some individuals diagnosed with Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant identified in the proband is not identified in either parent 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 If a parent of the proband is affected or has a germline If the proband has a known The sibs of a proband with clinically unaffected parents whose Each child of an individual with The likelihood that a child who inherits 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, have a germline Once the germline Note: Although molecular genetic testing can identify the presence of a germline 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 • Because of reduced penetrance, a parent may have a germline • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline • Because of reduced penetrance, a parent may have a germline • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline • Some individuals diagnosed with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant identified in the proband is not identified in either parent 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 • Because of reduced penetrance, a parent may have a germline • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline • 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 or has a germline • If the proband has a known • The sibs of a proband with clinically unaffected parents whose • Each child of an individual with • The likelihood that a child who inherits 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, have a germline ## Mode of Inheritance ## Risk to Family Members Some individuals diagnosed with Because of reduced penetrance, a parent may have a germline As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline Some individuals diagnosed with Molecular genetic testing is recommended for the parents of a proband with an apparent If the pathogenic variant identified in the proband is not identified in either parent 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 If a parent of the proband is affected or has a germline If the proband has a known The sibs of a proband with clinically unaffected parents whose Each child of an individual with The likelihood that a child who inherits the • Some individuals diagnosed with • Because of reduced penetrance, a parent may have a germline • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline • Because of reduced penetrance, a parent may have a germline • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline • Some individuals diagnosed with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the pathogenic variant identified in the proband is not identified in either parent 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 • Because of reduced penetrance, a parent may have a germline • As yet, no tumor types other than neuroblastoma, ganglioneuroma, or ganglioneuroblastoma have been reported to be associated with germline • 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 or has a germline • If the proband has a known • The sibs of a proband with clinically unaffected parents whose • Each child of an individual with • The likelihood that a child who inherits 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, have a germline • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, have a germline ## Prenatal Testing and Preimplantation Genetic Testing Once the germline Note: Although molecular genetic testing can identify the presence of a germline 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 ALK-Related Neuroblastic Tumor Susceptibility: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ALK-Related Neuroblastic Tumor Susceptibility ( Variants listed in the table have been provided by the authors. Preclinical data suggest that responsiveness to crizotinib may depend on the presence or absence and specific type of somatic Several recent clinical trials have incorporated ALK tyrosine kinase inhibitors into therapy. These trials are not specific to individuals with These data have been confirmed in other studies as well. For example, human neuroblastoma-derived cell lines containing mutated proteins with the p.Arg1275Gln substitution, the most common abnormal protein described in The variant p.Phe1174Leu, associated with amplification of the oncogene ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors Preclinical data suggest that responsiveness to crizotinib may depend on the presence or absence and specific type of somatic Several recent clinical trials have incorporated ALK tyrosine kinase inhibitors into therapy. These trials are not specific to individuals with These data have been confirmed in other studies as well. For example, human neuroblastoma-derived cell lines containing mutated proteins with the p.Arg1275Gln substitution, the most common abnormal protein described in The variant p.Phe1174Leu, associated with amplification of the oncogene ## Chapter Notes Melissa R Perrino, MD: Emily G Greengard, MD (2015-present)Rebecca H Johnson, MD; Seattle Children's Hospital (2009-2015)Julie R Park, MD (2009-present)Melissa R Perrino, MD (2024-present) 23 May 2024 (sw) Comprehensive update posted live 17 January 2019 (sw) Comprehensive update posted live 9 April 2015 (me) Comprehensive update posted live 27 September 2012 (me) Comprehensive update posted live 5 January 2010 (me) Review posted live 14 August 2009 (rhj) Original submission • 23 May 2024 (sw) Comprehensive update posted live • 17 January 2019 (sw) Comprehensive update posted live • 9 April 2015 (me) Comprehensive update posted live • 27 September 2012 (me) Comprehensive update posted live • 5 January 2010 (me) Review posted live • 14 August 2009 (rhj) Original submission ## Author Notes Melissa R Perrino, MD: ## Author History Emily G Greengard, MD (2015-present)Rebecca H Johnson, MD; Seattle Children's Hospital (2009-2015)Julie R Park, MD (2009-present)Melissa R Perrino, MD (2024-present) ## Revision History 23 May 2024 (sw) Comprehensive update posted live 17 January 2019 (sw) Comprehensive update posted live 9 April 2015 (me) Comprehensive update posted live 27 September 2012 (me) Comprehensive update posted live 5 January 2010 (me) Review posted live 14 August 2009 (rhj) Original submission • 23 May 2024 (sw) Comprehensive update posted live • 17 January 2019 (sw) Comprehensive update posted live • 9 April 2015 (me) Comprehensive update posted live • 27 September 2012 (me) Comprehensive update posted live • 5 January 2010 (me) Review posted live • 14 August 2009 (rhj) Original submission ## References American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available ## Published Guidelines / Consensus Statements American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available ## Literature Cited	[]	5/1/2010	23/5/2024	9/5/2013	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alkap	alkap	[ "Alcaptonuria", "Alcaptonuria", "Homogentisate 1,2-dioxygenase", "HGD", "Alkaptonuria" ]	Alkaptonuria	Wendy J Introne, Monique Perry, Marcus Chen	Summary Alkaptonuria is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to maleylacetoacetic acid in the tyrosine degradation pathway. The three major features of alkaptonuria are dark urine or urine that turns dark on standing, ochronosis (bluish-black pigmentation in connective tissue), and arthritis of the spine and larger joints. Ochronosis generally occurs after age 30 years; arthritis often begins in the third decade. Other manifestations can include pigment in the sclera, ear cartilage, and skin of the hands; aortic or mitral valve calcification or regurgitation and occasionally aortic dilatation; renal stones; prostate stones; and hypothyroidism. The biochemical diagnosis of alkaptonuria in a proband is based on the detection of a significant amount of HGA in the urine (usually 1 to 8 grams per day). The molecular diagnosis (needed to provide genetic counseling to family members) is based on identification of biallelic pathogenic variants in Treatment with nitisinone, which has been shown to slow the progression of symptoms, is approved for use in treatment of alkaptonuria in Europe but not the United States. Alkaptonuria is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No consensus clinical diagnostic criteria for alkaptonuria have been published. Alkaptonuria Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( Ear cartilage pigmentation is seen in the concha and antihelix ( Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. Note: In some individuals, the diagnosis of alkaptonuria is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery. The The 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 Used in Alkaptonuria 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. • Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( • Ear cartilage pigmentation is seen in the concha and antihelix ( • Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. • A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. • Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( • Ear cartilage pigmentation is seen in the concha and antihelix ( • Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. • A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. • Note: In some individuals, the diagnosis of alkaptonuria is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery. • Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( • Ear cartilage pigmentation is seen in the concha and antihelix ( • Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. • A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. ## Suggestive Findings Alkaptonuria Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( Ear cartilage pigmentation is seen in the concha and antihelix ( Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. Note: In some individuals, the diagnosis of alkaptonuria is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery. • Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( • Ear cartilage pigmentation is seen in the concha and antihelix ( • Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. • A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. • Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( • Ear cartilage pigmentation is seen in the concha and antihelix ( • Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. • A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. • Note: In some individuals, the diagnosis of alkaptonuria is identified only after the individual seeks medical attention for chronic joint pain or after black articular cartilage is noted during orthopedic surgery. • Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles. Pigment deposition may also be seen in the conjunctiva and cornea ( • Ear cartilage pigmentation is seen in the concha and antihelix ( • Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. • A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and index finger. ## Establishing the Diagnosis The The 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 Used in Alkaptonuria 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 clinical findings of alkaptonuria include connective tissue ochronosis and arthritis of the spine and larger joints. Urinary excretion of homogentisic acid (HGA) and disease severity can vary significantly within the same family. Alkaptonuria does not cause developmental delay or cognitive impairment and does not generally reduce the life span of affected individuals. In general, pigmentary changes are observed after age 30 years. Tendon-related findings, including a thickened Achilles tendon, tendonitis, and rupture, have also been observed clinically [ Ochronotic arthritis is a regular manifestation of longstanding alkaptonuria. Involvement of the spine usually appears in the third decade. In one large series, low back pain was observed prior to age 30 years in 49% of individuals and prior to age 40 years in 94% [ Lumbar and thoracic spine symptoms precede cervical spine symptoms. The sacroiliac region is usually spared. Limitation of spine flexion directly correlates with degree of disability. Individuals with decreased forward flexion demonstrate impaired function and increased fatigue [ Joint disease appears to start earlier and progress more rapidly in males than in females. Knees, hips, and shoulders are frequently affected. Fifty percent of individuals require at least one joint replacement by age 55 years [ Because the kidneys are responsible for secreting massive quantities of HGA, impaired renal function can accelerate the development of ochronosis and joint destruction [ Renal function is critical for individuals with alkaptonuria as the kidney actively secretes HGA. Kidney injury, either acute or chronic, may impair the elimination of HGA and cause HGA to accumulate in the blood and tissues. This may lead to acidosis, hemolysis, and methemoglobinemia, which may be fatal [ No correlation is observed between the type of While analysis of HGD variants from 172 individuals with alkaptonuria revealed that residual HGA activity ranged from 1% to more than 30%, there was no observed difference in serum HGA, urinary excretion of HGA, or clinical manifestations [ Occasionally alkaptonuria is referred to collectively (and incorrectly) as ochronosis. At least 1000 affected individuals have been described in the literature; this is likely an underestimate. The incidence of alkaptonuria in the US is estimated at 1:250,000 to 1:1,000,000 live births. Alkaptonuria occurs worldwide. The prevalence of alkaptonuria in Slovakia is estimated at 1:19,000 [ A high prevalence has been observed in the Dominican Republic due to the founder variant ## Clinical Description The clinical findings of alkaptonuria include connective tissue ochronosis and arthritis of the spine and larger joints. Urinary excretion of homogentisic acid (HGA) and disease severity can vary significantly within the same family. Alkaptonuria does not cause developmental delay or cognitive impairment and does not generally reduce the life span of affected individuals. In general, pigmentary changes are observed after age 30 years. Tendon-related findings, including a thickened Achilles tendon, tendonitis, and rupture, have also been observed clinically [ Ochronotic arthritis is a regular manifestation of longstanding alkaptonuria. Involvement of the spine usually appears in the third decade. In one large series, low back pain was observed prior to age 30 years in 49% of individuals and prior to age 40 years in 94% [ Lumbar and thoracic spine symptoms precede cervical spine symptoms. The sacroiliac region is usually spared. Limitation of spine flexion directly correlates with degree of disability. Individuals with decreased forward flexion demonstrate impaired function and increased fatigue [ Joint disease appears to start earlier and progress more rapidly in males than in females. Knees, hips, and shoulders are frequently affected. Fifty percent of individuals require at least one joint replacement by age 55 years [ Because the kidneys are responsible for secreting massive quantities of HGA, impaired renal function can accelerate the development of ochronosis and joint destruction [ Renal function is critical for individuals with alkaptonuria as the kidney actively secretes HGA. Kidney injury, either acute or chronic, may impair the elimination of HGA and cause HGA to accumulate in the blood and tissues. This may lead to acidosis, hemolysis, and methemoglobinemia, which may be fatal [ ## Connective Tissue In general, pigmentary changes are observed after age 30 years. Tendon-related findings, including a thickened Achilles tendon, tendonitis, and rupture, have also been observed clinically [ ## Joints Ochronotic arthritis is a regular manifestation of longstanding alkaptonuria. Involvement of the spine usually appears in the third decade. In one large series, low back pain was observed prior to age 30 years in 49% of individuals and prior to age 40 years in 94% [ Lumbar and thoracic spine symptoms precede cervical spine symptoms. The sacroiliac region is usually spared. Limitation of spine flexion directly correlates with degree of disability. Individuals with decreased forward flexion demonstrate impaired function and increased fatigue [ Joint disease appears to start earlier and progress more rapidly in males than in females. Knees, hips, and shoulders are frequently affected. Fifty percent of individuals require at least one joint replacement by age 55 years [ Because the kidneys are responsible for secreting massive quantities of HGA, impaired renal function can accelerate the development of ochronosis and joint destruction [ ## Other Organ Involvement Renal function is critical for individuals with alkaptonuria as the kidney actively secretes HGA. Kidney injury, either acute or chronic, may impair the elimination of HGA and cause HGA to accumulate in the blood and tissues. This may lead to acidosis, hemolysis, and methemoglobinemia, which may be fatal [ ## Genotype-Phenotype Correlations No correlation is observed between the type of While analysis of HGD variants from 172 individuals with alkaptonuria revealed that residual HGA activity ranged from 1% to more than 30%, there was no observed difference in serum HGA, urinary excretion of HGA, or clinical manifestations [ ## Nomenclature Occasionally alkaptonuria is referred to collectively (and incorrectly) as ochronosis. ## Prevalence At least 1000 affected individuals have been described in the literature; this is likely an underestimate. The incidence of alkaptonuria in the US is estimated at 1:250,000 to 1:1,000,000 live births. Alkaptonuria occurs worldwide. The prevalence of alkaptonuria in Slovakia is estimated at 1:19,000 [ A high prevalence has been observed in the Dominican Republic due to the founder variant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Chemically induced ochronosis has also been described following long-term use of either the antimalarial agent Atabrine A thorough history combined with lack of excessive HGA excretion in the urine should eliminate false positive diagnoses. ## Management No clinical practice guidelines for alkaptonuria have been published. To establish the extent of disease and needs in an individual diagnosed with alkaptonuria, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Complete history and physical examination with particular attention to range of motion in the spine and large joints Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs Electrocardiogram and echocardiogram in individuals older than age 40 years Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi Measurement of TSH and free thyroxine to evaluate for primary hypothyroidism 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 alkaptonuria in order to facilitate medical and personal decision making In the US, treatment of alkaptonuria remains symptomatic. While the European Medicines Agency has authorized marketing of nitisinone for treatment of alkaptonuria, to date the US Food and Drug Administration has not approved use of nitisinone for treatment of alkaptonuria. Physical and occupational therapy are important to promote optimal muscle strength and flexibility. Maintaining joint range of motion through moderate non-weight-bearing exercise such as swimming may have beneficial effects. Knee, hip, and shoulder replacement surgeries are options for managing significant arthritis. In general, the goal of joint replacement is pain relief rather than increased range of motion. Joint replacement in individuals with alkaptonuria is associated with prosthetic survival comparable to that found in individuals with osteoarthritis. In individuals with alkaptonuria total joint replacement significantly improves function compared with preoperative disability [ Nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (the enzyme that produces HGA), is approved for the treatment of A follow-up multi-center randomized controlled study ( Ineffective treatments include the following: Studies of dietary restriction of phenylalanine and tyrosine to reduce the production of HGA have not shown efficacy; furthermore, severe restriction of these amino acids is not practical in the long term and may be dangerous. Although high-dose vitamin C decreases urinary benzoquinone acetic acid (a derivative of HGA), it has no effect on HGA excretion [ Individuals with symptoms suggestive of coronary artery disease may be candidates for CT imaging, depending on the recommendation of a medical provider. Routine surveillance is not recommended, but awareness of this potential complication is advised. Ochronotic prostate stones appear on radiography; kidney stones can be identified by ultrasonography and helical abdominal CT. Avoidance of physical stress to the spine and large joints, including heavy manual labor or high-impact sports, may reduce the progression of severe arthritis. Younger individuals with alkaptonuria should be directed toward non-contact and lower-impact sports. It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from preventive measures. Evaluations can include: Biochemical testing for the presence of elevated urinary homogentisic acid (HGA); Molecular genetic testing if the Those found to have alkaptonuria should be counseled to avoid high-impact and contact sports. Career considerations include avoidance of occupations involving heavy physical labor. Instruction on joint strengthening and flexibility exercises, in conjunction with appropriate physical activity, can help preserve overall joint mobility and function. See Search • Complete history and physical examination with particular attention to range of motion in the spine and large joints • Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs • Electrocardiogram and echocardiogram in individuals older than age 40 years • Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi • Measurement of TSH and free thyroxine to evaluate for primary hypothyroidism • 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 alkaptonuria in order to facilitate medical and personal decision making • Studies of dietary restriction of phenylalanine and tyrosine to reduce the production of HGA have not shown efficacy; furthermore, severe restriction of these amino acids is not practical in the long term and may be dangerous. • Although high-dose vitamin C decreases urinary benzoquinone acetic acid (a derivative of HGA), it has no effect on HGA excretion [ • Routine surveillance is not recommended, but awareness of this potential complication is advised. • Ochronotic prostate stones appear on radiography; kidney stones can be identified by ultrasonography and helical abdominal CT. • Biochemical testing for the presence of elevated urinary homogentisic acid (HGA); • Molecular genetic testing if the ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with alkaptonuria, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Complete history and physical examination with particular attention to range of motion in the spine and large joints Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs Electrocardiogram and echocardiogram in individuals older than age 40 years Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi Measurement of TSH and free thyroxine to evaluate for primary hypothyroidism 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 alkaptonuria in order to facilitate medical and personal decision making • Complete history and physical examination with particular attention to range of motion in the spine and large joints • Physical medicine and rehabilitation evaluation if limited range of motion or joint pain occurs • Electrocardiogram and echocardiogram in individuals older than age 40 years • Renal ultrasound examination or helical abdominal CT to evaluate for the presence of renal calculi • Measurement of TSH and free thyroxine to evaluate for primary hypothyroidism • 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 alkaptonuria in order to facilitate medical and personal decision making ## Treatment of Manifestations In the US, treatment of alkaptonuria remains symptomatic. While the European Medicines Agency has authorized marketing of nitisinone for treatment of alkaptonuria, to date the US Food and Drug Administration has not approved use of nitisinone for treatment of alkaptonuria. Physical and occupational therapy are important to promote optimal muscle strength and flexibility. Maintaining joint range of motion through moderate non-weight-bearing exercise such as swimming may have beneficial effects. Knee, hip, and shoulder replacement surgeries are options for managing significant arthritis. In general, the goal of joint replacement is pain relief rather than increased range of motion. Joint replacement in individuals with alkaptonuria is associated with prosthetic survival comparable to that found in individuals with osteoarthritis. In individuals with alkaptonuria total joint replacement significantly improves function compared with preoperative disability [ Nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (the enzyme that produces HGA), is approved for the treatment of A follow-up multi-center randomized controlled study ( Ineffective treatments include the following: Studies of dietary restriction of phenylalanine and tyrosine to reduce the production of HGA have not shown efficacy; furthermore, severe restriction of these amino acids is not practical in the long term and may be dangerous. Although high-dose vitamin C decreases urinary benzoquinone acetic acid (a derivative of HGA), it has no effect on HGA excretion [ • Studies of dietary restriction of phenylalanine and tyrosine to reduce the production of HGA have not shown efficacy; furthermore, severe restriction of these amino acids is not practical in the long term and may be dangerous. • Although high-dose vitamin C decreases urinary benzoquinone acetic acid (a derivative of HGA), it has no effect on HGA excretion [ ## Symptomatic Management Physical and occupational therapy are important to promote optimal muscle strength and flexibility. Maintaining joint range of motion through moderate non-weight-bearing exercise such as swimming may have beneficial effects. Knee, hip, and shoulder replacement surgeries are options for managing significant arthritis. In general, the goal of joint replacement is pain relief rather than increased range of motion. Joint replacement in individuals with alkaptonuria is associated with prosthetic survival comparable to that found in individuals with osteoarthritis. In individuals with alkaptonuria total joint replacement significantly improves function compared with preoperative disability [ ## Nitisinone Nitisinone, an inhibitor of 4-hydroxyphenylpyruvate dioxygenase (the enzyme that produces HGA), is approved for the treatment of A follow-up multi-center randomized controlled study ( ## Ineffective Treatments Ineffective treatments include the following: Studies of dietary restriction of phenylalanine and tyrosine to reduce the production of HGA have not shown efficacy; furthermore, severe restriction of these amino acids is not practical in the long term and may be dangerous. Although high-dose vitamin C decreases urinary benzoquinone acetic acid (a derivative of HGA), it has no effect on HGA excretion [ • Studies of dietary restriction of phenylalanine and tyrosine to reduce the production of HGA have not shown efficacy; furthermore, severe restriction of these amino acids is not practical in the long term and may be dangerous. • Although high-dose vitamin C decreases urinary benzoquinone acetic acid (a derivative of HGA), it has no effect on HGA excretion [ ## Surveillance Individuals with symptoms suggestive of coronary artery disease may be candidates for CT imaging, depending on the recommendation of a medical provider. Routine surveillance is not recommended, but awareness of this potential complication is advised. Ochronotic prostate stones appear on radiography; kidney stones can be identified by ultrasonography and helical abdominal CT. • Routine surveillance is not recommended, but awareness of this potential complication is advised. • Ochronotic prostate stones appear on radiography; kidney stones can be identified by ultrasonography and helical abdominal CT. ## Agents/Circumstances to Avoid Avoidance of physical stress to the spine and large joints, including heavy manual labor or high-impact sports, may reduce the progression of severe arthritis. Younger individuals with alkaptonuria should be directed toward non-contact and lower-impact sports. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual in order to identify as early as possible those who would benefit from preventive measures. Evaluations can include: Biochemical testing for the presence of elevated urinary homogentisic acid (HGA); Molecular genetic testing if the Those found to have alkaptonuria should be counseled to avoid high-impact and contact sports. Career considerations include avoidance of occupations involving heavy physical labor. Instruction on joint strengthening and flexibility exercises, in conjunction with appropriate physical activity, can help preserve overall joint mobility and function. See • Biochemical testing for the presence of elevated urinary homogentisic acid (HGA); • Molecular genetic testing if the ## Therapies Under Investigation Search ## Genetic Counseling Alkaptonuria is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Urinary excretion of homogentisic acid and disease severity can vary significantly between sibs with the same Heterozygotes 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. 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) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Urinary excretion of homogentisic acid and disease severity can vary significantly between sibs with the same • Heterozygotes 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. ## Mode of Inheritance Alkaptonuria is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Urinary excretion of homogentisic acid and disease severity can vary significantly between sibs with the same Heterozygotes 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 • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • If both parents are known to be heterozygous for an • Urinary excretion of homogentisic acid and disease severity can vary significantly between sibs with the same • Heterozygotes 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. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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. ## 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 66 Devonshire Road Cambridge CB1 2BL United Kingdom National Institutes of Health United Kingdom • • • • 66 Devonshire Road • Cambridge CB1 2BL • United Kingdom • • • National Institutes of Health • • • • • United Kingdom • • • ## Molecular Genetics Alkaptonuria: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alkaptonuria ( Alkaptonuria is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD), the third enzyme of the tyrosine degradation pathway ( Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis Alkaptonuria is caused by a deficiency of the enzyme homogentisate 1,2-dioxygenase (HGD), the third enzyme of the tyrosine degradation pathway ( Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes Dr Introne is a pediatrician, clinical geneticist, and biochemical geneticist who has cared for more than 170 patients with alkaptonuria since 2000. Dr Perry is a physiatrist who has cared for more than 170 patients with alkaptonuria. Dr Chen is a cardiologist who specializes in cardiovascular CT and MRI, and has imaged more than 150 patients with alkaptonuria. This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. The authors would like to thank Dr William Gahl for his previous authorship on this review and his commitment to patients with alkaptonuria. We would also like to thank the AKU Society and all of the member chapters who have supported our research as well as patients, families, and health care providers. Marcus Chen, MD (2021-present)William A Gahl, MD, PhD; National Human Genome Research Institute (2003-2021) Wendy J Introne, MD (2003-present) Michael A Kayser, DO; Saint Francis Hospital, Tulsa (2007-2013) Monique Perry, MD (2021-present)Chanika Phornphutkul, MD; Brown University (2003-2007) Pim Suwannarat, MD; Mahidol University (2003-2007) 10 June 2021 (bp) Comprehensive update posted live 12 May 2016 (sw) Comprehensive update posted live 22 August 2013 (me) Comprehensive update posted live 10 March 2011 (me) Comprehensive update posted live 2 July 2009 (cd) Revision: sequence analysis available clinically 4 December 2007 (me) Comprehensive update posted live 26 June 2006 (ca) Revision: targeted mutation analysis available for eight mutations 24 May 2005 (me) Comprehensive update posted live 9 May 2003 (me) Review posted live 4 March 2003 (ps) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 10 June 2021 (bp) Comprehensive update posted live • 12 May 2016 (sw) Comprehensive update posted live • 22 August 2013 (me) Comprehensive update posted live • 10 March 2011 (me) Comprehensive update posted live • 2 July 2009 (cd) Revision: sequence analysis available clinically • 4 December 2007 (me) Comprehensive update posted live • 26 June 2006 (ca) Revision: targeted mutation analysis available for eight mutations • 24 May 2005 (me) Comprehensive update posted live • 9 May 2003 (me) Review posted live • 4 March 2003 (ps) Original submission ## Author Notes Dr Introne is a pediatrician, clinical geneticist, and biochemical geneticist who has cared for more than 170 patients with alkaptonuria since 2000. Dr Perry is a physiatrist who has cared for more than 170 patients with alkaptonuria. Dr Chen is a cardiologist who specializes in cardiovascular CT and MRI, and has imaged more than 150 patients with alkaptonuria. ## Acknowledgments This work was supported by the Intramural Research Program of the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. The authors would like to thank Dr William Gahl for his previous authorship on this review and his commitment to patients with alkaptonuria. We would also like to thank the AKU Society and all of the member chapters who have supported our research as well as patients, families, and health care providers. ## Author History Marcus Chen, MD (2021-present)William A Gahl, MD, PhD; National Human Genome Research Institute (2003-2021) Wendy J Introne, MD (2003-present) Michael A Kayser, DO; Saint Francis Hospital, Tulsa (2007-2013) Monique Perry, MD (2021-present)Chanika Phornphutkul, MD; Brown University (2003-2007) Pim Suwannarat, MD; Mahidol University (2003-2007) ## Revision History 10 June 2021 (bp) Comprehensive update posted live 12 May 2016 (sw) Comprehensive update posted live 22 August 2013 (me) Comprehensive update posted live 10 March 2011 (me) Comprehensive update posted live 2 July 2009 (cd) Revision: sequence analysis available clinically 4 December 2007 (me) Comprehensive update posted live 26 June 2006 (ca) Revision: targeted mutation analysis available for eight mutations 24 May 2005 (me) Comprehensive update posted live 9 May 2003 (me) Review posted live 4 March 2003 (ps) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 10 June 2021 (bp) Comprehensive update posted live • 12 May 2016 (sw) Comprehensive update posted live • 22 August 2013 (me) Comprehensive update posted live • 10 March 2011 (me) Comprehensive update posted live • 2 July 2009 (cd) Revision: sequence analysis available clinically • 4 December 2007 (me) Comprehensive update posted live • 26 June 2006 (ca) Revision: targeted mutation analysis available for eight mutations • 24 May 2005 (me) Comprehensive update posted live • 9 May 2003 (me) Review posted live • 4 March 2003 (ps) Original submission ## References ## Literature Cited A. 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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", "OK Skinsnes. Generalized ochronosis; report of an instance in which it was misdiagnosed as melanosarcoma, with resultant enucleation of an eye.. Arch Pathol (Chic) 1948;45:552-8", "JR Stichman, SG West. Minocycline-induced cartilage hyperpigmentation mimicking alkaptonuria in a patient with knee pain.. J Rheumatol 2016;43:825", "P Suwannarat, C Phornphutkul, I Bernardini, M Turner, WA Gahl. Minocycline-induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain.. Arthritis Rheum 2004;50:3698-701", "T Vilboux, M Kayser, W Introne, P Suwannarat, I Bernardini, R Fischer, K O’Brien, R Kleta, M Huizing, WA Gahl. Mutation spectrum of homogentisic acid oxidase (HGD) in alkaptonuria.. Hum Mutat 2009;30:1611-9", "JA Wolff, B Barshop, WL Nyhan, J Leslie, JE Seegmiller, H Gruber, M Garst, S Winter, K Michals, R Matalon. Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone acetic acid and an ontogenic effect in infancy.. Pediatr Res 1989;26:140-4", "A Zatkova, A Chmelikova, H Polakova, E Ferakova, L Kadasi. Rapid detection methods for five HGO gene mutations causing alkaptonuria.. Clin Genet 2003;63:145-9", "A Zatková, DB de Bernabé, H Poláková, M Zvarík, E Feráková, V Bosák, V Ferák, L Kádasi, SR de Córdoba. High frequency of alkaptonuria in Slovakia: evidence for the appearance of multiple mutations in HGO involving different mutational hot spots.. Am J Hum Genet 2000;67:1333-9" ]	9/5/2003	10/6/2021	2/7/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alpers	alpers	[ "Alpers-Huttenlocher Syndrome (AHS)", "Ataxia Neuropathy Spectrum (ANS)", "Autosomal Recessive Progressive External Ophthalmoplegia (arPEO)", "Autosomal Dominant Progressive External Ophthalmoplegia (adPEO)", "Childhood Myocerebrohepatopathy Spectrum (MCHS)", "Myoclonic Epilepsy Myopathy Sensory Ataxia (MEMSA)", "DNA polymerase subunit gamma-1", "POLG", "POLG-Related Disorders" ]		Bruce H Cohen, Patrick F Chinnery, William C Copeland	Summary Establishing the diagnosis of a Early-onset and juvenile/adult-onset Once the	Adapted from +++ = feature is typically present; + = feature is often present adPEO = autosomal dominant progressive external ophthalmoplegia; AHS = Alpers-Huttenlocher syndrome; ANS = ataxia neuropathy spectrum; arPEO = autosomal recessive progressive external ophthalmoplegia; MCHS = myocerebrohepatopathy spectrum; MEMSA = myoclonic epilepsy myopathy sensory ataxia ## Diagnosis Liver involvement (See Feeding difficulties Seizures Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) Ataxia Peripheral neuropathy Seizures Stroke-like episodes PEO (in individuals with longer survival) Ptosis PEO Ataxia Muscle weakness Developmental delay, especially in childhood-onset disease Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) Episodic psychomotor regression Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes Endocrinopathy (e.g., premature ovarian failure) Elevated serum lactate in serum and cerebrospinal fluid (CSF) is common throughout the spectrum of phenotypes but is more common in early-onset disease (however, normal values do not eliminate the likelihood of a CSF protein levels are generally elevated in individuals with Alpers-Huttenlocher syndrome (AHS) and other Evidence of liver dysfunction or failure can be present, which may occur following exposure to certain anti-seizure medications. This could result in elevation of liver enzymes (alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase) as well as synthetic liver dysfunction, causing hypoglycemia, hyperammonemia, elevated glutamine, hyperbilirubinemia, prolonged bleeding times (international normalized ratio, prothrombin time, partial thromboplastin time), hypoalbuminemia, and low cholesterol levels. Respiratory chain defect and/or a defect of mitochondrial DNA (mtDNA) (depletion or multiple deletions) can be present. This could result in respiratory chain dysfunction, identified by either enzymatic assays or polarographic assays. Depletion of mtDNA can be measured by comparing mtDNA to nuclear DNA content in an affected tissue (e.g., liver). Normal respiratory chain function or absence of mtDNA depletion does not rule out a In muscle biopsy samples, ragged-red fibers, COX-negative fibers, excessive lipid deposits, and abnormal respiratory chain activities can be present. However, biochemical findings on muscle biopsy can be normal. Brain computerized tomography (CT) or magnetic resonance imaging (MRI) may be normal early in the course of AHS. As AHS evolves, neuroimaging shows gliosis (initially more pronounced in occipital lobe regions) and generalized brain atrophy. These findings are also reported in some individuals with adult-onset Cortical focal lesions manifesting as T Abnormal epileptiform activity over the occipital lobes in individuals with epilepsy Abnormal nerve conduction studies (NCVs) The diagnosis of most Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: (1) In individuals with a suspected autosomal recessive 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. 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. • • Liver involvement (See • Feeding difficulties • Seizures • Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) • Liver involvement (See • Feeding difficulties • Seizures • Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) • • Ataxia • Peripheral neuropathy • Seizures • Stroke-like episodes • PEO (in individuals with longer survival) • Ataxia • Peripheral neuropathy • Seizures • Stroke-like episodes • PEO (in individuals with longer survival) • • Ptosis • PEO • Ataxia • Muscle weakness • Ptosis • PEO • Ataxia • Muscle weakness • • Developmental delay, especially in childhood-onset disease • Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) • Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) • Episodic psychomotor regression • Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes • Endocrinopathy (e.g., premature ovarian failure) • Developmental delay, especially in childhood-onset disease • Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) • Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) • Episodic psychomotor regression • Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes • Endocrinopathy (e.g., premature ovarian failure) • Liver involvement (See • Feeding difficulties • Seizures • Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) • Ataxia • Peripheral neuropathy • Seizures • Stroke-like episodes • PEO (in individuals with longer survival) • Ptosis • PEO • Ataxia • Muscle weakness • Developmental delay, especially in childhood-onset disease • Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) • Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) • Episodic psychomotor regression • Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes • Endocrinopathy (e.g., premature ovarian failure) • Elevated serum lactate in serum and cerebrospinal fluid (CSF) is common throughout the spectrum of phenotypes but is more common in early-onset disease (however, normal values do not eliminate the likelihood of a • CSF protein levels are generally elevated in individuals with Alpers-Huttenlocher syndrome (AHS) and other • Evidence of liver dysfunction or failure can be present, which may occur following exposure to certain anti-seizure medications. This could result in elevation of liver enzymes (alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase) as well as synthetic liver dysfunction, causing hypoglycemia, hyperammonemia, elevated glutamine, hyperbilirubinemia, prolonged bleeding times (international normalized ratio, prothrombin time, partial thromboplastin time), hypoalbuminemia, and low cholesterol levels. • Respiratory chain defect and/or a defect of mitochondrial DNA (mtDNA) (depletion or multiple deletions) can be present. This could result in respiratory chain dysfunction, identified by either enzymatic assays or polarographic assays. Depletion of mtDNA can be measured by comparing mtDNA to nuclear DNA content in an affected tissue (e.g., liver). Normal respiratory chain function or absence of mtDNA depletion does not rule out a • In muscle biopsy samples, ragged-red fibers, COX-negative fibers, excessive lipid deposits, and abnormal respiratory chain activities can be present. However, biochemical findings on muscle biopsy can be normal. • Brain computerized tomography (CT) or magnetic resonance imaging (MRI) may be normal early in the course of AHS. • As AHS evolves, neuroimaging shows gliosis (initially more pronounced in occipital lobe regions) and generalized brain atrophy. These findings are also reported in some individuals with adult-onset • Cortical focal lesions manifesting as T • Abnormal epileptiform activity over the occipital lobes in individuals with epilepsy • Abnormal nerve conduction studies (NCVs) ## Suggestive Findings Liver involvement (See Feeding difficulties Seizures Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) Ataxia Peripheral neuropathy Seizures Stroke-like episodes PEO (in individuals with longer survival) Ptosis PEO Ataxia Muscle weakness Developmental delay, especially in childhood-onset disease Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) Episodic psychomotor regression Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes Endocrinopathy (e.g., premature ovarian failure) Elevated serum lactate in serum and cerebrospinal fluid (CSF) is common throughout the spectrum of phenotypes but is more common in early-onset disease (however, normal values do not eliminate the likelihood of a CSF protein levels are generally elevated in individuals with Alpers-Huttenlocher syndrome (AHS) and other Evidence of liver dysfunction or failure can be present, which may occur following exposure to certain anti-seizure medications. This could result in elevation of liver enzymes (alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase) as well as synthetic liver dysfunction, causing hypoglycemia, hyperammonemia, elevated glutamine, hyperbilirubinemia, prolonged bleeding times (international normalized ratio, prothrombin time, partial thromboplastin time), hypoalbuminemia, and low cholesterol levels. Respiratory chain defect and/or a defect of mitochondrial DNA (mtDNA) (depletion or multiple deletions) can be present. This could result in respiratory chain dysfunction, identified by either enzymatic assays or polarographic assays. Depletion of mtDNA can be measured by comparing mtDNA to nuclear DNA content in an affected tissue (e.g., liver). Normal respiratory chain function or absence of mtDNA depletion does not rule out a In muscle biopsy samples, ragged-red fibers, COX-negative fibers, excessive lipid deposits, and abnormal respiratory chain activities can be present. However, biochemical findings on muscle biopsy can be normal. Brain computerized tomography (CT) or magnetic resonance imaging (MRI) may be normal early in the course of AHS. As AHS evolves, neuroimaging shows gliosis (initially more pronounced in occipital lobe regions) and generalized brain atrophy. These findings are also reported in some individuals with adult-onset Cortical focal lesions manifesting as T Abnormal epileptiform activity over the occipital lobes in individuals with epilepsy Abnormal nerve conduction studies (NCVs) • • Liver involvement (See • Feeding difficulties • Seizures • Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) • Liver involvement (See • Feeding difficulties • Seizures • Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) • • Ataxia • Peripheral neuropathy • Seizures • Stroke-like episodes • PEO (in individuals with longer survival) • Ataxia • Peripheral neuropathy • Seizures • Stroke-like episodes • PEO (in individuals with longer survival) • • Ptosis • PEO • Ataxia • Muscle weakness • Ptosis • PEO • Ataxia • Muscle weakness • • Developmental delay, especially in childhood-onset disease • Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) • Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) • Episodic psychomotor regression • Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes • Endocrinopathy (e.g., premature ovarian failure) • Developmental delay, especially in childhood-onset disease • Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) • Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) • Episodic psychomotor regression • Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes • Endocrinopathy (e.g., premature ovarian failure) • Liver involvement (See • Feeding difficulties • Seizures • Hypotonia and muscle weakness that can evolve into corticospinal tract dysfunction (spasticity and dystonia) • Ataxia • Peripheral neuropathy • Seizures • Stroke-like episodes • PEO (in individuals with longer survival) • Ptosis • PEO • Ataxia • Muscle weakness • Developmental delay, especially in childhood-onset disease • Movement disorder (e.g., myoclonus, dysarthria, choreoathetosis, parkinsonism) • Myopathy (e.g., proximal > distal limb weakness with fatigue and exercise intolerance) • Episodic psychomotor regression • Psychiatric illness (e.g., depression, mood disorder), more commonly reported in adult-onset phenotypes • Endocrinopathy (e.g., premature ovarian failure) • Elevated serum lactate in serum and cerebrospinal fluid (CSF) is common throughout the spectrum of phenotypes but is more common in early-onset disease (however, normal values do not eliminate the likelihood of a • CSF protein levels are generally elevated in individuals with Alpers-Huttenlocher syndrome (AHS) and other • Evidence of liver dysfunction or failure can be present, which may occur following exposure to certain anti-seizure medications. This could result in elevation of liver enzymes (alanine transaminase, aspartate transaminase, and gamma-glutamyl transferase) as well as synthetic liver dysfunction, causing hypoglycemia, hyperammonemia, elevated glutamine, hyperbilirubinemia, prolonged bleeding times (international normalized ratio, prothrombin time, partial thromboplastin time), hypoalbuminemia, and low cholesterol levels. • Respiratory chain defect and/or a defect of mitochondrial DNA (mtDNA) (depletion or multiple deletions) can be present. This could result in respiratory chain dysfunction, identified by either enzymatic assays or polarographic assays. Depletion of mtDNA can be measured by comparing mtDNA to nuclear DNA content in an affected tissue (e.g., liver). Normal respiratory chain function or absence of mtDNA depletion does not rule out a • In muscle biopsy samples, ragged-red fibers, COX-negative fibers, excessive lipid deposits, and abnormal respiratory chain activities can be present. However, biochemical findings on muscle biopsy can be normal. • Brain computerized tomography (CT) or magnetic resonance imaging (MRI) may be normal early in the course of AHS. • As AHS evolves, neuroimaging shows gliosis (initially more pronounced in occipital lobe regions) and generalized brain atrophy. These findings are also reported in some individuals with adult-onset • Cortical focal lesions manifesting as T • Abnormal epileptiform activity over the occipital lobes in individuals with epilepsy • Abnormal nerve conduction studies (NCVs) ## Establishing the Diagnosis The diagnosis of most Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: (1) In individuals with a suspected autosomal recessive 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. 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 Note: (1) In individuals with a suspected autosomal recessive For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 Although some affected individuals present with one of the clinical entities caused by Clinical Findings in Based on MCHS = childhood myocerebrohepatopathy spectrum Corresponds to the acronym SANDO (sensory ataxia neuropathy dysarthria and ophthalmoplegia) Typical features of early-onset AHS, one of the most severe phenotypic manifestations in the In some instances, the initial seizure type is epilepsia partialis continua (EPC), a classic motor seizure type that involves only one portion of the body (e.g., a limb) with constant and repetitive myoclonic jerking, continuing for hours or days with or without dramatic effects on consciousness. EPC is not always apparent as an abnormality on EEG and can be mistaken for a conversion reaction. EEG may be normal or show only focal slowing of the background rhythm. Over time, seizures can evolve into a complex epileptic disorder such as focal status epilepticus, EPC, or multifocal myoclonic epilepsy [ In some children, seizures are initially controllable with standard dosages of anti-seizure medications (ASM); in others, seizures, such as EPC, are refractory from the onset. Over time, seizures become increasingly resistant to ASMs. (See Of note, valproic acid (Depakene Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. MCHS presents between the first few months of life through age three years. In one study, it presented at a median age of 4.7 months (range: 0.9-7 months) with developmental delay or dementia, lactic acidosis, myopathy/hypotonia, and failure to thrive. Other features that may be present include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Seizures occur in about 75% of affected individuals. This is an ultimately fatal illness with a median age of death in one study of 15.8 months (range: 1.0-184.6 months). Major causes of death include liver failure, sepsis, and status epilepticus [ Typical features of juvenile/adult-onset Previously referred to as spinocerebellar ataxia with epilepsy (SCAE), MEMSA describes the spectrum of disorders presenting with myopathy, epilepsy, and ataxia without ophthalmoplegia. Cerebellar ataxia, generally the first sign, begins in young adulthood as a subclinical sensory polyneuropathy. Epilepsy develops in later years, often beginning focally and then spreading to become generalized. As in other ANS includes mitochondrial recessive ataxia syndrome (MIRAS) and a separate entity known as sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) [ Other features include myoclonus, blindness, and liver dysfunction [ Although muscle pathology may show COX-negative fibers, there may be no pathologic findings. Typical features of late-onset Progressive PEO without systemic involvement is the hallmark of arPEO. Caution needs to be exercised, however, when making the diagnosis of arPEO, as some The universal manifestation of this adult-onset disorder is progressive weakness of the extraocular eye muscles resulting in ptosis and strabismus [ No genotype-phenotype correlations have been identified. In a study of 155 individuals with AHS is reported to affect approximately 1:51,000 people [ The combined frequency of the most common autosomal recessive pathogenic variants in Frequency of the Most Common Based on Indicates two different pathogenic variants on the same allele (see Pathogenic variants in • Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. ## Clinical Description Although some affected individuals present with one of the clinical entities caused by Clinical Findings in Based on MCHS = childhood myocerebrohepatopathy spectrum Corresponds to the acronym SANDO (sensory ataxia neuropathy dysarthria and ophthalmoplegia) Typical features of early-onset AHS, one of the most severe phenotypic manifestations in the In some instances, the initial seizure type is epilepsia partialis continua (EPC), a classic motor seizure type that involves only one portion of the body (e.g., a limb) with constant and repetitive myoclonic jerking, continuing for hours or days with or without dramatic effects on consciousness. EPC is not always apparent as an abnormality on EEG and can be mistaken for a conversion reaction. EEG may be normal or show only focal slowing of the background rhythm. Over time, seizures can evolve into a complex epileptic disorder such as focal status epilepticus, EPC, or multifocal myoclonic epilepsy [ In some children, seizures are initially controllable with standard dosages of anti-seizure medications (ASM); in others, seizures, such as EPC, are refractory from the onset. Over time, seizures become increasingly resistant to ASMs. (See Of note, valproic acid (Depakene Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. MCHS presents between the first few months of life through age three years. In one study, it presented at a median age of 4.7 months (range: 0.9-7 months) with developmental delay or dementia, lactic acidosis, myopathy/hypotonia, and failure to thrive. Other features that may be present include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Seizures occur in about 75% of affected individuals. This is an ultimately fatal illness with a median age of death in one study of 15.8 months (range: 1.0-184.6 months). Major causes of death include liver failure, sepsis, and status epilepticus [ Typical features of juvenile/adult-onset Previously referred to as spinocerebellar ataxia with epilepsy (SCAE), MEMSA describes the spectrum of disorders presenting with myopathy, epilepsy, and ataxia without ophthalmoplegia. Cerebellar ataxia, generally the first sign, begins in young adulthood as a subclinical sensory polyneuropathy. Epilepsy develops in later years, often beginning focally and then spreading to become generalized. As in other ANS includes mitochondrial recessive ataxia syndrome (MIRAS) and a separate entity known as sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) [ Other features include myoclonus, blindness, and liver dysfunction [ Although muscle pathology may show COX-negative fibers, there may be no pathologic findings. Typical features of late-onset Progressive PEO without systemic involvement is the hallmark of arPEO. Caution needs to be exercised, however, when making the diagnosis of arPEO, as some The universal manifestation of this adult-onset disorder is progressive weakness of the extraocular eye muscles resulting in ptosis and strabismus [ • Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. ## Early-Onset Disease (Prior to Age 12 Years) Typical features of early-onset AHS, one of the most severe phenotypic manifestations in the In some instances, the initial seizure type is epilepsia partialis continua (EPC), a classic motor seizure type that involves only one portion of the body (e.g., a limb) with constant and repetitive myoclonic jerking, continuing for hours or days with or without dramatic effects on consciousness. EPC is not always apparent as an abnormality on EEG and can be mistaken for a conversion reaction. EEG may be normal or show only focal slowing of the background rhythm. Over time, seizures can evolve into a complex epileptic disorder such as focal status epilepticus, EPC, or multifocal myoclonic epilepsy [ In some children, seizures are initially controllable with standard dosages of anti-seizure medications (ASM); in others, seizures, such as EPC, are refractory from the onset. Over time, seizures become increasingly resistant to ASMs. (See Of note, valproic acid (Depakene Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. MCHS presents between the first few months of life through age three years. In one study, it presented at a median age of 4.7 months (range: 0.9-7 months) with developmental delay or dementia, lactic acidosis, myopathy/hypotonia, and failure to thrive. Other features that may be present include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Seizures occur in about 75% of affected individuals. This is an ultimately fatal illness with a median age of death in one study of 15.8 months (range: 1.0-184.6 months). Major causes of death include liver failure, sepsis, and status epilepticus [ • Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. ## AHS, one of the most severe phenotypic manifestations in the In some instances, the initial seizure type is epilepsia partialis continua (EPC), a classic motor seizure type that involves only one portion of the body (e.g., a limb) with constant and repetitive myoclonic jerking, continuing for hours or days with or without dramatic effects on consciousness. EPC is not always apparent as an abnormality on EEG and can be mistaken for a conversion reaction. EEG may be normal or show only focal slowing of the background rhythm. Over time, seizures can evolve into a complex epileptic disorder such as focal status epilepticus, EPC, or multifocal myoclonic epilepsy [ In some children, seizures are initially controllable with standard dosages of anti-seizure medications (ASM); in others, seizures, such as EPC, are refractory from the onset. Over time, seizures become increasingly resistant to ASMs. (See Of note, valproic acid (Depakene Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. • Microscopic abnormalities throughout the cerebral cortex evolve as the disease progresses. Early in the course of the disease, spongiosis, astrocytosis, and neuronal loss are prevalent in the superficial cortex. Later, the deeper laminae are affected. In the most advanced stages, the entire cortex becomes a thin dense gliotic scar. Usually, the striate cortex is the most affected part of the brain, followed by the thalamus, hippocampus, and cerebellum. These pathologic features differ from those resulting from hypoxic injury, recurrent seizures, or other causes of hepatic failure. ## MCHS presents between the first few months of life through age three years. In one study, it presented at a median age of 4.7 months (range: 0.9-7 months) with developmental delay or dementia, lactic acidosis, myopathy/hypotonia, and failure to thrive. Other features that may be present include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Seizures occur in about 75% of affected individuals. This is an ultimately fatal illness with a median age of death in one study of 15.8 months (range: 1.0-184.6 months). Major causes of death include liver failure, sepsis, and status epilepticus [ ## Juvenile/Adult-Onset Disease (Age 12-40 Years) Typical features of juvenile/adult-onset Previously referred to as spinocerebellar ataxia with epilepsy (SCAE), MEMSA describes the spectrum of disorders presenting with myopathy, epilepsy, and ataxia without ophthalmoplegia. Cerebellar ataxia, generally the first sign, begins in young adulthood as a subclinical sensory polyneuropathy. Epilepsy develops in later years, often beginning focally and then spreading to become generalized. As in other ANS includes mitochondrial recessive ataxia syndrome (MIRAS) and a separate entity known as sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) [ Other features include myoclonus, blindness, and liver dysfunction [ Although muscle pathology may show COX-negative fibers, there may be no pathologic findings. ## Previously referred to as spinocerebellar ataxia with epilepsy (SCAE), MEMSA describes the spectrum of disorders presenting with myopathy, epilepsy, and ataxia without ophthalmoplegia. Cerebellar ataxia, generally the first sign, begins in young adulthood as a subclinical sensory polyneuropathy. Epilepsy develops in later years, often beginning focally and then spreading to become generalized. As in other ## ANS includes mitochondrial recessive ataxia syndrome (MIRAS) and a separate entity known as sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) [ Other features include myoclonus, blindness, and liver dysfunction [ Although muscle pathology may show COX-negative fibers, there may be no pathologic findings. ## Late-Onset Disease (Age >40 Years) Typical features of late-onset Progressive PEO without systemic involvement is the hallmark of arPEO. Caution needs to be exercised, however, when making the diagnosis of arPEO, as some The universal manifestation of this adult-onset disorder is progressive weakness of the extraocular eye muscles resulting in ptosis and strabismus [ ## Progressive PEO without systemic involvement is the hallmark of arPEO. Caution needs to be exercised, however, when making the diagnosis of arPEO, as some ## The universal manifestation of this adult-onset disorder is progressive weakness of the extraocular eye muscles resulting in ptosis and strabismus [ ## Rare Phenotypes ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Nomenclature In a study of 155 individuals with ## Prevalence AHS is reported to affect approximately 1:51,000 people [ The combined frequency of the most common autosomal recessive pathogenic variants in Frequency of the Most Common Based on Indicates two different pathogenic variants on the same allele (see Pathogenic variants in ## Genetically Related (Allelic) Disorders To date, no phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: seizures are not well controlled w/ASMs but respond to large daily supplements of pyridoxine (vitamin B Neonatal-onset progressive encephalopathy w/refractory seizures Usually present earlier in infancy than AHS Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Oral biotin. Compliance w/biotin therapy can prevent development of disease & also improves symptoms in symptomatic persons. Epilepsia partialis continua has been described in some affected persons. Targeted therapy: Persons w/primary CoQ Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Oral administration of 5-formylTHF is usually sufficient to bring CSF folate levels into normal range for age. Multisystemic mitochondrial disorder characterized by myoclonus (often 1st symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, & dementia Onset can occur from childhood to adulthood, following normal early development Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias, & peripheral neuropathy Multisystemic mitochondrial disorder w/onset typically occurring in childhood Onset of symptoms is often ages 2-10 yrs. Most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, & recurrent vomiting. Seizures are often assoc w/stroke-like episodes of transient hemiparesis or cortical blindness. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, & mentation by adolescence or young adulthood. Sensorineural hearing loss is common. Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Pyridoxine is the first-line therapy. Most individuals have a favorable response to pyridoxine. Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: ~60% of persons are resistant to pyridoxine & require treatment with pyridoxal 5'-phosphate; ~40% respond to pyridoxine alone. Neonatal-onset hypotonia, lactic acidosis, & neurologic deterioration, w/ or w/o renal tubular dysfunction Adult-onset PEO, variable gastrointestinal dysmotility, multisystemic mitochondrial disease Neonatal-onset progressive encephalopathy w/refractory seizures Targeted therapy: Early treatment w/oral 5-formylTHF or, preferably, the active isomer of 5-formylTHF (Isovorin Neonatal-onset progressive encephalopathy w/refractory seizures Usually present earlier in infancy than AHS CPEO in a simplex case or when there is a maternal family history can be the result of a large-scale single deletion of mtDNA that may only be detected in limited tissues (e.g., skeletal muscle). CPEO is sometimes complicated by mild proximal muscle weakness & dysphagia & can be considered to lie on a spectrum of disease from pure CPEO to KSS. A multisystemic disorder defined by the triad of onset age 100 mg/dL, or cerebellar ataxia. Onset is usually in childhood. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), & variably severe proximal limb weakness, is relatively benign. 5-formytetrahydrofolate = 5-formylTHF; AD = autosomal dominant; AHS = Alpers-Huttenlocher syndrome; AR = autosomal recessive; ASM = anti-seizure medication; CSF = cerebrospinal fluid; GRACILE syndrome = Genes are ordered alphabetically. The m.8344A>G pathogenic variant in the mitochondrial gene Evidence to date suggests that diabetes and cardiomyopathy are not common in MERRF is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. The m.3243A>G pathogenic variant in the mitochondrial gene MELAS is caused by pathogenic variants in mtDNA and is transmitted by maternal inheritance. Most SLSMDSs are almost never inherited, suggesting that these disorders are typically caused by a Some individuals with CPEO (G). Most individuals with KSS have a common deletion of 4,977 nucleotides involving 12 mitochondrial genes. For additional disorders to consider in the differential diagnosis of individuals presenting with For additional disorders to consider in the differential diagnosis of individuals presenting with • Neonatal-onset progressive encephalopathy w/refractory seizures • Targeted therapy: seizures are not well controlled w/ASMs but respond to large daily supplements of pyridoxine (vitamin B • Neonatal-onset progressive encephalopathy w/refractory seizures • Usually present earlier in infancy than AHS • Neonatal-onset progressive encephalopathy w/refractory seizures • Targeted therapy: Oral biotin. Compliance w/biotin therapy can prevent development of disease & also improves symptoms in symptomatic persons. • Epilepsia partialis continua has been described in some affected persons. • Targeted therapy: Persons w/primary CoQ • Neonatal-onset progressive encephalopathy w/refractory seizures • Targeted therapy: Oral administration of 5-formylTHF is usually sufficient to bring CSF folate levels into normal range for age. • Multisystemic mitochondrial disorder characterized by myoclonus (often 1st symptom) followed by generalized epilepsy, ataxia, weakness, exercise intolerance, & dementia • Onset can occur from childhood to adulthood, following normal early development • Common findings are ptosis, hearing loss, short stature, optic atrophy, cardiomyopathy, cardiac dysrhythmias, & peripheral neuropathy • Multisystemic mitochondrial disorder w/onset typically occurring in childhood • Onset of symptoms is often ages 2-10 yrs. • Most common initial symptoms are generalized tonic-clonic seizures, recurrent headaches, anorexia, & recurrent vomiting. • Seizures are often assoc w/stroke-like episodes of transient hemiparesis or cortical blindness. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, & mentation by adolescence or young adulthood. • Sensorineural hearing loss is common. • Neonatal-onset progressive encephalopathy w/refractory seizures • Targeted therapy: Pyridoxine is the first-line therapy. Most individuals have a favorable response to pyridoxine. • Neonatal-onset progressive encephalopathy w/refractory seizures • Targeted therapy: ~60% of persons are resistant to pyridoxine & require treatment with pyridoxal 5'-phosphate; ~40% respond to pyridoxine alone. • Neonatal-onset hypotonia, lactic acidosis, & neurologic deterioration, w/ or w/o renal tubular dysfunction • Adult-onset PEO, variable gastrointestinal dysmotility, multisystemic mitochondrial disease • Neonatal-onset progressive encephalopathy w/refractory seizures • Targeted therapy: Early treatment w/oral 5-formylTHF or, preferably, the active isomer of 5-formylTHF (Isovorin • Neonatal-onset progressive encephalopathy w/refractory seizures • Usually present earlier in infancy than AHS • CPEO in a simplex case or when there is a maternal family history can be the result of a large-scale single deletion of mtDNA that may only be detected in limited tissues (e.g., skeletal muscle). CPEO is sometimes complicated by mild proximal muscle weakness & dysphagia & can be considered to lie on a spectrum of disease from pure CPEO to KSS. • A multisystemic disorder defined by the triad of onset age 100 mg/dL, or cerebellar ataxia. Onset is usually in childhood. PEO, characterized by ptosis, paralysis of the extraocular muscles (ophthalmoplegia), & variably severe proximal limb weakness, is relatively benign. ## Other Disorders to Consider For additional disorders to consider in the differential diagnosis of individuals presenting with For additional disorders to consider in the differential diagnosis of individuals presenting with ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To incl brain MRI Consider EEG & video 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) To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education, need for speech therapy Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Consideration of exercise program To incl liver function tests incl ALT & AST; serum concentrations of ammonia, glutamine & tyrosine, bilirubin, albumin, & cholesterol; fasting blood glucose levels; & coagulation factors (prothrombin time or INR) Consideration of liver ultrasound to evaluate for liver fibrosis To incl eval of aspiration risk incl swallow study for bulbar symptoms & 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; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate aminotransferase; INR = international normalized ratio; MOI = mode of inheritance; OT = occupational therapy; pCO In some instances, the first neuroimaging study may be normal, but with certain phenotypes, such as Alpers-Huttenlocher syndrome, changes may be seen in a relatively short amount of time. AST elevation, and to a lesser extent ALT elevation, may be due to muscle disease. Therefore, simultaneously obtaining a serum CK level helps differentiate between liver & muscle involvement, which can both be seen in individuals with Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Note: Valproic acid (Depakene Treatment of epilepsy is similar to non-mitochondrial disease w/seizures. Lamotrigine may worsen myoclonic seizures. Refractory epilepsy, esp EPC, may be impossible to control w/any treatment. In persons w/EPC, use of high-dose ASM may control the clinical seizures, but assoc obtundation & subsequent risk of aspiration & ventilatory failure may outweigh the benefit. Education of parents/caregivers Myoclonus & other non-epileptic movement disorders occur as part of AHS. The use of benzodiazepines often ↓ severity of abnormal movements & also assists in seizure control & reduction of spasticity. Chorea & athetosis may cause pain, & treatment w/muscle relaxants & pain medications, incl narcotics, is advised. Some movement disorders can be treated w/dopaminergic medication such as levodopa-carbidopa or tetrabenazine; a trial of either of these medications can be considered. Consider need for positioning & mobility devices, disability parking placard. Botulinum toxin can be used w/caution (w/consideration of systemic effects). Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Low threshold for renal eval in persons w/inadequate weight gain & linear growth or unexplained weight loss A feeding eval &/or radiographic swallowing study should be considered when showing clinical signs or symptoms of dysphagia. Treatment may incl small, frequent meals or continuous feeding to compensate for defective gluconeogenesis; reduction in dietary protein; use of non-absorbable sugars to create an osmotic diarrhea; & use of conjugating agents to treat hyperammonemia. Levocarnitine may have some benefit in the setting of liver failure & has a low risk, yet there is no evidence for routine use. Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Tracheostomy placement & artificial ventilation may be performed as needed. Assessment of nocturnal ventilatory function can be performed for evidence of central &/or obstructive apnea using polysomnography w/measurement of pCO 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 (esp for persons w/AHS) Consider involvement in adaptive sports or AHS = Alpers-Huttenlocher syndrome; ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; EPC = epilepsia partialis continua; OT = occupational therapy; PT = physical therapy; ST = speech 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, evaluations by a multidisciplinary team including neurologist, biochemical geneticist, hepatologist or gastroenterologist, physiatrist, psychiatrist, neuropsychologist and/or psychologist, ophthalmologist, and pulmonologist are recommended. No standard-of-care guidelines regarding the recommended frequency of evaluations exist; surveillance should be guided by clinical features, and the schedule should be modified if the clinical course is stable. For those with the most severe phenotypes, the recommendations in Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & movement disorders. EEG & video EEG monitoring (e.g., for suspicion of subclinical status epilepticus or EPC, to determine if events are seizures or non-epileptic movements) Measurement of growth parameters Eval of nutritional status & safety of oral intake Complete blood count Electrolytes Liver enzymes (AST, ALT, GGT) CK level Liver function tests incl preprandial serum glucose level; serum concentration of ammonia, albumin, bilirubin (free & conjugated), & cholesterol; coagulation factors incl prothrombin time or INR Urine analysis Lactic acid levels Liver ultrasound Plasma amino acids Plasma concentration of free & total carnitine (unless treated w/levocarnitine, in which case measure annually) ADHD = attention-deficit/hyperactivity disorder; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate transaminase; CK = creatine kinase; EPC = epilepsia partialis continua; GGT = gamma-glutamyl transferase; INR = international normalized ratio; OT = occupational therapy; PT = physical therapy Valproic acid (Depakene As with some other mitochondrial diseases, physical stressors such as infection, fever, dehydration, and anorexia can result in a sudden deterioration and should be avoided if possible. See Search Liver transplantation is not advised in children with Alpers-Huttenlocher syndrome (AHS) because transplanting the liver does not alter the rapid progression of the brain disease [ However, liver transplantation in adults who have an acceptable quality of life may be of benefit. In one report, one of two individuals undergoing liver transplantation survived [ In another report, a woman underwent liver transplantation at age 19 years, eight years after experiencing fulminant hepatic failure following onset of valproate therapy. Molecular genetic testing seven years after her liver transplantation confirmed the diagnosis of a The use of other treatments for refractory epilepsy, such as corticotropin or prednisone, ketogenic diet, and intravenous immunoglobulin G, are unproven in the treatment of AHS. The following, however, may be considered: Vitamin and cofactor therapy with the intent to fortify mitochondrial function may be offered, yet there is insufficient evidence demonstrating objective benefit in cohorts of persons. There have not been formal studies of the use of these vitamins and cofactors in AHS or other The use of folinic acid should be considered [ The use of levoarginine has been reported to be helpful in reducing the frequency and severity of the strokes associated with The use of levocarnitine should be reserved for individuals with reduced free carnitine levels in the blood, and the levels should be monitored [ Creatine monohydrate, coenzyme Q • To incl brain MRI • Consider EEG & video 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) • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education, need for speech therapy • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Consideration of exercise program • To incl liver function tests incl ALT & AST; serum concentrations of ammonia, glutamine & tyrosine, bilirubin, albumin, & cholesterol; fasting blood glucose levels; & coagulation factors (prothrombin time or INR) • Consideration of liver ultrasound to evaluate for liver fibrosis • To incl eval of aspiration risk incl swallow study for bulbar symptoms & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Note: Valproic acid (Depakene • Treatment of epilepsy is similar to non-mitochondrial disease w/seizures. Lamotrigine may worsen myoclonic seizures. • Refractory epilepsy, esp EPC, may be impossible to control w/any treatment. In persons w/EPC, use of high-dose ASM may control the clinical seizures, but assoc obtundation & subsequent risk of aspiration & ventilatory failure may outweigh the benefit. • Education of parents/caregivers • Myoclonus & other non-epileptic movement disorders occur as part of AHS. The use of benzodiazepines often ↓ severity of abnormal movements & also assists in seizure control & reduction of spasticity. • Chorea & athetosis may cause pain, & treatment w/muscle relaxants & pain medications, incl narcotics, is advised. Some movement disorders can be treated w/dopaminergic medication such as levodopa-carbidopa or tetrabenazine; a trial of either of these medications can be considered. • Consider need for positioning & mobility devices, disability parking placard. • Botulinum toxin can be used w/caution (w/consideration of systemic effects). • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Low threshold for renal eval in persons w/inadequate weight gain & linear growth or unexplained weight loss • A feeding eval &/or radiographic swallowing study should be considered when showing clinical signs or symptoms of dysphagia. • Treatment may incl small, frequent meals or continuous feeding to compensate for defective gluconeogenesis; reduction in dietary protein; use of non-absorbable sugars to create an osmotic diarrhea; & use of conjugating agents to treat hyperammonemia. • Levocarnitine may have some benefit in the setting of liver failure & has a low risk, yet there is no evidence for routine use. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Tracheostomy placement & artificial ventilation may be performed as needed. • Assessment of nocturnal ventilatory function can be performed for evidence of central &/or obstructive apnea using polysomnography w/measurement of pCO • 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 (esp for persons w/AHS) • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • EEG & video EEG monitoring (e.g., for suspicion of subclinical status epilepticus or EPC, to determine if events are seizures or non-epileptic movements) • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Complete blood count • Electrolytes • Liver enzymes (AST, ALT, GGT) • CK level • Liver function tests incl preprandial serum glucose level; serum concentration of ammonia, albumin, bilirubin (free & conjugated), & cholesterol; coagulation factors incl prothrombin time or INR • Urine analysis • Lactic acid levels • Liver ultrasound • Plasma amino acids • Plasma concentration of free & total carnitine (unless treated w/levocarnitine, in which case measure annually) • In one report, one of two individuals undergoing liver transplantation survived [ • In another report, a woman underwent liver transplantation at age 19 years, eight years after experiencing fulminant hepatic failure following onset of valproate therapy. Molecular genetic testing seven years after her liver transplantation confirmed the diagnosis of a • Vitamin and cofactor therapy with the intent to fortify mitochondrial function may be offered, yet there is insufficient evidence demonstrating objective benefit in cohorts of persons. There have not been formal studies of the use of these vitamins and cofactors in AHS or other • The use of folinic acid should be considered [ • The use of levoarginine has been reported to be helpful in reducing the frequency and severity of the strokes associated with • The use of levocarnitine should be reserved for individuals with reduced free carnitine levels in the blood, and the levels should be monitored [ • Creatine monohydrate, coenzyme Q ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with To incl brain MRI Consider EEG & video 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) To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education, need for speech therapy Gross motor & fine motor skills Contractures, clubfoot, & kyphoscoliosis Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Consideration of exercise program To incl liver function tests incl ALT & AST; serum concentrations of ammonia, glutamine & tyrosine, bilirubin, albumin, & cholesterol; fasting blood glucose levels; & coagulation factors (prothrombin time or INR) Consideration of liver ultrasound to evaluate for liver fibrosis To incl eval of aspiration risk incl swallow study for bulbar symptoms & 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; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate aminotransferase; INR = international normalized ratio; MOI = mode of inheritance; OT = occupational therapy; pCO In some instances, the first neuroimaging study may be normal, but with certain phenotypes, such as Alpers-Huttenlocher syndrome, changes may be seen in a relatively short amount of time. AST elevation, and to a lesser extent ALT elevation, may be due to muscle disease. Therefore, simultaneously obtaining a serum CK level helps differentiate between liver & muscle involvement, which can both be seen in individuals with Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl brain MRI • Consider EEG & video 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) • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education, need for speech therapy • Gross motor & fine motor skills • Contractures, clubfoot, & kyphoscoliosis • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Consideration of exercise program • To incl liver function tests incl ALT & AST; serum concentrations of ammonia, glutamine & tyrosine, bilirubin, albumin, & cholesterol; fasting blood glucose levels; & coagulation factors (prothrombin time or INR) • Consideration of liver ultrasound to evaluate for liver fibrosis • To incl eval of aspiration risk incl swallow study for bulbar symptoms & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations There is no cure for Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Note: Valproic acid (Depakene Treatment of epilepsy is similar to non-mitochondrial disease w/seizures. Lamotrigine may worsen myoclonic seizures. Refractory epilepsy, esp EPC, may be impossible to control w/any treatment. In persons w/EPC, use of high-dose ASM may control the clinical seizures, but assoc obtundation & subsequent risk of aspiration & ventilatory failure may outweigh the benefit. Education of parents/caregivers Myoclonus & other non-epileptic movement disorders occur as part of AHS. The use of benzodiazepines often ↓ severity of abnormal movements & also assists in seizure control & reduction of spasticity. Chorea & athetosis may cause pain, & treatment w/muscle relaxants & pain medications, incl narcotics, is advised. Some movement disorders can be treated w/dopaminergic medication such as levodopa-carbidopa or tetrabenazine; a trial of either of these medications can be considered. Consider need for positioning & mobility devices, disability parking placard. Botulinum toxin can be used w/caution (w/consideration of systemic effects). Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Low threshold for renal eval in persons w/inadequate weight gain & linear growth or unexplained weight loss A feeding eval &/or radiographic swallowing study should be considered when showing clinical signs or symptoms of dysphagia. Treatment may incl small, frequent meals or continuous feeding to compensate for defective gluconeogenesis; reduction in dietary protein; use of non-absorbable sugars to create an osmotic diarrhea; & use of conjugating agents to treat hyperammonemia. Levocarnitine may have some benefit in the setting of liver failure & has a low risk, yet there is no evidence for routine use. Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services Tracheostomy placement & artificial ventilation may be performed as needed. Assessment of nocturnal ventilatory function can be performed for evidence of central &/or obstructive apnea using polysomnography w/measurement of pCO 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 (esp for persons w/AHS) Consider involvement in adaptive sports or AHS = Alpers-Huttenlocher syndrome; ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; CPAP = continuous positive airway pressure; EPC = epilepsia partialis continua; OT = occupational therapy; PT = physical therapy; ST = speech 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. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Note: Valproic acid (Depakene • Treatment of epilepsy is similar to non-mitochondrial disease w/seizures. Lamotrigine may worsen myoclonic seizures. • Refractory epilepsy, esp EPC, may be impossible to control w/any treatment. In persons w/EPC, use of high-dose ASM may control the clinical seizures, but assoc obtundation & subsequent risk of aspiration & ventilatory failure may outweigh the benefit. • Education of parents/caregivers • Myoclonus & other non-epileptic movement disorders occur as part of AHS. The use of benzodiazepines often ↓ severity of abnormal movements & also assists in seizure control & reduction of spasticity. • Chorea & athetosis may cause pain, & treatment w/muscle relaxants & pain medications, incl narcotics, is advised. Some movement disorders can be treated w/dopaminergic medication such as levodopa-carbidopa or tetrabenazine; a trial of either of these medications can be considered. • Consider need for positioning & mobility devices, disability parking placard. • Botulinum toxin can be used w/caution (w/consideration of systemic effects). • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Low threshold for renal eval in persons w/inadequate weight gain & linear growth or unexplained weight loss • A feeding eval &/or radiographic swallowing study should be considered when showing clinical signs or symptoms of dysphagia. • Treatment may incl small, frequent meals or continuous feeding to compensate for defective gluconeogenesis; reduction in dietary protein; use of non-absorbable sugars to create an osmotic diarrhea; & use of conjugating agents to treat hyperammonemia. • Levocarnitine may have some benefit in the setting of liver failure & has a low risk, yet there is no evidence for routine use. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • Tracheostomy placement & artificial ventilation may be performed as needed. • Assessment of nocturnal ventilatory function can be performed for evidence of central &/or obstructive apnea using polysomnography w/measurement of pCO • 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 (esp for persons w/AHS) • 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, evaluations by a multidisciplinary team including neurologist, biochemical geneticist, hepatologist or gastroenterologist, physiatrist, psychiatrist, neuropsychologist and/or psychologist, ophthalmologist, and pulmonologist are recommended. No standard-of-care guidelines regarding the recommended frequency of evaluations exist; surveillance should be guided by clinical features, and the schedule should be modified if the clinical course is stable. For those with the most severe phenotypes, the recommendations in Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & movement disorders. EEG & video EEG monitoring (e.g., for suspicion of subclinical status epilepticus or EPC, to determine if events are seizures or non-epileptic movements) Measurement of growth parameters Eval of nutritional status & safety of oral intake Complete blood count Electrolytes Liver enzymes (AST, ALT, GGT) CK level Liver function tests incl preprandial serum glucose level; serum concentration of ammonia, albumin, bilirubin (free & conjugated), & cholesterol; coagulation factors incl prothrombin time or INR Urine analysis Lactic acid levels Liver ultrasound Plasma amino acids Plasma concentration of free & total carnitine (unless treated w/levocarnitine, in which case measure annually) ADHD = attention-deficit/hyperactivity disorder; ALT = alanine transaminase; ASD = autism spectrum disorder; AST = aspartate transaminase; CK = creatine kinase; EPC = epilepsia partialis continua; GGT = gamma-glutamyl transferase; INR = international normalized ratio; OT = occupational therapy; PT = physical therapy • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • EEG & video EEG monitoring (e.g., for suspicion of subclinical status epilepticus or EPC, to determine if events are seizures or non-epileptic movements) • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Complete blood count • Electrolytes • Liver enzymes (AST, ALT, GGT) • CK level • Liver function tests incl preprandial serum glucose level; serum concentration of ammonia, albumin, bilirubin (free & conjugated), & cholesterol; coagulation factors incl prothrombin time or INR • Urine analysis • Lactic acid levels • Liver ultrasound • Plasma amino acids • Plasma concentration of free & total carnitine (unless treated w/levocarnitine, in which case measure annually) ## Agents/Circumstances to Avoid Valproic acid (Depakene As with some other mitochondrial diseases, physical stressors such as infection, fever, dehydration, and anorexia can result in a sudden deterioration and should be avoided if possible. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Other Liver transplantation is not advised in children with Alpers-Huttenlocher syndrome (AHS) because transplanting the liver does not alter the rapid progression of the brain disease [ However, liver transplantation in adults who have an acceptable quality of life may be of benefit. In one report, one of two individuals undergoing liver transplantation survived [ In another report, a woman underwent liver transplantation at age 19 years, eight years after experiencing fulminant hepatic failure following onset of valproate therapy. Molecular genetic testing seven years after her liver transplantation confirmed the diagnosis of a The use of other treatments for refractory epilepsy, such as corticotropin or prednisone, ketogenic diet, and intravenous immunoglobulin G, are unproven in the treatment of AHS. The following, however, may be considered: Vitamin and cofactor therapy with the intent to fortify mitochondrial function may be offered, yet there is insufficient evidence demonstrating objective benefit in cohorts of persons. There have not been formal studies of the use of these vitamins and cofactors in AHS or other The use of folinic acid should be considered [ The use of levoarginine has been reported to be helpful in reducing the frequency and severity of the strokes associated with The use of levocarnitine should be reserved for individuals with reduced free carnitine levels in the blood, and the levels should be monitored [ Creatine monohydrate, coenzyme Q • In one report, one of two individuals undergoing liver transplantation survived [ • In another report, a woman underwent liver transplantation at age 19 years, eight years after experiencing fulminant hepatic failure following onset of valproate therapy. Molecular genetic testing seven years after her liver transplantation confirmed the diagnosis of a • Vitamin and cofactor therapy with the intent to fortify mitochondrial function may be offered, yet there is insufficient evidence demonstrating objective benefit in cohorts of persons. There have not been formal studies of the use of these vitamins and cofactors in AHS or other • The use of folinic acid should be considered [ • The use of levoarginine has been reported to be helpful in reducing the frequency and severity of the strokes associated with • The use of levocarnitine should be reserved for individuals with reduced free carnitine levels in the blood, and the levels should be monitored [ • Creatine monohydrate, coenzyme Q ## Genetic Counseling Early-onset and juvenile/adult-onset Note: Digenic inheritance involving pathogenic variants in 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 resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygous parents of a child with an autosomal recessive If both parents are known to be heterozygous for a The Heterozygous sibs of a proband with an autosomal recessive Unless an affected individual's reproductive partner also has Individuals with early-onset Most individuals with PEO caused by a heterozygous Some individuals diagnosed with adPEO have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents include molecular genetic testing for the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of 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. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation, 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. 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 are at risk of having a Carrier testing should be considered for the reproductive partners of individuals known to have a 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 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 resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygous parents of a child with an autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and 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 a proband with an autosomal recessive • Unless an affected individual's reproductive partner also has • Individuals with early-onset • Most individuals with PEO caused by a heterozygous • Some individuals diagnosed with adPEO have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents include molecular genetic testing for the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of 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. • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation, 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. 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 are at risk of having a • Carrier testing should be considered for the reproductive partners of individuals known to have a ## Mode of Inheritance Early-onset and juvenile/adult-onset Note: Digenic inheritance involving pathogenic variants in ## Autosomal Recessive 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 resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygous parents of a child with an autosomal recessive If both parents are known to be heterozygous for a The Heterozygous sibs of a proband with an autosomal recessive Unless an affected individual's reproductive partner also has Individuals with early-onset • 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 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 resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygous parents of a child with an autosomal recessive • A single- or multiexon deletion in the proband that was not detected by sequence analysis and 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 a proband with an autosomal recessive • Unless an affected individual's reproductive partner also has • Individuals with early-onset ## Autosomal Dominant Inheritance – Risk to Family Members Most individuals with PEO caused by a heterozygous Some individuals diagnosed with adPEO have the disorder as the result of a If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents include molecular genetic testing for the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of 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. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation, 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The If the If the parents have not been tested for the • Most individuals with PEO caused by a heterozygous • Some individuals diagnosed with adPEO have the disorder as the result of a • If the proband appears to be the only affected family member (i.e., a simplex case), recommendations for the evaluation of the parents include molecular genetic testing for the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of 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. • Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation, 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 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 pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. 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 are at risk of having a Carrier testing should be considered for the reproductive partners of individuals known to have 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 or are at risk of having a • Carrier testing should be considered for the reproductive partners of individuals known to have 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 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 United Kingdom • • • • • • United Kingdom • • • • • • • • • • • United Kingdom • • • United Kingdom • • • • • • • ## Molecular Genetics POLG-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for POLG-Related Disorders ( The mitochondrion comprises almost 1,500 proteins, but only the 13 that comprise small portions of the respiratory chain complexes I, III, IV, and V are encoded by the mitochondrial genome. The mitochondrial genome is a circular molecule that in humans contains 15,569 base pairs including 37 genes – 13 genes encoding for subunits of complexes I, III, IV, and V, as well as 22 tRNAs and 2 rRNAs – that are distinct and necessary for mitochondrial translation. The terminal portion of energy production occurs in the respiratory chain; disruption of the production and/or assembly of any component leads to a deficiency of ATP and resultant cellular energy failure. The cause of clinical symptoms likely includes insufficient ATP production, but also excessive free radical production, disturbed calcium handling, and other factors. Unlike nuclear DNA, mitochondrial DNA (mtDNA) replicates continuously and independently of cell division. Polymerase (pol) gamma is the major DNA polymerase in humans required for replication and repair of mtDNA. Replication of mtDNA requires a heterotrimer of one catalytic subunit of pol gamma and two accessory subunits, encoded by Exonuclease, responsible for proofreading (first third of the protein) Linker region (center of the protein) Polymerase, responsible for replication (last third of the protein) The clinical features Variants listed in the table have been provided by the authors. AHS = Alpers-Huttenlocher syndrome; ANS = ataxia neuropathy spectrum; arPEO = autosomal recessive progressive external ophthalmoplegia; dNTP = deoxyribonucleotide triphosphate An up-to-date listing of all pathogenic variants is available at • Exonuclease, responsible for proofreading (first third of the protein) • Linker region (center of the protein) • Polymerase, responsible for replication (last third of the protein) ## Molecular Pathogenesis The mitochondrion comprises almost 1,500 proteins, but only the 13 that comprise small portions of the respiratory chain complexes I, III, IV, and V are encoded by the mitochondrial genome. The mitochondrial genome is a circular molecule that in humans contains 15,569 base pairs including 37 genes – 13 genes encoding for subunits of complexes I, III, IV, and V, as well as 22 tRNAs and 2 rRNAs – that are distinct and necessary for mitochondrial translation. The terminal portion of energy production occurs in the respiratory chain; disruption of the production and/or assembly of any component leads to a deficiency of ATP and resultant cellular energy failure. The cause of clinical symptoms likely includes insufficient ATP production, but also excessive free radical production, disturbed calcium handling, and other factors. Unlike nuclear DNA, mitochondrial DNA (mtDNA) replicates continuously and independently of cell division. Polymerase (pol) gamma is the major DNA polymerase in humans required for replication and repair of mtDNA. Replication of mtDNA requires a heterotrimer of one catalytic subunit of pol gamma and two accessory subunits, encoded by Exonuclease, responsible for proofreading (first third of the protein) Linker region (center of the protein) Polymerase, responsible for replication (last third of the protein) The clinical features Variants listed in the table have been provided by the authors. AHS = Alpers-Huttenlocher syndrome; ANS = ataxia neuropathy spectrum; arPEO = autosomal recessive progressive external ophthalmoplegia; dNTP = deoxyribonucleotide triphosphate An up-to-date listing of all pathogenic variants is available at • Exonuclease, responsible for proofreading (first third of the protein) • Linker region (center of the protein) • Polymerase, responsible for replication (last third of the protein) ## Chapter Notes Web pages: William C Copeland, PhDChief, Genome Integrity and Structural Biology Laboratory;Principal Investigator, Mitochondrial DNA Replication Group,National Institute of Environmental Health Sciences111 TW Alexander DrResearch Triangle Park, NC 27709Phone: 984-287-4269Email: Web pages: Patrick F Chinnery, FRCP, FMedSciProfessor of Neurology, University of CambridgeDepartment of Clinical NeurosciencesUniversity Neurology UnitLevel 5 'A' Block, Box 165Cambridge Biomedical CampusCambridge, CB2 0QQ, United KingdomEmail: Bruce Cohen ( Bruce Cohen ( Contact Dr Bill Copeland ( The Mitochondrial Medicine Society (MMS) represents an international group of physicians, researchers, and clinicians working toward advancing education, research, and global collaboration in clinical mitochondrial medicine. Information about the MMS and educational resources can be found at Funding: This work was funded in part by the Intramural Research Program of the NIEHS, National Institutes of Health [Z01ES065078 and Z01ES065080] to W.C.C. P.F.C. is currently funded by a Wellcome Discovery Award (226653/Z/22/Z), a Wellcome Collaborative Award (224486/Z/21/Z), the Medical Research Council Mitochondrial Biology Unit (MC_UU_00028/7), the Biological and Biotechnology Research Council (BB/Y003209/1), and the LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito). His research is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. 29 February 2024 (gm) Comprehensive update posted live 1 March 2018 (sw) Comprehensive update posted live 18 December 2014 (me) Comprehensive update posted live 11 October 2012 (me) Comprehensive update posted live 16 March 2010 (me) Review posted live 9 December 2007 (bhc) Original submission • 29 February 2024 (gm) Comprehensive update posted live • 1 March 2018 (sw) Comprehensive update posted live • 18 December 2014 (me) Comprehensive update posted live • 11 October 2012 (me) Comprehensive update posted live • 16 March 2010 (me) Review posted live • 9 December 2007 (bhc) Original submission ## Author Notes Web pages: William C Copeland, PhDChief, Genome Integrity and Structural Biology Laboratory;Principal Investigator, Mitochondrial DNA Replication Group,National Institute of Environmental Health Sciences111 TW Alexander DrResearch Triangle Park, NC 27709Phone: 984-287-4269Email: Web pages: Patrick F Chinnery, FRCP, FMedSciProfessor of Neurology, University of CambridgeDepartment of Clinical NeurosciencesUniversity Neurology UnitLevel 5 'A' Block, Box 165Cambridge Biomedical CampusCambridge, CB2 0QQ, United KingdomEmail: Bruce Cohen ( Bruce Cohen ( Contact Dr Bill Copeland ( The Mitochondrial Medicine Society (MMS) represents an international group of physicians, researchers, and clinicians working toward advancing education, research, and global collaboration in clinical mitochondrial medicine. Information about the MMS and educational resources can be found at ## Acknowledgments Funding: This work was funded in part by the Intramural Research Program of the NIEHS, National Institutes of Health [Z01ES065078 and Z01ES065080] to W.C.C. P.F.C. is currently funded by a Wellcome Discovery Award (226653/Z/22/Z), a Wellcome Collaborative Award (224486/Z/21/Z), the Medical Research Council Mitochondrial Biology Unit (MC_UU_00028/7), the Biological and Biotechnology Research Council (BB/Y003209/1), and the LifeArc Centre to Treat Mitochondrial Diseases (LAC-TreatMito). His research is supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. ## Revision History 29 February 2024 (gm) Comprehensive update posted live 1 March 2018 (sw) Comprehensive update posted live 18 December 2014 (me) Comprehensive update posted live 11 October 2012 (me) Comprehensive update posted live 16 March 2010 (me) Review posted live 9 December 2007 (bhc) Original submission • 29 February 2024 (gm) Comprehensive update posted live • 1 March 2018 (sw) Comprehensive update posted live • 18 December 2014 (me) Comprehensive update posted live • 11 October 2012 (me) Comprehensive update posted live • 16 March 2010 (me) Review posted live • 9 December 2007 (bhc) Original submission ## References ## Literature Cited	[]	16/3/2010	29/2/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alpha1-a	alpha1-a	[ "AAT Deficiency", "A1AT Deficiency", "AATD", "Alpha-1 Antiprotease Deficiency", "AAT Deficiency", "A1AT Deficiency", "AATD", "Alpha-1 Antiprotease Deficiency", "Alpha-1-antitrypsin", "SERPINA1", "Alpha-1 Antitrypsin Deficiency" ]	Alpha-1 Antitrypsin Deficiency	James K Stoller, Vera Hupertz, Loutfi S Aboussouan	Summary Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD. The diagnosis of AATD relies on demonstration of low serum concentration of alpha-1 antitrypsin (AAT) and either identification of biallelic pathogenic variants in AATD is inherited in an autosomal codominant manner. If both parents are heterozygous for one	## Diagnosis Alpha-1 antitrypsin deficiency (AATD) should be suspected in individuals with evidence of: Chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, chronic bronchitis, and/or bronchiectasis); AND/OR Any of the following: Liver disease at any age, including obstructive jaundice in infancy C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) Necrotizing panniculitis The diagnosis of AATD relies on A variety of techniques have been used to measure serum AAT concentration; currently the most commonly used technique is nephelometry. Normal serum levels are 20-53 µmol/L or approximately 100-220 mg/dL by nephelometry. Serum levels observed in AATD with lung disease are usually <57 mg/dL. 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 AATD is broad, individuals with the distinctive findings described in Sequence analysis of Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Note: The nomenclature of Molecular Genetic Testing Used in AATD See See Targeted analysis for pathogenic variants is typically specific for detecting the pathogenic alleles PIZ and PIS, which account for 95% of AATD [ 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. Rare exon and whole-gene deletions have been reported [ PI typing is performed by polyacrylamide gel isoelectric focusing (IEF) electrophoresis of serum in a gradient between pH 4 and 5. Note: IEF is no longer in common use in clinical practice. Electrophoretic AAT protein variants (isoforms) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the proband. Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [ The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than molecular genetic testing. Though the optimal algorithm for laboratory testing is not well defined and recommendations in available guidelines differ [ Clinical Indications for Genetic Testing Adapted from AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; GPA = granulomatosis with polyangiitis • Chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, chronic bronchitis, and/or bronchiectasis); AND/OR • Any of the following: • Liver disease at any age, including obstructive jaundice in infancy • C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) • Necrotizing panniculitis • Liver disease at any age, including obstructive jaundice in infancy • C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) • Necrotizing panniculitis • Liver disease at any age, including obstructive jaundice in infancy • C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) • Necrotizing panniculitis • • • Normal serum levels are 20-53 µmol/L or approximately 100-220 mg/dL by nephelometry. • Serum levels observed in AATD with lung disease are usually <57 mg/dL. • Sequence analysis of • Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • Electrophoretic AAT protein variants (isoforms) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the proband. • Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [ • The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a • IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than molecular genetic testing. ## Suggestive Findings Alpha-1 antitrypsin deficiency (AATD) should be suspected in individuals with evidence of: Chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, chronic bronchitis, and/or bronchiectasis); AND/OR Any of the following: Liver disease at any age, including obstructive jaundice in infancy C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) Necrotizing panniculitis • Chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, chronic bronchitis, and/or bronchiectasis); AND/OR • Any of the following: • Liver disease at any age, including obstructive jaundice in infancy • C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) • Necrotizing panniculitis • Liver disease at any age, including obstructive jaundice in infancy • C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) • Necrotizing panniculitis • Liver disease at any age, including obstructive jaundice in infancy • C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis) • Necrotizing panniculitis ## Establishing the Diagnosis The diagnosis of AATD relies on A variety of techniques have been used to measure serum AAT concentration; currently the most commonly used technique is nephelometry. Normal serum levels are 20-53 µmol/L or approximately 100-220 mg/dL by nephelometry. Serum levels observed in AATD with lung disease are usually <57 mg/dL. 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 AATD is broad, individuals with the distinctive findings described in Sequence analysis of Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Note: The nomenclature of Molecular Genetic Testing Used in AATD See See Targeted analysis for pathogenic variants is typically specific for detecting the pathogenic alleles PIZ and PIS, which account for 95% of AATD [ 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. Rare exon and whole-gene deletions have been reported [ PI typing is performed by polyacrylamide gel isoelectric focusing (IEF) electrophoresis of serum in a gradient between pH 4 and 5. Note: IEF is no longer in common use in clinical practice. Electrophoretic AAT protein variants (isoforms) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the proband. Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [ The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than molecular genetic testing. Though the optimal algorithm for laboratory testing is not well defined and recommendations in available guidelines differ [ Clinical Indications for Genetic Testing Adapted from AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; GPA = granulomatosis with polyangiitis • • • Normal serum levels are 20-53 µmol/L or approximately 100-220 mg/dL by nephelometry. • Serum levels observed in AATD with lung disease are usually <57 mg/dL. • Sequence analysis of • Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click • Electrophoretic AAT protein variants (isoforms) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the proband. • Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [ • The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a • IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than molecular genetic testing. ## Demonstration of Low Serum Concentration of the Protein Alpha-1 Antitrypsin (AAT) A variety of techniques have been used to measure serum AAT concentration; currently the most commonly used technique is nephelometry. Normal serum levels are 20-53 µmol/L or approximately 100-220 mg/dL by nephelometry. Serum levels observed in AATD with lung disease are usually <57 mg/dL. • Normal serum levels are 20-53 µmol/L or approximately 100-220 mg/dL by nephelometry. • Serum levels observed in AATD with lung disease are usually <57 mg/dL. ## Identification of Biallelic Pathogenic Variants in Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of AATD is broad, individuals with the distinctive findings described in Sequence analysis of Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Note: The nomenclature of Molecular Genetic Testing Used in AATD See See Targeted analysis for pathogenic variants is typically specific for detecting the pathogenic alleles PIZ and PIS, which account for 95% of AATD [ 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. Rare exon and whole-gene deletions have been reported [ • Sequence analysis of • Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. • For an introduction to multigene panels click ## Detection of a Functionally Deficient AAT Protein Variant by Protease Inhibitor (PI) Typing PI typing is performed by polyacrylamide gel isoelectric focusing (IEF) electrophoresis of serum in a gradient between pH 4 and 5. Note: IEF is no longer in common use in clinical practice. Electrophoretic AAT protein variants (isoforms) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the proband. Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [ The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than molecular genetic testing. Though the optimal algorithm for laboratory testing is not well defined and recommendations in available guidelines differ [ Clinical Indications for Genetic Testing Adapted from AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; GPA = granulomatosis with polyangiitis • Electrophoretic AAT protein variants (isoforms) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the proband. • Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [ • The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a • IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than molecular genetic testing. ## Clinical Characteristics Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with obstructive lung disease and/or bronchiectasis, characteristically in individuals older than age 30 years. Phenotypic expression varies within and between families. The severity of AATD depends on the genotype and resultant serum alpha-1 antitrypsin (AAT) level. Individuals homozygous for severe deficiency alleles (i.e., PIZZ) have low serum AAT levels, placing them at increased risk for chronic obstructive pulmonary disease (COPD) (see Under-recognition of AATD often causes a long delay between first symptoms and initial diagnosis of AATD (i.e., 5-7 years) and many individuals report seeing multiple physicians before the diagnosis is first established. Diagnostic delay is associated with worsened clinical status at the time of initial diagnosis [ To date, approximately 5,000-10,000 individuals in the United States have been identified with a pathogenic variant in Select Features of AATD AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; GPA = granulomatosis with polyangiitis In adults, smoking is the major factor in accelerating the development of COPD. Although the natural history of AATD varies, depending in part on what has brought the individual to medical attention (e.g., lung symptoms, liver symptoms, asymptomatic relative of an affected individual), the onset of respiratory disease in smokers with AATD is characteristically between ages 40 and 50 years [ Individuals with severe AATD may manifest the usual signs and symptoms of obstructive lung disease, asthma, and chronic bronchitis (e.g., dyspnea, cough, wheezing, and sputum production) [ Most individuals (~95%) with severe AATD have evidence of bronchiectasis on chest CT, with 27% demonstrating clinical symptoms of bronchiectasis [ Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [ Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of individuals with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200-mL and 12% increase in the post-bronchodilator FEV Studies that followed newborns with severe AAT deficiency through age 32 years showed that most adults did not smoke and lacked physiologic and CT evidence of emphysema [ Relationship of AAT Protein Variants to Serum AAT Levels and Emphysema Risk in Adults Adapted from AAT = alpha-1 antitrypsin; NA = North America µmol/L mg/dL Note: An attempt to correlate serum AAT levels with protein variants in children showed trends similar to those seen in adults [ Liver abnormalities develop in only a portion of children with AATD. In a study of 200,000 Swedish children who were followed up after newborn screening for AATD, 18% of those with the PIZZ genotype developed clinically recognized liver abnormalities and 2.4% developed liver cirrhosis with death in childhood [ In a follow-up study of 44 children with AATD-associated liver disease initially manifesting as cirrhosis or portal hypertension, outcomes ranged from liver transplantation in two to relatively healthy lives up to 23 years after diagnosis in seven [ It is not known why only a small proportion of children with early hyperbilirubinemia have continued liver destruction leading to cirrhosis. The overall risk that an individual with the PIZZ genotype will develop severe liver disease in childhood is generally low (~2%); the risk is higher among sibs of a child with the PIZZ genotype and liver disease. When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PIZZ genotype is approximately 13%. When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PIZZ genotype may be approximately 40% [ The PIMZ and PISZ genotypes are not associated with an increased risk for childhood liver disease; however, on occasion, elevated levels of liver enzymes that resolve have been observed. In a study of 58 children with heterozygous genotypes showing signs of liver involvement during the first six months of life, almost all had normal values of liver enzymes at ages 12 months, five years, and ten years [ The risk for liver disease at age 20-40 years is approximately 2% and at age 41-50 years approximately 4% [ Autopsy studies suggest that the prevalence of liver disease may be as high as 40% in older individuals who have never smoked and do not have COPD [ In infants with AATD, inclusions may be fine and granular and difficult to identify in percutaneous liver biopsy specimens. They are also observed in bile duct epithelium [ Liver inclusions indicate the presence of at least one PIZ allele; histologic examination of the liver cannot confidently distinguish between PIMZ heterozygotes and PIZZ homozygotes, although inclusions are generally more profuse in PIZZ homozygotes. Visualization of inclusions may be variable among PIMZ heterozygotes. Panniculitis occurs in an estimated one in 1,000 individuals with AATD [ Individuals with AATD appear to have increased susceptibility to C-ANCA-positive vasculitis (e.g., granulomatosis with polyangiitis [GPA], previously called Wegener granulomatosis) [ The risk for lung disease associated with the following In some publications, the term alpha-1-protease inhibitor is substituted for alpha-1 antitrypsin (AAT). PIM is used to describe normal alleles. Different normal alleles are given numeric designations (e.g., PIM1, PIM2). AATD is one of the most common metabolic disorders in persons of northern European heritage, occurring in approximately one in 5,000-7,000 individuals in North America and one in 1,500-3,000 in Scandinavia. AATD also occurs (in lower frequencies) in all other racial subgroups worldwide [ • Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [ • Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of individuals with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200-mL and 12% increase in the post-bronchodilator FEV • When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PIZZ genotype is approximately 13%. • When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PIZZ genotype may be approximately 40% [ ## Clinical Description Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with obstructive lung disease and/or bronchiectasis, characteristically in individuals older than age 30 years. Phenotypic expression varies within and between families. The severity of AATD depends on the genotype and resultant serum alpha-1 antitrypsin (AAT) level. Individuals homozygous for severe deficiency alleles (i.e., PIZZ) have low serum AAT levels, placing them at increased risk for chronic obstructive pulmonary disease (COPD) (see Under-recognition of AATD often causes a long delay between first symptoms and initial diagnosis of AATD (i.e., 5-7 years) and many individuals report seeing multiple physicians before the diagnosis is first established. Diagnostic delay is associated with worsened clinical status at the time of initial diagnosis [ To date, approximately 5,000-10,000 individuals in the United States have been identified with a pathogenic variant in Select Features of AATD AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; GPA = granulomatosis with polyangiitis In adults, smoking is the major factor in accelerating the development of COPD. Although the natural history of AATD varies, depending in part on what has brought the individual to medical attention (e.g., lung symptoms, liver symptoms, asymptomatic relative of an affected individual), the onset of respiratory disease in smokers with AATD is characteristically between ages 40 and 50 years [ Individuals with severe AATD may manifest the usual signs and symptoms of obstructive lung disease, asthma, and chronic bronchitis (e.g., dyspnea, cough, wheezing, and sputum production) [ Most individuals (~95%) with severe AATD have evidence of bronchiectasis on chest CT, with 27% demonstrating clinical symptoms of bronchiectasis [ Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [ Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of individuals with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200-mL and 12% increase in the post-bronchodilator FEV Studies that followed newborns with severe AAT deficiency through age 32 years showed that most adults did not smoke and lacked physiologic and CT evidence of emphysema [ Relationship of AAT Protein Variants to Serum AAT Levels and Emphysema Risk in Adults Adapted from AAT = alpha-1 antitrypsin; NA = North America µmol/L mg/dL Note: An attempt to correlate serum AAT levels with protein variants in children showed trends similar to those seen in adults [ Liver abnormalities develop in only a portion of children with AATD. In a study of 200,000 Swedish children who were followed up after newborn screening for AATD, 18% of those with the PIZZ genotype developed clinically recognized liver abnormalities and 2.4% developed liver cirrhosis with death in childhood [ In a follow-up study of 44 children with AATD-associated liver disease initially manifesting as cirrhosis or portal hypertension, outcomes ranged from liver transplantation in two to relatively healthy lives up to 23 years after diagnosis in seven [ It is not known why only a small proportion of children with early hyperbilirubinemia have continued liver destruction leading to cirrhosis. The overall risk that an individual with the PIZZ genotype will develop severe liver disease in childhood is generally low (~2%); the risk is higher among sibs of a child with the PIZZ genotype and liver disease. When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PIZZ genotype is approximately 13%. When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PIZZ genotype may be approximately 40% [ The PIMZ and PISZ genotypes are not associated with an increased risk for childhood liver disease; however, on occasion, elevated levels of liver enzymes that resolve have been observed. In a study of 58 children with heterozygous genotypes showing signs of liver involvement during the first six months of life, almost all had normal values of liver enzymes at ages 12 months, five years, and ten years [ The risk for liver disease at age 20-40 years is approximately 2% and at age 41-50 years approximately 4% [ Autopsy studies suggest that the prevalence of liver disease may be as high as 40% in older individuals who have never smoked and do not have COPD [ In infants with AATD, inclusions may be fine and granular and difficult to identify in percutaneous liver biopsy specimens. They are also observed in bile duct epithelium [ Liver inclusions indicate the presence of at least one PIZ allele; histologic examination of the liver cannot confidently distinguish between PIMZ heterozygotes and PIZZ homozygotes, although inclusions are generally more profuse in PIZZ homozygotes. Visualization of inclusions may be variable among PIMZ heterozygotes. Panniculitis occurs in an estimated one in 1,000 individuals with AATD [ Individuals with AATD appear to have increased susceptibility to C-ANCA-positive vasculitis (e.g., granulomatosis with polyangiitis [GPA], previously called Wegener granulomatosis) [ • Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [ • Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of individuals with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200-mL and 12% increase in the post-bronchodilator FEV • When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PIZZ genotype is approximately 13%. • When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PIZZ genotype may be approximately 40% [ ## Lung Disease In adults, smoking is the major factor in accelerating the development of COPD. Although the natural history of AATD varies, depending in part on what has brought the individual to medical attention (e.g., lung symptoms, liver symptoms, asymptomatic relative of an affected individual), the onset of respiratory disease in smokers with AATD is characteristically between ages 40 and 50 years [ Individuals with severe AATD may manifest the usual signs and symptoms of obstructive lung disease, asthma, and chronic bronchitis (e.g., dyspnea, cough, wheezing, and sputum production) [ Most individuals (~95%) with severe AATD have evidence of bronchiectasis on chest CT, with 27% demonstrating clinical symptoms of bronchiectasis [ Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [ Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of individuals with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200-mL and 12% increase in the post-bronchodilator FEV Studies that followed newborns with severe AAT deficiency through age 32 years showed that most adults did not smoke and lacked physiologic and CT evidence of emphysema [ Relationship of AAT Protein Variants to Serum AAT Levels and Emphysema Risk in Adults Adapted from AAT = alpha-1 antitrypsin; NA = North America µmol/L mg/dL Note: An attempt to correlate serum AAT levels with protein variants in children showed trends similar to those seen in adults [ • Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [ • Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of individuals with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200-mL and 12% increase in the post-bronchodilator FEV ## Liver Disease Liver abnormalities develop in only a portion of children with AATD. In a study of 200,000 Swedish children who were followed up after newborn screening for AATD, 18% of those with the PIZZ genotype developed clinically recognized liver abnormalities and 2.4% developed liver cirrhosis with death in childhood [ In a follow-up study of 44 children with AATD-associated liver disease initially manifesting as cirrhosis or portal hypertension, outcomes ranged from liver transplantation in two to relatively healthy lives up to 23 years after diagnosis in seven [ It is not known why only a small proportion of children with early hyperbilirubinemia have continued liver destruction leading to cirrhosis. The overall risk that an individual with the PIZZ genotype will develop severe liver disease in childhood is generally low (~2%); the risk is higher among sibs of a child with the PIZZ genotype and liver disease. When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PIZZ genotype is approximately 13%. When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PIZZ genotype may be approximately 40% [ The PIMZ and PISZ genotypes are not associated with an increased risk for childhood liver disease; however, on occasion, elevated levels of liver enzymes that resolve have been observed. In a study of 58 children with heterozygous genotypes showing signs of liver involvement during the first six months of life, almost all had normal values of liver enzymes at ages 12 months, five years, and ten years [ The risk for liver disease at age 20-40 years is approximately 2% and at age 41-50 years approximately 4% [ Autopsy studies suggest that the prevalence of liver disease may be as high as 40% in older individuals who have never smoked and do not have COPD [ In infants with AATD, inclusions may be fine and granular and difficult to identify in percutaneous liver biopsy specimens. They are also observed in bile duct epithelium [ Liver inclusions indicate the presence of at least one PIZ allele; histologic examination of the liver cannot confidently distinguish between PIMZ heterozygotes and PIZZ homozygotes, although inclusions are generally more profuse in PIZZ homozygotes. Visualization of inclusions may be variable among PIMZ heterozygotes. • When liver abnormalities in the proband are mild and resolve, the risk of liver disease in sibs with the PIZZ genotype is approximately 13%. • When liver disease in the proband is severe, the risk for severe liver disease in sibs with the PIZZ genotype may be approximately 40% [ ## Other Disease Associations Panniculitis occurs in an estimated one in 1,000 individuals with AATD [ Individuals with AATD appear to have increased susceptibility to C-ANCA-positive vasculitis (e.g., granulomatosis with polyangiitis [GPA], previously called Wegener granulomatosis) [ ## Genotype-Phenotype Correlations The risk for lung disease associated with the following ## Nomenclature In some publications, the term alpha-1-protease inhibitor is substituted for alpha-1 antitrypsin (AAT). PIM is used to describe normal alleles. Different normal alleles are given numeric designations (e.g., PIM1, PIM2). ## Prevalence AATD is one of the most common metabolic disorders in persons of northern European heritage, occurring in approximately one in 5,000-7,000 individuals in North America and one in 1,500-3,000 in Scandinavia. AATD also occurs (in lower frequencies) in all other racial subgroups worldwide [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Differential diagnoses include disorders causing chronic obstructive pulmonary disease (COPD), such as emphysema, chronic bronchitis, and bronchiectasis. See Genetic Disorders Associated with Liver Disease in the Differential Diagnosis of Alpha-1 Antitrypsin Deficiency Cholestasis can be prominent; presentation in infancy is common. Risk for hepatocellular carcinoma in PFIC2 & AATD is higher than in other liver diseases. Often ↓ or normal GGT, differing histologic appearance on liver biopsy Other extrahepatic manifestations may incl hearing loss, diarrhea, pancreatitis, failure to thrive, fat-soluble vitamin deficiencies. Normal liver histology is normal (though liver is black in color); ALT & AST also normal ↑ fractional excretion of coproporphyrin I Chronic liver disease May present beyond newborn period; presentation in teen yrs common May be accompanied by neurologic &/or psychiatric symptoms; Kayser-Fleischer rings in 50% of those w/hepatic disease; ↓ serum ceruloplasmin & ↑ urinary copper excretion Acute liver failure is assoc w/hemolysis & ↓ serum alkaline phosphatase. Liver biopsy shows excess copper accumulation & steatosis. Cholestasis in infancy Liver disease can become more apparent in older children. Presentation can be in early childhood & adolescence. Liver disease may not be prominent. ↑ serum ferritin & transferrin saturations Greater likelihood of cardiac involvement (cardiomyopathy), ↓ glucose tolerance, & hypogonadism Liver disease can be relatively asymptomatic. ↑ risk for hepatocellular carcinoma ↑ ferritin Iron overload in liver & other organs, primarily after age 40 yrs Presents in early infancy Cholestasis Ferroportin disease caused by loss-of-function variants is characterized by ↑ ferritin levels, ↑ macrophage iron, ↓ transferrin saturation, mild anemia, & minimal hepatic iron deposition. Ferroportin disease caused by gain-of-function variants is similar to classic HFE. Normal liver histology; normal color liver tissue, normal ALT & AST ↑ total urinary coproporphyrin excretion w/↑ fractional excretion of coprophyrin I AATD = alpha-1 antitrypsin deficiency; AD = autosomal dominant; ALT = alanine aminotransferase; AR = autosomal recessive; AST = aspartate transaminase; GGT = gamma-glutamyl transferase; HFE = hemochromatosis; MOI = mode of inheritance • Cholestasis can be prominent; presentation in infancy is common. • Risk for hepatocellular carcinoma in PFIC2 & AATD is higher than in other liver diseases. • Often ↓ or normal GGT, differing histologic appearance on liver biopsy • Other extrahepatic manifestations may incl hearing loss, diarrhea, pancreatitis, failure to thrive, fat-soluble vitamin deficiencies. • Normal liver histology is normal (though liver is black in color); ALT & AST also normal • ↑ fractional excretion of coproporphyrin I • Chronic liver disease • May present beyond newborn period; presentation in teen yrs common • May be accompanied by neurologic &/or psychiatric symptoms; Kayser-Fleischer rings in 50% of those w/hepatic disease; ↓ serum ceruloplasmin & ↑ urinary copper excretion • Acute liver failure is assoc w/hemolysis & ↓ serum alkaline phosphatase. • Liver biopsy shows excess copper accumulation & steatosis. • Cholestasis in infancy • Liver disease can become more apparent in older children. • Presentation can be in early childhood & adolescence. • Liver disease may not be prominent. • ↑ serum ferritin & transferrin saturations • Greater likelihood of cardiac involvement (cardiomyopathy), ↓ glucose tolerance, & hypogonadism • Liver disease can be relatively asymptomatic. • ↑ risk for hepatocellular carcinoma • ↑ ferritin • Iron overload in liver & other organs, primarily after age 40 yrs • Presents in early infancy • Cholestasis • Ferroportin disease caused by loss-of-function variants is characterized by ↑ ferritin levels, ↑ macrophage iron, ↓ transferrin saturation, mild anemia, & minimal hepatic iron deposition. • Ferroportin disease caused by gain-of-function variants is similar to classic HFE. • Normal liver histology; normal color liver tissue, normal ALT & AST • ↑ total urinary coproporphyrin excretion w/↑ fractional excretion of coprophyrin I ## Lung Disease Differential diagnoses include disorders causing chronic obstructive pulmonary disease (COPD), such as emphysema, chronic bronchitis, and bronchiectasis. ## Liver Disease See Genetic Disorders Associated with Liver Disease in the Differential Diagnosis of Alpha-1 Antitrypsin Deficiency Cholestasis can be prominent; presentation in infancy is common. Risk for hepatocellular carcinoma in PFIC2 & AATD is higher than in other liver diseases. Often ↓ or normal GGT, differing histologic appearance on liver biopsy Other extrahepatic manifestations may incl hearing loss, diarrhea, pancreatitis, failure to thrive, fat-soluble vitamin deficiencies. Normal liver histology is normal (though liver is black in color); ALT & AST also normal ↑ fractional excretion of coproporphyrin I Chronic liver disease May present beyond newborn period; presentation in teen yrs common May be accompanied by neurologic &/or psychiatric symptoms; Kayser-Fleischer rings in 50% of those w/hepatic disease; ↓ serum ceruloplasmin & ↑ urinary copper excretion Acute liver failure is assoc w/hemolysis & ↓ serum alkaline phosphatase. Liver biopsy shows excess copper accumulation & steatosis. Cholestasis in infancy Liver disease can become more apparent in older children. Presentation can be in early childhood & adolescence. Liver disease may not be prominent. ↑ serum ferritin & transferrin saturations Greater likelihood of cardiac involvement (cardiomyopathy), ↓ glucose tolerance, & hypogonadism Liver disease can be relatively asymptomatic. ↑ risk for hepatocellular carcinoma ↑ ferritin Iron overload in liver & other organs, primarily after age 40 yrs Presents in early infancy Cholestasis Ferroportin disease caused by loss-of-function variants is characterized by ↑ ferritin levels, ↑ macrophage iron, ↓ transferrin saturation, mild anemia, & minimal hepatic iron deposition. Ferroportin disease caused by gain-of-function variants is similar to classic HFE. Normal liver histology; normal color liver tissue, normal ALT & AST ↑ total urinary coproporphyrin excretion w/↑ fractional excretion of coprophyrin I AATD = alpha-1 antitrypsin deficiency; AD = autosomal dominant; ALT = alanine aminotransferase; AR = autosomal recessive; AST = aspartate transaminase; GGT = gamma-glutamyl transferase; HFE = hemochromatosis; MOI = mode of inheritance • Cholestasis can be prominent; presentation in infancy is common. • Risk for hepatocellular carcinoma in PFIC2 & AATD is higher than in other liver diseases. • Often ↓ or normal GGT, differing histologic appearance on liver biopsy • Other extrahepatic manifestations may incl hearing loss, diarrhea, pancreatitis, failure to thrive, fat-soluble vitamin deficiencies. • Normal liver histology is normal (though liver is black in color); ALT & AST also normal • ↑ fractional excretion of coproporphyrin I • Chronic liver disease • May present beyond newborn period; presentation in teen yrs common • May be accompanied by neurologic &/or psychiatric symptoms; Kayser-Fleischer rings in 50% of those w/hepatic disease; ↓ serum ceruloplasmin & ↑ urinary copper excretion • Acute liver failure is assoc w/hemolysis & ↓ serum alkaline phosphatase. • Liver biopsy shows excess copper accumulation & steatosis. • Cholestasis in infancy • Liver disease can become more apparent in older children. • Presentation can be in early childhood & adolescence. • Liver disease may not be prominent. • ↑ serum ferritin & transferrin saturations • Greater likelihood of cardiac involvement (cardiomyopathy), ↓ glucose tolerance, & hypogonadism • Liver disease can be relatively asymptomatic. • ↑ risk for hepatocellular carcinoma • ↑ ferritin • Iron overload in liver & other organs, primarily after age 40 yrs • Presents in early infancy • Cholestasis • Ferroportin disease caused by loss-of-function variants is characterized by ↑ ferritin levels, ↑ macrophage iron, ↓ transferrin saturation, mild anemia, & minimal hepatic iron deposition. • Ferroportin disease caused by gain-of-function variants is similar to classic HFE. • Normal liver histology; normal color liver tissue, normal ALT & AST • ↑ total urinary coproporphyrin excretion w/↑ fractional excretion of coprophyrin I ## Management To establish the extent of disease and needs in an individual diagnosed with alpha-1 antitrypsin deficiency (AATD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with AATD Spirometry (w/post-bronchodilator testing) Lung volumes Diffusing capacity Measures of oxygenation AATD = alpha-1 antitrypsin deficiency; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations in Individuals with AATD Used in those w/established emphysema The greatest benefit of this therapy is observed in individuals w/moderate degrees of airflow obstruction (e.g., FEV Hospitalizations & COPD exacerbations may ↑ after interruption of augmentation [ AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; LABA = long-acting beta agonists Recommended Surveillance for Individuals with AATD MRI = magnetic resonance imaging Avoid the following: Smoking (both active and passive) Occupational exposure (including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes) Excessive use of alcohol The Alpha-1 Foundation-sponsored update of the ATS/ERS guidelines [ Extended pedigree analysis beyond first-degree relatives may be indicated in selected instances. For example, the presence of an AATD-associated condition (e.g., chronic obstructive pulmonary disease [COPD], liver disease, panniculitis) in a more distant family member and/or the finding that a parent of the proband has the PIZZ genotype would justify extensive family testing (i.e., of family members beyond parents, sibs, and offspring) [ See Management of women with AATD during pregnancy should be guided by usual care principles, both for women without clinical disease and for those with liver disease. As noted, emphysema, especially in nonsmokers, would not commonly be expected during the usual childbearing age range. Many novel therapies for AATD are currently under investigation. Studies to slow the progression of lung disease include a variety of strategies: inhaled alpha-1 antitrypsin (AAT), liquid AAT, recombinant AAT, alternate dosing regimens of intravenous augmentation therapy (including double-dose strategies), an oral neutrophil elastase inhibitor, an orally available corrector molecule designed to restore secretion and acute phase reactivity, molecules to block polymer formation, and gene therapy using various viral vectors and delivery routes. Placement of valves endoscopically to improve lung function and functional status is also being studied. Examples of studies directed at the AATD-related liver disease include use of carbamazepine or sirolimus to increase autophagy and use of small interfering RNA to suppress aberrant AAT protein translation. Search • Spirometry (w/post-bronchodilator testing) • Lung volumes • Diffusing capacity • Measures of oxygenation • Used in those w/established emphysema • The greatest benefit of this therapy is observed in individuals w/moderate degrees of airflow obstruction (e.g., FEV • Hospitalizations & COPD exacerbations may ↑ after interruption of augmentation [ • Smoking (both active and passive) • Occupational exposure (including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes) • Excessive use of alcohol ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with alpha-1 antitrypsin deficiency (AATD), the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with AATD Spirometry (w/post-bronchodilator testing) Lung volumes Diffusing capacity Measures of oxygenation AATD = alpha-1 antitrypsin deficiency; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Spirometry (w/post-bronchodilator testing) • Lung volumes • Diffusing capacity • Measures of oxygenation ## Treatment of Manifestations Treatment of Manifestations in Individuals with AATD Used in those w/established emphysema The greatest benefit of this therapy is observed in individuals w/moderate degrees of airflow obstruction (e.g., FEV Hospitalizations & COPD exacerbations may ↑ after interruption of augmentation [ AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; LABA = long-acting beta agonists • Used in those w/established emphysema • The greatest benefit of this therapy is observed in individuals w/moderate degrees of airflow obstruction (e.g., FEV • Hospitalizations & COPD exacerbations may ↑ after interruption of augmentation [ ## Surveillance Recommended Surveillance for Individuals with AATD MRI = magnetic resonance imaging ## Agents/Circumstances to Avoid Avoid the following: Smoking (both active and passive) Occupational exposure (including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes) Excessive use of alcohol • Smoking (both active and passive) • Occupational exposure (including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes) • Excessive use of alcohol ## Evaluation of Relatives at Risk The Alpha-1 Foundation-sponsored update of the ATS/ERS guidelines [ Extended pedigree analysis beyond first-degree relatives may be indicated in selected instances. For example, the presence of an AATD-associated condition (e.g., chronic obstructive pulmonary disease [COPD], liver disease, panniculitis) in a more distant family member and/or the finding that a parent of the proband has the PIZZ genotype would justify extensive family testing (i.e., of family members beyond parents, sibs, and offspring) [ See ## Pregnancy Management Management of women with AATD during pregnancy should be guided by usual care principles, both for women without clinical disease and for those with liver disease. As noted, emphysema, especially in nonsmokers, would not commonly be expected during the usual childbearing age range. ## Therapies Under Investigation Many novel therapies for AATD are currently under investigation. Studies to slow the progression of lung disease include a variety of strategies: inhaled alpha-1 antitrypsin (AAT), liquid AAT, recombinant AAT, alternate dosing regimens of intravenous augmentation therapy (including double-dose strategies), an oral neutrophil elastase inhibitor, an orally available corrector molecule designed to restore secretion and acute phase reactivity, molecules to block polymer formation, and gene therapy using various viral vectors and delivery routes. Placement of valves endoscopically to improve lung function and functional status is also being studied. Examples of studies directed at the AATD-related liver disease include use of carbamazepine or sirolimus to increase autophagy and use of small interfering RNA to suppress aberrant AAT protein translation. Search ## Genetic Counseling Alpha-1 antitrypsin deficiency (AATD) is inherited in an autosomal codominant manner. Either both parents of an individual with AATD are heterozygous for one Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk assessment (see also Management, In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see If both parents are heterozygous (e.g., PIMZ) for a pathogenic variant, each sib of an affected individual has a 25% chance of being affected (i.e., PIZZ), a 50% chance of being heterozygous (i.e., PIMZ), and a 25% chance of inheriting neither of the pathogenic variants (i.e., PIMM). If one parent is homozygous (i.e., PIZZ) for biallelic pathogenic variants and the other parent is heterozygous (e.g., PIMZ) for a pathogenic variant, each sib has a 50% chance of being affected (i.e., PIZZ) and a 50% chance of being heterozygous (e.g., PIMZ). In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see Molecular genetic testing should be offered to all sibs in order to clarify their genetic status and identify as early as possible those who would benefit from Unless an individual with AATD has children with an affected individual or a heterozygote, offspring will be heterozygous for a pathogenic variant (e.g., PIMZ). In populations with a high carrier frequency and/or a high rate of consanguinity, the reproductive partner of the proband may also have one or more Targeted molecular genetic testing for at-risk relatives requires prior identification of the Note: Measurement of serum AAT level is not reliable for determining carrier status because the range of serum AAT levels among most carriers may overlap the normal serum range [ See Management, If the parents are heterozygotes (e.g., PIMZ) but have not had a child with severe liver disease, the risk to offspring of having AATD (25%) AND severe liver disease in childhood (13.6%) is less than 1% (0.64%). If an affected individual died from severe liver disease in childhood, the risk to sibs of having AATD (25%) AND severe liver disease in childhood (40%) is 10%. If an affected individual did not have severe liver disease in childhood or if the liver disease resolved, the risk to sibs of having AATD (25%) AND liver disease (13%) is 3.3%. Once the Note: Prenatal testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression of the disorder. Fetal testing is not recommended in the American Thoracic Society/European Respiratory Society 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. • Either both parents of an individual with AATD are heterozygous for one • Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk assessment (see also Management, • In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see • If both parents are heterozygous (e.g., PIMZ) for a pathogenic variant, each sib of an affected individual has a 25% chance of being affected (i.e., PIZZ), a 50% chance of being heterozygous (i.e., PIMZ), and a 25% chance of inheriting neither of the pathogenic variants (i.e., PIMM). • If one parent is homozygous (i.e., PIZZ) for biallelic pathogenic variants and the other parent is heterozygous (e.g., PIMZ) for a pathogenic variant, each sib has a 50% chance of being affected (i.e., PIZZ) and a 50% chance of being heterozygous (e.g., PIMZ). • In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see • Molecular genetic testing should be offered to all sibs in order to clarify their genetic status and identify as early as possible those who would benefit from • Unless an individual with AATD has children with an affected individual or a heterozygote, offspring will be heterozygous for a pathogenic variant (e.g., PIMZ). • In populations with a high carrier frequency and/or a high rate of consanguinity, the reproductive partner of the proband may also have one or more • If the parents are heterozygotes (e.g., PIMZ) but have not had a child with severe liver disease, the risk to offspring of having AATD (25%) AND severe liver disease in childhood (13.6%) is less than 1% (0.64%). • If an affected individual died from severe liver disease in childhood, the risk to sibs of having AATD (25%) AND severe liver disease in childhood (40%) is 10%. • If an affected individual did not have severe liver disease in childhood or if the liver disease resolved, the risk to sibs of having AATD (25%) AND liver disease (13%) is 3.3%. ## Mode of Inheritance Alpha-1 antitrypsin deficiency (AATD) is inherited in an autosomal codominant manner. ## Risk to Family Members Either both parents of an individual with AATD are heterozygous for one Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk assessment (see also Management, In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see If both parents are heterozygous (e.g., PIMZ) for a pathogenic variant, each sib of an affected individual has a 25% chance of being affected (i.e., PIZZ), a 50% chance of being heterozygous (i.e., PIMZ), and a 25% chance of inheriting neither of the pathogenic variants (i.e., PIMM). If one parent is homozygous (i.e., PIZZ) for biallelic pathogenic variants and the other parent is heterozygous (e.g., PIMZ) for a pathogenic variant, each sib has a 50% chance of being affected (i.e., PIZZ) and a 50% chance of being heterozygous (e.g., PIMZ). In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see Molecular genetic testing should be offered to all sibs in order to clarify their genetic status and identify as early as possible those who would benefit from Unless an individual with AATD has children with an affected individual or a heterozygote, offspring will be heterozygous for a pathogenic variant (e.g., PIMZ). In populations with a high carrier frequency and/or a high rate of consanguinity, the reproductive partner of the proband may also have one or more • Either both parents of an individual with AATD are heterozygous for one • Molecular genetic testing is recommended for the parents of a proband to confirm their genetic status and to allow reliable recurrence risk assessment (see also Management, • In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see • If both parents are heterozygous (e.g., PIMZ) for a pathogenic variant, each sib of an affected individual has a 25% chance of being affected (i.e., PIZZ), a 50% chance of being heterozygous (i.e., PIMZ), and a 25% chance of inheriting neither of the pathogenic variants (i.e., PIMM). • If one parent is homozygous (i.e., PIZZ) for biallelic pathogenic variants and the other parent is heterozygous (e.g., PIMZ) for a pathogenic variant, each sib has a 50% chance of being affected (i.e., PIZZ) and a 50% chance of being heterozygous (e.g., PIMZ). • In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PIMZ heterozygotes who have smoked are at increased risk for emphysema (see • Molecular genetic testing should be offered to all sibs in order to clarify their genetic status and identify as early as possible those who would benefit from • Unless an individual with AATD has children with an affected individual or a heterozygote, offspring will be heterozygous for a pathogenic variant (e.g., PIMZ). • In populations with a high carrier frequency and/or a high rate of consanguinity, the reproductive partner of the proband may also have one or more ## Heterozygote Detection Targeted molecular genetic testing for at-risk relatives requires prior identification of the Note: Measurement of serum AAT level is not reliable for determining carrier status because the range of serum AAT levels among most carriers may overlap the normal serum range [ ## Related Genetic Counseling Issues See Management, If the parents are heterozygotes (e.g., PIMZ) but have not had a child with severe liver disease, the risk to offspring of having AATD (25%) AND severe liver disease in childhood (13.6%) is less than 1% (0.64%). If an affected individual died from severe liver disease in childhood, the risk to sibs of having AATD (25%) AND severe liver disease in childhood (40%) is 10%. If an affected individual did not have severe liver disease in childhood or if the liver disease resolved, the risk to sibs of having AATD (25%) AND liver disease (13%) is 3.3%. • If the parents are heterozygotes (e.g., PIMZ) but have not had a child with severe liver disease, the risk to offspring of having AATD (25%) AND severe liver disease in childhood (13.6%) is less than 1% (0.64%). • If an affected individual died from severe liver disease in childhood, the risk to sibs of having AATD (25%) AND severe liver disease in childhood (40%) is 10%. • If an affected individual did not have severe liver disease in childhood or if the liver disease resolved, the risk to sibs of having AATD (25%) AND liver disease (13%) is 3.3%. ## Prenatal Testing and Preimplantation Genetic Testing Once the Note: Prenatal testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression of the disorder. Fetal testing is not recommended in the American Thoracic Society/European Respiratory Society 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 103 Rapidan Church Lane PO Box 202 Wolftown VA 22748 13300 Tecumseh Road East, Suite 241 Tecumseh Ontario N8N 4R8 Canada 3300 Ponce de Leon Boulevard Coral Gables FL 33134 Canada United Kingdom Toronto Western Hospital 399 Bathurst Street 7th Floor, East Wing, Room 445 Toronto Ontario M5T 2S8 Canada • • 103 Rapidan Church Lane • PO Box 202 • Wolftown VA 22748 • • • 13300 Tecumseh Road East, • Suite 241 • Tecumseh Ontario N8N 4R8 • Canada • • • 3300 Ponce de Leon Boulevard • Coral Gables FL 33134 • • • • • • • • • Canada • • • • • United Kingdom • • • • • Toronto Western Hospital • 399 Bathurst Street • 7th Floor, East Wing, Room 445 • Toronto Ontario M5T 2S8 • Canada • • • ## Molecular Genetics Alpha-1 Antitrypsin Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alpha-1 Antitrypsin Deficiency ( Protein variants, such as the PIS variant, are more easily degraded. The PIZ variant polymerizes within hepatocytes and alveolar macrophages where it was shown to be chemotactic for neutrophils. Thus, in addition to a loss-of-function mechanism, lung destruction may be fueled by an inflammatory reaction related to the polymers of Z protein variants in the lung [ Notable AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions; historical nomenclature does not include the signal sequence of the reference protein ## Molecular Pathogenesis Protein variants, such as the PIS variant, are more easily degraded. The PIZ variant polymerizes within hepatocytes and alveolar macrophages where it was shown to be chemotactic for neutrophils. Thus, in addition to a loss-of-function mechanism, lung destruction may be fueled by an inflammatory reaction related to the polymers of Z protein variants in the lung [ Notable AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions; historical nomenclature does not include the signal sequence of the reference protein ## Chapter Notes Research Support, Non-US Government Research Support, US Government, PHS Loutfi S Aboussouan, MD (2014-present)Diane W Cox, PhD, FCCMG, FRSC; University of Alberta (2005-2014)Felicitas L Lacbawan, MD; Cleveland Clinic (2014-2020)Kamilla Schlade-Bartusiak, PhD; University of Alberta (2005-2014)James K Stoller, MD, MS (2014-present)Vera Hupertz, MD (2020-present) 1 June 2023 (aa) Revision: 21 May 2020 (ha) Comprehensive update posted live 19 January 2017 (jks) Revision: clarification re serum levels of AAT in heterozygotes 1 May 2014 (me) Comprehensive update posted live 6 February 2008 (cd) Revision: sequence analysis available on a clinical basis 27 October 2006 (me) Review posted live 15 February 2005 (dc) Original submission • 1 June 2023 (aa) Revision: • 21 May 2020 (ha) Comprehensive update posted live • 19 January 2017 (jks) Revision: clarification re serum levels of AAT in heterozygotes • 1 May 2014 (me) Comprehensive update posted live • 6 February 2008 (cd) Revision: sequence analysis available on a clinical basis • 27 October 2006 (me) Review posted live • 15 February 2005 (dc) Original submission ## Author Notes Research Support, Non-US Government Research Support, US Government, PHS ## Author History Loutfi S Aboussouan, MD (2014-present)Diane W Cox, PhD, FCCMG, FRSC; University of Alberta (2005-2014)Felicitas L Lacbawan, MD; Cleveland Clinic (2014-2020)Kamilla Schlade-Bartusiak, PhD; University of Alberta (2005-2014)James K Stoller, MD, MS (2014-present)Vera Hupertz, MD (2020-present) ## Revision History 1 June 2023 (aa) Revision: 21 May 2020 (ha) Comprehensive update posted live 19 January 2017 (jks) Revision: clarification re serum levels of AAT in heterozygotes 1 May 2014 (me) Comprehensive update posted live 6 February 2008 (cd) Revision: sequence analysis available on a clinical basis 27 October 2006 (me) Review posted live 15 February 2005 (dc) Original submission • 1 June 2023 (aa) Revision: • 21 May 2020 (ha) Comprehensive update posted live • 19 January 2017 (jks) Revision: clarification re serum levels of AAT in heterozygotes • 1 May 2014 (me) Comprehensive update posted live • 6 February 2008 (cd) Revision: sequence analysis available on a clinical basis • 27 October 2006 (me) Review posted live • 15 February 2005 (dc) Original submission ## References American Thoracic Society, European Respiratory Society. American Thoracic Society / European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Available Marciniuk DD, Hernandez P, Balter M, Bourbeau J, Chapman KR, Ford GT, Lauzon JL, Maltais F, O'Donnell DE, Goodridge D, Strange C, Cave AJ, Curren K, Muthuri S, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Available Sandhaus RA, Turino G, Brantly M, Campos M, Cross C, Goodman K, Hogarth K, Knight S, Stocks J, Stoller JK, Strange C, Teckman J. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Available • American Thoracic Society, European Respiratory Society. American Thoracic Society / European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Available • Marciniuk DD, Hernandez P, Balter M, Bourbeau J, Chapman KR, Ford GT, Lauzon JL, Maltais F, O'Donnell DE, Goodridge D, Strange C, Cave AJ, Curren K, Muthuri S, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Available • Sandhaus RA, Turino G, Brantly M, Campos M, Cross C, Goodman K, Hogarth K, Knight S, Stocks J, Stoller JK, Strange C, Teckman J. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Available ## Published Guidelines / Consensus Statements American Thoracic Society, European Respiratory Society. American Thoracic Society / European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Available Marciniuk DD, Hernandez P, Balter M, Bourbeau J, Chapman KR, Ford GT, Lauzon JL, Maltais F, O'Donnell DE, Goodridge D, Strange C, Cave AJ, Curren K, Muthuri S, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Available Sandhaus RA, Turino G, Brantly M, Campos M, Cross C, Goodman K, Hogarth K, Knight S, Stocks J, Stoller JK, Strange C, Teckman J. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Available • American Thoracic Society, European Respiratory Society. American Thoracic Society / European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Available • Marciniuk DD, Hernandez P, Balter M, Bourbeau J, Chapman KR, Ford GT, Lauzon JL, Maltais F, O'Donnell DE, Goodridge D, Strange C, Cave AJ, Curren K, Muthuri S, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. 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alpk1-auto	alpk1-auto	[ "ROSAH Syndrome", "ROSAH Syndrome", "Alpha-protein kinase 1", "ALPK1", "ALPK1-Related Autoinflammatory Disease" ]		Christina Kozycki, Dan Kastner, Laryssa Huryn, Shilpa Kodati, Blake M Warner	Summary The diagnosis of	## Diagnosis Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). Intraocular inflammation (uveitis, retinal vasculitis) Limited data suggest that it is often present in adolescence and early adulthood. Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. Retinal dystrophy (degeneration) Timing of onset varies. Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. Transient (cyclical) cytopenias with absolute neutrophil count occasionally dropping below 1,000 cells/µL and platelets occasionally dropping below 100,000 cells/µL Intermittently elevated C-reactive protein (CRP) ranging from mild (>10 mg/L) to severe (>100 mg/L) The risk of AA amyloidosis (previously known as secondary [AA] amyloidosis) is unknown; however, it was noted on biopsy of one individual who presented with renal dysfunction [C Kozycki, personal observation]. 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 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. 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 such variants have not been identified as a cause of this disorder and would not be expected given the gain-of-function mechanism of disease causation. • Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). • Intraocular inflammation (uveitis, retinal vasculitis) • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Retinal dystrophy (degeneration) • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). • Intraocular inflammation (uveitis, retinal vasculitis) • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Retinal dystrophy (degeneration) • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). • Intraocular inflammation (uveitis, retinal vasculitis) • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Retinal dystrophy (degeneration) • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Transient (cyclical) cytopenias with absolute neutrophil count occasionally dropping below 1,000 cells/µL and platelets occasionally dropping below 100,000 cells/µL • Intermittently elevated C-reactive protein (CRP) ranging from mild (>10 mg/L) to severe (>100 mg/L) • The risk of AA amyloidosis (previously known as secondary [AA] amyloidosis) is unknown; however, it was noted on biopsy of one individual who presented with renal dysfunction [C Kozycki, personal observation]. ## Suggestive Findings Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). Intraocular inflammation (uveitis, retinal vasculitis) Limited data suggest that it is often present in adolescence and early adulthood. Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. Retinal dystrophy (degeneration) Timing of onset varies. Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. Transient (cyclical) cytopenias with absolute neutrophil count occasionally dropping below 1,000 cells/µL and platelets occasionally dropping below 100,000 cells/µL Intermittently elevated C-reactive protein (CRP) ranging from mild (>10 mg/L) to severe (>100 mg/L) The risk of AA amyloidosis (previously known as secondary [AA] amyloidosis) is unknown; however, it was noted on biopsy of one individual who presented with renal dysfunction [C Kozycki, personal observation]. • Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). • Intraocular inflammation (uveitis, retinal vasculitis) • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Retinal dystrophy (degeneration) • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). • Intraocular inflammation (uveitis, retinal vasculitis) • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Retinal dystrophy (degeneration) • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Optic nerve edema (elevation) is often present on initial evaluation even in early childhood (i.e., age <10 years). Can be observed on fundoscopic evaluation and on measurement of retinal nerve fiber layer thickness obtained by optical coherence tomography (OCT). • Intraocular inflammation (uveitis, retinal vasculitis) • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Retinal dystrophy (degeneration) • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Limited data suggest that it is often present in adolescence and early adulthood. • Slit lamp examination and dilated fundoscopic examination can identify signs of ocular inflammation. Additional testing, including OCT and fluorescein angiography (FA), can further investigate cystoid macular edema and retinal vascular leakage, respectively. • Timing of onset varies. • Signs of retinal dystrophy (including retinal atrophy, vascular attenuation, and pigment migration) can be identified on fundus examination and retinal fundus autofluorescence (FAF) imaging. • Electroretinogram (ERG) can identify early changes in photoreceptor function before signs of retinal dystrophy are observed on examination. • Transient (cyclical) cytopenias with absolute neutrophil count occasionally dropping below 1,000 cells/µL and platelets occasionally dropping below 100,000 cells/µL • Intermittently elevated C-reactive protein (CRP) ranging from mild (>10 mg/L) to severe (>100 mg/L) • The risk of AA amyloidosis (previously known as secondary [AA] amyloidosis) is unknown; however, it was noted on biopsy of one individual who presented with renal dysfunction [C Kozycki, personal observation]. ## 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 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. 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 such variants have not been identified as a cause of this disorder and would not be expected given the gain-of-function mechanism of disease causation. ## Option 1 Sequence analysis of For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 such variants have not been identified as a cause of this disorder and would not be expected given the gain-of-function mechanism of disease causation. ## Clinical Characteristics Although significant intrafamilial variability can occur, most individuals with To date, 41 individuals from 19 families with a pathogenic variant in Based on ++ often present; + rarely present Joint pain and arthritis can affect both small and large joints, including hands, wrists, elbows, spine, knees, ankles, and feet. Reported gastrointestinal involvement includes episodic abdominal pain, gastroesophageal reflux disease, dysphagia, constipation, and ileus. Abdominal discomfort can also occur in the setting of massive splenomegaly. Although recurrent headaches are common, cognitive deficits have only been reported in individuals who have other unrelated neurologic issues. No genotype-phenotype correlations have been identified. To date, all individuals with an ## Clinical Description Although significant intrafamilial variability can occur, most individuals with To date, 41 individuals from 19 families with a pathogenic variant in Based on ++ often present; + rarely present Joint pain and arthritis can affect both small and large joints, including hands, wrists, elbows, spine, knees, ankles, and feet. Reported gastrointestinal involvement includes episodic abdominal pain, gastroesophageal reflux disease, dysphagia, constipation, and ileus. Abdominal discomfort can also occur in the setting of massive splenomegaly. Although recurrent headaches are common, cognitive deficits have only been reported in individuals who have other unrelated neurologic issues. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Penetrance To date, all individuals with an ## Nomenclature ## Prevalence ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with By specialists in uveitis & retinal disorders &/or ophthalmic genetics Determine need for referral to low vision services. Dental prophylaxis Fluoride application Full series of radiographs to evaluate infections of dental roots Evaluate for dry mouth. Educate re salivary hypofunction. Community or Social work involvement for parental support There is no cure for Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) 2-3x/day brushing w/fluoridated dentifrice, daily high-fluoride oral rinse/mouthwash, or use of custom fluoride trays 2-3x per year dental prophylaxis incl professional fluoride application Because short roots have limited anchorage value over which to distribute the orthodontic force, consider enhancing anchorage value (e.g., adding more teeth in the anchored unit). Because of reduced root support, use of headgear on taurodont molars is contraindicated. Fluoride treatments per treating dentist Consider other approaches to prevent dental caries such as pit & fissure sealants. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Dilated eye exam w/OCT & FA Consider ERG to evaluate retinal function. Dental exam to monitor (1) existing treatments & (2) tooth & maxillary/mandibular development To provide anticipatory guidance for parents & continued interventions as needed ERG = electroretinogram; FA = fluorescein angiography; OCT = optical coherence tomography 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 may benefit from initiation of treatment with targeted immunomodulatory therapy. See To date, there is no evidence that a pregnant woman or fetus with Search • By specialists in uveitis & retinal disorders &/or ophthalmic genetics • Determine need for referral to low vision services. • Dental prophylaxis • Fluoride application • Full series of radiographs to evaluate infections of dental roots • Evaluate for dry mouth. • Educate re salivary hypofunction. • Community or • Social work involvement for parental support • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) • Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) • 2-3x/day brushing w/fluoridated dentifrice, daily high-fluoride oral rinse/mouthwash, or use of custom fluoride trays • 2-3x per year dental prophylaxis incl professional fluoride application • Because short roots have limited anchorage value over which to distribute the orthodontic force, consider enhancing anchorage value (e.g., adding more teeth in the anchored unit). • Because of reduced root support, use of headgear on taurodont molars is contraindicated. • Fluoride treatments per treating dentist • Consider other approaches to prevent dental caries such as pit & fissure sealants. • Dilated eye exam w/OCT & FA • Consider ERG to evaluate retinal function. • Dental exam to monitor (1) existing treatments & (2) tooth & maxillary/mandibular development • To provide anticipatory guidance for parents & continued interventions as needed ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with By specialists in uveitis & retinal disorders &/or ophthalmic genetics Determine need for referral to low vision services. Dental prophylaxis Fluoride application Full series of radiographs to evaluate infections of dental roots Evaluate for dry mouth. Educate re salivary hypofunction. Community or Social work involvement for parental support • By specialists in uveitis & retinal disorders &/or ophthalmic genetics • Determine need for referral to low vision services. • Dental prophylaxis • Fluoride application • Full series of radiographs to evaluate infections of dental roots • Evaluate for dry mouth. • Educate re salivary hypofunction. • Community or • Social work involvement for parental support ## Treatment of Manifestations There is no cure for Children: through early intervention programs &/or school district Adults: low vision clinic &/or community vision services / OT / mobility services During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) 2-3x/day brushing w/fluoridated dentifrice, daily high-fluoride oral rinse/mouthwash, or use of custom fluoride trays 2-3x per year dental prophylaxis incl professional fluoride application Because short roots have limited anchorage value over which to distribute the orthodontic force, consider enhancing anchorage value (e.g., adding more teeth in the anchored unit). Because of reduced root support, use of headgear on taurodont molars is contraindicated. Fluoride treatments per treating dentist Consider other approaches to prevent dental caries such as pit & fissure sealants. • Children: through early intervention programs &/or school district • Adults: low vision clinic &/or community vision services / OT / mobility services • During hot weather: access to adequate water supply & cool environment (e.g., air conditioning, wet T-shirt, &/or spray bottle of water) • Skin care products for mgmt of dry skin, eczema, & rashes assoc w/certain outdoor exposures (e.g., swimming) • 2-3x/day brushing w/fluoridated dentifrice, daily high-fluoride oral rinse/mouthwash, or use of custom fluoride trays • 2-3x per year dental prophylaxis incl professional fluoride application • Because short roots have limited anchorage value over which to distribute the orthodontic force, consider enhancing anchorage value (e.g., adding more teeth in the anchored unit). • Because of reduced root support, use of headgear on taurodont molars is contraindicated. • Fluoride treatments per treating dentist • Consider other approaches to prevent dental caries such as pit & fissure sealants. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Dilated eye exam w/OCT & FA Consider ERG to evaluate retinal function. Dental exam to monitor (1) existing treatments & (2) tooth & maxillary/mandibular development To provide anticipatory guidance for parents & continued interventions as needed ERG = electroretinogram; FA = fluorescein angiography; OCT = optical coherence tomography • Dilated eye exam w/OCT & FA • Consider ERG to evaluate retinal function. • Dental exam to monitor (1) existing treatments & (2) tooth & maxillary/mandibular development • To provide anticipatory guidance for parents & continued interventions as needed ## 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 may benefit from initiation of treatment with targeted immunomodulatory therapy. See ## Pregnancy Management To date, there is no evidence that a pregnant woman or fetus with ## Therapies Under Investigation Search ## Genetic Counseling Some 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 and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The 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%. Intrafamilial variability may be observed among heterozygous family members. Affected family members may present with variable clinical features, and ophthalmologic involvement is not always present. 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. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • Some 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 and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Intrafamilial variability may be observed among heterozygous family members. Affected family members may present with variable clinical features, and ophthalmologic involvement is not always present. • 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 Some 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 and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The 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%. Intrafamilial variability may be observed among heterozygous family members. Affected family members may present with variable clinical features, and ophthalmologic involvement is not always present. If the If the parents have not been tested for the • Some 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 and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • Intrafamilial variability may be observed among heterozygous family members. Affected family members may present with variable clinical features, and ophthalmologic involvement is not always present. • 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. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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 ALPK1-Related Autoinflammatory Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ALPK1-Related Autoinflammatory Disease ( Of note, 40 of the 41 individuals identified in the literature with Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Of note, 40 of the 41 individuals identified in the literature with Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Christina Kozycki runs a clinical and translational research program focused on Dr Kozycki is currently following individuals with We express our greatest gratitude to patients and their families who have entrusted us with their care and dedicated their time and tissues to advancing our understanding of this rare disease. 27 June 2024 (bp) Review posted live 2 June 2023 (ck) Original submission • 27 June 2024 (bp) Review posted live • 2 June 2023 (ck) Original submission ## Author Notes Dr Christina Kozycki runs a clinical and translational research program focused on Dr Kozycki is currently following individuals with ## Acknowledgments We express our greatest gratitude to patients and their families who have entrusted us with their care and dedicated their time and tissues to advancing our understanding of this rare disease. ## Revision History 27 June 2024 (bp) Review posted live 2 June 2023 (ck) Original submission • 27 June 2024 (bp) Review posted live • 2 June 2023 (ck) Original submission ## References ## Literature Cited	[]	27/6/2024			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alport	alport	[ "Familial Nephritis", "Hereditary Nephritis", "Familial Nephritis", "Hereditary Nephritis", "Collagen alpha-3(IV) chain", "Collagen alpha-4(IV) chain", "Collagen alpha-5(IV) chain", "COL4A3", "COL4A4", "COL4A5", "Alport Syndrome" ]	Alport Syndrome	Kandai Nozu, Tomohiko Yamamura, Tomoko Horinouchi	Summary Alport syndrome is characterized by kidney manifestations, sensorineural hearing loss (SNHL), and ocular manifestations. In the absence of treatment, kidney disease progresses from microhematuria to proteinuria, progressive kidney insufficiency, and end-stage kidney disease (ESKD) in most males with X-linked Alport syndrome (XLAS), and in most males and females with autosomal recessive Alport syndrome (ARAS). Progressive SNHL is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion. In females with XLAS and individuals with autosomal dominant Alport syndrome (ADAS), ESKD is frequently delayed until later adulthood, SNHL is relatively late in onset, and ocular involvement is rare. The molecular diagnosis of Alport syndrome is established in a proband with suggestive findings and a pathogenic variant(s) in Once the Alport syndrome-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.	## Diagnosis Diagnostic criteria for Alport syndrome have been published [ Molecular genetic testing for Alport syndrome Sensorineural deafness Anterior lenticonus and/or characteristic retinopathy Diffuse leiomyomatosis Hematuria Chronic kidney disease / kidney failure Deafness associated with chronic kidney disease Negative or nonspecific routine immunofluorescence Type IV collagen abnormal expression Thin glomerular basement membranes Characteristic glomerular basement membrane thickening, lamellation, and scalloping Family history of hematuria, chronic kidney disease, kidney failure, or deafness associated with chronic kidney disease; OR Diagnoses of immunoglobulin A nephropathy, membranous nephropathy, and membranoproliferative glomerular glomerulonephritis (C3 nephropathy) have been ruled out. The molecular diagnosis of Alport syndrome Biallelic pathogenic (or likely pathogenic) variants involving A hemizygous pathogenic (or likely pathogenic) variant involving A heterozygous pathogenic (or likely pathogenic) variant involving Note: Digenic inheritance has been described, typically due to pathogenic variants in both Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / 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 When the phenotypic and laboratory findings suggest the diagnosis of Alport syndrome, the recommended molecular genetic testing approach is the use of a For an introduction to multigene panels click Note: (1) Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish ancestry. (2) Some laboratories may offer targeted analysis for pathogenic variants particularly common in the United States, including p.Cys1564Ser, p.Leu1649Arg, and p.Arg1677Gln (see When the diagnosis of Alport syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alport Syndrome AS = Alport syndrome; MOI = mode of inheritance Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. Pathognomonic findings of Alport syndrome when diffusely present are: Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); Lacunae between these strands, sometimes with findings of podocyte infolding; Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). When kidney biopsy is contraindicated (and molecular genetic testing is not possible), a skin biopsy with monoclonal antibody staining for collagen IV α5 chains could be performed in place of the kidney biopsy. Note: Diagnostic findings on skin biopsy are only informative in some individuals with XLAS. Individuals with ARAS and ADAS have normal skin immunostaining for collagen IV α5 chains. In rare circumstances, if there is no access to molecular genetic testing or kidney biopsy, or if genetic testing fails to detect a pathogenic variant(s), the diagnosis is established in a proband with Family history of kidney disease Bilateral sensorineural deafness Characteristic ocular abnormalities including anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion Diffuse leiomyomatosis • Sensorineural deafness • Anterior lenticonus and/or characteristic retinopathy • Diffuse leiomyomatosis • Hematuria • Chronic kidney disease / kidney failure • Deafness associated with chronic kidney disease • Negative or nonspecific routine immunofluorescence • Type IV collagen abnormal expression • Thin glomerular basement membranes • Characteristic glomerular basement membrane thickening, lamellation, and scalloping • Family history of hematuria, chronic kidney disease, kidney failure, or deafness associated with chronic kidney disease; OR • Diagnoses of immunoglobulin A nephropathy, membranous nephropathy, and membranoproliferative glomerular glomerulonephritis (C3 nephropathy) have been ruled out. • Biallelic pathogenic (or likely pathogenic) variants involving • A hemizygous pathogenic (or likely pathogenic) variant involving • A heterozygous pathogenic (or likely pathogenic) variant involving • The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. • Pathognomonic findings of Alport syndrome when diffusely present are: • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Family history of kidney disease • Bilateral sensorineural deafness • Characteristic ocular abnormalities including anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion • Diffuse leiomyomatosis ## Suggestive Findings Molecular genetic testing for Alport syndrome Sensorineural deafness Anterior lenticonus and/or characteristic retinopathy Diffuse leiomyomatosis Hematuria Chronic kidney disease / kidney failure Deafness associated with chronic kidney disease Negative or nonspecific routine immunofluorescence Type IV collagen abnormal expression Thin glomerular basement membranes Characteristic glomerular basement membrane thickening, lamellation, and scalloping Family history of hematuria, chronic kidney disease, kidney failure, or deafness associated with chronic kidney disease; OR Diagnoses of immunoglobulin A nephropathy, membranous nephropathy, and membranoproliferative glomerular glomerulonephritis (C3 nephropathy) have been ruled out. • Sensorineural deafness • Anterior lenticonus and/or characteristic retinopathy • Diffuse leiomyomatosis • Hematuria • Chronic kidney disease / kidney failure • Deafness associated with chronic kidney disease • Negative or nonspecific routine immunofluorescence • Type IV collagen abnormal expression • Thin glomerular basement membranes • Characteristic glomerular basement membrane thickening, lamellation, and scalloping • Family history of hematuria, chronic kidney disease, kidney failure, or deafness associated with chronic kidney disease; OR • Diagnoses of immunoglobulin A nephropathy, membranous nephropathy, and membranoproliferative glomerular glomerulonephritis (C3 nephropathy) have been ruled out. ## Establishing the Diagnosis The molecular diagnosis of Alport syndrome Biallelic pathogenic (or likely pathogenic) variants involving A hemizygous pathogenic (or likely pathogenic) variant involving A heterozygous pathogenic (or likely pathogenic) variant involving Note: Digenic inheritance has been described, typically due to pathogenic variants in both Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / 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 When the phenotypic and laboratory findings suggest the diagnosis of Alport syndrome, the recommended molecular genetic testing approach is the use of a For an introduction to multigene panels click Note: (1) Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish ancestry. (2) Some laboratories may offer targeted analysis for pathogenic variants particularly common in the United States, including p.Cys1564Ser, p.Leu1649Arg, and p.Arg1677Gln (see When the diagnosis of Alport syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alport Syndrome AS = Alport syndrome; MOI = mode of inheritance Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. Pathognomonic findings of Alport syndrome when diffusely present are: Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); Lacunae between these strands, sometimes with findings of podocyte infolding; Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). When kidney biopsy is contraindicated (and molecular genetic testing is not possible), a skin biopsy with monoclonal antibody staining for collagen IV α5 chains could be performed in place of the kidney biopsy. Note: Diagnostic findings on skin biopsy are only informative in some individuals with XLAS. Individuals with ARAS and ADAS have normal skin immunostaining for collagen IV α5 chains. In rare circumstances, if there is no access to molecular genetic testing or kidney biopsy, or if genetic testing fails to detect a pathogenic variant(s), the diagnosis is established in a proband with Family history of kidney disease Bilateral sensorineural deafness Characteristic ocular abnormalities including anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion Diffuse leiomyomatosis • Biallelic pathogenic (or likely pathogenic) variants involving • A hemizygous pathogenic (or likely pathogenic) variant involving • A heterozygous pathogenic (or likely pathogenic) variant involving • The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. • Pathognomonic findings of Alport syndrome when diffusely present are: • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Family history of kidney disease • Bilateral sensorineural deafness • Characteristic ocular abnormalities including anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion • Diffuse leiomyomatosis ## Molecular Diagnosis The molecular diagnosis of Alport syndrome Biallelic pathogenic (or likely pathogenic) variants involving A hemizygous pathogenic (or likely pathogenic) variant involving A heterozygous pathogenic (or likely pathogenic) variant involving Note: Digenic inheritance has been described, typically due to pathogenic variants in both Note: (1) Per American College of Medical Genetics and Genomics (ACMG) / 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 When the phenotypic and laboratory findings suggest the diagnosis of Alport syndrome, the recommended molecular genetic testing approach is the use of a For an introduction to multigene panels click Note: (1) Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish ancestry. (2) Some laboratories may offer targeted analysis for pathogenic variants particularly common in the United States, including p.Cys1564Ser, p.Leu1649Arg, and p.Arg1677Gln (see When the diagnosis of Alport syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alport Syndrome AS = Alport syndrome; MOI = mode of inheritance Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. • Biallelic pathogenic (or likely pathogenic) variants involving • A hemizygous pathogenic (or likely pathogenic) variant involving • A heterozygous pathogenic (or likely pathogenic) variant involving ## When the phenotypic and laboratory findings suggest the diagnosis of Alport syndrome, the recommended molecular genetic testing approach is the use of a For an introduction to multigene panels click Note: (1) Targeted analysis for pathogenic variants can be performed first in individuals of Ashkenazi Jewish ancestry. (2) Some laboratories may offer targeted analysis for pathogenic variants particularly common in the United States, including p.Cys1564Ser, p.Leu1649Arg, and p.Arg1677Gln (see ## When the diagnosis of Alport syndrome has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alport Syndrome AS = Alport syndrome; MOI = mode of inheritance Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. ## Other Testing The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. Pathognomonic findings of Alport syndrome when diffusely present are: Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); Lacunae between these strands, sometimes with findings of podocyte infolding; Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). When kidney biopsy is contraindicated (and molecular genetic testing is not possible), a skin biopsy with monoclonal antibody staining for collagen IV α5 chains could be performed in place of the kidney biopsy. Note: Diagnostic findings on skin biopsy are only informative in some individuals with XLAS. Individuals with ARAS and ADAS have normal skin immunostaining for collagen IV α5 chains. • The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. • Pathognomonic findings of Alport syndrome when diffusely present are: • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). ## The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. Pathognomonic findings of Alport syndrome when diffusely present are: Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); Lacunae between these strands, sometimes with findings of podocyte infolding; Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • The earliest finding is diffuse thinning of the glomerular basement membrane. Children with XLAS and ARAS frequently exhibit only glomerular basement membrane thinning on kidney biopsy. Women with XLAS and individuals with ADAS also may exhibit only glomerular basement membrane thinning. Marked variability in glomerular basement membrane width within a glomerulus in an individual with persistent microhematuria should raise suspicion of Alport syndrome. • Pathognomonic findings of Alport syndrome when diffusely present are: • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). • Lamina densa that appears to be split into multiple interlacing strands of electron-dense material, resembling basket weaving (also sometimes described as lamellation or splitting); • Lacunae between these strands, sometimes with findings of podocyte infolding; • Diffusely thickened glomerular basement membrane with effacement of foot process. Note: A variety of techniques have been used to measure glomerular basement membrane width. The cutoff value in adults ranges from 250 to 330 nm, depending on technique. The cutoff value in children ranges from 200 to 250 nm, depending on technique (250 nm is within 2 standard deviations of the mean at age 11 years). ## When kidney biopsy is contraindicated (and molecular genetic testing is not possible), a skin biopsy with monoclonal antibody staining for collagen IV α5 chains could be performed in place of the kidney biopsy. Note: Diagnostic findings on skin biopsy are only informative in some individuals with XLAS. Individuals with ARAS and ADAS have normal skin immunostaining for collagen IV α5 chains. ## Clinical Diagnosis In rare circumstances, if there is no access to molecular genetic testing or kidney biopsy, or if genetic testing fails to detect a pathogenic variant(s), the diagnosis is established in a proband with Family history of kidney disease Bilateral sensorineural deafness Characteristic ocular abnormalities including anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion Diffuse leiomyomatosis • Family history of kidney disease • Bilateral sensorineural deafness • Characteristic ocular abnormalities including anterior lenticonus (which is virtually pathognomonic), maculopathy (whitish or yellowish flecks or granulations in the perimacular region), corneal endothelial vesicles (posterior polymorphous dystrophy), and recurrent corneal erosion • Diffuse leiomyomatosis ## Clinical Characteristics Alport syndrome is characterized by kidney manifestations (ranging from isolated hematuria to progressive kidney disease), sensorineural hearing loss (SNHL), and ocular manifestations. Kidney insufficiency and SNHL may not develop until relatively late in life. Alport Syndrome: Frequency of Select Features ADAS = autosomal dominant Alport syndrome: ARAS = autosomal recessive Alport syndrome; ESKD = end-stage kidney disease; ND = no data; SNHL = sensorineural hearing loss; XLAS = X-linked Alport syndrome In those with autosomal dominant The hallmark of Alport syndrome is microhematuria. All males with XLAS and males and females with ARAS have persistent microhematuria from early in life. Episodic gross hematuria can occur, especially during childhood. Microhematuria is also very common in females with XLAS. Individuals with a heterozygous All males with XLAS develop proteinuria and most develop progressive kidney insufficiency, which leads to end-stage kidney disease (ESKD). Overall, an estimated 50% of males with XLAS reach ESKD by age 35 years [ SNHL in individuals with Alport syndrome is never congenital. Diminished hearing is frequently detected in late childhood or early adolescence in boys with XLAS. In its early stages, the hearing deficit is detectable only by audiometry, with bilateral reduction in sensitivity to tones in the range of 2,000-8,000 Hz. In affected males, the hearing loss is progressive and eventually extends to other frequencies, including those of conversational speech. Hearing loss is frequently identifiable by formal assessment of hearing in late childhood, but in some families hearing loss is not detectable until relatively late in life. SNHL develops in 50%-60% of males with XLAS [ The course of the hearing loss depends on the pathogenic variant (see A histologic study of cochleas in individuals with Alport syndrome suggests that defective adhesion of the organ of Corti to the basilar membrane may underlie the hearing deficit [ Ocular lesions are common in Alport syndrome, occurring in up to 70% of individuals with Alport syndrome [ Anterior lenticonus, in which the central portion of the lens protrudes into the anterior chamber, is virtually pathognomonic of Alport syndrome. When present, anterior lenticonus is bilateral in approximately 75% of individuals. It is absent at birth, usually appearing during the second to third decade of life. Progressive distortion of the lens may occur, accompanied by increasing myopia. Lens opacities may be seen in conjunction with lenticonus, occasionally resulting from rupture of the anterior lens capsule. All reported individuals with anterior lenticonus who have been adequately examined have exhibited evidence of chronic nephritis and SNHL. It is far more common in affected males but can occur in females with XLAS. The frequency of lenticonus in males with XLAS is 50% [ Maculopathy consisting of whitish or yellowish flecks or granulations in the perimacular region can be observed in males with XLAS and individuals with ARAS. While the maculopathy is usually not associated with any visual abnormalities, some individuals have developed macular holes associated with severe thinning of the retina. Central or perimacular fleck retinopathy, characterized by asymmetric patches of confluent flecks, is observed in 70% of males with XLAS and in 20% of females with XLAS, making it a valuable diagnostic clue for Alport syndrome [ Corneal endothelial vesicles (posterior polymorphous dystrophy) and recurrent corneal erosion may also be seen in individuals with Alport syndrome. Bilateral posterior subcapsular cataracts also occur frequently in individuals with Alport syndrome with diffuse leiomyomatosis (see Phenotype Correlations by Gene AD = autosomal dominant; AR = autosomal recessive; ESKD = end-stage kidney disease; SNHL = sensorineural hearing loss; XL = X-linked In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years [ Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years [ In males with large rearrangements of In males with missense variants, the risk for deafness does not reach 50% until age 20 years [ Anterior lenticonus occurs in approximately 50% of males with XLAS [ Anterior lenticonus and central retinopathy typically indicate the onset of kidney failure before age 30 years in males with XLAS. Additionally, these features are more commonly observed in individuals with a Note: Lenticonus and central retinopathy also seem to be more common in individuals with ARAS caused by nonsense pathogenic variants [ All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of Leiomyomatosis does not occur in individuals with deletions of Pathogenic variants of In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis is 100% penetrant, occurring equally in both males and females. The presence of Other terms used to refer to individuals with Thin basement membrane nephropathy Type IV collagen-associated kidney disease Alport spectrum nephropathy The variation in these terms reflects differences in diagnostic methods and criteria. There is a strong consensus that the term "benign familial hematuria" should no longer be used to refer to individuals with The combined phenotype-based prevalence of XLAS and ARAS estimated from historical literature ranges from 1:5,000 to 1:50,000 [ • In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years [ • Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years [ • In males with large rearrangements of • In males with missense variants, the risk for deafness does not reach 50% until age 20 years [ • Anterior lenticonus occurs in approximately 50% of males with XLAS [ • Anterior lenticonus and central retinopathy typically indicate the onset of kidney failure before age 30 years in males with XLAS. Additionally, these features are more commonly observed in individuals with a • Note: Lenticonus and central retinopathy also seem to be more common in individuals with ARAS caused by nonsense pathogenic variants [ • All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of • Leiomyomatosis does not occur in individuals with deletions of • Pathogenic variants of • In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis is 100% penetrant, occurring equally in both males and females. • Thin basement membrane nephropathy • Type IV collagen-associated kidney disease • Alport spectrum nephropathy ## Clinical Description Alport syndrome is characterized by kidney manifestations (ranging from isolated hematuria to progressive kidney disease), sensorineural hearing loss (SNHL), and ocular manifestations. Kidney insufficiency and SNHL may not develop until relatively late in life. Alport Syndrome: Frequency of Select Features ADAS = autosomal dominant Alport syndrome: ARAS = autosomal recessive Alport syndrome; ESKD = end-stage kidney disease; ND = no data; SNHL = sensorineural hearing loss; XLAS = X-linked Alport syndrome In those with autosomal dominant The hallmark of Alport syndrome is microhematuria. All males with XLAS and males and females with ARAS have persistent microhematuria from early in life. Episodic gross hematuria can occur, especially during childhood. Microhematuria is also very common in females with XLAS. Individuals with a heterozygous All males with XLAS develop proteinuria and most develop progressive kidney insufficiency, which leads to end-stage kidney disease (ESKD). Overall, an estimated 50% of males with XLAS reach ESKD by age 35 years [ SNHL in individuals with Alport syndrome is never congenital. Diminished hearing is frequently detected in late childhood or early adolescence in boys with XLAS. In its early stages, the hearing deficit is detectable only by audiometry, with bilateral reduction in sensitivity to tones in the range of 2,000-8,000 Hz. In affected males, the hearing loss is progressive and eventually extends to other frequencies, including those of conversational speech. Hearing loss is frequently identifiable by formal assessment of hearing in late childhood, but in some families hearing loss is not detectable until relatively late in life. SNHL develops in 50%-60% of males with XLAS [ The course of the hearing loss depends on the pathogenic variant (see A histologic study of cochleas in individuals with Alport syndrome suggests that defective adhesion of the organ of Corti to the basilar membrane may underlie the hearing deficit [ Ocular lesions are common in Alport syndrome, occurring in up to 70% of individuals with Alport syndrome [ Anterior lenticonus, in which the central portion of the lens protrudes into the anterior chamber, is virtually pathognomonic of Alport syndrome. When present, anterior lenticonus is bilateral in approximately 75% of individuals. It is absent at birth, usually appearing during the second to third decade of life. Progressive distortion of the lens may occur, accompanied by increasing myopia. Lens opacities may be seen in conjunction with lenticonus, occasionally resulting from rupture of the anterior lens capsule. All reported individuals with anterior lenticonus who have been adequately examined have exhibited evidence of chronic nephritis and SNHL. It is far more common in affected males but can occur in females with XLAS. The frequency of lenticonus in males with XLAS is 50% [ Maculopathy consisting of whitish or yellowish flecks or granulations in the perimacular region can be observed in males with XLAS and individuals with ARAS. While the maculopathy is usually not associated with any visual abnormalities, some individuals have developed macular holes associated with severe thinning of the retina. Central or perimacular fleck retinopathy, characterized by asymmetric patches of confluent flecks, is observed in 70% of males with XLAS and in 20% of females with XLAS, making it a valuable diagnostic clue for Alport syndrome [ Corneal endothelial vesicles (posterior polymorphous dystrophy) and recurrent corneal erosion may also be seen in individuals with Alport syndrome. Bilateral posterior subcapsular cataracts also occur frequently in individuals with Alport syndrome with diffuse leiomyomatosis (see ## Kidney Manifestations The hallmark of Alport syndrome is microhematuria. All males with XLAS and males and females with ARAS have persistent microhematuria from early in life. Episodic gross hematuria can occur, especially during childhood. Microhematuria is also very common in females with XLAS. Individuals with a heterozygous All males with XLAS develop proteinuria and most develop progressive kidney insufficiency, which leads to end-stage kidney disease (ESKD). Overall, an estimated 50% of males with XLAS reach ESKD by age 35 years [ ## Cochlear Manifestations SNHL in individuals with Alport syndrome is never congenital. Diminished hearing is frequently detected in late childhood or early adolescence in boys with XLAS. In its early stages, the hearing deficit is detectable only by audiometry, with bilateral reduction in sensitivity to tones in the range of 2,000-8,000 Hz. In affected males, the hearing loss is progressive and eventually extends to other frequencies, including those of conversational speech. Hearing loss is frequently identifiable by formal assessment of hearing in late childhood, but in some families hearing loss is not detectable until relatively late in life. SNHL develops in 50%-60% of males with XLAS [ The course of the hearing loss depends on the pathogenic variant (see A histologic study of cochleas in individuals with Alport syndrome suggests that defective adhesion of the organ of Corti to the basilar membrane may underlie the hearing deficit [ ## Ocular Manifestations Ocular lesions are common in Alport syndrome, occurring in up to 70% of individuals with Alport syndrome [ Anterior lenticonus, in which the central portion of the lens protrudes into the anterior chamber, is virtually pathognomonic of Alport syndrome. When present, anterior lenticonus is bilateral in approximately 75% of individuals. It is absent at birth, usually appearing during the second to third decade of life. Progressive distortion of the lens may occur, accompanied by increasing myopia. Lens opacities may be seen in conjunction with lenticonus, occasionally resulting from rupture of the anterior lens capsule. All reported individuals with anterior lenticonus who have been adequately examined have exhibited evidence of chronic nephritis and SNHL. It is far more common in affected males but can occur in females with XLAS. The frequency of lenticonus in males with XLAS is 50% [ Maculopathy consisting of whitish or yellowish flecks or granulations in the perimacular region can be observed in males with XLAS and individuals with ARAS. While the maculopathy is usually not associated with any visual abnormalities, some individuals have developed macular holes associated with severe thinning of the retina. Central or perimacular fleck retinopathy, characterized by asymmetric patches of confluent flecks, is observed in 70% of males with XLAS and in 20% of females with XLAS, making it a valuable diagnostic clue for Alport syndrome [ Corneal endothelial vesicles (posterior polymorphous dystrophy) and recurrent corneal erosion may also be seen in individuals with Alport syndrome. Bilateral posterior subcapsular cataracts also occur frequently in individuals with Alport syndrome with diffuse leiomyomatosis (see ## Other ## Phenotype Correlations by Gene Phenotype Correlations by Gene AD = autosomal dominant; AR = autosomal recessive; ESKD = end-stage kidney disease; SNHL = sensorineural hearing loss; XL = X-linked ## Genotype-Phenotype Correlations In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years [ Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years [ In males with large rearrangements of In males with missense variants, the risk for deafness does not reach 50% until age 20 years [ Anterior lenticonus occurs in approximately 50% of males with XLAS [ Anterior lenticonus and central retinopathy typically indicate the onset of kidney failure before age 30 years in males with XLAS. Additionally, these features are more commonly observed in individuals with a Note: Lenticonus and central retinopathy also seem to be more common in individuals with ARAS caused by nonsense pathogenic variants [ All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of Leiomyomatosis does not occur in individuals with deletions of Pathogenic variants of In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis is 100% penetrant, occurring equally in both males and females. • In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years [ • Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years [ • In males with large rearrangements of • In males with missense variants, the risk for deafness does not reach 50% until age 20 years [ • Anterior lenticonus occurs in approximately 50% of males with XLAS [ • Anterior lenticonus and central retinopathy typically indicate the onset of kidney failure before age 30 years in males with XLAS. Additionally, these features are more commonly observed in individuals with a • Note: Lenticonus and central retinopathy also seem to be more common in individuals with ARAS caused by nonsense pathogenic variants [ • All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of • Leiomyomatosis does not occur in individuals with deletions of • Pathogenic variants of • In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis is 100% penetrant, occurring equally in both males and females. In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years [ Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years [ In males with large rearrangements of In males with missense variants, the risk for deafness does not reach 50% until age 20 years [ Anterior lenticonus occurs in approximately 50% of males with XLAS [ Anterior lenticonus and central retinopathy typically indicate the onset of kidney failure before age 30 years in males with XLAS. Additionally, these features are more commonly observed in individuals with a Note: Lenticonus and central retinopathy also seem to be more common in individuals with ARAS caused by nonsense pathogenic variants [ All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of Leiomyomatosis does not occur in individuals with deletions of Pathogenic variants of In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis is 100% penetrant, occurring equally in both males and females. • In affected males with splice site variants, the probability of ESKD before age 30 years is around 65%, with 50% of males reaching ESKD by age 25 years [ • Missense variants are associated with only a 30% probability of ESKD before age 30 years and a 50% probability of ESKD by age 40 years [ • In males with large rearrangements of • In males with missense variants, the risk for deafness does not reach 50% until age 20 years [ • Anterior lenticonus occurs in approximately 50% of males with XLAS [ • Anterior lenticonus and central retinopathy typically indicate the onset of kidney failure before age 30 years in males with XLAS. Additionally, these features are more commonly observed in individuals with a • Note: Lenticonus and central retinopathy also seem to be more common in individuals with ARAS caused by nonsense pathogenic variants [ • All families in which XLAS cosegregates with diffuse leiomyomatosis exhibit large deletions that span the adjacent 5' ends of • Leiomyomatosis does not occur in individuals with deletions of • Pathogenic variants of • In individuals with these deletions, kidney disease is severe in males and mild in females. However, leiomyomatosis is 100% penetrant, occurring equally in both males and females. ## Penetrance The presence of ## Nomenclature Other terms used to refer to individuals with Thin basement membrane nephropathy Type IV collagen-associated kidney disease Alport spectrum nephropathy The variation in these terms reflects differences in diagnostic methods and criteria. There is a strong consensus that the term "benign familial hematuria" should no longer be used to refer to individuals with • Thin basement membrane nephropathy • Type IV collagen-associated kidney disease • Alport spectrum nephropathy ## Prevalence The combined phenotype-based prevalence of XLAS and ARAS estimated from historical literature ranges from 1:5,000 to 1:50,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Alport syndrome must be distinguished from other genetic disorders associated with persistent (>6 months in duration) hematuria and/or combined nephritis and hearing loss (see Of note, in a child with no known family history of hematuria, the most likely diagnoses are immunoglobin A nephropathy, Alport syndrome, and Genetic Disorders of Interest in the Differential Diagnosis of Alport Syndrome Hematuria Proteinuria Hearing loss Kidney failure FSGS Cataracts External ear anomalies such as eustachian fistulas & accessory ear Branchial fistulae Lamellated GBM FSGS Kidney failure Pulmonary defects Skin abnormalities Neurodevelopmental delay Lamellated GBM FSGS Kidney failure Ocular changes Congenital nephrotic syndrome Neurodevelopmental delay Microcoria (Pierson syndrome) Lamellated GBM FSGS Kidney failure Nail dysplasia Patellar hypoplasia Combined nephritis & hearing loss Some persons exhibit ultrastructural changes of glomerular capillary wall reminiscent of those seen in persons w/Alport syndrome. AD = autosomal dominant; AR = autosomal recessive; GBM = glomerular basement membrane; FSGS = focal segmental glomerular sclerosis; MOI = mode of inheritance C3 glomerulopathy (C3G) is a complex genetic disorder that is rarely inherited in a simple mendelian fashion. In most persons with C3G, inheritance is complex and incompletely understood. Although In the past, the phenotypes included in • Hematuria • Proteinuria • Hearing loss • Kidney failure • FSGS • Cataracts • External ear anomalies such as eustachian fistulas & accessory ear • Branchial fistulae • Lamellated GBM FSGS • Kidney failure • Pulmonary defects • Skin abnormalities • Neurodevelopmental delay • Lamellated GBM FSGS • Kidney failure • Ocular changes • Congenital nephrotic syndrome • Neurodevelopmental delay • Microcoria (Pierson syndrome) • Lamellated GBM FSGS • Kidney failure • Nail dysplasia • Patellar hypoplasia • Combined nephritis & hearing loss • Some persons exhibit ultrastructural changes of glomerular capillary wall reminiscent of those seen in persons w/Alport syndrome. ## Management To establish the extent of disease and needs in an individual diagnosed with Alport syndrome, the evaluations summarized in Alport Syndrome: Recommended Evaluations Following Initial Diagnosis MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Clinical practice recommendations for the treatment of individuals with Alport syndrome have been published [ Alport Syndrome: Treatment of Manifestations XLAS (males): at diagnosis, if age >12-24 mos XLAS (females): presence of microalbuminuria ARAS: at diagnosis, if age >12-24 mos ADAS: presence of microalbuminuria ADAS = autosomal dominant Alport syndrome; ARAS = autosomal recessive Alport syndrome; AS = Alport syndrome; ESKD = end-stage kidney disease; XLAS = X-linked Alport syndrome It is recommended to determine the exact genotype in all potential donors. Heterozygous relatives (males or females with pathogenic variants in Living kidney donation is not advisable for individuals younger than age 40 years with a heterozygous pathogenic variant in For individuals older than age 40 years with a heterozygous pathogenic variant in Individuals with a heterozygous pathogenic variant in Clinical practice recommendations for health surveillance of individuals with Alport syndrome have been published [ Alport Syndrome: Recommended Surveillance Annually if urine microalbumin-to-creatinine ratio <30 mg/g or urine protein-to-creatinine ratio <0.2 mg/mg Every 6 mos if urine microalbumin-to-creatinine ratio >30 mg/g or urine protein-to-creatinine ratio >0.2 mg/mg Although most females with XLAS exhibit only asymptomatic microhematuria, there can be a significant risk for progression to ESKD [ Males with XLAS and a truncating pathogenic variant in Dehydration should be avoided. Individuals who suffer recurrent corneal erosions may need to take measures (e.g., wearing goggles when riding a bicycle) to protect their corneas from minor trauma. Exposure to loud noise should be minimized. Molecular genetic testing if the pathogenic variant(s) in the family are known; If the pathogenic variant(s) in the family are not known, urinalysis for proteinuria and hematuria and blood pressure measurement should be done. In the absence of microalbuminuria, overt proteinuria, hematuria, or elevated blood pressure, relatives at risk should, at a minimum, have annual urinalysis and blood pressure measurement. See Women with Alport syndrome are at risk for pregnancy complications including increased proteinuria, kidney insufficiency, worsened hypertension, and preeclampsia. The risks of these complications are higher in women with preexisting kidney insufficiency, proteinuria, or hypertension. Optimal maternal and fetal outcomes may require the involvement of a nephrologist as well as high-risk obstetrics. A list of Alport syndrome clinical trials can be found at Search • XLAS (males): at diagnosis, if age >12-24 mos • XLAS (females): presence of microalbuminuria • ARAS: at diagnosis, if age >12-24 mos • ADAS: presence of microalbuminuria • It is recommended to determine the exact genotype in all potential donors. • Heterozygous relatives (males or females with pathogenic variants in • Living kidney donation is not advisable for individuals younger than age 40 years with a heterozygous pathogenic variant in • For individuals older than age 40 years with a heterozygous pathogenic variant in • Individuals with a heterozygous pathogenic variant in • Annually if urine microalbumin-to-creatinine ratio <30 mg/g or urine protein-to-creatinine ratio <0.2 mg/mg • Every 6 mos if urine microalbumin-to-creatinine ratio >30 mg/g or urine protein-to-creatinine ratio >0.2 mg/mg • Molecular genetic testing if the pathogenic variant(s) in the family are known; • If the pathogenic variant(s) in the family are not known, urinalysis for proteinuria and hematuria and blood pressure measurement should be done. In the absence of microalbuminuria, overt proteinuria, hematuria, or elevated blood pressure, relatives at risk should, at a minimum, have annual urinalysis and blood pressure measurement. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Alport syndrome, the evaluations summarized in Alport Syndrome: Recommended Evaluations Following Initial Diagnosis MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations Clinical practice recommendations for the treatment of individuals with Alport syndrome have been published [ Alport Syndrome: Treatment of Manifestations XLAS (males): at diagnosis, if age >12-24 mos XLAS (females): presence of microalbuminuria ARAS: at diagnosis, if age >12-24 mos ADAS: presence of microalbuminuria ADAS = autosomal dominant Alport syndrome; ARAS = autosomal recessive Alport syndrome; AS = Alport syndrome; ESKD = end-stage kidney disease; XLAS = X-linked Alport syndrome It is recommended to determine the exact genotype in all potential donors. Heterozygous relatives (males or females with pathogenic variants in Living kidney donation is not advisable for individuals younger than age 40 years with a heterozygous pathogenic variant in For individuals older than age 40 years with a heterozygous pathogenic variant in Individuals with a heterozygous pathogenic variant in • XLAS (males): at diagnosis, if age >12-24 mos • XLAS (females): presence of microalbuminuria • ARAS: at diagnosis, if age >12-24 mos • ADAS: presence of microalbuminuria • It is recommended to determine the exact genotype in all potential donors. • Heterozygous relatives (males or females with pathogenic variants in • Living kidney donation is not advisable for individuals younger than age 40 years with a heterozygous pathogenic variant in • For individuals older than age 40 years with a heterozygous pathogenic variant in • Individuals with a heterozygous pathogenic variant in ## Surveillance Clinical practice recommendations for health surveillance of individuals with Alport syndrome have been published [ Alport Syndrome: Recommended Surveillance Annually if urine microalbumin-to-creatinine ratio <30 mg/g or urine protein-to-creatinine ratio <0.2 mg/mg Every 6 mos if urine microalbumin-to-creatinine ratio >30 mg/g or urine protein-to-creatinine ratio >0.2 mg/mg Although most females with XLAS exhibit only asymptomatic microhematuria, there can be a significant risk for progression to ESKD [ Males with XLAS and a truncating pathogenic variant in • Annually if urine microalbumin-to-creatinine ratio <30 mg/g or urine protein-to-creatinine ratio <0.2 mg/mg • Every 6 mos if urine microalbumin-to-creatinine ratio >30 mg/g or urine protein-to-creatinine ratio >0.2 mg/mg ## Agents/Circumstances to Avoid Dehydration should be avoided. Individuals who suffer recurrent corneal erosions may need to take measures (e.g., wearing goggles when riding a bicycle) to protect their corneas from minor trauma. Exposure to loud noise should be minimized. ## Evaluation of Relatives at Risk Molecular genetic testing if the pathogenic variant(s) in the family are known; If the pathogenic variant(s) in the family are not known, urinalysis for proteinuria and hematuria and blood pressure measurement should be done. In the absence of microalbuminuria, overt proteinuria, hematuria, or elevated blood pressure, relatives at risk should, at a minimum, have annual urinalysis and blood pressure measurement. See • Molecular genetic testing if the pathogenic variant(s) in the family are known; • If the pathogenic variant(s) in the family are not known, urinalysis for proteinuria and hematuria and blood pressure measurement should be done. In the absence of microalbuminuria, overt proteinuria, hematuria, or elevated blood pressure, relatives at risk should, at a minimum, have annual urinalysis and blood pressure measurement. ## Pregnancy Management Women with Alport syndrome are at risk for pregnancy complications including increased proteinuria, kidney insufficiency, worsened hypertension, and preeclampsia. The risks of these complications are higher in women with preexisting kidney insufficiency, proteinuria, or hypertension. Optimal maternal and fetal outcomes may require the involvement of a nephrologist as well as high-risk obstetrics. ## Therapies Under Investigation A list of Alport syndrome clinical trials can be found at Search ## Genetic Counseling Digenic Alport syndrome is caused by pathogenic variants in more than one Alport syndrome-related gene: typically pathogenic variants in both See The father of a male with XLAS will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a The following evaluations are recommended for the mother of a male known to have XLAS in order to confirm her genetic status, allow reliable recurrence risk assessment, and assess her need for kidney Molecular genetic testing for the Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a If the mother of an affected male is not found to have proteinuria or hypertension and if molecular genetic testing is not possible, she should have, at a minimum, annual urinalysis and measurement of blood pressure. A female proband may have inherited the Evaluation of the parents of a female proband with XLAS proceeds (for both parents) as described for the mother of a male proband. If the mother of the proband has a All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ If the proband represents a simplex case and the If the mother of the proband has a If the father of the proband has a If the proband represents a simplex case and the Affected males transmit the Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. The parents of a child with biallelic Molecular genetic testing for the pathogenic variants identified in the proband 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. While risk of kidney manifestations in individuals who are heterozygous for a If both parents are known to be heterozygous for a Some individuals who are heterozygous for a Most individuals diagnosed with ADAS have the disorder as the result of a Some individuals diagnosed with ADAS have the disorder as the result of a If the proband appears to be the only affected family member, molecular genetic testing for the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the 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 are clinically asymptomatic (e.g., urinalysis is normal in both parents) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. If a proband has digenic Alport syndrome caused by If a proband has digenic Alport syndrome caused by Molecular genetic testing for the pathogenic variants identified in the proband is recommended for both parents of the proband to confirm their genetic status, allow reliable recurrence risk assessment, and determine their need for kidney If one parent is heterozygous for a 25% chance of inheriting two pathogenic variants; 50% chance of inheriting one pathogenic variant; 25% chance of inheriting neither of the familial pathogenic variants. If one parent is heterozygous for a 50% chance of inheriting two pathogenic variants on the same chromosome; 50% chance of inheriting neither of the familial pathogenic variants. If the mother of the proband has a 25% chance of inheriting both the maternal 25% chance of inheriting only the maternal 25% chance of inheriting only the paternal 25% chance of inheriting neither of the familial pathogenic variants. If the father of the proband has a Male sibs have a 50% risk of inheriting the All female sibs will inherit the paternal Sibs who inherit pathogenic variants in both Sibs who inherit a single Alport syndrome-related pathogenic variant are at risk for ADAS (if they are heterozygous for a All offspring of a proband with Offspring of a proband with If a female proband has a If a male proband has a See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Alport syndrome-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 in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The father of a male with XLAS will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • The following evaluations are recommended for the mother of a male known to have XLAS in order to confirm her genetic status, allow reliable recurrence risk assessment, and assess her need for kidney • Molecular genetic testing for the • Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a • Molecular genetic testing for the • Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a • If the mother of an affected male is not found to have proteinuria or hypertension and if molecular genetic testing is not possible, she should have, at a minimum, annual urinalysis and measurement of blood pressure. • Molecular genetic testing for the • Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a • A female proband may have inherited the • Evaluation of the parents of a female proband with XLAS proceeds (for both parents) as described for the mother of a male proband. • If the mother of the proband has a • All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ • Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ • All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ • Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ • If the proband represents a simplex case and the • All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ • Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ • If the mother of the proband has a • If the father of the proband has a • If the proband represents a simplex case and the • Affected males transmit the • Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. • The parents of a child with biallelic • Molecular genetic testing for the pathogenic variants identified in the proband 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. • While risk of kidney manifestations in individuals who 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. • If both parents are known to be heterozygous for a • Some individuals who are heterozygous for a • Most individuals diagnosed with ADAS have the disorder as the result of a • Some individuals diagnosed with ADAS have the disorder as the result of a • If the proband appears to be the only affected family member, molecular genetic testing for the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • 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 are clinically asymptomatic (e.g., urinalysis is normal in both parents) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. • If a proband has digenic Alport syndrome caused by • If a proband has digenic Alport syndrome caused by • Molecular genetic testing for the pathogenic variants identified in the proband is recommended for both parents of the proband to confirm their genetic status, allow reliable recurrence risk assessment, and determine their need for kidney • If one parent is heterozygous for a • 25% chance of inheriting two pathogenic variants; • 50% chance of inheriting one pathogenic variant; • 25% chance of inheriting neither of the familial pathogenic variants. • 25% chance of inheriting two pathogenic variants; • 50% chance of inheriting one pathogenic variant; • 25% chance of inheriting neither of the familial pathogenic variants. • If one parent is heterozygous for a • 50% chance of inheriting two pathogenic variants on the same chromosome; • 50% chance of inheriting neither of the familial pathogenic variants. • 50% chance of inheriting two pathogenic variants on the same chromosome; • 50% chance of inheriting neither of the familial pathogenic variants. • If the mother of the proband has a • 25% chance of inheriting both the maternal • 25% chance of inheriting only the maternal • 25% chance of inheriting only the paternal • 25% chance of inheriting neither of the familial pathogenic variants. • 25% chance of inheriting both the maternal • 25% chance of inheriting only the maternal • 25% chance of inheriting only the paternal • 25% chance of inheriting neither of the familial pathogenic variants. • If the father of the proband has a • Male sibs have a 50% risk of inheriting the • All female sibs will inherit the paternal • Male sibs have a 50% risk of inheriting the • All female sibs will inherit the paternal • Sibs who inherit pathogenic variants in both • Sibs who inherit a single Alport syndrome-related pathogenic variant are at risk for ADAS (if they are heterozygous for a • 25% chance of inheriting two pathogenic variants; • 50% chance of inheriting one pathogenic variant; • 25% chance of inheriting neither of the familial pathogenic variants. • 50% chance of inheriting two pathogenic variants on the same chromosome; • 50% chance of inheriting neither of the familial pathogenic variants. • 25% chance of inheriting both the maternal • 25% chance of inheriting only the maternal • 25% chance of inheriting only the paternal • 25% chance of inheriting neither of the familial pathogenic variants. • Male sibs have a 50% risk of inheriting the • All female sibs will inherit the paternal • All offspring of a proband with • Offspring of a proband with • If a female proband has a • If a male proband has 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 or at risk. ## Mode of Inheritance Digenic Alport syndrome is caused by pathogenic variants in more than one Alport syndrome-related gene: typically pathogenic variants in both See ## XLAS – Risk to Family Members The father of a male with XLAS will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a The following evaluations are recommended for the mother of a male known to have XLAS in order to confirm her genetic status, allow reliable recurrence risk assessment, and assess her need for kidney Molecular genetic testing for the Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a If the mother of an affected male is not found to have proteinuria or hypertension and if molecular genetic testing is not possible, she should have, at a minimum, annual urinalysis and measurement of blood pressure. A female proband may have inherited the Evaluation of the parents of a female proband with XLAS proceeds (for both parents) as described for the mother of a male proband. If the mother of the proband has a All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ If the proband represents a simplex case and the If the mother of the proband has a If the father of the proband has a If the proband represents a simplex case and the Affected males transmit the Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. • The father of a male with XLAS will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • The following evaluations are recommended for the mother of a male known to have XLAS in order to confirm her genetic status, allow reliable recurrence risk assessment, and assess her need for kidney • Molecular genetic testing for the • Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a • Molecular genetic testing for the • Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a • If the mother of an affected male is not found to have proteinuria or hypertension and if molecular genetic testing is not possible, she should have, at a minimum, annual urinalysis and measurement of blood pressure. • Molecular genetic testing for the • Urinalysis. The presence of microhematuria indicates that the mother of a male proband is likely to be heterozygous for a • A female proband may have inherited the • Evaluation of the parents of a female proband with XLAS proceeds (for both parents) as described for the mother of a male proband. • If the mother of the proband has a • All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ • Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ • All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ • Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ • If the proband represents a simplex case and the • All males with XLAS develop proteinuria, and an overall estimated 50% of males reach ESKD by age 35 years [ • Microhematuria is very common in females with XLAS, with a median age for developing ESKD of 65 years [ • If the mother of the proband has a • If the father of the proband has a • If the proband represents a simplex case and the • Affected males transmit the • Heterozygous females have a 50% chance of transmitting the pathogenic variant to each child. ## ARAS – Risk to Family Members The parents of a child with biallelic Molecular genetic testing for the pathogenic variants identified in the proband 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. While risk of kidney manifestations in individuals who are heterozygous for a If both parents are known to be heterozygous for a Some individuals who are heterozygous for a • The parents of a child with biallelic • Molecular genetic testing for the pathogenic variants identified in the proband 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. • While risk of kidney manifestations in individuals who 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. • If both parents are known to be heterozygous for a • Some individuals who are heterozygous for a ## ADAS – Risk to Family Members Most individuals diagnosed with ADAS have the disorder as the result of a Some individuals diagnosed with ADAS have the disorder as the result of a If the proband appears to be the only affected family member, molecular genetic testing for the If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the 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 are clinically asymptomatic (e.g., urinalysis is normal in both parents) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. • Most individuals diagnosed with ADAS have the disorder as the result of a • Some individuals diagnosed with ADAS have the disorder as the result of a • If the proband appears to be the only affected family member, molecular genetic testing for the • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • 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 are clinically asymptomatic (e.g., urinalysis is normal in both parents) but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. ## Digenic Inheritance – Risk to Family Members If a proband has digenic Alport syndrome caused by If a proband has digenic Alport syndrome caused by Molecular genetic testing for the pathogenic variants identified in the proband is recommended for both parents of the proband to confirm their genetic status, allow reliable recurrence risk assessment, and determine their need for kidney If one parent is heterozygous for a 25% chance of inheriting two pathogenic variants; 50% chance of inheriting one pathogenic variant; 25% chance of inheriting neither of the familial pathogenic variants. If one parent is heterozygous for a 50% chance of inheriting two pathogenic variants on the same chromosome; 50% chance of inheriting neither of the familial pathogenic variants. If the mother of the proband has a 25% chance of inheriting both the maternal 25% chance of inheriting only the maternal 25% chance of inheriting only the paternal 25% chance of inheriting neither of the familial pathogenic variants. If the father of the proband has a Male sibs have a 50% risk of inheriting the All female sibs will inherit the paternal Sibs who inherit pathogenic variants in both Sibs who inherit a single Alport syndrome-related pathogenic variant are at risk for ADAS (if they are heterozygous for a All offspring of a proband with Offspring of a proband with If a female proband has a If a male proband has a • If a proband has digenic Alport syndrome caused by • If a proband has digenic Alport syndrome caused by • Molecular genetic testing for the pathogenic variants identified in the proband is recommended for both parents of the proband to confirm their genetic status, allow reliable recurrence risk assessment, and determine their need for kidney • If one parent is heterozygous for a • 25% chance of inheriting two pathogenic variants; • 50% chance of inheriting one pathogenic variant; • 25% chance of inheriting neither of the familial pathogenic variants. • 25% chance of inheriting two pathogenic variants; • 50% chance of inheriting one pathogenic variant; • 25% chance of inheriting neither of the familial pathogenic variants. • If one parent is heterozygous for a • 50% chance of inheriting two pathogenic variants on the same chromosome; • 50% chance of inheriting neither of the familial pathogenic variants. • 50% chance of inheriting two pathogenic variants on the same chromosome; • 50% chance of inheriting neither of the familial pathogenic variants. • If the mother of the proband has a • 25% chance of inheriting both the maternal • 25% chance of inheriting only the maternal • 25% chance of inheriting only the paternal • 25% chance of inheriting neither of the familial pathogenic variants. • 25% chance of inheriting both the maternal • 25% chance of inheriting only the maternal • 25% chance of inheriting only the paternal • 25% chance of inheriting neither of the familial pathogenic variants. • If the father of the proband has a • Male sibs have a 50% risk of inheriting the • All female sibs will inherit the paternal • Male sibs have a 50% risk of inheriting the • All female sibs will inherit the paternal • Sibs who inherit pathogenic variants in both • Sibs who inherit a single Alport syndrome-related pathogenic variant are at risk for ADAS (if they are heterozygous for a • 25% chance of inheriting two pathogenic variants; • 50% chance of inheriting one pathogenic variant; • 25% chance of inheriting neither of the familial pathogenic variants. • 50% chance of inheriting two pathogenic variants on the same chromosome; • 50% chance of inheriting neither of the familial pathogenic variants. • 25% chance of inheriting both the maternal • 25% chance of inheriting only the maternal • 25% chance of inheriting only the paternal • 25% chance of inheriting neither of the familial pathogenic variants. • Male sibs have a 50% risk of inheriting the • All female sibs will inherit the paternal • All offspring of a proband with • Offspring of a proband with • If a female proband has a • If a male proband has a ## 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 Alport syndrome-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 in families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada University of Minnesota, Department of Pediatrics • • • • • • • • Canada • • • • • • • University of Minnesota, Department of Pediatrics • ## Molecular Genetics Alport Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alport Syndrome ( A (Gly)-X-Y collagenous domain of approximately 1,400 residues A carboxy-terminal non-collagenous (NC1) domain of approximately 230 residues and 12 conserved cysteine residues, which participate in intrachain and interchain disulfide bonds A non-collagenous amino-terminal sequence of 15-20 residues Approximately 20 interruptions of the collagenous triplet sequence are present in the collagenous domain. Collagen IV chains form helical heterotrimers through associations between their COO End-to-end linkages between the COO Covalent interactions between four heterotrimers at their NH Lateral associations between heterotrimers via binding of the COO Linkages between collagen IV molecules form a scaffolding for the deposition of other matrix glycoproteins and for cell attachment. In the normal developing kidney: Collagen IV α1 and α2 chains predominate in the primordial glomerular basement membrane of immature glomeruli; The formation of capillary loops within the maturing glomeruli is associated with the appearance of collagen IV α3, α4, and α5 chains in the glomerular basement membrane. As glomerular maturation progresses, the collagen IV α3, α4, and α5 chains become the predominant collagen IV chains in the glomerular basement membrane. A pathogenic variant affecting one of the chains involved in the collagen IV α3/α4/α5 network can prevent basement membrane expression not only of that chain but of the other two chains as well. Similarly, a pathogenic variant involving the collagen IV α5 chain can interfere with basement membrane expression of the collagen IV α6 chain. Most missense collagen IV variants occur in glycine-encoding codons. The presence of a bulkier amino acid in a glycine position presumably creates a kink or an unfolding in the triple helix, as is observed in the collagen I α1 chain (see Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. Genes from • A (Gly)-X-Y collagenous domain of approximately 1,400 residues • A carboxy-terminal non-collagenous (NC1) domain of approximately 230 residues and 12 conserved cysteine residues, which participate in intrachain and interchain disulfide bonds • A non-collagenous amino-terminal sequence of 15-20 residues • End-to-end linkages between the COO • Covalent interactions between four heterotrimers at their NH • Lateral associations between heterotrimers via binding of the COO • Collagen IV α1 and α2 chains predominate in the primordial glomerular basement membrane of immature glomeruli; • The formation of capillary loops within the maturing glomeruli is associated with the appearance of collagen IV α3, α4, and α5 chains in the glomerular basement membrane. • As glomerular maturation progresses, the collagen IV α3, α4, and α5 chains become the predominant collagen IV chains in the glomerular basement membrane. ## Molecular Pathogenesis A (Gly)-X-Y collagenous domain of approximately 1,400 residues A carboxy-terminal non-collagenous (NC1) domain of approximately 230 residues and 12 conserved cysteine residues, which participate in intrachain and interchain disulfide bonds A non-collagenous amino-terminal sequence of 15-20 residues Approximately 20 interruptions of the collagenous triplet sequence are present in the collagenous domain. Collagen IV chains form helical heterotrimers through associations between their COO End-to-end linkages between the COO Covalent interactions between four heterotrimers at their NH Lateral associations between heterotrimers via binding of the COO Linkages between collagen IV molecules form a scaffolding for the deposition of other matrix glycoproteins and for cell attachment. In the normal developing kidney: Collagen IV α1 and α2 chains predominate in the primordial glomerular basement membrane of immature glomeruli; The formation of capillary loops within the maturing glomeruli is associated with the appearance of collagen IV α3, α4, and α5 chains in the glomerular basement membrane. As glomerular maturation progresses, the collagen IV α3, α4, and α5 chains become the predominant collagen IV chains in the glomerular basement membrane. A pathogenic variant affecting one of the chains involved in the collagen IV α3/α4/α5 network can prevent basement membrane expression not only of that chain but of the other two chains as well. Similarly, a pathogenic variant involving the collagen IV α5 chain can interfere with basement membrane expression of the collagen IV α6 chain. Most missense collagen IV variants occur in glycine-encoding codons. The presence of a bulkier amino acid in a glycine position presumably creates a kink or an unfolding in the triple helix, as is observed in the collagen I α1 chain (see Pathogenic Variants Referenced in This Variants listed in the table have been provided by the authors. Genes from • A (Gly)-X-Y collagenous domain of approximately 1,400 residues • A carboxy-terminal non-collagenous (NC1) domain of approximately 230 residues and 12 conserved cysteine residues, which participate in intrachain and interchain disulfide bonds • A non-collagenous amino-terminal sequence of 15-20 residues • End-to-end linkages between the COO • Covalent interactions between four heterotrimers at their NH • Lateral associations between heterotrimers via binding of the COO • Collagen IV α1 and α2 chains predominate in the primordial glomerular basement membrane of immature glomeruli; • The formation of capillary loops within the maturing glomeruli is associated with the appearance of collagen IV α3, α4, and α5 chains in the glomerular basement membrane. • As glomerular maturation progresses, the collagen IV α3, α4, and α5 chains become the predominant collagen IV chains in the glomerular basement membrane. ## Chapter Notes Prof Kandai Nozu, MD, PhDDepartment of Pediatrics, Kobe University Graduate School of MedicineEmail: Tomoko Horinouchi, MD, PhD (2025-present)Clifford E Kashtan, MD; University of Minnesota (2001-2025)Kandai Nozu, MD, PhD (2025-present)Tomohiko Yamamura, MD, PhD (2025-present) 14 August 2025 (aa) Revision: 27 February 2025 (sw) Comprehensive update posted live 21 February 2019 (ha) Comprehensive update posted live 25 November 2015 (me) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 15 July 2010 (me) Comprehensive update posted live 23 January 2008 (me) Comprehensive update posted live 26 September 2005 (me) Comprehensive update posted live 28 August 2003 (me) Comprehensive update posted live 28 August 2001 (me) Review posted live March 2001 (ck) Original submission • 14 August 2025 (aa) Revision: • 27 February 2025 (sw) Comprehensive update posted live • 21 February 2019 (ha) Comprehensive update posted live • 25 November 2015 (me) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 15 July 2010 (me) Comprehensive update posted live • 23 January 2008 (me) Comprehensive update posted live • 26 September 2005 (me) Comprehensive update posted live • 28 August 2003 (me) Comprehensive update posted live • 28 August 2001 (me) Review posted live • March 2001 (ck) Original submission ## Author Notes Prof Kandai Nozu, MD, PhDDepartment of Pediatrics, Kobe University Graduate School of MedicineEmail: ## Author History Tomoko Horinouchi, MD, PhD (2025-present)Clifford E Kashtan, MD; University of Minnesota (2001-2025)Kandai Nozu, MD, PhD (2025-present)Tomohiko Yamamura, MD, PhD (2025-present) ## Revision History 14 August 2025 (aa) Revision: 27 February 2025 (sw) Comprehensive update posted live 21 February 2019 (ha) Comprehensive update posted live 25 November 2015 (me) Comprehensive update posted live 28 February 2013 (me) Comprehensive update posted live 15 July 2010 (me) Comprehensive update posted live 23 January 2008 (me) Comprehensive update posted live 26 September 2005 (me) Comprehensive update posted live 28 August 2003 (me) Comprehensive update posted live 28 August 2001 (me) Review posted live March 2001 (ck) Original submission • 14 August 2025 (aa) Revision: • 27 February 2025 (sw) Comprehensive update posted live • 21 February 2019 (ha) Comprehensive update posted live • 25 November 2015 (me) Comprehensive update posted live • 28 February 2013 (me) Comprehensive update posted live • 15 July 2010 (me) Comprehensive update posted live • 23 January 2008 (me) Comprehensive update posted live • 26 September 2005 (me) Comprehensive update posted live • 28 August 2003 (me) Comprehensive update posted live • 28 August 2001 (me) Review posted live • March 2001 (ck) Original submission ## References ## Literature Cited	[]	28/8/2001	27/2/2025	14/8/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alps	alps	[ "ALPS", "ALPS", "Canale-Smith Syndrome", "Caspase-10", "Tumor necrosis factor ligand superfamily member 6", "Tumor necrosis factor receptor superfamily member 6", "CASP10", "FAS", "FASLG", "Autoimmune Lymphoproliferative Syndrome" ]	Autoimmune Lymphoproliferative Syndrome	Jack JH Bleesing, Chinmayee B Nagaraj, Kejian Zhang	Summary Autoimmune lymphoproliferative syndrome (ALPS), caused by defective lymphocyte homeostasis, is characterized by the following: Non-malignant lymphoproliferation (lymphadenopathy, hepatosplenomegaly with or without hypersplenism) that often improves with age Autoimmune disease, mostly directed toward blood cells Lifelong increased risk for both Hodgkin and non-Hodgkin lymphoma In ALPS-FAS (the most common and best-characterized type of ALPS, associated with heterozygous germline pathogenic variants in In ALPS-FAS caused by homozygous or compound heterozygous (biallelic) pathogenic variants in ALPS-sFAS, resulting from somatic The diagnosis of ALPS is based on the following: Clinical findings Laboratory abnormalities: Abnormal biomarker testing (soluble interleukin-10 [IL-10], Fas ligand [FasL], IL-18, and vitamin B Defective in vitro tumor necrosis factor receptor superfamily member 6 (Fas)-mediated apoptosis T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called "α/β-DNT cells") Identification of pathogenic variants in genes relevant for the Fas pathway of apoptosis. These genes include Up to 20% of those with clinical ALPS have not had a genetic etiology identified. Splenectomy is reserved as an option of last resort in the treatment of life-threatening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in persons with ALPS. Inheritance of ALPS-CASP10, most cases of ALPS-FAS, and some cases of ALPS-FASLG is autosomal dominant. Each child of an individual with autosomal dominant ALPS has a 50% chance of inheriting the pathogenic variant. Inheritance of most cases of ALPS-FASLG and severe ALPS associated with biallelic Prenatal testing for a pregnancy at increased risk is possible if the pathogenic variant(s) have been identified in an affected family member. ALPS-FAS can also be the result of somatic mosaicism. Somatic pathogenic variants have not been reported in ALPS-FASLG or ALPS-CASP10 to date.	## Diagnosis The diagnosis of autoimmune lymphoproliferative syndrome (ALPS) is based on a constellation of clinical findings, laboratory abnormalities, and identification of pathogenic variants in genes relevant for the tumor necrosis factor receptor superfamily member 6 (Fas) pathway of apoptosis. ALPS Chronic non-malignant lymphoproliferation Chronic and/or recurrent lymphadenopathy Splenomegaly with/without hypersplenism Hepatomegaly Lymphocytic interstitial pneumonia (less common) Autoimmune disease Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia Note: The combination of AIHA and ITP is often referred to as Evans syndrome. Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome Lymphoma, both Hodgkin lymphoma and non-Hodgkin lymphoma Skin rashes, often but not exclusively of an urticarial nature Family history of ALPS or ALPS-like features The diagnosis of ALPS A revised set of diagnostic criteria have been proposed [ A A Chronic (>6 months) non-malignant, noninfectious lymphadenopathy and/or splenomegaly Elevated α/β-DNT cells with normal or elevated lymphocyte counts Defective lymphocyte apoptosis (repeated at least once) Germline or somatic pathogenic variants in Elevated levels of one of the following: Plasma soluble FASL Plasma interleukin-10 Serum vitamin B Plasma interleukin-18 Typical immunohistologic findings as determined by an experienced hematopathologist Autoimmune cytopenias with elevated (polyclonal) immunoglobulin G levels Positive family history Although no specific laboratory abnormality alone is diagnostic of ALPS, the detection of the following facilitates the diagnosis [ Defective Fas-mediated apoptosis in vitro T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta double-negative T cells [α/β-DNT cells] in peripheral blood or tissue specimens). Detected by flow cytometric immunophenotyping, these terminally differentiated in vivo-activated T cells are rare in healthy individuals and other immune-mediated (lymphoproliferative) disorders; typically they constitute less than 2% of the lymphocyte pool. Increased levels of the ALPS-specific biomarkers: soluble IL-10, IL-18, FasL, and vitamin B Hematology Lymphocytosis, lymphopenia (primary or secondary in response to treatment) Coombs-positive hemolytic anemia Dyserythropoiesis Reticulocytosis Thrombocytopenia Neutropenia Eosinophilia Immunology Expansion of other lymphocyte subsets Gamma/delta-DNT cells CD8+/CD57+ T cells HLA-DR+ T cells CD5+ B cells Decreased numbers of CD4+/CD25+ T cells Decreased numbers of CD27+ B cells Elevated concentration of IL-10 and IL-18 in serum/plasma Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) Other Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) Monoclonal gammopathy Decreased antibody responses to polysaccharide antigens [ Chemistry Liver function abnormalities (in case of autoimmune hepatitis) Proteinuria (in case of glomerulonephritis) Elevated serum concentration of vitamin B Neutrophil function Complement factors concentrations and function In vitro proliferative responses of T cells (e.g., in response to common mitogens and antigens) NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS-FASLG). Antibody responses to protein antigens (e.g., diphtheria, tetanus) Note: (1) The abnormal and normal laboratory findings listed have been most reliably established for individuals with ALPS caused by either germline or somatic pathogenic variants in Molecular genetic testing approaches can include For this disorder, it is recommended that In the absence of a germline If neither a germline nor a somatic A Fas-mediated apoptosis assay should be performed if germline pathogenic variants in Notes: (1) Absence of a positive family history is suggestive of ALPS-sFAS. (2) Loss of heterozygosity of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ALPS See See Pathogenic variants listed in Human Gene Mutation Database (HGMD) considered to assess the proportion of variants detectable by each methodology Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Note that of the two pathogenic variants in In two individuals, ALPS was presumed to result from coinherited pathogenic variants in No data on detection rate of gene-targeted deletion/duplication analysis are available. Generally heterozygous germline pathogenic variants occur in Individuals with an inherited germline pathogenic variant in addition to a second acquired pathogenic variant [ Somatic pathogenic variants are observed in selected cell populations, including α/β-DNT cells [ Detection of Homozygous or heterozygous germline pathogenic variants in Approximately 20%-25% of individuals with ALPS lack a genetic diagnosis [ • Chronic non-malignant lymphoproliferation • Chronic and/or recurrent lymphadenopathy • Splenomegaly with/without hypersplenism • Hepatomegaly • Lymphocytic interstitial pneumonia (less common) • Chronic and/or recurrent lymphadenopathy • Splenomegaly with/without hypersplenism • Hepatomegaly • Lymphocytic interstitial pneumonia (less common) • Autoimmune disease • Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia • Note: The combination of AIHA and ITP is often referred to as Evans syndrome. • Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome • Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia • Note: The combination of AIHA and ITP is often referred to as Evans syndrome. • Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome • Lymphoma, both Hodgkin lymphoma and non-Hodgkin lymphoma • Skin rashes, often but not exclusively of an urticarial nature • Family history of ALPS or ALPS-like features • Chronic and/or recurrent lymphadenopathy • Splenomegaly with/without hypersplenism • Hepatomegaly • Lymphocytic interstitial pneumonia (less common) • Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia • Note: The combination of AIHA and ITP is often referred to as Evans syndrome. • Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome • A • A • Chronic (>6 months) non-malignant, noninfectious lymphadenopathy and/or splenomegaly • Elevated α/β-DNT cells with normal or elevated lymphocyte counts • Defective lymphocyte apoptosis (repeated at least once) • Germline or somatic pathogenic variants in • Elevated levels of one of the following: • Plasma soluble FASL • Plasma interleukin-10 • Serum vitamin B • Plasma interleukin-18 • Plasma soluble FASL • Plasma interleukin-10 • Serum vitamin B • Plasma interleukin-18 • Typical immunohistologic findings as determined by an experienced hematopathologist • Autoimmune cytopenias with elevated (polyclonal) immunoglobulin G levels • Positive family history • Plasma soluble FASL • Plasma interleukin-10 • Serum vitamin B • Plasma interleukin-18 • Defective Fas-mediated apoptosis in vitro • T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta double-negative T cells [α/β-DNT cells] in peripheral blood or tissue specimens). Detected by flow cytometric immunophenotyping, these terminally differentiated in vivo-activated T cells are rare in healthy individuals and other immune-mediated (lymphoproliferative) disorders; typically they constitute less than 2% of the lymphocyte pool. • Increased levels of the ALPS-specific biomarkers: soluble IL-10, IL-18, FasL, and vitamin B • Hematology • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Immunology • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Other • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Chemistry • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Neutrophil function • Complement factors concentrations and function • In vitro proliferative responses of T cells (e.g., in response to common mitogens and antigens) • NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS-FASLG). • Antibody responses to protein antigens (e.g., diphtheria, tetanus) • For this disorder, it is recommended that • In the absence of a germline • If neither a germline nor a somatic • A Fas-mediated apoptosis assay should be performed if germline pathogenic variants in ## Suggestive Findings The diagnosis of autoimmune lymphoproliferative syndrome (ALPS) is based on a constellation of clinical findings, laboratory abnormalities, and identification of pathogenic variants in genes relevant for the tumor necrosis factor receptor superfamily member 6 (Fas) pathway of apoptosis. ALPS Chronic non-malignant lymphoproliferation Chronic and/or recurrent lymphadenopathy Splenomegaly with/without hypersplenism Hepatomegaly Lymphocytic interstitial pneumonia (less common) Autoimmune disease Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia Note: The combination of AIHA and ITP is often referred to as Evans syndrome. Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome Lymphoma, both Hodgkin lymphoma and non-Hodgkin lymphoma Skin rashes, often but not exclusively of an urticarial nature Family history of ALPS or ALPS-like features • Chronic non-malignant lymphoproliferation • Chronic and/or recurrent lymphadenopathy • Splenomegaly with/without hypersplenism • Hepatomegaly • Lymphocytic interstitial pneumonia (less common) • Chronic and/or recurrent lymphadenopathy • Splenomegaly with/without hypersplenism • Hepatomegaly • Lymphocytic interstitial pneumonia (less common) • Autoimmune disease • Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia • Note: The combination of AIHA and ITP is often referred to as Evans syndrome. • Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome • Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia • Note: The combination of AIHA and ITP is often referred to as Evans syndrome. • Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome • Lymphoma, both Hodgkin lymphoma and non-Hodgkin lymphoma • Skin rashes, often but not exclusively of an urticarial nature • Family history of ALPS or ALPS-like features • Chronic and/or recurrent lymphadenopathy • Splenomegaly with/without hypersplenism • Hepatomegaly • Lymphocytic interstitial pneumonia (less common) • Cytopenia, particularly combinations of autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP), and autoimmune neutropenia • Note: The combination of AIHA and ITP is often referred to as Evans syndrome. • Other, including autoimmune hepatitis, autoimmune glomerulonephritis, autoimmune thyroiditis and (less commonly) uveitis and Guillain-Barré syndrome ## Establishing the Diagnosis The diagnosis of ALPS A revised set of diagnostic criteria have been proposed [ A A Chronic (>6 months) non-malignant, noninfectious lymphadenopathy and/or splenomegaly Elevated α/β-DNT cells with normal or elevated lymphocyte counts Defective lymphocyte apoptosis (repeated at least once) Germline or somatic pathogenic variants in Elevated levels of one of the following: Plasma soluble FASL Plasma interleukin-10 Serum vitamin B Plasma interleukin-18 Typical immunohistologic findings as determined by an experienced hematopathologist Autoimmune cytopenias with elevated (polyclonal) immunoglobulin G levels Positive family history Although no specific laboratory abnormality alone is diagnostic of ALPS, the detection of the following facilitates the diagnosis [ Defective Fas-mediated apoptosis in vitro T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta double-negative T cells [α/β-DNT cells] in peripheral blood or tissue specimens). Detected by flow cytometric immunophenotyping, these terminally differentiated in vivo-activated T cells are rare in healthy individuals and other immune-mediated (lymphoproliferative) disorders; typically they constitute less than 2% of the lymphocyte pool. Increased levels of the ALPS-specific biomarkers: soluble IL-10, IL-18, FasL, and vitamin B Hematology Lymphocytosis, lymphopenia (primary or secondary in response to treatment) Coombs-positive hemolytic anemia Dyserythropoiesis Reticulocytosis Thrombocytopenia Neutropenia Eosinophilia Immunology Expansion of other lymphocyte subsets Gamma/delta-DNT cells CD8+/CD57+ T cells HLA-DR+ T cells CD5+ B cells Decreased numbers of CD4+/CD25+ T cells Decreased numbers of CD27+ B cells Elevated concentration of IL-10 and IL-18 in serum/plasma Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) Other Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) Monoclonal gammopathy Decreased antibody responses to polysaccharide antigens [ Chemistry Liver function abnormalities (in case of autoimmune hepatitis) Proteinuria (in case of glomerulonephritis) Elevated serum concentration of vitamin B Neutrophil function Complement factors concentrations and function In vitro proliferative responses of T cells (e.g., in response to common mitogens and antigens) NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS-FASLG). Antibody responses to protein antigens (e.g., diphtheria, tetanus) Note: (1) The abnormal and normal laboratory findings listed have been most reliably established for individuals with ALPS caused by either germline or somatic pathogenic variants in Molecular genetic testing approaches can include For this disorder, it is recommended that In the absence of a germline If neither a germline nor a somatic A Fas-mediated apoptosis assay should be performed if germline pathogenic variants in Notes: (1) Absence of a positive family history is suggestive of ALPS-sFAS. (2) Loss of heterozygosity of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ALPS See See Pathogenic variants listed in Human Gene Mutation Database (HGMD) considered to assess the proportion of variants detectable by each methodology Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Note that of the two pathogenic variants in In two individuals, ALPS was presumed to result from coinherited pathogenic variants in No data on detection rate of gene-targeted deletion/duplication analysis are available. Generally heterozygous germline pathogenic variants occur in Individuals with an inherited germline pathogenic variant in addition to a second acquired pathogenic variant [ Somatic pathogenic variants are observed in selected cell populations, including α/β-DNT cells [ Detection of Homozygous or heterozygous germline pathogenic variants in Approximately 20%-25% of individuals with ALPS lack a genetic diagnosis [ • A • A • Chronic (>6 months) non-malignant, noninfectious lymphadenopathy and/or splenomegaly • Elevated α/β-DNT cells with normal or elevated lymphocyte counts • Defective lymphocyte apoptosis (repeated at least once) • Germline or somatic pathogenic variants in • Elevated levels of one of the following: • Plasma soluble FASL • Plasma interleukin-10 • Serum vitamin B • Plasma interleukin-18 • Plasma soluble FASL • Plasma interleukin-10 • Serum vitamin B • Plasma interleukin-18 • Typical immunohistologic findings as determined by an experienced hematopathologist • Autoimmune cytopenias with elevated (polyclonal) immunoglobulin G levels • Positive family history • Plasma soluble FASL • Plasma interleukin-10 • Serum vitamin B • Plasma interleukin-18 • Defective Fas-mediated apoptosis in vitro • T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta double-negative T cells [α/β-DNT cells] in peripheral blood or tissue specimens). Detected by flow cytometric immunophenotyping, these terminally differentiated in vivo-activated T cells are rare in healthy individuals and other immune-mediated (lymphoproliferative) disorders; typically they constitute less than 2% of the lymphocyte pool. • Increased levels of the ALPS-specific biomarkers: soluble IL-10, IL-18, FasL, and vitamin B • Hematology • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Immunology • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Other • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Chemistry • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Neutrophil function • Complement factors concentrations and function • In vitro proliferative responses of T cells (e.g., in response to common mitogens and antigens) • NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS-FASLG). • Antibody responses to protein antigens (e.g., diphtheria, tetanus) • For this disorder, it is recommended that • In the absence of a germline • If neither a germline nor a somatic • A Fas-mediated apoptosis assay should be performed if germline pathogenic variants in ## Laboratory Findings Although no specific laboratory abnormality alone is diagnostic of ALPS, the detection of the following facilitates the diagnosis [ Defective Fas-mediated apoptosis in vitro T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta double-negative T cells [α/β-DNT cells] in peripheral blood or tissue specimens). Detected by flow cytometric immunophenotyping, these terminally differentiated in vivo-activated T cells are rare in healthy individuals and other immune-mediated (lymphoproliferative) disorders; typically they constitute less than 2% of the lymphocyte pool. Increased levels of the ALPS-specific biomarkers: soluble IL-10, IL-18, FasL, and vitamin B Hematology Lymphocytosis, lymphopenia (primary or secondary in response to treatment) Coombs-positive hemolytic anemia Dyserythropoiesis Reticulocytosis Thrombocytopenia Neutropenia Eosinophilia Immunology Expansion of other lymphocyte subsets Gamma/delta-DNT cells CD8+/CD57+ T cells HLA-DR+ T cells CD5+ B cells Decreased numbers of CD4+/CD25+ T cells Decreased numbers of CD27+ B cells Elevated concentration of IL-10 and IL-18 in serum/plasma Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) Other Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) Monoclonal gammopathy Decreased antibody responses to polysaccharide antigens [ Chemistry Liver function abnormalities (in case of autoimmune hepatitis) Proteinuria (in case of glomerulonephritis) Elevated serum concentration of vitamin B Neutrophil function Complement factors concentrations and function In vitro proliferative responses of T cells (e.g., in response to common mitogens and antigens) NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS-FASLG). Antibody responses to protein antigens (e.g., diphtheria, tetanus) Note: (1) The abnormal and normal laboratory findings listed have been most reliably established for individuals with ALPS caused by either germline or somatic pathogenic variants in • Defective Fas-mediated apoptosis in vitro • T cells that express the alpha/beta T-cell receptor but lack both CD4 and CD8 (so-called alpha/beta double-negative T cells [α/β-DNT cells] in peripheral blood or tissue specimens). Detected by flow cytometric immunophenotyping, these terminally differentiated in vivo-activated T cells are rare in healthy individuals and other immune-mediated (lymphoproliferative) disorders; typically they constitute less than 2% of the lymphocyte pool. • Increased levels of the ALPS-specific biomarkers: soluble IL-10, IL-18, FasL, and vitamin B • Hematology • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Immunology • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Other • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Chemistry • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Lymphocytosis, lymphopenia (primary or secondary in response to treatment) • Coombs-positive hemolytic anemia • Dyserythropoiesis • Reticulocytosis • Thrombocytopenia • Neutropenia • Eosinophilia • Expansion of other lymphocyte subsets • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Decreased numbers of CD4+/CD25+ T cells • Decreased numbers of CD27+ B cells • Elevated concentration of IL-10 and IL-18 in serum/plasma • Elevated concentrations of IgG, IgA, and IgE; normal or decreased concentrations of IgM • Autoantibodies (most often positive direct or indirect antiglobulin test, antiplatelet antibody, antineutrophil antibody, antiphospholipid antibody, antinuclear antibody, rheumatoid factor) • Lymph node pathology (paracortical expansion with immunoblasts/plasma cells and DNT cells in interfollicular areas, florid follicular hyperplasia, progressive transformation of germinal centers [PTGC]) • Gamma/delta-DNT cells • CD8+/CD57+ T cells • HLA-DR+ T cells • CD5+ B cells • Increased soluble CD25 (sIL-2R alpha), CD27, CD30, and Fas ligand (FasL) • Monoclonal gammopathy • Decreased antibody responses to polysaccharide antigens [ • Liver function abnormalities (in case of autoimmune hepatitis) • Proteinuria (in case of glomerulonephritis) • Elevated serum concentration of vitamin B • Neutrophil function • Complement factors concentrations and function • In vitro proliferative responses of T cells (e.g., in response to common mitogens and antigens) • NK-cell and cytotoxic T-lymphocyte (CTL) function; possibly decreased CTL activity in ALPS on the basis of defective FasL (i.e., ALPS-FASLG). • Antibody responses to protein antigens (e.g., diphtheria, tetanus) ## Molecular Genetic Testing Molecular genetic testing approaches can include For this disorder, it is recommended that In the absence of a germline If neither a germline nor a somatic A Fas-mediated apoptosis assay should be performed if germline pathogenic variants in Notes: (1) Absence of a positive family history is suggestive of ALPS-sFAS. (2) Loss of heterozygosity of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ALPS See See Pathogenic variants listed in Human Gene Mutation Database (HGMD) considered to assess the proportion of variants detectable by each methodology Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Note that of the two pathogenic variants in In two individuals, ALPS was presumed to result from coinherited pathogenic variants in No data on detection rate of gene-targeted deletion/duplication analysis are available. Generally heterozygous germline pathogenic variants occur in Individuals with an inherited germline pathogenic variant in addition to a second acquired pathogenic variant [ Somatic pathogenic variants are observed in selected cell populations, including α/β-DNT cells [ Detection of Homozygous or heterozygous germline pathogenic variants in Approximately 20%-25% of individuals with ALPS lack a genetic diagnosis [ • For this disorder, it is recommended that • In the absence of a germline • If neither a germline nor a somatic • A Fas-mediated apoptosis assay should be performed if germline pathogenic variants in ## Clinical Characteristics Autoimmune lymphoproliferative syndrome (ALPS) can be considered a prototypic disorder of defective lymphocyte homeostasis [ The manifestations are lymphadenopathy, hepatosplenomegaly with or without hypersplenism, and autoimmune disease, mostly directed toward blood cells. In addition, the risk of lymphoma is increased. Lymphadenopathy Splenomegaly (± hypersplenism) Hepatomegaly Autoimmune hemolytic anemia Autoimmune thrombocytopenia Autoimmune neutropenia Glomerulonephritis Autoimmune hepatitis Guillain Barré syndrome Uveitis, iridocyclitis Other autoimmune disorders (in individual cases) Lymphoma (Hodgkin and non-Hodgkin lymphoma) Carcinoma (thyroid, breast, skin, tongue, liver) Multiple neoplastic lesions (thyroid/breast adenomas, gliomas) Urticaria and other skin rashes Vasculitis Panniculitis Arthritis and arthralgia Recurrent oral ulcers Humoral immunodeficiency Pulmonary infiltrates Premature ovarian insufficiency Hydrops fetalis Organic brain syndrome (mental status changes, seizures, headaches) The natural history of ALPS is not well understood. While non-malignant lymphoproliferative manifestations often regress or improve over time, autoimmunity appears to show no permanent remission with advancing age. Moreover, the risk for development of lymphoma likely is lifelong. Thus, in the absence of curative treatment, the overall prognosis for ALPS remains guarded, necessitating long-term clinical studies to better understand its natural history. Two publications have provided significant new insights into the features, complications, natural history, and prognosis of ALPS. These studies are subsequently referred to in this ALPS-FAS is the most common and best-characterized type of ALPS. The following are the main consequences of perturbed lymphocyte homeostasis in ALPS-FAS. The median age of onset was three years in the French cohort and 2.7 years in the NIH cohort. Lymphadenopathy was present in 85% in the French cohort and 97% in the NIH cohort, while splenomegaly was present in 94% in the French cohort (with 73% showing hypersplenism) and 95% in the NIH cohort [ In many individuals, lymphadenopathy tends to decrease early in the second decade, whereas splenomegaly often does not. Furthermore, long-term follow up in several individuals has shown that diminution of lymphadenopathy is not accompanied by significant changes in the overall expansion of lymphocyte subsets in peripheral blood [ The overall prognosis of lymphoproliferation is relatively good; few individuals require long-term treatment with immunosuppressive agents to control lymphoproliferation [ Laboratory findings of lymphoproliferation show expansion of most lymphocyte subsets including the pathognomonic α/β-DNT cells as well as other T- and B-cell subsets. The French cohort and NIH cohort revealed that, in general, affected individuals with later disease onset often present with autoimmune disease, while younger individuals typically present with lymphoproliferative disease, followed by autoimmune disease, with a two- to three-year delay between lymphoproliferative disease onset and autoimmune disease onset. However, many affected individuals in both age groups presented with autoimmune disease as their first manifestation of ALPS [ Although autoimmune manifestations can also wax and wane, current knowledge suggests that autoimmune disease poses a lifelong burden. In the NIH cohort, 37% of affected individuals were described as having a severe autoimmune disease phenotype (as determined by the presence of grade 3 or 4 cytopenias) within two years of disease onset [ Autoimmunity most often involves combinations of Coombs-positive hemolytic anemia and immune thrombocytopenia (together referred to as Evans syndrome); autoimmune neutropenia is less common. The observation of primary lymphopenia, contrasting with the typical presence of lymphocytosis, suggests the possibility of autoimmune lymphopenia (as seen in other autoimmune diseases). The presence of Evans syndrome without significant lymphoproliferation can be consistent with ALPS, especially if α/β-DNT cells are present [ Autoimmune cytopenias may be difficult to distinguish from the effects of concomitant hypersplenism; examination of blood smears for evidence of hemolysis and measurement of autoantibodies and the degree of reticulocytosis may help in establishing the distinction. Additional autoimmune features can be found, often in patterns that appear to be family specific, suggesting the influence of other (background) genetic information [ Laboratory findings include among others: autoantibodies detected by direct and indirect antiglobulin tests (Coombs' test), antiplatelet antibodies, antineutrophil antibodies, antinuclear antibodies (ANA), and antiphospholipid antibodies. More recently, updated risk calculations were provided through the French cohort and the NIH cohort. The French cohort provided a 15% cumulative risk of lymphoma before age 30 years. This represented seven cases of lymphoma (3 cases of HL and 4 cases of NHL) out of a total of 90 affected individuals [ In the NIH cohort, 18 cases of lymphoma out of a total of 150 affected individuals were identified with a median age of detection of 18 years and a male-to-female ratio of 3.5 to 1. Sixteen (89%) of 18 cases were of B-cell origin. It was determined that 17/18 cases occurred in individuals with pathogenic variants affecting the death domain of FAS. Using published expected cases of HL and NHL in the general population, the 16 cases of B-cell lymphoma conferred a standardized incidence ratio of 149 for HL and 61 for NHL. These numbers are significantly different from those previously published by the NIH group [ Lymphoma typically originates in B cells, but has been found in T cells as well, although much less frequently (2/18 cases in the NIH cohort) [ Current experience suggests that lymphomas can occur at any age in ALPS-FAS and do respond to conventional chemotherapeutic treatment. Individuals with other forms of ALPS may also be at an increased risk for lymphoma; however, further data are needed to provide a detailed risk assessment. Because of the frequent concomitant presence of benign (i.e., "typical") lymphadenopathy and splenomegaly, distinguishing a "good" node from a "bad" node is a diagnostic challenge. Important clues are B-type symptoms including fever, night sweats, itching, and weight loss. In addition, PET-based imaging may be helpful in distinguishing "good" from "bad" nodes on the basis of presumed higher metabolic activity of malignant lymphoid tissue [ A number of studies have looked at associations between Fas and neoplasms, including somatic pathogenic variants in solid tumors, leukemias, and lymphomas. For further discussion, see Somatic The population of α/β-DNT cells is expanded; however, as noted initially [ The phenotype of ALPS results from defective apoptosis of lymphocytes mediated through the Fas/Fas ligand (FasL) pathway. This pathway normally limits the size of the lymphocyte compartment by eliminating/removing autoreactive lymphocytes; therefore, defects in this pathway lead to expansion of antigen-specific lymphocyte populations. Although Fas also appears to play a role in suppression of malignant transformation of lymphocytes, it remains to be firmly established whether this involves the Fas/FasL pathway in a similar way. It should be noted that the pathogenesis of ALPS remains an ongoing topic of research. Somatic In the majority of affected individuals, heterozygous Family studies to date suggest that penetrance for the defective Fas-mediated apoptosis cellular phenotype approximates 100% (i.e., every individual heterozygous for an inherited [germline] pathogenic variant has defective apoptosis) whereas the penetrance for the clinical phenotype is reduced because a significant proportion of relatives heterozygous for the pathogenic variant have no clinical findings of ALPS. In addition, other relatives have laboratory findings of ALPS (e.g., expansion of lymphocyte subsets and/or autoantibodies) without clinical evidence of either lymphoproliferation or autoimmunity [ The factors that determine the penetrance of clinical ALPS are not entirely understood. Penetrance appears to be determined by the location and type of pathogenic variant [ In the French cohort ECD pathogenic variants had a penetrance of 52% (higher than previous data) and ICD pathogenic variants had a 63% penetrance (lower than previously reported). The penetrance of missense variants affecting the death domain (part of the ICD) was 73% [ The reduced penetrance for ALPS in some families suggests that one or more additional pathogenic factors interact with defective Fas-mediated apoptosis. However, the high penetrance for the clinical phenotype in certain families associated with specific types of An observation that may shed more light on the issue of penetrance, particularly as it relates to pathogenic variants affecting intracellular vs extracellular domains (as well as on pathogenesis and natural history of ALPS): in a small subset of affected individuals, clinical disease appeared to develop as a consequence of both an inherited heterozygous (germline) Disease penetrance differs between males and females. In the French cohort, the likelihood of a male with a heterozygous germline Anticipation has not been documented in ALPS. Revised Classification of ALPS ALPS has also been referred to as Canale-Smith syndrome. Nearly 500 individuals with ALPS in more than 300 families have been reported worldwide with no racial or ethnic predilection. However, the true prevalence of ALPS is still unknown as many individuals are undiagnosed or misdiagnosed [ • Lymphadenopathy • Splenomegaly (± hypersplenism) • Hepatomegaly • Autoimmune hemolytic anemia • Autoimmune thrombocytopenia • Autoimmune neutropenia • Glomerulonephritis • Autoimmune hepatitis • Guillain Barré syndrome • Uveitis, iridocyclitis • Other autoimmune disorders (in individual cases) • Lymphoma (Hodgkin and non-Hodgkin lymphoma) • Carcinoma (thyroid, breast, skin, tongue, liver) • Multiple neoplastic lesions (thyroid/breast adenomas, gliomas) • Urticaria and other skin rashes • Vasculitis • Panniculitis • Arthritis and arthralgia • Recurrent oral ulcers • Humoral immunodeficiency • Pulmonary infiltrates • Premature ovarian insufficiency • Hydrops fetalis • Organic brain syndrome (mental status changes, seizures, headaches) ## Clinical Description Autoimmune lymphoproliferative syndrome (ALPS) can be considered a prototypic disorder of defective lymphocyte homeostasis [ The manifestations are lymphadenopathy, hepatosplenomegaly with or without hypersplenism, and autoimmune disease, mostly directed toward blood cells. In addition, the risk of lymphoma is increased. Lymphadenopathy Splenomegaly (± hypersplenism) Hepatomegaly Autoimmune hemolytic anemia Autoimmune thrombocytopenia Autoimmune neutropenia Glomerulonephritis Autoimmune hepatitis Guillain Barré syndrome Uveitis, iridocyclitis Other autoimmune disorders (in individual cases) Lymphoma (Hodgkin and non-Hodgkin lymphoma) Carcinoma (thyroid, breast, skin, tongue, liver) Multiple neoplastic lesions (thyroid/breast adenomas, gliomas) Urticaria and other skin rashes Vasculitis Panniculitis Arthritis and arthralgia Recurrent oral ulcers Humoral immunodeficiency Pulmonary infiltrates Premature ovarian insufficiency Hydrops fetalis Organic brain syndrome (mental status changes, seizures, headaches) The natural history of ALPS is not well understood. While non-malignant lymphoproliferative manifestations often regress or improve over time, autoimmunity appears to show no permanent remission with advancing age. Moreover, the risk for development of lymphoma likely is lifelong. Thus, in the absence of curative treatment, the overall prognosis for ALPS remains guarded, necessitating long-term clinical studies to better understand its natural history. Two publications have provided significant new insights into the features, complications, natural history, and prognosis of ALPS. These studies are subsequently referred to in this ALPS-FAS is the most common and best-characterized type of ALPS. The following are the main consequences of perturbed lymphocyte homeostasis in ALPS-FAS. The median age of onset was three years in the French cohort and 2.7 years in the NIH cohort. Lymphadenopathy was present in 85% in the French cohort and 97% in the NIH cohort, while splenomegaly was present in 94% in the French cohort (with 73% showing hypersplenism) and 95% in the NIH cohort [ In many individuals, lymphadenopathy tends to decrease early in the second decade, whereas splenomegaly often does not. Furthermore, long-term follow up in several individuals has shown that diminution of lymphadenopathy is not accompanied by significant changes in the overall expansion of lymphocyte subsets in peripheral blood [ The overall prognosis of lymphoproliferation is relatively good; few individuals require long-term treatment with immunosuppressive agents to control lymphoproliferation [ Laboratory findings of lymphoproliferation show expansion of most lymphocyte subsets including the pathognomonic α/β-DNT cells as well as other T- and B-cell subsets. The French cohort and NIH cohort revealed that, in general, affected individuals with later disease onset often present with autoimmune disease, while younger individuals typically present with lymphoproliferative disease, followed by autoimmune disease, with a two- to three-year delay between lymphoproliferative disease onset and autoimmune disease onset. However, many affected individuals in both age groups presented with autoimmune disease as their first manifestation of ALPS [ Although autoimmune manifestations can also wax and wane, current knowledge suggests that autoimmune disease poses a lifelong burden. In the NIH cohort, 37% of affected individuals were described as having a severe autoimmune disease phenotype (as determined by the presence of grade 3 or 4 cytopenias) within two years of disease onset [ Autoimmunity most often involves combinations of Coombs-positive hemolytic anemia and immune thrombocytopenia (together referred to as Evans syndrome); autoimmune neutropenia is less common. The observation of primary lymphopenia, contrasting with the typical presence of lymphocytosis, suggests the possibility of autoimmune lymphopenia (as seen in other autoimmune diseases). The presence of Evans syndrome without significant lymphoproliferation can be consistent with ALPS, especially if α/β-DNT cells are present [ Autoimmune cytopenias may be difficult to distinguish from the effects of concomitant hypersplenism; examination of blood smears for evidence of hemolysis and measurement of autoantibodies and the degree of reticulocytosis may help in establishing the distinction. Additional autoimmune features can be found, often in patterns that appear to be family specific, suggesting the influence of other (background) genetic information [ Laboratory findings include among others: autoantibodies detected by direct and indirect antiglobulin tests (Coombs' test), antiplatelet antibodies, antineutrophil antibodies, antinuclear antibodies (ANA), and antiphospholipid antibodies. More recently, updated risk calculations were provided through the French cohort and the NIH cohort. The French cohort provided a 15% cumulative risk of lymphoma before age 30 years. This represented seven cases of lymphoma (3 cases of HL and 4 cases of NHL) out of a total of 90 affected individuals [ In the NIH cohort, 18 cases of lymphoma out of a total of 150 affected individuals were identified with a median age of detection of 18 years and a male-to-female ratio of 3.5 to 1. Sixteen (89%) of 18 cases were of B-cell origin. It was determined that 17/18 cases occurred in individuals with pathogenic variants affecting the death domain of FAS. Using published expected cases of HL and NHL in the general population, the 16 cases of B-cell lymphoma conferred a standardized incidence ratio of 149 for HL and 61 for NHL. These numbers are significantly different from those previously published by the NIH group [ Lymphoma typically originates in B cells, but has been found in T cells as well, although much less frequently (2/18 cases in the NIH cohort) [ Current experience suggests that lymphomas can occur at any age in ALPS-FAS and do respond to conventional chemotherapeutic treatment. Individuals with other forms of ALPS may also be at an increased risk for lymphoma; however, further data are needed to provide a detailed risk assessment. Because of the frequent concomitant presence of benign (i.e., "typical") lymphadenopathy and splenomegaly, distinguishing a "good" node from a "bad" node is a diagnostic challenge. Important clues are B-type symptoms including fever, night sweats, itching, and weight loss. In addition, PET-based imaging may be helpful in distinguishing "good" from "bad" nodes on the basis of presumed higher metabolic activity of malignant lymphoid tissue [ A number of studies have looked at associations between Fas and neoplasms, including somatic pathogenic variants in solid tumors, leukemias, and lymphomas. For further discussion, see Somatic The population of α/β-DNT cells is expanded; however, as noted initially [ The phenotype of ALPS results from defective apoptosis of lymphocytes mediated through the Fas/Fas ligand (FasL) pathway. This pathway normally limits the size of the lymphocyte compartment by eliminating/removing autoreactive lymphocytes; therefore, defects in this pathway lead to expansion of antigen-specific lymphocyte populations. Although Fas also appears to play a role in suppression of malignant transformation of lymphocytes, it remains to be firmly established whether this involves the Fas/FasL pathway in a similar way. It should be noted that the pathogenesis of ALPS remains an ongoing topic of research. Somatic • Lymphadenopathy • Splenomegaly (± hypersplenism) • Hepatomegaly • Autoimmune hemolytic anemia • Autoimmune thrombocytopenia • Autoimmune neutropenia • Glomerulonephritis • Autoimmune hepatitis • Guillain Barré syndrome • Uveitis, iridocyclitis • Other autoimmune disorders (in individual cases) • Lymphoma (Hodgkin and non-Hodgkin lymphoma) • Carcinoma (thyroid, breast, skin, tongue, liver) • Multiple neoplastic lesions (thyroid/breast adenomas, gliomas) • Urticaria and other skin rashes • Vasculitis • Panniculitis • Arthritis and arthralgia • Recurrent oral ulcers • Humoral immunodeficiency • Pulmonary infiltrates • Premature ovarian insufficiency • Hydrops fetalis • Organic brain syndrome (mental status changes, seizures, headaches) ## Summary of Clinical Manifestations of ALPS Lymphadenopathy Splenomegaly (± hypersplenism) Hepatomegaly Autoimmune hemolytic anemia Autoimmune thrombocytopenia Autoimmune neutropenia Glomerulonephritis Autoimmune hepatitis Guillain Barré syndrome Uveitis, iridocyclitis Other autoimmune disorders (in individual cases) Lymphoma (Hodgkin and non-Hodgkin lymphoma) Carcinoma (thyroid, breast, skin, tongue, liver) Multiple neoplastic lesions (thyroid/breast adenomas, gliomas) Urticaria and other skin rashes Vasculitis Panniculitis Arthritis and arthralgia Recurrent oral ulcers Humoral immunodeficiency Pulmonary infiltrates Premature ovarian insufficiency Hydrops fetalis Organic brain syndrome (mental status changes, seizures, headaches) The natural history of ALPS is not well understood. While non-malignant lymphoproliferative manifestations often regress or improve over time, autoimmunity appears to show no permanent remission with advancing age. Moreover, the risk for development of lymphoma likely is lifelong. Thus, in the absence of curative treatment, the overall prognosis for ALPS remains guarded, necessitating long-term clinical studies to better understand its natural history. Two publications have provided significant new insights into the features, complications, natural history, and prognosis of ALPS. These studies are subsequently referred to in this • Lymphadenopathy • Splenomegaly (± hypersplenism) • Hepatomegaly • Autoimmune hemolytic anemia • Autoimmune thrombocytopenia • Autoimmune neutropenia • Glomerulonephritis • Autoimmune hepatitis • Guillain Barré syndrome • Uveitis, iridocyclitis • Other autoimmune disorders (in individual cases) • Lymphoma (Hodgkin and non-Hodgkin lymphoma) • Carcinoma (thyroid, breast, skin, tongue, liver) • Multiple neoplastic lesions (thyroid/breast adenomas, gliomas) • Urticaria and other skin rashes • Vasculitis • Panniculitis • Arthritis and arthralgia • Recurrent oral ulcers • Humoral immunodeficiency • Pulmonary infiltrates • Premature ovarian insufficiency • Hydrops fetalis • Organic brain syndrome (mental status changes, seizures, headaches) ## ALPS-FAS ALPS-FAS is the most common and best-characterized type of ALPS. The following are the main consequences of perturbed lymphocyte homeostasis in ALPS-FAS. The median age of onset was three years in the French cohort and 2.7 years in the NIH cohort. Lymphadenopathy was present in 85% in the French cohort and 97% in the NIH cohort, while splenomegaly was present in 94% in the French cohort (with 73% showing hypersplenism) and 95% in the NIH cohort [ In many individuals, lymphadenopathy tends to decrease early in the second decade, whereas splenomegaly often does not. Furthermore, long-term follow up in several individuals has shown that diminution of lymphadenopathy is not accompanied by significant changes in the overall expansion of lymphocyte subsets in peripheral blood [ The overall prognosis of lymphoproliferation is relatively good; few individuals require long-term treatment with immunosuppressive agents to control lymphoproliferation [ Laboratory findings of lymphoproliferation show expansion of most lymphocyte subsets including the pathognomonic α/β-DNT cells as well as other T- and B-cell subsets. The French cohort and NIH cohort revealed that, in general, affected individuals with later disease onset often present with autoimmune disease, while younger individuals typically present with lymphoproliferative disease, followed by autoimmune disease, with a two- to three-year delay between lymphoproliferative disease onset and autoimmune disease onset. However, many affected individuals in both age groups presented with autoimmune disease as their first manifestation of ALPS [ Although autoimmune manifestations can also wax and wane, current knowledge suggests that autoimmune disease poses a lifelong burden. In the NIH cohort, 37% of affected individuals were described as having a severe autoimmune disease phenotype (as determined by the presence of grade 3 or 4 cytopenias) within two years of disease onset [ Autoimmunity most often involves combinations of Coombs-positive hemolytic anemia and immune thrombocytopenia (together referred to as Evans syndrome); autoimmune neutropenia is less common. The observation of primary lymphopenia, contrasting with the typical presence of lymphocytosis, suggests the possibility of autoimmune lymphopenia (as seen in other autoimmune diseases). The presence of Evans syndrome without significant lymphoproliferation can be consistent with ALPS, especially if α/β-DNT cells are present [ Autoimmune cytopenias may be difficult to distinguish from the effects of concomitant hypersplenism; examination of blood smears for evidence of hemolysis and measurement of autoantibodies and the degree of reticulocytosis may help in establishing the distinction. Additional autoimmune features can be found, often in patterns that appear to be family specific, suggesting the influence of other (background) genetic information [ Laboratory findings include among others: autoantibodies detected by direct and indirect antiglobulin tests (Coombs' test), antiplatelet antibodies, antineutrophil antibodies, antinuclear antibodies (ANA), and antiphospholipid antibodies. More recently, updated risk calculations were provided through the French cohort and the NIH cohort. The French cohort provided a 15% cumulative risk of lymphoma before age 30 years. This represented seven cases of lymphoma (3 cases of HL and 4 cases of NHL) out of a total of 90 affected individuals [ In the NIH cohort, 18 cases of lymphoma out of a total of 150 affected individuals were identified with a median age of detection of 18 years and a male-to-female ratio of 3.5 to 1. Sixteen (89%) of 18 cases were of B-cell origin. It was determined that 17/18 cases occurred in individuals with pathogenic variants affecting the death domain of FAS. Using published expected cases of HL and NHL in the general population, the 16 cases of B-cell lymphoma conferred a standardized incidence ratio of 149 for HL and 61 for NHL. These numbers are significantly different from those previously published by the NIH group [ Lymphoma typically originates in B cells, but has been found in T cells as well, although much less frequently (2/18 cases in the NIH cohort) [ Current experience suggests that lymphomas can occur at any age in ALPS-FAS and do respond to conventional chemotherapeutic treatment. Individuals with other forms of ALPS may also be at an increased risk for lymphoma; however, further data are needed to provide a detailed risk assessment. Because of the frequent concomitant presence of benign (i.e., "typical") lymphadenopathy and splenomegaly, distinguishing a "good" node from a "bad" node is a diagnostic challenge. Important clues are B-type symptoms including fever, night sweats, itching, and weight loss. In addition, PET-based imaging may be helpful in distinguishing "good" from "bad" nodes on the basis of presumed higher metabolic activity of malignant lymphoid tissue [ A number of studies have looked at associations between Fas and neoplasms, including somatic pathogenic variants in solid tumors, leukemias, and lymphomas. For further discussion, see ## ALPS-FAS Caused by Biallelic Pathogenic Variants ## ALPS-sFAS Somatic The population of α/β-DNT cells is expanded; however, as noted initially [ ## Pathogenesis of ALPS The phenotype of ALPS results from defective apoptosis of lymphocytes mediated through the Fas/Fas ligand (FasL) pathway. This pathway normally limits the size of the lymphocyte compartment by eliminating/removing autoreactive lymphocytes; therefore, defects in this pathway lead to expansion of antigen-specific lymphocyte populations. Although Fas also appears to play a role in suppression of malignant transformation of lymphocytes, it remains to be firmly established whether this involves the Fas/FasL pathway in a similar way. It should be noted that the pathogenesis of ALPS remains an ongoing topic of research. Somatic ## Genotype-Phenotype Correlations In the majority of affected individuals, heterozygous ## Penetrance Family studies to date suggest that penetrance for the defective Fas-mediated apoptosis cellular phenotype approximates 100% (i.e., every individual heterozygous for an inherited [germline] pathogenic variant has defective apoptosis) whereas the penetrance for the clinical phenotype is reduced because a significant proportion of relatives heterozygous for the pathogenic variant have no clinical findings of ALPS. In addition, other relatives have laboratory findings of ALPS (e.g., expansion of lymphocyte subsets and/or autoantibodies) without clinical evidence of either lymphoproliferation or autoimmunity [ The factors that determine the penetrance of clinical ALPS are not entirely understood. Penetrance appears to be determined by the location and type of pathogenic variant [ In the French cohort ECD pathogenic variants had a penetrance of 52% (higher than previous data) and ICD pathogenic variants had a 63% penetrance (lower than previously reported). The penetrance of missense variants affecting the death domain (part of the ICD) was 73% [ The reduced penetrance for ALPS in some families suggests that one or more additional pathogenic factors interact with defective Fas-mediated apoptosis. However, the high penetrance for the clinical phenotype in certain families associated with specific types of An observation that may shed more light on the issue of penetrance, particularly as it relates to pathogenic variants affecting intracellular vs extracellular domains (as well as on pathogenesis and natural history of ALPS): in a small subset of affected individuals, clinical disease appeared to develop as a consequence of both an inherited heterozygous (germline) Disease penetrance differs between males and females. In the French cohort, the likelihood of a male with a heterozygous germline ## Anticipation Anticipation has not been documented in ALPS. ## Nomenclature Revised Classification of ALPS ALPS has also been referred to as Canale-Smith syndrome. ## Prevalence Nearly 500 individuals with ALPS in more than 300 families have been reported worldwide with no racial or ethnic predilection. However, the true prevalence of ALPS is still unknown as many individuals are undiagnosed or misdiagnosed [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Within the differential diagnosis for ALPS are other immunodeficiency disorders characterized or complicated by lymphoproliferation, autoimmune disease, and lymphoma. These include the following: The overlap between ALPS and CVID is also illustrated by the report of two individuals with CVID who were found to have heterozygous pathogenic variants in HIGM2 (OMIM HIGM3, HIGM4, and HIGM5 are other forms of non-X-linked hyper IgM syndrome (OMIM • The overlap between ALPS and CVID is also illustrated by the report of two individuals with CVID who were found to have heterozygous pathogenic variants in • HIGM2 (OMIM • HIGM3, HIGM4, and HIGM5 are other forms of non-X-linked hyper IgM syndrome (OMIM ## Management To determine the presence and extent of disease and needs in an individual diagnosed with autoimmune lymphoproliferative syndrome (ALPS), the following evaluations are recommended: Complete blood counts and flow cytometric immunophenotyping of lymphocytes, especially with regard to α/β-DNT cells, in combination with physical examination and imaging studies to assess lymphadenopathy and hepatosplenomegaly If significant lymphadenopathy is present, more extensive diagnostic procedures to detect lymphoma, especially if constitutional symptoms (e.g., fever, night sweats, weight loss) are present Measurement of autoantibodies to assess for autoimmunity Consultation with a clinical geneticist and/or genetic counselor In the absence of curative treatment, current management is focused on the following: Monitoring for and treatment of lymphoproliferation, hypersplensim, and lymphomas Management of cytopenias and other autoimmune diseases [ Manifestations of lymphoproliferation require close clinical observation, as well as serial CT and PET scans every two to three years. Biopsy is indicated whenever there is a clinical suspicion of lymphoma. Corticosteroids and immunosuppressive drugs do not decrease lymphadenopathy long term in individuals with ALPS, and are generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations. Experience with sirolimus suggests that it is the preferred agent in treating lymphoproliferation in a more sustained manner, including for maintenance of remission after initial treatment followed by a period of discontinued use [ In severe cases, more potent (lympho-depleting) agents may be required to sufficiently control lymphoproliferative manifestations. Agents include cyclophosphamide, antithymocyte globulin (ATG), and select monoclonal antibodies such as alemtuzumab (Campath Autoimmune cytopenias are typically treated by immune suppression with corticosteroids as well as corticosteroid-sparing agents, if prolonged treatment of autoimmune cytopenias is required and/or in cases of refractory cytopenias. Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. Individuals with severe autoimmune hemolytic anemia may benefit from IVIG in combination with corticosteroids. Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS. However, because of its immune toxicity, its use is generally avoided until other immunosuppression therapies have failed [ Splenectomy is reserved as an option of last resort in the treatment of life-threatening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in those with ALPS [ Individuals with isolated chronic neutropenia may improve on low-dose G-CSF [ Bone marrow (hematopoietic stem cell) transplantation (BMT/HSCT) is currently the only curative treatment for ALPS. Because of the risks associated with BMT, it has so far been performed mostly in individuals with ALPS with severe clinical phenotypes, such as those with homozygous or compound heterozygous pathogenic variants in Successful (reported) BMT in several individuals indicates that defective Fas-mediated apoptosis does not pose a barrier to this treatment option [ Vaccinations pre-splenectomy (with consideration of post-splenectomy boost vaccinations) and penicillin prophylaxis are strongly recommended for individuals who undergo splenectomy. Clinical assessment, imaging, and laboratory studies outlined in Specialized imaging studies such as combined PET and CT scanning in combination with clinical and laboratory surveillance may be helpful in detection of malignant transformation, keeping in mind that PET/CT scanning is often abnormal in ALPS, such that distinguishing between "typical" ALPS findings and a new malignancy (lymphoma) can be difficult [ The use of over-the-counter medications such as aspirin and other nonsteroidal anti-inflammatory drugs should be discussed with a physician as some of these medications can interfere with platelet function. It is appropriate to perform molecular genetic testing on relatives at risk for ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 if the pathogenic variant has been identified in the proband. Relatives who have the family-specific pathogenic variant should: Be advised of their increased risk for ALPS if the type and location of the ALPS-related pathogenic variant is predicted to have a high penetrance for clinical ALPS; Undergo ALPS-specific evaluations at initial diagnosis (e.g., enumeration of α/β-DNT cells, detection of autoantibodies, IL-10/soluble FasL measurement) (see Be advised that ALPS-specific evaluations or other assessments may need to be repeated at regular intervals, particularly if the family member is young and/or if new health-related issues consistent with ALPS or ALPS-related complications (e.g., lymphoma) become apparent (see See In addition to the risks and benefits to a woman with ALPS associated with treatment with corticosteroids, mycophenylate mofitil, or sirolimus during pregnancy, the potential teratogenic risks of these exposures to the fetus must also be weighed. See Search • Complete blood counts and flow cytometric immunophenotyping of lymphocytes, especially with regard to α/β-DNT cells, in combination with physical examination and imaging studies to assess lymphadenopathy and hepatosplenomegaly • If significant lymphadenopathy is present, more extensive diagnostic procedures to detect lymphoma, especially if constitutional symptoms (e.g., fever, night sweats, weight loss) are present • Measurement of autoantibodies to assess for autoimmunity • Consultation with a clinical geneticist and/or genetic counselor • Monitoring for and treatment of lymphoproliferation, hypersplensim, and lymphomas • Management of cytopenias and other autoimmune diseases [ • Manifestations of lymphoproliferation require close clinical observation, as well as serial CT and PET scans every two to three years. • Biopsy is indicated whenever there is a clinical suspicion of lymphoma. • Corticosteroids and immunosuppressive drugs do not decrease lymphadenopathy long term in individuals with ALPS, and are generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations. • Experience with sirolimus suggests that it is the preferred agent in treating lymphoproliferation in a more sustained manner, including for maintenance of remission after initial treatment followed by a period of discontinued use [ • In severe cases, more potent (lympho-depleting) agents may be required to sufficiently control lymphoproliferative manifestations. Agents include cyclophosphamide, antithymocyte globulin (ATG), and select monoclonal antibodies such as alemtuzumab (Campath • Autoimmune cytopenias are typically treated by immune suppression with corticosteroids as well as corticosteroid-sparing agents, if prolonged treatment of autoimmune cytopenias is required and/or in cases of refractory cytopenias. • Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ • Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. • Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ • Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. • Individuals with severe autoimmune hemolytic anemia may benefit from IVIG in combination with corticosteroids. • Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS. However, because of its immune toxicity, its use is generally avoided until other immunosuppression therapies have failed [ • Splenectomy is reserved as an option of last resort in the treatment of life-threatening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in those with ALPS [ • Individuals with isolated chronic neutropenia may improve on low-dose G-CSF [ • Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ • Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. • Be advised of their increased risk for ALPS if the type and location of the ALPS-related pathogenic variant is predicted to have a high penetrance for clinical ALPS; • Undergo ALPS-specific evaluations at initial diagnosis (e.g., enumeration of α/β-DNT cells, detection of autoantibodies, IL-10/soluble FasL measurement) (see • Be advised that ALPS-specific evaluations or other assessments may need to be repeated at regular intervals, particularly if the family member is young and/or if new health-related issues consistent with ALPS or ALPS-related complications (e.g., lymphoma) become apparent (see ## Evaluations Following Initial Diagnosis To determine the presence and extent of disease and needs in an individual diagnosed with autoimmune lymphoproliferative syndrome (ALPS), the following evaluations are recommended: Complete blood counts and flow cytometric immunophenotyping of lymphocytes, especially with regard to α/β-DNT cells, in combination with physical examination and imaging studies to assess lymphadenopathy and hepatosplenomegaly If significant lymphadenopathy is present, more extensive diagnostic procedures to detect lymphoma, especially if constitutional symptoms (e.g., fever, night sweats, weight loss) are present Measurement of autoantibodies to assess for autoimmunity Consultation with a clinical geneticist and/or genetic counselor • Complete blood counts and flow cytometric immunophenotyping of lymphocytes, especially with regard to α/β-DNT cells, in combination with physical examination and imaging studies to assess lymphadenopathy and hepatosplenomegaly • If significant lymphadenopathy is present, more extensive diagnostic procedures to detect lymphoma, especially if constitutional symptoms (e.g., fever, night sweats, weight loss) are present • Measurement of autoantibodies to assess for autoimmunity • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations In the absence of curative treatment, current management is focused on the following: Monitoring for and treatment of lymphoproliferation, hypersplensim, and lymphomas Management of cytopenias and other autoimmune diseases [ Manifestations of lymphoproliferation require close clinical observation, as well as serial CT and PET scans every two to three years. Biopsy is indicated whenever there is a clinical suspicion of lymphoma. Corticosteroids and immunosuppressive drugs do not decrease lymphadenopathy long term in individuals with ALPS, and are generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations. Experience with sirolimus suggests that it is the preferred agent in treating lymphoproliferation in a more sustained manner, including for maintenance of remission after initial treatment followed by a period of discontinued use [ In severe cases, more potent (lympho-depleting) agents may be required to sufficiently control lymphoproliferative manifestations. Agents include cyclophosphamide, antithymocyte globulin (ATG), and select monoclonal antibodies such as alemtuzumab (Campath Autoimmune cytopenias are typically treated by immune suppression with corticosteroids as well as corticosteroid-sparing agents, if prolonged treatment of autoimmune cytopenias is required and/or in cases of refractory cytopenias. Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. Individuals with severe autoimmune hemolytic anemia may benefit from IVIG in combination with corticosteroids. Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS. However, because of its immune toxicity, its use is generally avoided until other immunosuppression therapies have failed [ Splenectomy is reserved as an option of last resort in the treatment of life-threatening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in those with ALPS [ Individuals with isolated chronic neutropenia may improve on low-dose G-CSF [ • Monitoring for and treatment of lymphoproliferation, hypersplensim, and lymphomas • Management of cytopenias and other autoimmune diseases [ • Manifestations of lymphoproliferation require close clinical observation, as well as serial CT and PET scans every two to three years. • Biopsy is indicated whenever there is a clinical suspicion of lymphoma. • Corticosteroids and immunosuppressive drugs do not decrease lymphadenopathy long term in individuals with ALPS, and are generally reserved for severe complications of lymphoproliferation (e.g., airway obstruction, significant hypersplenism associated with splenomegaly) and/or autoimmune manifestations. • Experience with sirolimus suggests that it is the preferred agent in treating lymphoproliferation in a more sustained manner, including for maintenance of remission after initial treatment followed by a period of discontinued use [ • In severe cases, more potent (lympho-depleting) agents may be required to sufficiently control lymphoproliferative manifestations. Agents include cyclophosphamide, antithymocyte globulin (ATG), and select monoclonal antibodies such as alemtuzumab (Campath • Autoimmune cytopenias are typically treated by immune suppression with corticosteroids as well as corticosteroid-sparing agents, if prolonged treatment of autoimmune cytopenias is required and/or in cases of refractory cytopenias. • Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ • Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. • Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ • Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. • Individuals with severe autoimmune hemolytic anemia may benefit from IVIG in combination with corticosteroids. • Rituximab has been used successfully in the treatment of refractory cytopenias in ALPS. However, because of its immune toxicity, its use is generally avoided until other immunosuppression therapies have failed [ • Splenectomy is reserved as an option of last resort in the treatment of life-threatening refractory cytopenias and/or severe hypersplenia because of the high risk of recurrence of cytopenias and sepsis post-splenectomy in those with ALPS [ • Individuals with isolated chronic neutropenia may improve on low-dose G-CSF [ • Recent data from a multi-institutional study suggest that sirolimus should be considered as a first-line – corticosteroid-sparing – agent [ • Mycophenolate mofetil (MMF) can be used in cases when a less immunosuppressive drug (e.g., compared with sirolimus) seems sufficient, as steroids are tapered. In addition, if drug level and toxic side effects cannot be adequately monitored, MMF could be used as a first-line agent. ## Prevention of Primary Manifestations Bone marrow (hematopoietic stem cell) transplantation (BMT/HSCT) is currently the only curative treatment for ALPS. Because of the risks associated with BMT, it has so far been performed mostly in individuals with ALPS with severe clinical phenotypes, such as those with homozygous or compound heterozygous pathogenic variants in Successful (reported) BMT in several individuals indicates that defective Fas-mediated apoptosis does not pose a barrier to this treatment option [ ## Prevention of Secondary Complications Vaccinations pre-splenectomy (with consideration of post-splenectomy boost vaccinations) and penicillin prophylaxis are strongly recommended for individuals who undergo splenectomy. ## Surveillance Clinical assessment, imaging, and laboratory studies outlined in Specialized imaging studies such as combined PET and CT scanning in combination with clinical and laboratory surveillance may be helpful in detection of malignant transformation, keeping in mind that PET/CT scanning is often abnormal in ALPS, such that distinguishing between "typical" ALPS findings and a new malignancy (lymphoma) can be difficult [ ## Agents/Circumstances to Avoid The use of over-the-counter medications such as aspirin and other nonsteroidal anti-inflammatory drugs should be discussed with a physician as some of these medications can interfere with platelet function. ## Evaluation of Relatives at Risk It is appropriate to perform molecular genetic testing on relatives at risk for ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 if the pathogenic variant has been identified in the proband. Relatives who have the family-specific pathogenic variant should: Be advised of their increased risk for ALPS if the type and location of the ALPS-related pathogenic variant is predicted to have a high penetrance for clinical ALPS; Undergo ALPS-specific evaluations at initial diagnosis (e.g., enumeration of α/β-DNT cells, detection of autoantibodies, IL-10/soluble FasL measurement) (see Be advised that ALPS-specific evaluations or other assessments may need to be repeated at regular intervals, particularly if the family member is young and/or if new health-related issues consistent with ALPS or ALPS-related complications (e.g., lymphoma) become apparent (see See • Be advised of their increased risk for ALPS if the type and location of the ALPS-related pathogenic variant is predicted to have a high penetrance for clinical ALPS; • Undergo ALPS-specific evaluations at initial diagnosis (e.g., enumeration of α/β-DNT cells, detection of autoantibodies, IL-10/soluble FasL measurement) (see • Be advised that ALPS-specific evaluations or other assessments may need to be repeated at regular intervals, particularly if the family member is young and/or if new health-related issues consistent with ALPS or ALPS-related complications (e.g., lymphoma) become apparent (see ## Pregnancy Management In addition to the risks and benefits to a woman with ALPS associated with treatment with corticosteroids, mycophenylate mofitil, or sirolimus during pregnancy, the potential teratogenic risks of these exposures to the fetus must also be weighed. See ## Therapies Under Investigation Search ## Genetic Counseling Inheritance of ALPS-CASP10, most cases of ALPS-FAS, and some cases of ALPS-FASLG is autosomal dominant. Inheritance of most cases of ALPS-FASLG and severe ALPS associated with biallelic ALPS-FAS can also be the result of somatic mosaicism. Somatic pathogenic variants have not been reported in ALPS-FASLG or ALPS-CASP10 to date. Most individuals diagnosed with ALPS-FAS have a parent who has a An insufficient number of cases of ALPS-FASLG and ALPS-CASP10 are available to determine the likelihood that the A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with a possible If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Although most individuals diagnosed with ALPS have a parent with a If a parent of the proband has a If the Each child of an individual with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 has a 50% chance of inheriting the The risk to a child who has inherited the pathogenic variant of developing ALPS-related complications depends on the nature of the pathogenic variant as well as the presence of other as-yet incompletely understood genetic or environmental factors (see The parents of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants are likely to be heterozygotes, in which case each parent would have one Heterozygotes may present with ALPS-related findings or may be clinically asymptomatic. At conception, each sib of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants has: An overall 75% chance of having one or two A 25% chance of inheriting two A 50% chance of inheriting a single A 25% chance of inheriting one normal Heterozygotes may present with ALPS-related symptoms or may be clinically asymptomatic. See Management, Molecular genetic testing of asymptomatic individuals should in general be undertaken following thorough genetic counseling and assessment of family-specific risks. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. 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. Prior to pregnancy, affected women should be advised about the teratogenic risks associated with medications used to treat ALPS. Once the • Most individuals diagnosed with ALPS-FAS have a parent who has a • An insufficient number of cases of ALPS-FASLG and ALPS-CASP10 are available to determine the likelihood that the • A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with a possible • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Although most individuals diagnosed with ALPS have a parent with a • If a parent of the proband has a • If the • Each child of an individual with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 has a 50% chance of inheriting the • The risk to a child who has inherited the pathogenic variant of developing ALPS-related complications depends on the nature of the pathogenic variant as well as the presence of other as-yet incompletely understood genetic or environmental factors (see • The parents of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants are likely to be heterozygotes, in which case each parent would have one • Heterozygotes may present with ALPS-related findings or may be clinically asymptomatic. • At conception, each sib of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants has: • An overall 75% chance of having one or two • A 25% chance of inheriting two • A 50% chance of inheriting a single • A 25% chance of inheriting one normal • An overall 75% chance of having one or two • A 25% chance of inheriting two • A 50% chance of inheriting a single • A 25% chance of inheriting one normal • Heterozygotes may present with ALPS-related symptoms or may be clinically asymptomatic. • An overall 75% chance of having one or two • A 25% chance of inheriting two • A 50% chance of inheriting a single • A 25% chance of inheriting one normal • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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. • Prior to pregnancy, affected women should be advised about the teratogenic risks associated with medications used to treat ALPS. ## Mode of Inheritance Inheritance of ALPS-CASP10, most cases of ALPS-FAS, and some cases of ALPS-FASLG is autosomal dominant. Inheritance of most cases of ALPS-FASLG and severe ALPS associated with biallelic ALPS-FAS can also be the result of somatic mosaicism. Somatic pathogenic variants have not been reported in ALPS-FASLG or ALPS-CASP10 to date. ## Autosomal Dominant ALPS – Risk to Family Members Most individuals diagnosed with ALPS-FAS have a parent who has a An insufficient number of cases of ALPS-FASLG and ALPS-CASP10 are available to determine the likelihood that the A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of a Recommendations for the evaluation of parents of a proband with a possible If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a Although most individuals diagnosed with ALPS have a parent with a If a parent of the proband has a If the Each child of an individual with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 has a 50% chance of inheriting the The risk to a child who has inherited the pathogenic variant of developing ALPS-related complications depends on the nature of the pathogenic variant as well as the presence of other as-yet incompletely understood genetic or environmental factors (see • Most individuals diagnosed with ALPS-FAS have a parent who has a • An insufficient number of cases of ALPS-FASLG and ALPS-CASP10 are available to determine the likelihood that the • A proband with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband with a possible • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a • Although most individuals diagnosed with ALPS have a parent with a • If a parent of the proband has a • If the • Each child of an individual with ALPS-FAS, ALPS-FASLG, or ALPS-CASP10 has a 50% chance of inheriting the • The risk to a child who has inherited the pathogenic variant of developing ALPS-related complications depends on the nature of the pathogenic variant as well as the presence of other as-yet incompletely understood genetic or environmental factors (see ## Autosomal Recessive ALPS – Risk to Family Members The parents of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants are likely to be heterozygotes, in which case each parent would have one Heterozygotes may present with ALPS-related findings or may be clinically asymptomatic. At conception, each sib of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants has: An overall 75% chance of having one or two A 25% chance of inheriting two A 50% chance of inheriting a single A 25% chance of inheriting one normal Heterozygotes may present with ALPS-related symptoms or may be clinically asymptomatic. • The parents of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants are likely to be heterozygotes, in which case each parent would have one • Heterozygotes may present with ALPS-related findings or may be clinically asymptomatic. • At conception, each sib of a child with ALPS-FAS or ALPS-FASLG resulting from biallelic pathogenic variants has: • An overall 75% chance of having one or two • A 25% chance of inheriting two • A 50% chance of inheriting a single • A 25% chance of inheriting one normal • An overall 75% chance of having one or two • A 25% chance of inheriting two • A 50% chance of inheriting a single • A 25% chance of inheriting one normal • Heterozygotes may present with ALPS-related symptoms or may be clinically asymptomatic. • An overall 75% chance of having one or two • A 25% chance of inheriting two • A 50% chance of inheriting a single • A 25% chance of inheriting one normal ## Related Genetic Counseling Issues See Management, Molecular genetic testing of asymptomatic individuals should in general be undertaken following thorough genetic counseling and assessment of family-specific risks. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. 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. Prior to pregnancy, affected women should be advised about the teratogenic risks associated with medications used to treat ALPS. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • 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. • Prior to pregnancy, affected women should be advised about the teratogenic risks associated with medications used to treat ALPS. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources NIAID Office of Communications and Government Relations 6610 Rockledge Drive MSC 6612 Bethesda MD 20892-6612 22100 Gratiot Avenue East Detroit MI 48021 Canada • • NIAID Office of Communications and Government Relations • 6610 Rockledge Drive • MSC 6612 • Bethesda MD 20892-6612 • • • 22100 Gratiot Avenue • East Detroit MI 48021 • • • Canada • • • • • • • ## Molecular Genetics Autoimmune Lymphoproliferative Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Autoimmune Lymphoproliferative Syndrome ( Autoimmune lymphoproliferative syndrome (ALPS) can be considered a prototypic disorder of defective lymphocyte homeostasis [ Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions The discovery of individuals with ALPS with somatic pathogenic variants in The protein encoded by Extracellular heterozygous pathogenic variants affecting the FasL-binding domain (CRD2 and CRD3) are also associated with dominant-negative interference because Fas proteins self-associate into trimers prior to FasL interaction [ In individuals with homozygous or compound heterozygous pathogenic variants, defective Fas-mediated apoptosis can be explained by loss of function [ Selected Variants listed in the table have been provided by the authors. Note: All variants are associated with ALPS except p.Met158_Glu185del, which was observed in a patient with systemic lupus erythematosus and lymphadenopathy. AD = autosomal dominant; AICD = activation-induced cell death; AR = autosomal recessive; MOI = mode of inheritance; ND = not determined; ↑ = increased; ↓ = diminished This patient developed peripheral T-cell lymphoma [ Observed in two affected sibs [ ## Molecular Pathogenesis Autoimmune lymphoproliferative syndrome (ALPS) can be considered a prototypic disorder of defective lymphocyte homeostasis [ Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions The discovery of individuals with ALPS with somatic pathogenic variants in The protein encoded by Extracellular heterozygous pathogenic variants affecting the FasL-binding domain (CRD2 and CRD3) are also associated with dominant-negative interference because Fas proteins self-associate into trimers prior to FasL interaction [ In individuals with homozygous or compound heterozygous pathogenic variants, defective Fas-mediated apoptosis can be explained by loss of function [ Selected Variants listed in the table have been provided by the authors. Note: All variants are associated with ALPS except p.Met158_Glu185del, which was observed in a patient with systemic lupus erythematosus and lymphadenopathy. AD = autosomal dominant; AICD = activation-induced cell death; AR = autosomal recessive; MOI = mode of inheritance; ND = not determined; ↑ = increased; ↓ = diminished This patient developed peripheral T-cell lymphoma [ Observed in two affected sibs [ ## Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## The discovery of individuals with ALPS with somatic pathogenic variants in The protein encoded by Extracellular heterozygous pathogenic variants affecting the FasL-binding domain (CRD2 and CRD3) are also associated with dominant-negative interference because Fas proteins self-associate into trimers prior to FasL interaction [ In individuals with homozygous or compound heterozygous pathogenic variants, defective Fas-mediated apoptosis can be explained by loss of function [ ## Selected Variants listed in the table have been provided by the authors. Note: All variants are associated with ALPS except p.Met158_Glu185del, which was observed in a patient with systemic lupus erythematosus and lymphadenopathy. AD = autosomal dominant; AICD = activation-induced cell death; AR = autosomal recessive; MOI = mode of inheritance; ND = not determined; ↑ = increased; ↓ = diminished This patient developed peripheral T-cell lymphoma [ Observed in two affected sibs [ ## Chapter Notes Jack JH Bleesing, MD, PhD (2006-present)Judith Johnson, MS, CGC; Cincinnati Children's Hospital (2006-2017)Chinmayee Nagaraj, MS, CGC (2017-present)Kejian Zhang, MD, MBA (2006-present) 24 August 2017 (ha) Comprehensive update posted live 11 September 2014 (me) Comprehensive update posted live 8 September 2011 (me) Comprehensive update posted live 7 April 2009 (me) Comprehensive update posted live 9 July 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for 14 September 2006 (me) Review posted live 2 December 2005 (jj) Original submission • 24 August 2017 (ha) Comprehensive update posted live • 11 September 2014 (me) Comprehensive update posted live • 8 September 2011 (me) Comprehensive update posted live • 7 April 2009 (me) Comprehensive update posted live • 9 July 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for • 14 September 2006 (me) Review posted live • 2 December 2005 (jj) Original submission ## Author History Jack JH Bleesing, MD, PhD (2006-present)Judith Johnson, MS, CGC; Cincinnati Children's Hospital (2006-2017)Chinmayee Nagaraj, MS, CGC (2017-present)Kejian Zhang, MD, MBA (2006-present) ## Revision History 24 August 2017 (ha) Comprehensive update posted live 11 September 2014 (me) Comprehensive update posted live 8 September 2011 (me) Comprehensive update posted live 7 April 2009 (me) Comprehensive update posted live 9 July 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for 14 September 2006 (me) Review posted live 2 December 2005 (jj) Original submission • 24 August 2017 (ha) Comprehensive update posted live • 11 September 2014 (me) Comprehensive update posted live • 8 September 2011 (me) Comprehensive update posted live • 7 April 2009 (me) Comprehensive update posted live • 9 July 2007 (cd) Revision: sequence analysis and prenatal diagnosis available clinically for • 14 September 2006 (me) Review posted live • 2 December 2005 (jj) Original submission ## References ## Literature Cited One proposed algorithm for the diagnostic evaluation of an individual suspected of having ALPS	[]	14/9/2006	24/8/2017	9/7/2007	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
als-ftd	als-ftd	[ "C9orf72-FTD/ALS", "C9orf72-FTD/ALS", "Guanine nucleotide exchange factor C9orf72", "C9orf72", "C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis" ]		Helena Gossye, Sebastiaan Engelborghs, Christine Van Broeckhoven, Julie van der Zee	Summary The diagnosis of	## Diagnosis In this Manifestations specific to Behavioral variant FTD (31.4%) Nonfluent/agrammatic variant PPA (1.8%) Semantic variant PPA (0.9%) Other tauopathy: corticobasal degeneration, progressive supranuclear palsy, other PPA (0.7%) Alzheimer disease, Parkinson disease, Huntington disease, & dementia w/Lewy bodies are common. Also incl vascular dementia & dementia not otherwise specified Atypical parkinsonian syndromes Based on ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; PPA = primary progressive aphasia Family history may be positive and consistent with autosomal dominant inheritance (e.g., males and females in multiple generations with ALS, FTD, and/or other manifestations within the Note: Simplex cases are sometimes referred to as "sporadic cases"; however, because the term "sporadic" can imply a non-recurring (non-genetic) cause, the term "simplex" is preferred. The diagnosis of Note: Pathogenic G Repeats in this range are rare in the general population and typically do not segregate in families with The shortest G Pathogenic expansions >60 to hundreds or thousands of G Molecular Genetic Testing Used in See Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene. • Manifestations specific to • Behavioral variant FTD (31.4%) • Nonfluent/agrammatic variant PPA (1.8%) • Semantic variant PPA (0.9%) • Other tauopathy: corticobasal degeneration, progressive supranuclear palsy, other PPA (0.7%) • Alzheimer disease, Parkinson disease, Huntington disease, & dementia w/Lewy bodies are common. • Also incl vascular dementia & dementia not otherwise specified • Atypical parkinsonian syndromes • Repeats in this range are rare in the general population and typically do not segregate in families with • The shortest G • Repeats in this range are rare in the general population and typically do not segregate in families with • The shortest G • Pathogenic expansions >60 to hundreds or thousands of G • Repeats in this range are rare in the general population and typically do not segregate in families with • The shortest G ## Suggestive Findings Manifestations specific to Behavioral variant FTD (31.4%) Nonfluent/agrammatic variant PPA (1.8%) Semantic variant PPA (0.9%) Other tauopathy: corticobasal degeneration, progressive supranuclear palsy, other PPA (0.7%) Alzheimer disease, Parkinson disease, Huntington disease, & dementia w/Lewy bodies are common. Also incl vascular dementia & dementia not otherwise specified Atypical parkinsonian syndromes Based on ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; PPA = primary progressive aphasia Family history may be positive and consistent with autosomal dominant inheritance (e.g., males and females in multiple generations with ALS, FTD, and/or other manifestations within the Note: Simplex cases are sometimes referred to as "sporadic cases"; however, because the term "sporadic" can imply a non-recurring (non-genetic) cause, the term "simplex" is preferred. • Manifestations specific to • Behavioral variant FTD (31.4%) • Nonfluent/agrammatic variant PPA (1.8%) • Semantic variant PPA (0.9%) • Other tauopathy: corticobasal degeneration, progressive supranuclear palsy, other PPA (0.7%) • Alzheimer disease, Parkinson disease, Huntington disease, & dementia w/Lewy bodies are common. • Also incl vascular dementia & dementia not otherwise specified • Atypical parkinsonian syndromes ## Clinical Findings Manifestations specific to Behavioral variant FTD (31.4%) Nonfluent/agrammatic variant PPA (1.8%) Semantic variant PPA (0.9%) Other tauopathy: corticobasal degeneration, progressive supranuclear palsy, other PPA (0.7%) Alzheimer disease, Parkinson disease, Huntington disease, & dementia w/Lewy bodies are common. Also incl vascular dementia & dementia not otherwise specified Atypical parkinsonian syndromes Based on ALS = amyotrophic lateral sclerosis; FTD = frontotemporal dementia; PPA = primary progressive aphasia • Manifestations specific to • Behavioral variant FTD (31.4%) • Nonfluent/agrammatic variant PPA (1.8%) • Semantic variant PPA (0.9%) • Other tauopathy: corticobasal degeneration, progressive supranuclear palsy, other PPA (0.7%) • Alzheimer disease, Parkinson disease, Huntington disease, & dementia w/Lewy bodies are common. • Also incl vascular dementia & dementia not otherwise specified • Atypical parkinsonian syndromes ## Neuroimaging ## Family History Family history may be positive and consistent with autosomal dominant inheritance (e.g., males and females in multiple generations with ALS, FTD, and/or other manifestations within the Note: Simplex cases are sometimes referred to as "sporadic cases"; however, because the term "sporadic" can imply a non-recurring (non-genetic) cause, the term "simplex" is preferred. ## Establishing the Diagnosis The diagnosis of Note: Pathogenic G Repeats in this range are rare in the general population and typically do not segregate in families with The shortest G Pathogenic expansions >60 to hundreds or thousands of G Molecular Genetic Testing Used in See Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene. • Repeats in this range are rare in the general population and typically do not segregate in families with • The shortest G • Repeats in this range are rare in the general population and typically do not segregate in families with • The shortest G • Pathogenic expansions >60 to hundreds or thousands of G • Repeats in this range are rare in the general population and typically do not segregate in families with • The shortest G ## Clinical Characteristics Like the age of onset, life expectancy is highly variable and mainly associated with the clinical manifestations. MND = motor neuron disease; OCD = obsessive compulsive disorder Features are ranked as common if present in >33%, if frequency was mentioned. Initial manifestations may be pure FTD or ALS; additional manifestations in the The three main FTD clinical syndromes are behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent/agrammatic variant PPA (nfvPPA). Most individuals with Cognitive deficits associated with FTD are mostly early loss of executive functions, memory impairment, and language problems (mostly dynamic aphasia). Other findings, such as parietal lobe involvement (dyscalculia, apraxia), are common as the disease progresses. The entire clinical spectrum of ALS (which includes abnormal muscle tone and tendon reflexes, fasciculations, muscle cramps, and gait disturbances) may be present in Atypical presentations of the A The association of A Rarely, Life expectancy for individuals with For For Another individual, compound heterozygous for two expanded alleles (one with ±50 G Heterozygosity for a pathogenic ~0% at age 35 years 50% at age 58 years Near 100% at age 80 years A decreasing age of onset in consecutive generations of family members heterozygous for a Thus, to date, G Detailed epidemiologic studies of the prevalence of the With the prevalence of FTD estimated at 1-461:100,000 [ The prevalence of ALS is estimated at 5-12:100,000. Among individuals with ALS, about 10% have a family history consistent with autosomal dominant inheritance and about 90% have no family history of the disorder [ It is important to note that the frequency of The highest repeat expansion frequencies are observed in individuals of northern European heritage. Markedly elevated expansion frequencies were reported in Scandinavian countries [ By contrast, in Asian populations, expansion frequency is much lower [ Few studies have investigated the effect of repeat expansions in cohorts of African heritage [ • For • For • ~0% at age 35 years • 50% at age 58 years • Near 100% at age 80 years • With the prevalence of FTD estimated at 1-461:100,000 [ • The prevalence of ALS is estimated at 5-12:100,000. Among individuals with ALS, about 10% have a family history consistent with autosomal dominant inheritance and about 90% have no family history of the disorder [ • The highest repeat expansion frequencies are observed in individuals of northern European heritage. • Markedly elevated expansion frequencies were reported in Scandinavian countries [ • By contrast, in Asian populations, expansion frequency is much lower [ • Few studies have investigated the effect of repeat expansions in cohorts of African heritage [ ## Clinical Description Like the age of onset, life expectancy is highly variable and mainly associated with the clinical manifestations. MND = motor neuron disease; OCD = obsessive compulsive disorder Features are ranked as common if present in >33%, if frequency was mentioned. Initial manifestations may be pure FTD or ALS; additional manifestations in the The three main FTD clinical syndromes are behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent/agrammatic variant PPA (nfvPPA). Most individuals with Cognitive deficits associated with FTD are mostly early loss of executive functions, memory impairment, and language problems (mostly dynamic aphasia). Other findings, such as parietal lobe involvement (dyscalculia, apraxia), are common as the disease progresses. The entire clinical spectrum of ALS (which includes abnormal muscle tone and tendon reflexes, fasciculations, muscle cramps, and gait disturbances) may be present in Atypical presentations of the A The association of A Rarely, Life expectancy for individuals with For For • For • For ## FTD The three main FTD clinical syndromes are behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and nonfluent/agrammatic variant PPA (nfvPPA). Most individuals with Cognitive deficits associated with FTD are mostly early loss of executive functions, memory impairment, and language problems (mostly dynamic aphasia). Other findings, such as parietal lobe involvement (dyscalculia, apraxia), are common as the disease progresses. ## ALS The entire clinical spectrum of ALS (which includes abnormal muscle tone and tendon reflexes, fasciculations, muscle cramps, and gait disturbances) may be present in ## Atypical Presentations Atypical presentations of the A The association of A Rarely, ## Life Expectancy Life expectancy for individuals with For For • For • For ## Genotype-Phenotype Correlations Another individual, compound heterozygous for two expanded alleles (one with ±50 G ## Penetrance Heterozygosity for a pathogenic ~0% at age 35 years 50% at age 58 years Near 100% at age 80 years • ~0% at age 35 years • 50% at age 58 years • Near 100% at age 80 years ## Anticipation A decreasing age of onset in consecutive generations of family members heterozygous for a Thus, to date, G ## Prevalence Detailed epidemiologic studies of the prevalence of the With the prevalence of FTD estimated at 1-461:100,000 [ The prevalence of ALS is estimated at 5-12:100,000. Among individuals with ALS, about 10% have a family history consistent with autosomal dominant inheritance and about 90% have no family history of the disorder [ It is important to note that the frequency of The highest repeat expansion frequencies are observed in individuals of northern European heritage. Markedly elevated expansion frequencies were reported in Scandinavian countries [ By contrast, in Asian populations, expansion frequency is much lower [ Few studies have investigated the effect of repeat expansions in cohorts of African heritage [ • With the prevalence of FTD estimated at 1-461:100,000 [ • The prevalence of ALS is estimated at 5-12:100,000. Among individuals with ALS, about 10% have a family history consistent with autosomal dominant inheritance and about 90% have no family history of the disorder [ • The highest repeat expansion frequencies are observed in individuals of northern European heritage. • Markedly elevated expansion frequencies were reported in Scandinavian countries [ • By contrast, in Asian populations, expansion frequency is much lower [ • Few studies have investigated the effect of repeat expansions in cohorts of African heritage [ ## Genetically Related (Allelic) Disorders In the vast majority of individuals, ## Differential Diagnosis The frequency of 25% of familial FTD; 30%-50% of familial ALS (Of note, only 10% of individuals with ALS have a positive family history and simplex cases [i.e., a single occurrence in a family] outnumber familial cases among individuals with Up to 88% of individuals with manifestations of both FTD and ALS and a positive family history of these disorders [ Some individuals with Age of onset of A rare ALS/FTD variant of • 25% of familial FTD; • 30%-50% of familial ALS (Of note, only 10% of individuals with ALS have a positive family history and simplex cases [i.e., a single occurrence in a family] outnumber familial cases among individuals with • Up to 88% of individuals with manifestations of both FTD and ALS and a positive family history of these disorders [ • Some individuals with • Age of onset of • A rare ALS/FTD variant of ## Management Consensus clinical management recommendations for To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with UMN involvement: spasticity, Babinski signs, hyperreflexia; LMN involvement: weakness, amyotrophy, fasciculations; EMG. Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores Need for adaptive devices Footwear needs PT needs Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) Fine motor function, e.g., hands, feet, face, fingers, & toes; Home adaptations for ADL & safety. Attention to possible alcohol or drug abuse Referral for psychiatric eval as needed Nutritional status; Aspiration risk. Community or Social work involvement for parental support; Home nursing referral. Early discussion of advanced care planning The affected person's perspective & burden must be considered in clinical decision making. The presence of cognitive impairment may raise ethical concerns. ADL = activities of daily living; EMG = electromyography; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Many individuals benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor. For ALS-related treatment options, see also Treatment of Manifestations in Individuals with Physical medicine & rehab / PT & OT Riluzol Edaravone Ankle-foot braces, walkers, wheelchairs, hospital beds, toileting equipment, lifts to improve functionality Note: Edaravone is not approved worldwide. For severe manifestations (agitation, aggressiveness, psychosis) refractory to SSRIs Often a temporizing measure until affected person becomes more apathetic Note: Risk of iatrogenic extrapyramidal syndrome Based on ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor; UMN = upper motor neuron Recommended Surveillance for Individuals with Based on ADL = activities of daily living; OT = occupational therapy; PT = physical therapy See Although results in a preclinical setting only are available to date, antisense oligonucleotide therapy may be promising as a disease-modifying therapy in Other potential RNA therapies include the use of duplex and single-stranded small interfering RNAs to silence Promising results have been achieved in a Phase II/III clinical trial with the selective tyrosine kinase inhibitor masitinib, as an add-on therapy to riluzole in persons with ALS [ Search • UMN involvement: spasticity, Babinski signs, hyperreflexia; • LMN involvement: weakness, amyotrophy, fasciculations; EMG. • Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores • Need for adaptive devices • Footwear needs • PT needs • Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) • Fine motor function, e.g., hands, feet, face, fingers, & toes; • Home adaptations for ADL & safety. • Attention to possible alcohol or drug abuse • Referral for psychiatric eval as needed • Nutritional status; • Aspiration risk. • Community or • Social work involvement for parental support; • Home nursing referral. • Early discussion of advanced care planning • The affected person's perspective & burden must be considered in clinical decision making. • The presence of cognitive impairment may raise ethical concerns. • Physical medicine & rehab / PT & OT • Riluzol • Edaravone • Ankle-foot braces, walkers, wheelchairs, hospital beds, toileting equipment, lifts to improve functionality • Note: Edaravone is not approved worldwide. • For severe manifestations (agitation, aggressiveness, psychosis) refractory to SSRIs • Often a temporizing measure until affected person becomes more apathetic • Note: Risk of iatrogenic extrapyramidal syndrome ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with UMN involvement: spasticity, Babinski signs, hyperreflexia; LMN involvement: weakness, amyotrophy, fasciculations; EMG. Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores Need for adaptive devices Footwear needs PT needs Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) Fine motor function, e.g., hands, feet, face, fingers, & toes; Home adaptations for ADL & safety. Attention to possible alcohol or drug abuse Referral for psychiatric eval as needed Nutritional status; Aspiration risk. Community or Social work involvement for parental support; Home nursing referral. Early discussion of advanced care planning The affected person's perspective & burden must be considered in clinical decision making. The presence of cognitive impairment may raise ethical concerns. ADL = activities of daily living; EMG = electromyography; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • UMN involvement: spasticity, Babinski signs, hyperreflexia; • LMN involvement: weakness, amyotrophy, fasciculations; EMG. • Muscle tone, joint range of motion, posture, mobility, strength, coordination & endurance, pain, bedsores • Need for adaptive devices • Footwear needs • PT needs • Need for assistive walking devices (e.g., canes, walker, walker w/wheels, walker w/seat, wheelchairs) • Fine motor function, e.g., hands, feet, face, fingers, & toes; • Home adaptations for ADL & safety. • Attention to possible alcohol or drug abuse • Referral for psychiatric eval as needed • Nutritional status; • Aspiration risk. • Community or • Social work involvement for parental support; • Home nursing referral. • Early discussion of advanced care planning • The affected person's perspective & burden must be considered in clinical decision making. • The presence of cognitive impairment may raise ethical concerns. ## Treatment of Manifestations Many individuals benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor. For ALS-related treatment options, see also Treatment of Manifestations in Individuals with Physical medicine & rehab / PT & OT Riluzol Edaravone Ankle-foot braces, walkers, wheelchairs, hospital beds, toileting equipment, lifts to improve functionality Note: Edaravone is not approved worldwide. For severe manifestations (agitation, aggressiveness, psychosis) refractory to SSRIs Often a temporizing measure until affected person becomes more apathetic Note: Risk of iatrogenic extrapyramidal syndrome Based on ADL = activities of daily living; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SSRI = selective serotonin reuptake inhibitor; UMN = upper motor neuron • Physical medicine & rehab / PT & OT • Riluzol • Edaravone • Ankle-foot braces, walkers, wheelchairs, hospital beds, toileting equipment, lifts to improve functionality • Note: Edaravone is not approved worldwide. • For severe manifestations (agitation, aggressiveness, psychosis) refractory to SSRIs • Often a temporizing measure until affected person becomes more apathetic • Note: Risk of iatrogenic extrapyramidal syndrome ## Surveillance Recommended Surveillance for Individuals with Based on ADL = activities of daily living; OT = occupational therapy; PT = physical therapy ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Although results in a preclinical setting only are available to date, antisense oligonucleotide therapy may be promising as a disease-modifying therapy in Other potential RNA therapies include the use of duplex and single-stranded small interfering RNAs to silence Promising results have been achieved in a Phase II/III clinical trial with the selective tyrosine kinase inhibitor masitinib, as an add-on therapy to riluzole in persons with ALS [ Search ## Genetic Counseling To date, almost all individuals diagnosed with In most families the heterozygous parent is affected; however, a heterozygous parent may not have clinical manifestations of the disorder due to age-dependent reduced penetrance (i.e., the parent may be too young to manifest the disorder) (see Molecular genetic testing is recommended for the parents of a proband who appears to be the only affected family member. If the The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism for a The family history of some individuals with If a parent of the proband is affected and/or is known to have a The clinical presentation of the If both parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once 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. For more information, see the National Society of Genetic Counselors • To date, almost all individuals diagnosed with • In most families the heterozygous parent is affected; however, a heterozygous parent may not have clinical manifestations of the disorder due to age-dependent reduced penetrance (i.e., the parent may be too young to manifest the disorder) (see • Molecular genetic testing is recommended for the parents of a proband who appears to be the only affected family member. • If the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or 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 for a • The family history of some individuals with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism for a • If a parent of the proband is affected and/or is known to have a • The clinical presentation of the • If both parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members To date, almost all individuals diagnosed with In most families the heterozygous parent is affected; however, a heterozygous parent may not have clinical manifestations of the disorder due to age-dependent reduced penetrance (i.e., the parent may be too young to manifest the disorder) (see Molecular genetic testing is recommended for the parents of a proband who appears to be the only affected family member. If the The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism for a The family history of some individuals with If a parent of the proband is affected and/or is known to have a The clinical presentation of the If both parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for • To date, almost all individuals diagnosed with • In most families the heterozygous parent is affected; however, a heterozygous parent may not have clinical manifestations of the disorder due to age-dependent reduced penetrance (i.e., the parent may be too young to manifest the disorder) (see • Molecular genetic testing is recommended for the parents of a proband who appears to be the only affected family member. • If the • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or 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 for a • The family history of some individuals with • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism for a • If a parent of the proband is affected and/or is known to have a • The clinical presentation of the • If both parents are clinically unaffected but their genetic status is unknown, sibs are still at increased risk for ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. For more information, see the National Society of Genetic Counselors In a family with an established diagnosis of The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • Predictive testing for at-risk relatives is possible once the • Potential consequences of such testing (including but not limited to socioeconomic changes and the need for long-term follow up and evaluation arrangements for individuals with a positive test result) as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing. • For asymptomatic minors at risk for adult-onset conditions for which early treatment would have no beneficial effect on disease morbidity and mortality, predictive genetic testing is considered inappropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential unhealthy adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause. • For more information, see the National Society of Genetic Counselors • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once 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. For more information, see the National Society of Genetic Counselors ## Resources Canada 1333 Race Street PO Box 40777 Philadelphia PA 19107 5550 West Touhy Avenue Suite 302 Skokie IL 60077-3254 United Kingdom • • • • Canada • • • • • 1333 Race Street • PO Box 40777 • Philadelphia PA 19107 • • • 5550 West Touhy Avenue • Suite 302 • Skokie IL 60077-3254 • • • United Kingdom • • • ## Molecular Genetics C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for C9orf72-Related Amyotrophic Lateral Sclerosis and/or Frontotemporal Dementia ( The G RNA toxicity caused by sequestration of RNA-binding proteins and normal G Methods to Characterize 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 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 due to competition by the normal allele during amplification. Further improvements in single-molecule long-read DNA sequencing technologies will allow more accurate sizing of the repeat and unravel possible interruptions in the repeat sequence, which may influence its stability, pathogenicity, and clinical manifestation [ The smallest unstable repeat reported is ~50 G Detection of an apparently homozygous repeat does not rule out the presence of an expanded G Southern blotting for the G Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated. RP-PCR for the G Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded repeat. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient due to competition by the normal allele during amplification. Notable Variants listed in the table have been provided by the authors. • • RNA toxicity caused by sequestration of RNA-binding proteins and normal • G • RNA toxicity caused by sequestration of RNA-binding proteins and normal • G • RNA toxicity caused by sequestration of RNA-binding proteins and normal • G ## Molecular Pathogenesis The G RNA toxicity caused by sequestration of RNA-binding proteins and normal G Methods to Characterize 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 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 due to competition by the normal allele during amplification. Further improvements in single-molecule long-read DNA sequencing technologies will allow more accurate sizing of the repeat and unravel possible interruptions in the repeat sequence, which may influence its stability, pathogenicity, and clinical manifestation [ The smallest unstable repeat reported is ~50 G Detection of an apparently homozygous repeat does not rule out the presence of an expanded G Southern blotting for the G Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated. RP-PCR for the G Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded repeat. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient due to competition by the normal allele during amplification. Notable Variants listed in the table have been provided by the authors. • • RNA toxicity caused by sequestration of RNA-binding proteins and normal • G • RNA toxicity caused by sequestration of RNA-binding proteins and normal • G • RNA toxicity caused by sequestration of RNA-binding proteins and normal • G ## Chapter Notes The Neurodegenerative Brain Diseases group investigates the molecular mechanisms underlying neurodegenerative dementias and related disorders. We identify novel key proteins in neurodegeneration as potential targets for early diagnosis, risk prediction, and drug and biomarker development. Concurrently, we study the post-genomic consequences of disease-related genetic defects to improve our knowledge of the molecular mechanisms underlying these brain diseases and accelerate the development of more effective treatments. The expertise of the group is in genetics, genomics and functional genomics of Alzheimer disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson disease. The research is in part funded by the Flemish Government initiated Methusalem Excellence program and the Flanders Impulse Program on Networks for Dementia, Belgium. Marc Cruts, PhD; University of Antwerp (2015-2020)Sebastiaan Engelborghs, MD, PhD (2015-present)Helena Gossye, MD (2020-present)Christine Van Broeckhoven, PhD, DSc (2015-present)Julie van der Zee, PhD (2015-present) 17 December 2020 (bp) Comprehensive update posted live 8 January 2015 (me) Review posted live 28 July 2014 (mc) Original submission • 17 December 2020 (bp) Comprehensive update posted live • 8 January 2015 (me) Review posted live • 28 July 2014 (mc) Original submission ## Author Notes The Neurodegenerative Brain Diseases group investigates the molecular mechanisms underlying neurodegenerative dementias and related disorders. We identify novel key proteins in neurodegeneration as potential targets for early diagnosis, risk prediction, and drug and biomarker development. Concurrently, we study the post-genomic consequences of disease-related genetic defects to improve our knowledge of the molecular mechanisms underlying these brain diseases and accelerate the development of more effective treatments. The expertise of the group is in genetics, genomics and functional genomics of Alzheimer disease, frontotemporal lobar degeneration, dementia with Lewy bodies, and Parkinson disease. ## Acknowledgments The research is in part funded by the Flemish Government initiated Methusalem Excellence program and the Flanders Impulse Program on Networks for Dementia, Belgium. ## Author History Marc Cruts, PhD; University of Antwerp (2015-2020)Sebastiaan Engelborghs, MD, PhD (2015-present)Helena Gossye, MD (2020-present)Christine Van Broeckhoven, PhD, DSc (2015-present)Julie van der Zee, PhD (2015-present) ## Revision History 17 December 2020 (bp) Comprehensive update posted live 8 January 2015 (me) Review posted live 28 July 2014 (mc) Original submission • 17 December 2020 (bp) Comprehensive update posted live • 8 January 2015 (me) Review posted live • 28 July 2014 (mc) 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. 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als-overview	als-overview	[ "Lou Gehrig Disease", "ALS", "Lou Gehrig Disease", "ALS2-Related Disorder", "SETX-Related Amyotrophic Lateral Sclerosis", "SOD1-Related Amyotrophic Lateral Sclerosis", "TARDBP-Related Amyotrophic Lateral Sclerosis-Frontotemporal Dementia", "VAPB-Related Amyotrophic Lateral Sclerosis", "ANG-Related Amyotrophic Lateral Sclerosis", "FUS-Related Amyotrophic Lateral Sclerosis", "FIG4-Related Amyotrophic Lateral Sclerosis", "VCP-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia", "OPTN-Related Amyotrophic Lateral Sclerosis", "C9orf72 Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis", "UBQLN2-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia", "PFN1-Related Amyotrophic Lateral Sclerosis", "Alsin", "Angiogenin", "Annexin A11", "Charged multivesicular body protein 2b", "Cilia- and flagella-associated protein 410", "Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial", "D-amino-acid oxidase", "Dynactin subunit 1", "Guanine nucleotide exchange factor C9orf72", "Heterogeneous nuclear ribonucleoprotein A1", "Matrin-3", "Myelin-associated oligodendrocyte basic protein", "Optineurin", "Polyphosphoinositide phosphatase", "Probable helicase senataxin", "Profilin-1", "Protein unc-13 homolog A", "Receptor tyrosine-protein kinase erbB-4", "RNA-binding protein FUS", "Sec1 family domain-containing protein 1", "Sequestosome-1", "Serine/threonine-protein kinase Nek1", "Serine/threonine-protein kinase TBK1", "Spatacsin", "Superoxide dismutase [Cu-Zn]", "TAR DNA-binding protein 43", "TATA-binding protein-associated factor 2N", "Transitional endoplasmic reticulum ATPase", "Tubulin alpha-4A chain", "Ubiquilin-2", "Vesicle-associated membrane protein-associated protein B/C", "ALS2", "ANG", "ANXA11", "C9orf72", "CFAP410", "CHCHD10", "CHMP2B", "DAO", "DCTN1", "ERBB4", "FIG4", "FUS", "HNRNPA1", "MATR3", "MOBP", "NEK1", "OPTN", "PFN1", "SCFD1", "SETX", "SOD1", "SPG11", "SQSTM1", "TAF15", "TARDBP", "TBK1", "TUBA4A", "UBQLN2", "UNC13A", "VAPB", "VCP", "Amyotrophic Lateral Sclerosis", "Overview" ]	Amyotrophic Lateral Sclerosis Overview	Nailah Siddique, Teepu Siddique	Summary The purpose of this overview is to: Describe the Review Provide an Provide a high-level view of Inform	## Clinical Characteristics of ALS Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease involving both the brain and spinal cord. While it has traditionally been perceived to be a syndrome primarily affecting motor neurons, there is increasing recognition that additional areas within the frontal and temporal lobes are involved to varying degrees in a subset of individuals. In addition, other systems outside the nervous system may be involved, such as bone (Paget disease of the bone) and muscle (inclusion body myopathy). The location and extent of the degeneration determines the clinical picture, which by definition includes motor decline, and may include cognitive and/or behavioral symptoms as well. There is wide variability in presentation, progression, and survival [ Motor symptoms occur as the result of degeneration of both upper and lower motor neurons. Upper motor neurons (UMNs), located in the motor cortex of the frontal lobe, send their axons through the great corticofugal tracts to the brain stem (corticobulbar neurons) and the spinal cord (corticospinal neurons) to influence patterned activity of the lower motor neurons (LMNs). Additional UMN influences on the LMN are carried over descending pathways of the brain stem. UMN signs in ALS include hyperreflexia, extensor plantar response, and increased muscle tone. LMNs, located in the brain stem and spinal cord, innervate striated muscle. LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations. Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and lability of affect, but not necessarily mood. A diagnostic feature of ALS, typically not seen in other neurodegenerative disorders, is the presence of hyperreflexia in segmental regions of muscle atrophy, unaccompanied by sensory disturbance. At presentation, limb involvement occurs more often than bulbar involvement. Various subtypes of ALS have been identified: "Progressive bulbar palsy," which presents with speech disturbance and swallowing difficulties Limb-onset ALS Progressive muscular atrophy, where lower motor neurons are primarily involved UMN-predominant ALS Recent studies of both the genetics and neuropathology of ALS have reinforced the understanding that while the syndrome of ALS by definition involves the motor system, wider frontotemporal degeneration may give rise to at least some degree of cognitive and behavioral dysfunction. White matter structural abnormalities in the frontal and temporal lobes of individuals with ALS who do not demonstrate evidence of cognitive decline have also been identified [ It has been reported that upwards of 45% of individuals with ALS have some degree of cognitive impairment at some time during their illness [ Symptoms can range from mild to severe. On the severe end of the spectrum, frontotemporal dementia (FTD), particularly the behavioral variant of FTD (bvFTD), marked by severe apathy and progressive declines in socially appropriate behavior, judgment, and self-control, as well as personality change, has been reported to range from 5% to 27% in various series [ ALS/FTD tends to be associated with bulbar-onset ALS, with its incidence reported to be 39%-61% [ Individuals with ALS with milder neuropsychological manifestations may exhibit executive dysfunction and deficits in verbal and nonverbal fluency and concept formation early in the disease course, particularly in the presence of bulbar onset of disease [ Regardless of the initial manifestations, atrophy and weakness eventually spread to other muscles in additional regions. Oculomotor neurons are generally resistant to degeneration in ALS but may be affected in individuals with a long disease course, particularly when life is extended by ventilatory support. Once all muscles of communication and expression are paralyzed, the individual is "locked in." In some instances, eye movements may remain intact, allowing communication by way of special devices. Death most often results from failure of the respiratory muscles, but other causes, such as pulmonary embolism or cardiac arrhythmias, may supervene. Overall, ALS is a highly heterogeneous disorder with widely varying ages of onset, ranging from childhood to the ninth decade. Males are more commonly affected than females in a ratio of about 1.3/1. The mean age of onset in males is approximately 55 years, while females are most commonly affected in their mid-60s. Individuals with genetic forms of ALS tend to have an earlier onset of symptoms. Disease duration is similarly variable, ranging from months to several decades. About half of affected individuals expire within five years of symptom onset. Individuals (both male and female) younger than age 55 years at onset tend to survive longer [ Traditionally, ALS has been discussed in light of the individual's family history, with "familial ALS" indicating that two or more close relatives are known to be affected with ALS and "sporadic ALS" indicating that no other relatives are known to have ALS. As genetic research in ALS has evolved and the clinical use of genetic testing has increased, this terminology is shifting. In this It is estimated that about 10%-15% of individuals with ALS have genetic ALS. Some of the genetic forms of ALS may confer particular clinical characteristics, although intra- and interfamilial variability of age at onset and disease progression is common (see The diagnosis of ALS requires characteristic clinical features and specific findings on electrodiagnostic testing, as well as exclusion of other health conditions with related manifestations (see The The Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination Evidence of upper motor neuron (UMN) degeneration by clinical examination Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination Together with the Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs Clinical evidence of UMN and LMN signs in the four regions of the central nervous system (i.e., brain stem, cervical, thoracic, or lumbosacral spinal cord) can be obtained through detailed or focused history and physical and neurologic examinations. The clinical diagnosis of ALS, without pathologic confirmation, may be categorized into various levels of certainty by clinical and laboratory assessment based on the revised Escorial criteria [ Electromyography (EMG) can demonstrate electrophysiologic evidence of LMN involvement in clinically affected or clinically uninvolved regions. The Awaji consensus criteria [ Level 1 of the Axis 1. Defining the motor neuron disease variant using the Escorial criteria while incorporating the Awaji recommendations and testing for genetic variants known to cause ALS Axis 2. Defining neuropsychological deficits: ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. Axis 3. Identification of any additional nonmotor manifestations, such as extrapyramidal signs, cerebellar or autonomic dysfunction, sensory impairment, and/or eye movement abnormalities The gold standard for neuropsychological evaluation is a neuropsychological examination administered by a neuropsychologist that includes an interview and a series of standardized tests that assess intelligence, executive function (including planning, abstraction, and conceptualization), attention, memory, language, perception, sensorimotor functions, motivation, mood state and emotion, quality of life, and personality style. Since this testing requires several hours and a specialized practitioner, it is generally not readily available in most clinical settings. Therefore, several tools have been developed that are appropriate for screening and brief assessments. The revised Strong criteria recommend use of the following: It is helpful to remember that both ALS and FTD are clinical diagnoses. Pathologic verification is required for either diagnosis to be considered definitive. See Depending on the clinical presentation, several other hereditary and acquired conditions may need to be considered before establishing the diagnosis of ALS ( Single-Gene Disorders of Interest in the Differential Diagnosis of ALS No UMN involvement Proximal weakness Sensory involvement Slowly progressive Males only affected May have gynecomastia, testicular atrophy, & ↓ fertility Slowly progressive Abnormal vibration sense Slowly progressive Distal sensory loss Early neurogenic bladder Cerebellar dysfunction Spinocerebellar degeneration Dystonia Slowly progressive Onset typically in 2nd-3rd decade No UMN involvement Symmetric weakness & atrophy AD = autosomal dominant; AR = autosomal recessive; LMN = lower motor neuron; MOI = mode of inheritance; UMN = upper motor neuron; XL = X-linked Genes are in alphabetic order. The spectrum of The distal hereditary motor neuropathies, or Charcot-Marie-Tooth disease (CMT). See The hereditary spastic paraplegias, or HSP. See Primary lateral sclerosis (PLS) refers to the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated. Controversy exists as to whether PLS is a separate disorder or a subtype of ALS. Upper motor neuron-predominant ALS has little, often late, involvement of LMNs. Adult-onset PLS is not known to be a genetic disorder, although at least a portion of juvenile-onset PLS is an autosomal recessive genetic condition that may present as a progressive ascending paralysis first noted in infancy [ If there are UMN signs in the legs and LMN signs in the arms, cervical spondylosis with cervical stenosis should be considered as well. However, cervical spondylosis is common, so it may be identified concomitantly in individuals who have ALS. An excess of ALS cases has been reported in younger Gulf War veterans, particularly in the decade following the war [ • "Progressive bulbar palsy," which presents with speech disturbance and swallowing difficulties • Limb-onset ALS • Progressive muscular atrophy, where lower motor neurons are primarily involved • UMN-predominant ALS • The • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Together with the • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Axis 1. Defining the motor neuron disease variant using the Escorial criteria while incorporating the Awaji recommendations and testing for genetic variants known to cause ALS • Axis 2. Defining neuropsychological deficits: • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. • Axis 3. Identification of any additional nonmotor manifestations, such as extrapyramidal signs, cerebellar or autonomic dysfunction, sensory impairment, and/or eye movement abnormalities • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. • No UMN involvement • Proximal weakness • Sensory involvement • Slowly progressive • Males only affected • May have gynecomastia, testicular atrophy, & ↓ fertility • Slowly progressive • Abnormal vibration sense • Slowly progressive • Distal sensory loss • Early neurogenic bladder • Cerebellar dysfunction • Spinocerebellar degeneration • Dystonia • Slowly progressive • Onset typically in 2nd-3rd decade • No UMN involvement • Symmetric weakness & atrophy • The distal hereditary motor neuropathies, or Charcot-Marie-Tooth disease (CMT). See • The hereditary spastic paraplegias, or HSP. See • Primary lateral sclerosis (PLS) refers to the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated. Controversy exists as to whether PLS is a separate disorder or a subtype of ALS. Upper motor neuron-predominant ALS has little, often late, involvement of LMNs. Adult-onset PLS is not known to be a genetic disorder, although at least a portion of juvenile-onset PLS is an autosomal recessive genetic condition that may present as a progressive ascending paralysis first noted in infancy [ ## Clinical Manifestations of ALS Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disease involving both the brain and spinal cord. While it has traditionally been perceived to be a syndrome primarily affecting motor neurons, there is increasing recognition that additional areas within the frontal and temporal lobes are involved to varying degrees in a subset of individuals. In addition, other systems outside the nervous system may be involved, such as bone (Paget disease of the bone) and muscle (inclusion body myopathy). The location and extent of the degeneration determines the clinical picture, which by definition includes motor decline, and may include cognitive and/or behavioral symptoms as well. There is wide variability in presentation, progression, and survival [ Motor symptoms occur as the result of degeneration of both upper and lower motor neurons. Upper motor neurons (UMNs), located in the motor cortex of the frontal lobe, send their axons through the great corticofugal tracts to the brain stem (corticobulbar neurons) and the spinal cord (corticospinal neurons) to influence patterned activity of the lower motor neurons (LMNs). Additional UMN influences on the LMN are carried over descending pathways of the brain stem. UMN signs in ALS include hyperreflexia, extensor plantar response, and increased muscle tone. LMNs, located in the brain stem and spinal cord, innervate striated muscle. LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations. Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and lability of affect, but not necessarily mood. A diagnostic feature of ALS, typically not seen in other neurodegenerative disorders, is the presence of hyperreflexia in segmental regions of muscle atrophy, unaccompanied by sensory disturbance. At presentation, limb involvement occurs more often than bulbar involvement. Various subtypes of ALS have been identified: "Progressive bulbar palsy," which presents with speech disturbance and swallowing difficulties Limb-onset ALS Progressive muscular atrophy, where lower motor neurons are primarily involved UMN-predominant ALS Recent studies of both the genetics and neuropathology of ALS have reinforced the understanding that while the syndrome of ALS by definition involves the motor system, wider frontotemporal degeneration may give rise to at least some degree of cognitive and behavioral dysfunction. White matter structural abnormalities in the frontal and temporal lobes of individuals with ALS who do not demonstrate evidence of cognitive decline have also been identified [ It has been reported that upwards of 45% of individuals with ALS have some degree of cognitive impairment at some time during their illness [ Symptoms can range from mild to severe. On the severe end of the spectrum, frontotemporal dementia (FTD), particularly the behavioral variant of FTD (bvFTD), marked by severe apathy and progressive declines in socially appropriate behavior, judgment, and self-control, as well as personality change, has been reported to range from 5% to 27% in various series [ ALS/FTD tends to be associated with bulbar-onset ALS, with its incidence reported to be 39%-61% [ Individuals with ALS with milder neuropsychological manifestations may exhibit executive dysfunction and deficits in verbal and nonverbal fluency and concept formation early in the disease course, particularly in the presence of bulbar onset of disease [ Regardless of the initial manifestations, atrophy and weakness eventually spread to other muscles in additional regions. Oculomotor neurons are generally resistant to degeneration in ALS but may be affected in individuals with a long disease course, particularly when life is extended by ventilatory support. Once all muscles of communication and expression are paralyzed, the individual is "locked in." In some instances, eye movements may remain intact, allowing communication by way of special devices. Death most often results from failure of the respiratory muscles, but other causes, such as pulmonary embolism or cardiac arrhythmias, may supervene. Overall, ALS is a highly heterogeneous disorder with widely varying ages of onset, ranging from childhood to the ninth decade. Males are more commonly affected than females in a ratio of about 1.3/1. The mean age of onset in males is approximately 55 years, while females are most commonly affected in their mid-60s. Individuals with genetic forms of ALS tend to have an earlier onset of symptoms. Disease duration is similarly variable, ranging from months to several decades. About half of affected individuals expire within five years of symptom onset. Individuals (both male and female) younger than age 55 years at onset tend to survive longer [ Traditionally, ALS has been discussed in light of the individual's family history, with "familial ALS" indicating that two or more close relatives are known to be affected with ALS and "sporadic ALS" indicating that no other relatives are known to have ALS. As genetic research in ALS has evolved and the clinical use of genetic testing has increased, this terminology is shifting. In this It is estimated that about 10%-15% of individuals with ALS have genetic ALS. Some of the genetic forms of ALS may confer particular clinical characteristics, although intra- and interfamilial variability of age at onset and disease progression is common (see • "Progressive bulbar palsy," which presents with speech disturbance and swallowing difficulties • Limb-onset ALS • Progressive muscular atrophy, where lower motor neurons are primarily involved • UMN-predominant ALS ## Motor Involvement Motor symptoms occur as the result of degeneration of both upper and lower motor neurons. Upper motor neurons (UMNs), located in the motor cortex of the frontal lobe, send their axons through the great corticofugal tracts to the brain stem (corticobulbar neurons) and the spinal cord (corticospinal neurons) to influence patterned activity of the lower motor neurons (LMNs). Additional UMN influences on the LMN are carried over descending pathways of the brain stem. UMN signs in ALS include hyperreflexia, extensor plantar response, and increased muscle tone. LMNs, located in the brain stem and spinal cord, innervate striated muscle. LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations. Early manifestations may vary, with affected individuals most often presenting with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and lability of affect, but not necessarily mood. A diagnostic feature of ALS, typically not seen in other neurodegenerative disorders, is the presence of hyperreflexia in segmental regions of muscle atrophy, unaccompanied by sensory disturbance. At presentation, limb involvement occurs more often than bulbar involvement. Various subtypes of ALS have been identified: "Progressive bulbar palsy," which presents with speech disturbance and swallowing difficulties Limb-onset ALS Progressive muscular atrophy, where lower motor neurons are primarily involved UMN-predominant ALS • "Progressive bulbar palsy," which presents with speech disturbance and swallowing difficulties • Limb-onset ALS • Progressive muscular atrophy, where lower motor neurons are primarily involved • UMN-predominant ALS ## Neuropsychological Involvement Recent studies of both the genetics and neuropathology of ALS have reinforced the understanding that while the syndrome of ALS by definition involves the motor system, wider frontotemporal degeneration may give rise to at least some degree of cognitive and behavioral dysfunction. White matter structural abnormalities in the frontal and temporal lobes of individuals with ALS who do not demonstrate evidence of cognitive decline have also been identified [ It has been reported that upwards of 45% of individuals with ALS have some degree of cognitive impairment at some time during their illness [ Symptoms can range from mild to severe. On the severe end of the spectrum, frontotemporal dementia (FTD), particularly the behavioral variant of FTD (bvFTD), marked by severe apathy and progressive declines in socially appropriate behavior, judgment, and self-control, as well as personality change, has been reported to range from 5% to 27% in various series [ ALS/FTD tends to be associated with bulbar-onset ALS, with its incidence reported to be 39%-61% [ Individuals with ALS with milder neuropsychological manifestations may exhibit executive dysfunction and deficits in verbal and nonverbal fluency and concept formation early in the disease course, particularly in the presence of bulbar onset of disease [ ## Course Regardless of the initial manifestations, atrophy and weakness eventually spread to other muscles in additional regions. Oculomotor neurons are generally resistant to degeneration in ALS but may be affected in individuals with a long disease course, particularly when life is extended by ventilatory support. Once all muscles of communication and expression are paralyzed, the individual is "locked in." In some instances, eye movements may remain intact, allowing communication by way of special devices. Death most often results from failure of the respiratory muscles, but other causes, such as pulmonary embolism or cardiac arrhythmias, may supervene. Overall, ALS is a highly heterogeneous disorder with widely varying ages of onset, ranging from childhood to the ninth decade. Males are more commonly affected than females in a ratio of about 1.3/1. The mean age of onset in males is approximately 55 years, while females are most commonly affected in their mid-60s. Individuals with genetic forms of ALS tend to have an earlier onset of symptoms. Disease duration is similarly variable, ranging from months to several decades. About half of affected individuals expire within five years of symptom onset. Individuals (both male and female) younger than age 55 years at onset tend to survive longer [ Traditionally, ALS has been discussed in light of the individual's family history, with "familial ALS" indicating that two or more close relatives are known to be affected with ALS and "sporadic ALS" indicating that no other relatives are known to have ALS. As genetic research in ALS has evolved and the clinical use of genetic testing has increased, this terminology is shifting. In this It is estimated that about 10%-15% of individuals with ALS have genetic ALS. Some of the genetic forms of ALS may confer particular clinical characteristics, although intra- and interfamilial variability of age at onset and disease progression is common (see ## Establishing the Diagnosis of ALS The diagnosis of ALS requires characteristic clinical features and specific findings on electrodiagnostic testing, as well as exclusion of other health conditions with related manifestations (see The The Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination Evidence of upper motor neuron (UMN) degeneration by clinical examination Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination Together with the Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs Clinical evidence of UMN and LMN signs in the four regions of the central nervous system (i.e., brain stem, cervical, thoracic, or lumbosacral spinal cord) can be obtained through detailed or focused history and physical and neurologic examinations. The clinical diagnosis of ALS, without pathologic confirmation, may be categorized into various levels of certainty by clinical and laboratory assessment based on the revised Escorial criteria [ Electromyography (EMG) can demonstrate electrophysiologic evidence of LMN involvement in clinically affected or clinically uninvolved regions. The Awaji consensus criteria [ Level 1 of the Axis 1. Defining the motor neuron disease variant using the Escorial criteria while incorporating the Awaji recommendations and testing for genetic variants known to cause ALS Axis 2. Defining neuropsychological deficits: ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. Axis 3. Identification of any additional nonmotor manifestations, such as extrapyramidal signs, cerebellar or autonomic dysfunction, sensory impairment, and/or eye movement abnormalities The gold standard for neuropsychological evaluation is a neuropsychological examination administered by a neuropsychologist that includes an interview and a series of standardized tests that assess intelligence, executive function (including planning, abstraction, and conceptualization), attention, memory, language, perception, sensorimotor functions, motivation, mood state and emotion, quality of life, and personality style. Since this testing requires several hours and a specialized practitioner, it is generally not readily available in most clinical settings. Therefore, several tools have been developed that are appropriate for screening and brief assessments. The revised Strong criteria recommend use of the following: It is helpful to remember that both ALS and FTD are clinical diagnoses. Pathologic verification is required for either diagnosis to be considered definitive. See • The • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Together with the • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Axis 1. Defining the motor neuron disease variant using the Escorial criteria while incorporating the Awaji recommendations and testing for genetic variants known to cause ALS • Axis 2. Defining neuropsychological deficits: • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. • Axis 3. Identification of any additional nonmotor manifestations, such as extrapyramidal signs, cerebellar or autonomic dysfunction, sensory impairment, and/or eye movement abnormalities • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. ## Clinical Features The The Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination Evidence of upper motor neuron (UMN) degeneration by clinical examination Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination Together with the Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs Clinical evidence of UMN and LMN signs in the four regions of the central nervous system (i.e., brain stem, cervical, thoracic, or lumbosacral spinal cord) can be obtained through detailed or focused history and physical and neurologic examinations. The clinical diagnosis of ALS, without pathologic confirmation, may be categorized into various levels of certainty by clinical and laboratory assessment based on the revised Escorial criteria [ • The • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Together with the • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs • Evidence of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or neuropathologic examination • Evidence of upper motor neuron (UMN) degeneration by clinical examination • Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination • Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration • Neuroimaging evidence of other disease processes that could explain the observed clinical and electrophysiologic signs ## Electrodiagnostic Testing Electromyography (EMG) can demonstrate electrophysiologic evidence of LMN involvement in clinically affected or clinically uninvolved regions. The Awaji consensus criteria [ ## Establishing Frontotemporal Spectrum Involvement Level 1 of the Axis 1. Defining the motor neuron disease variant using the Escorial criteria while incorporating the Awaji recommendations and testing for genetic variants known to cause ALS Axis 2. Defining neuropsychological deficits: ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. Axis 3. Identification of any additional nonmotor manifestations, such as extrapyramidal signs, cerebellar or autonomic dysfunction, sensory impairment, and/or eye movement abnormalities • Axis 1. Defining the motor neuron disease variant using the Escorial criteria while incorporating the Awaji recommendations and testing for genetic variants known to cause ALS • Axis 2. Defining neuropsychological deficits: • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. • Axis 3. Identification of any additional nonmotor manifestations, such as extrapyramidal signs, cerebellar or autonomic dysfunction, sensory impairment, and/or eye movement abnormalities • ALS with behavioral impairment (ALSbi): presence of apathy with or without behavior change OR presence of two non-overlapping supportive diagnostic features from the Raskovsky criteria [2011], which include disinhibition, inertia, loss of sympathy/empathy, perseverative/compulsive behaviors, hyperorality, and dysexecutive neuropsychological profile. • ALS with cognitive impairment (ALSci): evidence of either executive dysfunction (including social cognition) or language dysfunction, or a combination of both. Executive impairment is defined as impaired verbal frequency (letter) OR impairment in two other non-overlapping measures of executive function, which may include social cognition. • ALS with both behavioral and cognitive impairment (ALScbi): both criteria for ALSci and ALSbi are met. • ALS/FTD: evidence of progressive deterioration of behavior and/or cognition by observation or history AND the presence of three behavioral/cognitive symptoms from Raskovsky criteria (2011) OR the presence of at least two behavioral/cognitive symptoms together with loss of insight and/or psychotic symptoms OR the presence of language impairment meeting criteria for semantic dementia / semantic variant of primary progressive aphasia (PPA) or nonfluent PPA. ## Neuropsychological Evaluation The gold standard for neuropsychological evaluation is a neuropsychological examination administered by a neuropsychologist that includes an interview and a series of standardized tests that assess intelligence, executive function (including planning, abstraction, and conceptualization), attention, memory, language, perception, sensorimotor functions, motivation, mood state and emotion, quality of life, and personality style. Since this testing requires several hours and a specialized practitioner, it is generally not readily available in most clinical settings. Therefore, several tools have been developed that are appropriate for screening and brief assessments. The revised Strong criteria recommend use of the following: ## Pathologic Criteria It is helpful to remember that both ALS and FTD are clinical diagnoses. Pathologic verification is required for either diagnosis to be considered definitive. See ## Differential Diagnosis of ALS Depending on the clinical presentation, several other hereditary and acquired conditions may need to be considered before establishing the diagnosis of ALS ( Single-Gene Disorders of Interest in the Differential Diagnosis of ALS No UMN involvement Proximal weakness Sensory involvement Slowly progressive Males only affected May have gynecomastia, testicular atrophy, & ↓ fertility Slowly progressive Abnormal vibration sense Slowly progressive Distal sensory loss Early neurogenic bladder Cerebellar dysfunction Spinocerebellar degeneration Dystonia Slowly progressive Onset typically in 2nd-3rd decade No UMN involvement Symmetric weakness & atrophy AD = autosomal dominant; AR = autosomal recessive; LMN = lower motor neuron; MOI = mode of inheritance; UMN = upper motor neuron; XL = X-linked Genes are in alphabetic order. The spectrum of The distal hereditary motor neuropathies, or Charcot-Marie-Tooth disease (CMT). See The hereditary spastic paraplegias, or HSP. See Primary lateral sclerosis (PLS) refers to the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated. Controversy exists as to whether PLS is a separate disorder or a subtype of ALS. Upper motor neuron-predominant ALS has little, often late, involvement of LMNs. Adult-onset PLS is not known to be a genetic disorder, although at least a portion of juvenile-onset PLS is an autosomal recessive genetic condition that may present as a progressive ascending paralysis first noted in infancy [ If there are UMN signs in the legs and LMN signs in the arms, cervical spondylosis with cervical stenosis should be considered as well. However, cervical spondylosis is common, so it may be identified concomitantly in individuals who have ALS. An excess of ALS cases has been reported in younger Gulf War veterans, particularly in the decade following the war [ • No UMN involvement • Proximal weakness • Sensory involvement • Slowly progressive • Males only affected • May have gynecomastia, testicular atrophy, & ↓ fertility • Slowly progressive • Abnormal vibration sense • Slowly progressive • Distal sensory loss • Early neurogenic bladder • Cerebellar dysfunction • Spinocerebellar degeneration • Dystonia • Slowly progressive • Onset typically in 2nd-3rd decade • No UMN involvement • Symmetric weakness & atrophy • The distal hereditary motor neuropathies, or Charcot-Marie-Tooth disease (CMT). See • The hereditary spastic paraplegias, or HSP. See • Primary lateral sclerosis (PLS) refers to the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated. Controversy exists as to whether PLS is a separate disorder or a subtype of ALS. Upper motor neuron-predominant ALS has little, often late, involvement of LMNs. Adult-onset PLS is not known to be a genetic disorder, although at least a portion of juvenile-onset PLS is an autosomal recessive genetic condition that may present as a progressive ascending paralysis first noted in infancy [ ## Genetic Causes of ALS For the purposes of this It is estimated that 10% of individuals with ALS have at least one other family member affected with ALS. Although the frequency of known genetic causes reported in such families ranges widely in various series, it is safe to say that the ALS genes that have been identified account for at least half of ALS that occurs in families with a history of more than one affected relative. Thirty genes implicated with varying degrees of certainty are presented below, with the four most robust and common genes presented in order of prevalence ( Genetic Amyotrophic Lateral Sclerosis: Most Common Genes and Associated Clinical Features PLS PSP Psychiatric symptoms Parkinsonism Chorea 50% are symptomatic by age 58 yrs. ~100% by 80 yrs 50% symptomatic by age 46 yrs 90% by 70 yrs Earlier average onset than 50%-70% symptomatic by age 51 >90% by 71 yrs ALS occurs w/or w/out mild cognitive impairment. 1/3 of affected individuals have bulbar onset. More common in Asian cohorts AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; bvFTD = behavioral variant of FTD; FTD = frontotemporal dementia; LMN = lower motor neuron; MOI = mode of inheritance; PLS = primary lateral sclerosis; PSP = progressive supranuclear palsy; UMN = upper motor neuron Genetic Amyotrophic Lateral Sclerosis: Less Common Genes and Associated Clinical Features ALS is UMN-predominant. Onset from infancy to mid-childhood Long course: bedridden by age 12-50 Not observed in adult-onset ALS Phenotype is primarily ALS (may present as FTD or parkinsonism). To date, primarily limited to families of European ancestry 1st decade to adult onset; most commonly in adolescence (juvenile ALS) Also referred to as distal hereditary motor neuropathy No bulbar involvement Juvenile ALS w/onset in 1st or 2nd decade; very slowly progressive Multiple ethnicities; often consanguineous parents Cognitive impairment not reported Thin corpus callosum not reported ALS occurs w/or w/out mild cognitive impairment. Risk gene for simplex ALS Disease-modifyihg gene for familial ALS ALS occurs w/or w/out postural tremor. To date, reported primarily in Brazilians ALS occurs w/or w/o mild cognitive impairment. Clinical course may be rapid. May include parkinsonism AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; EMG = electromyography; FTD = frontotemporal dementia; LMN = lower motor neuron; MOI = mode of inheritance; NCV = nerve conduction velocity; PLS = primary lateral sclerosis; UMN = upper motor neuron; XLD = X-linked Genes are listed alphabetically. Susceptibility gene (i.e., a genetic variant that increases a person's predisposition for developing a given disorder) About 85% of ALS occurs in individuals with no family history of ALS; in common parlance such individuals are often said to have "sporadic" ALS. ALS that occurs within a family with a known history of ALS but no known genetic cause yet identified may be called "familial ALS without a known cause." It is possible that genetic ALS or familial ALS of unknown cause may The etiology of simplex ALS is not well understood. It has long been thought to be multifactorial, with both susceptibility genes and multiple environmental factors contributing. Genome-wide association studies (GWAS) have not yielded the anticipated results, although the 60% heritability reported in a twin study would suggest that complex genetics plays a large role [ A study of heritability in the Irish population reported that genetic factors account for nearly 40% of the variation in risk for developing ALS in individuals who did not have disease-causing variants in known ALS genes [ Variants in several genes have been identified as modifiers of disease onset or course: 31 or more polyQ repeats in Variants in several other genes have been shown to reduce risk for ALS, including variants in Statistical analysis of more than 6,000 European cases of ALS suggests that the disease may develop as the result of a series of six "steps" – some genetic and some environmental – that occur over time [ • PLS • PSP • Psychiatric symptoms • Parkinsonism • Chorea • 50% are symptomatic by age 58 yrs. • ~100% by 80 yrs • 50% symptomatic by age 46 yrs • 90% by 70 yrs • Earlier average onset than • 50%-70% symptomatic by age 51 • >90% by 71 yrs • ALS occurs w/or w/out mild cognitive impairment. • 1/3 of affected individuals have bulbar onset. • More common in Asian cohorts • ALS is UMN-predominant. • Onset from infancy to mid-childhood • Long course: bedridden by age 12-50 • Not observed in adult-onset ALS • Phenotype is primarily ALS (may present as FTD or parkinsonism). • To date, primarily limited to families of European ancestry • 1st decade to adult onset; most commonly in adolescence (juvenile ALS) • Also referred to as distal hereditary motor neuropathy • No bulbar involvement • Juvenile ALS w/onset in 1st or 2nd decade; very slowly progressive • Multiple ethnicities; often consanguineous parents • Cognitive impairment not reported • Thin corpus callosum not reported • ALS occurs w/or w/out mild cognitive impairment. • Risk gene for simplex ALS • Disease-modifyihg gene for familial ALS • ALS occurs w/or w/out postural tremor. • To date, reported primarily in Brazilians • ALS occurs w/or w/o mild cognitive impairment. • Clinical course may be rapid. • May include parkinsonism • Genome-wide association studies (GWAS) have not yielded the anticipated results, although the 60% heritability reported in a twin study would suggest that complex genetics plays a large role [ • A study of heritability in the Irish population reported that genetic factors account for nearly 40% of the variation in risk for developing ALS in individuals who did not have disease-causing variants in known ALS genes [ • Variants in several genes have been identified as modifiers of disease onset or course: • 31 or more polyQ repeats in • Variants in several other genes have been shown to reduce risk for ALS, including variants in • 31 or more polyQ repeats in • Variants in several other genes have been shown to reduce risk for ALS, including variants in • Statistical analysis of more than 6,000 European cases of ALS suggests that the disease may develop as the result of a series of six "steps" – some genetic and some environmental – that occur over time [ • 31 or more polyQ repeats in • Variants in several other genes have been shown to reduce risk for ALS, including variants in ## Notable Variants Genetic Amyotrophic Lateral Sclerosis: Less Common Genes and Associated Clinical Features ALS is UMN-predominant. Onset from infancy to mid-childhood Long course: bedridden by age 12-50 Not observed in adult-onset ALS Phenotype is primarily ALS (may present as FTD or parkinsonism). To date, primarily limited to families of European ancestry 1st decade to adult onset; most commonly in adolescence (juvenile ALS) Also referred to as distal hereditary motor neuropathy No bulbar involvement Juvenile ALS w/onset in 1st or 2nd decade; very slowly progressive Multiple ethnicities; often consanguineous parents Cognitive impairment not reported Thin corpus callosum not reported ALS occurs w/or w/out mild cognitive impairment. Risk gene for simplex ALS Disease-modifyihg gene for familial ALS ALS occurs w/or w/out postural tremor. To date, reported primarily in Brazilians ALS occurs w/or w/o mild cognitive impairment. Clinical course may be rapid. May include parkinsonism AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; EMG = electromyography; FTD = frontotemporal dementia; LMN = lower motor neuron; MOI = mode of inheritance; NCV = nerve conduction velocity; PLS = primary lateral sclerosis; UMN = upper motor neuron; XLD = X-linked Genes are listed alphabetically. Susceptibility gene (i.e., a genetic variant that increases a person's predisposition for developing a given disorder) • ALS is UMN-predominant. • Onset from infancy to mid-childhood • Long course: bedridden by age 12-50 • Not observed in adult-onset ALS • Phenotype is primarily ALS (may present as FTD or parkinsonism). • To date, primarily limited to families of European ancestry • 1st decade to adult onset; most commonly in adolescence (juvenile ALS) • Also referred to as distal hereditary motor neuropathy • No bulbar involvement • Juvenile ALS w/onset in 1st or 2nd decade; very slowly progressive • Multiple ethnicities; often consanguineous parents • Cognitive impairment not reported • Thin corpus callosum not reported • ALS occurs w/or w/out mild cognitive impairment. • Risk gene for simplex ALS • Disease-modifyihg gene for familial ALS • ALS occurs w/or w/out postural tremor. • To date, reported primarily in Brazilians • ALS occurs w/or w/o mild cognitive impairment. • Clinical course may be rapid. • May include parkinsonism ## Simplex ALS About 85% of ALS occurs in individuals with no family history of ALS; in common parlance such individuals are often said to have "sporadic" ALS. ALS that occurs within a family with a known history of ALS but no known genetic cause yet identified may be called "familial ALS without a known cause." It is possible that genetic ALS or familial ALS of unknown cause may The etiology of simplex ALS is not well understood. It has long been thought to be multifactorial, with both susceptibility genes and multiple environmental factors contributing. Genome-wide association studies (GWAS) have not yielded the anticipated results, although the 60% heritability reported in a twin study would suggest that complex genetics plays a large role [ A study of heritability in the Irish population reported that genetic factors account for nearly 40% of the variation in risk for developing ALS in individuals who did not have disease-causing variants in known ALS genes [ Variants in several genes have been identified as modifiers of disease onset or course: 31 or more polyQ repeats in Variants in several other genes have been shown to reduce risk for ALS, including variants in Statistical analysis of more than 6,000 European cases of ALS suggests that the disease may develop as the result of a series of six "steps" – some genetic and some environmental – that occur over time [ • Genome-wide association studies (GWAS) have not yielded the anticipated results, although the 60% heritability reported in a twin study would suggest that complex genetics plays a large role [ • A study of heritability in the Irish population reported that genetic factors account for nearly 40% of the variation in risk for developing ALS in individuals who did not have disease-causing variants in known ALS genes [ • Variants in several genes have been identified as modifiers of disease onset or course: • 31 or more polyQ repeats in • Variants in several other genes have been shown to reduce risk for ALS, including variants in • 31 or more polyQ repeats in • Variants in several other genes have been shown to reduce risk for ALS, including variants in • Statistical analysis of more than 6,000 European cases of ALS suggests that the disease may develop as the result of a series of six "steps" – some genetic and some environmental – that occur over time [ • 31 or more polyQ repeats in • Variants in several other genes have been shown to reduce risk for ALS, including variants in ## Evaluation Strategies to Identify the Genetic Cause of ALS in a Proband Establishing a specific genetic cause of ALS: Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. For an introduction to multigene panels click If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. • For an introduction to multigene panels click • If exome sequencing is not diagnostic, • For an introduction to comprehensive genomic testing click ## Management of ALS Treatment is palliative. Many individuals benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetic counselor. Data suggest that individuals under the care of such a team may have a better prognosis [ The following three drugs are currently approved by the FDA for treatment of ALS: See ClinicalTrials.gov study A Phase III study is under way to determine whether tofersen use may delay onset of manifestations in Oral secretions in individuals with bulbar symptoms can be reduced with tricylic antidepressants and anticholinergic agents, thus reducing the need for suctioning. Pseudobulbar affect can be managed with antidepressants such as Nuedexta Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration. Nutritional management, a prognostic factor for survival, has become a focus in the clinical setting. Medications such as baclofen and benzodiazepines can help relieve spasticity and muscle cramps; however, weakness and lethargy are common side effects. Individualized moderate-intensity endurance-type exercises for the trunk and limbs may help to reduce spasticity [ Low-tech (e.g., alphabet board) and high-tech (i.e., computer-assisted) devices can aid speech and communication. The recent development of the eye movement-controlled on-screen keyboard may enable communication for individuals without any remaining limb function. Assistive devices, such as walkers or wheelchairs, can aid mobility; and others, such as bathroom installments, hospital bed, and Hoyer lift, can aid in activities of daily living at home. Ventilatory assistance may include use of bilevel positive airway pressure, which has played an increasing role in preserving and prolonging quality of life in persons with ALS. In 1999, the American Academy of Neurology published norms recommending the initiation of noninvasive ventilation (NIV) in individuals with a theoretic forced vital capacity (FVC) less than 50% of predicted [ Although tracheostomy and ventilatory support can extend life span, affected individuals often decline these interventions [ The tremendous psychological and social impact of ALS on both affected individuals and caregivers needs to be continually addressed [ Individuals with ALS commonly supplement their diets with vitamin E, vitamin C, B vitamins, selenium, zinc, coenzyme Q • See ClinicalTrials.gov study • A Phase III study is under way to determine whether tofersen use may delay onset of manifestations in ## Symptom Management Oral secretions in individuals with bulbar symptoms can be reduced with tricylic antidepressants and anticholinergic agents, thus reducing the need for suctioning. Pseudobulbar affect can be managed with antidepressants such as Nuedexta Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration. Nutritional management, a prognostic factor for survival, has become a focus in the clinical setting. Medications such as baclofen and benzodiazepines can help relieve spasticity and muscle cramps; however, weakness and lethargy are common side effects. Individualized moderate-intensity endurance-type exercises for the trunk and limbs may help to reduce spasticity [ Low-tech (e.g., alphabet board) and high-tech (i.e., computer-assisted) devices can aid speech and communication. The recent development of the eye movement-controlled on-screen keyboard may enable communication for individuals without any remaining limb function. Assistive devices, such as walkers or wheelchairs, can aid mobility; and others, such as bathroom installments, hospital bed, and Hoyer lift, can aid in activities of daily living at home. Ventilatory assistance may include use of bilevel positive airway pressure, which has played an increasing role in preserving and prolonging quality of life in persons with ALS. In 1999, the American Academy of Neurology published norms recommending the initiation of noninvasive ventilation (NIV) in individuals with a theoretic forced vital capacity (FVC) less than 50% of predicted [ Although tracheostomy and ventilatory support can extend life span, affected individuals often decline these interventions [ The tremendous psychological and social impact of ALS on both affected individuals and caregivers needs to be continually addressed [ Individuals with ALS commonly supplement their diets with vitamin E, vitamin C, B vitamins, selenium, zinc, coenzyme Q ## Genetic Counseling Genetic counseling for individuals with amyotrophic lateral sclerosis (ALS) and their families is reviewed for the following clinical contexts: Most individuals diagnosed with autosomal dominant ALS have an affected parent. A proband with adult-onset ALS may have the disorder as the result of a 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 ALS may appear to be negative because of failure to recognize it or another disorder (e.g., FTD, Paget disease of bone) caused by the same disease variant in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. If the proband has a known ALS-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 ALS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ALS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism [ The parents of an individual diagnosed with autosomal recessive ALS are obligate heterozygotes (i.e., carriers of one ALS-related pathogenic variant). Heterozygotes are asymptomatic and are not at risk of developing the disorder. At conception, each sib has a 25% chance of inheriting two copies of the disease-causing genetic variant and later developing the disease, a 50% chance of inheriting one copy of the disease-causing variant (i.e., being a carrier), and a 25% chance of inheriting two copies of the gene without the disease-causing variant so that the sib is neither affected nor a carrier. Heterozygotes remain asymptomatic, but with each of their children they have a 50% chance of passing on the disease-causing variant. To date, A male proband may have inherited the A female proband may have inherited the The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has the The risk to sibs of a female proband depends on the genetic status of the parents. If the mother of the proband has a Male and female offspring who inherit a Even if the mode of inheritance cannot be firmly established, the risk of inheriting the disease-causing variant is likely to follow an autosomal dominant pattern, given what is known to date about genetic ALS. However, it is also quite likely that the penetrance of some variants may be reduced, making it more difficult to predict which persons will go on to develop disease. Given what is known about ALS-related genes, when FTD or Paget disease is present in the family (even if not manifest in the proband), it is reasonable to assume that those individuals are also heterozygous for the variant identified in the person with ALS and, thus, have the same genetic risk of passing the variant on to their children. Most ALS disease-causing variants identified to date have at least some intrafamilial variability in terms of age of onset, site of onset, and disease duration. As noted in Predictive testing for at-risk relatives is possible once the ALS-related pathogenic variant(s) have been identified in an affected family member. Potential consequences of such testing (including, but not limited to, socioeconomic changes, 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 ALS, it is appropriate to consider testing of symptomatic individuals regardless of age. • Most individuals diagnosed with autosomal dominant ALS have an affected parent. • A proband with adult-onset ALS may have the disorder as the result of a • 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 ALS may appear to be negative because of failure to recognize it or another disorder (e.g., FTD, Paget disease of bone) caused by the same disease variant in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. • If the proband has a known ALS-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 ALS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ALS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism [ • The parents of an individual diagnosed with autosomal recessive ALS are obligate heterozygotes (i.e., carriers of one ALS-related pathogenic variant). • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • At conception, each sib has a 25% chance of inheriting two copies of the disease-causing genetic variant and later developing the disease, a 50% chance of inheriting one copy of the disease-causing variant (i.e., being a carrier), and a 25% chance of inheriting two copies of the gene without the disease-causing variant so that the sib is neither affected nor a carrier. • Heterozygotes remain asymptomatic, but with each of their children they have a 50% chance of passing on the disease-causing variant. • A male proband may have inherited the • A female proband may have inherited the • The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has the • The risk to sibs of a female proband depends on the genetic status of the parents. If the mother of the proband has a • Male and female offspring who inherit a • Predictive testing for at-risk relatives is possible once the ALS-related pathogenic variant(s) have been identified in an affected family member. • Potential consequences of such testing (including, but not limited to, socioeconomic changes, 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 ## Genetic ALS Most individuals diagnosed with autosomal dominant ALS have an affected parent. A proband with adult-onset ALS may have the disorder as the result of a 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 ALS may appear to be negative because of failure to recognize it or another disorder (e.g., FTD, Paget disease of bone) caused by the same disease variant in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. If the proband has a known ALS-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 ALS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ALS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism [ The parents of an individual diagnosed with autosomal recessive ALS are obligate heterozygotes (i.e., carriers of one ALS-related pathogenic variant). Heterozygotes are asymptomatic and are not at risk of developing the disorder. At conception, each sib has a 25% chance of inheriting two copies of the disease-causing genetic variant and later developing the disease, a 50% chance of inheriting one copy of the disease-causing variant (i.e., being a carrier), and a 25% chance of inheriting two copies of the gene without the disease-causing variant so that the sib is neither affected nor a carrier. Heterozygotes remain asymptomatic, but with each of their children they have a 50% chance of passing on the disease-causing variant. To date, A male proband may have inherited the A female proband may have inherited the The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has the The risk to sibs of a female proband depends on the genetic status of the parents. If the mother of the proband has a Male and female offspring who inherit a • Most individuals diagnosed with autosomal dominant ALS have an affected parent. • A proband with adult-onset ALS may have the disorder as the result of a • 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 ALS may appear to be negative because of failure to recognize it or another disorder (e.g., FTD, Paget disease of bone) caused by the same disease variant in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. • If the proband has a known ALS-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 ALS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ALS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism [ • The parents of an individual diagnosed with autosomal recessive ALS are obligate heterozygotes (i.e., carriers of one ALS-related pathogenic variant). • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • At conception, each sib has a 25% chance of inheriting two copies of the disease-causing genetic variant and later developing the disease, a 50% chance of inheriting one copy of the disease-causing variant (i.e., being a carrier), and a 25% chance of inheriting two copies of the gene without the disease-causing variant so that the sib is neither affected nor a carrier. • Heterozygotes remain asymptomatic, but with each of their children they have a 50% chance of passing on the disease-causing variant. • A male proband may have inherited the • A female proband may have inherited the • The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has the • The risk to sibs of a female proband depends on the genetic status of the parents. If the mother of the proband has a • Male and female offspring who inherit a ## Mode of Inheritance ## Autosomal Dominant ALS – Risk to Family Members Most individuals diagnosed with autosomal dominant ALS have an affected parent. A proband with adult-onset ALS may have the disorder as the result of a 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 ALS may appear to be negative because of failure to recognize it or another disorder (e.g., FTD, Paget disease of bone) caused by the same disease variant in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. If the proband has a known ALS-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 ALS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ALS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism [ • Most individuals diagnosed with autosomal dominant ALS have an affected parent. • A proband with adult-onset ALS may have the disorder as the result of a • 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 ALS may appear to be negative because of failure to recognize it or another disorder (e.g., FTD, Paget disease of bone) caused by the same disease variant in family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. • If the proband has a known ALS-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 ALS-related pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for ALS because of the possibility of reduced penetrance in a parent or the theoretic possibility of parental germline mosaicism [ ## Autosomal Recessive ALS – Risk to Family Members The parents of an individual diagnosed with autosomal recessive ALS are obligate heterozygotes (i.e., carriers of one ALS-related pathogenic variant). Heterozygotes are asymptomatic and are not at risk of developing the disorder. At conception, each sib has a 25% chance of inheriting two copies of the disease-causing genetic variant and later developing the disease, a 50% chance of inheriting one copy of the disease-causing variant (i.e., being a carrier), and a 25% chance of inheriting two copies of the gene without the disease-causing variant so that the sib is neither affected nor a carrier. Heterozygotes remain asymptomatic, but with each of their children they have a 50% chance of passing on the disease-causing variant. • The parents of an individual diagnosed with autosomal recessive ALS are obligate heterozygotes (i.e., carriers of one ALS-related pathogenic variant). • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • At conception, each sib has a 25% chance of inheriting two copies of the disease-causing genetic variant and later developing the disease, a 50% chance of inheriting one copy of the disease-causing variant (i.e., being a carrier), and a 25% chance of inheriting two copies of the gene without the disease-causing variant so that the sib is neither affected nor a carrier. • Heterozygotes remain asymptomatic, but with each of their children they have a 50% chance of passing on the disease-causing variant. ## X-Linked ALS – Risk to Family Members To date, A male proband may have inherited the A female proband may have inherited the The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has the The risk to sibs of a female proband depends on the genetic status of the parents. If the mother of the proband has a Male and female offspring who inherit a • A male proband may have inherited the • A female proband may have inherited the • The risk to sibs of a male proband depends on the genetic status of the mother: if the mother of the proband has the • The risk to sibs of a female proband depends on the genetic status of the parents. If the mother of the proband has a • Male and female offspring who inherit a ## ALS of Unknown Cause Even if the mode of inheritance cannot be firmly established, the risk of inheriting the disease-causing variant is likely to follow an autosomal dominant pattern, given what is known to date about genetic ALS. However, it is also quite likely that the penetrance of some variants may be reduced, making it more difficult to predict which persons will go on to develop disease. Given what is known about ALS-related genes, when FTD or Paget disease is present in the family (even if not manifest in the proband), it is reasonable to assume that those individuals are also heterozygous for the variant identified in the person with ALS and, thus, have the same genetic risk of passing the variant on to their children. Most ALS disease-causing variants identified to date have at least some intrafamilial variability in terms of age of onset, site of onset, and disease duration. As noted in ## Related Genetic Counseling Issues Predictive testing for at-risk relatives is possible once the ALS-related pathogenic variant(s) have been identified in an affected family member. Potential consequences of such testing (including, but not limited to, socioeconomic changes, 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 ALS, it is appropriate to consider testing of symptomatic individuals regardless of age. • Predictive testing for at-risk relatives is possible once the ALS-related pathogenic variant(s) have been identified in an affected family member. • Potential consequences of such testing (including, but not limited to, socioeconomic changes, 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 ## Resources Canada United Kingdom Agency for Toxic Substances and Disease Registry 4770 Buford Highway Northeast Atlanta GA 30341 • • • • Canada • • • • • • • • • • • • • United Kingdom • • • Agency for Toxic Substances and Disease Registry • 4770 Buford Highway Northeast • Atlanta GA 30341 • ## Chapter Notes Lisa Dellefave, MS, CGC; University of Chicago (2000-2009)Sandra Donkervoort, MS, CGC; Northwestern University Feinberg School of Medicine (2009-2012)Mara Gaudette, MS; Northwestern University Medical School (2000-2006)Lisa Kinsley, MS, CGC; Northwestern University Feinberg School of Medicine (2012-2019)Nailah Siddique, RN, MSN (2019-present)Teepu Siddique, MD (2000-present) 28 September 2023 (aa) Revision: FDA approval of antisense oligonucleotide therapy tofersen (Qalsody 30 September 2021 (aa) Revision: mutation of 3 October 2019 (bp) Comprehensive update posted live 31 May 2012 (me) Comprehensive update posted live 28 July 2009 (me) Comprehensive update posted live 23 June 2006 (ca) Comprehensive update posted live 26 February 2004 (me) Comprehensive update posted live 23 March 2001 (tk) Overview posted live August 2000 (mg) Original submission • 28 September 2023 (aa) Revision: FDA approval of antisense oligonucleotide therapy tofersen (Qalsody • 30 September 2021 (aa) Revision: mutation of • 3 October 2019 (bp) Comprehensive update posted live • 31 May 2012 (me) Comprehensive update posted live • 28 July 2009 (me) Comprehensive update posted live • 23 June 2006 (ca) Comprehensive update posted live • 26 February 2004 (me) Comprehensive update posted live • 23 March 2001 (tk) Overview posted live • August 2000 (mg) Original submission ## Author History Lisa Dellefave, MS, CGC; University of Chicago (2000-2009)Sandra Donkervoort, MS, CGC; Northwestern University Feinberg School of Medicine (2009-2012)Mara Gaudette, MS; Northwestern University Medical School (2000-2006)Lisa Kinsley, MS, CGC; Northwestern University Feinberg School of Medicine (2012-2019)Nailah Siddique, RN, MSN (2019-present)Teepu Siddique, MD (2000-present) ## Revision History 28 September 2023 (aa) Revision: FDA approval of antisense oligonucleotide therapy tofersen (Qalsody 30 September 2021 (aa) Revision: mutation of 3 October 2019 (bp) Comprehensive update posted live 31 May 2012 (me) Comprehensive update posted live 28 July 2009 (me) Comprehensive update posted live 23 June 2006 (ca) Comprehensive update posted live 26 February 2004 (me) Comprehensive update posted live 23 March 2001 (tk) Overview posted live August 2000 (mg) Original submission • 28 September 2023 (aa) Revision: FDA approval of antisense oligonucleotide therapy tofersen (Qalsody • 30 September 2021 (aa) Revision: mutation of • 3 October 2019 (bp) Comprehensive update posted live • 31 May 2012 (me) Comprehensive update posted live • 28 July 2009 (me) Comprehensive update posted live • 23 June 2006 (ca) Comprehensive update posted live • 26 February 2004 (me) Comprehensive update posted live • 23 March 2001 (tk) Overview posted live • August 2000 (mg) 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 ## Suggested Reading	[]	23/3/2001	3/10/2019	28/9/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alstrom	alstrom	[ "Centrosome-associated protein ALMS1", "ALMS1", "Alstrom Syndrome" ]	Alström Syndrome	Richard B Paisey, Rick Steeds, Tim Barrett, Denise Williams, Tarekegn Geberhiwot, Meral Gunay-Aygun	Summary Alström syndrome is characterized by cone-rod dystrophy, obesity, progressive bilateral sensorineural hearing impairment, acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy, insulin resistance / type 2 diabetes mellitus (T2DM), nonalcoholic fatty liver disease (NAFLD), and chronic progressive kidney disease. Cone-rod dystrophy presents as progressive visual impairment, photophobia, and nystagmus usually starting between birth and age 15 months. Many individuals lose all perception of light by the end of the second decade, but a minority retain the ability to read large print into the third decade. Children usually have normal birth weight but develop truncal obesity during their first year. Sensorineural hearing loss presents in the first decade in as many as 70% of individuals and may progress to the severe or moderately severe range (40-70 db) by the end of the first to second decade. Insulin resistance is typically accompanied by the skin changes of acanthosis nigricans, and proceeds to T2DM in the majority by the third decade. Nearly all demonstrate hypertriglyceridemia. Other findings can include endocrine abnormalities (hypothyroidism, hypogonadotropic hypogonadism in males, and hyperandrogenism in females), urologic dysfunction / detrusor instability, progressive decrease in renal function, and hepatic disease (ranging from elevated transaminases to steatohepatitis/NAFLD). Approximately 20% of affected individuals have delay in early developmental milestones, most commonly in gross and fine motor skills. About 30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Wide clinical variability is observed among affected individuals, even within the same family. The clinical diagnosis of Alström syndrome is based on cardinal clinical features that emerge throughout infancy, childhood, and young adulthood. The molecular diagnosis of Alström syndrome is established in individuals of all ages by identification of biallelic pathogenic variants in Alström syndrome is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. When the	## Diagnosis Alström syndrome Cone-rod dystrophy with decreased vision and secondary nystagmus and photodysphoria (light sensitivity / photophobia) usually within the first year of life. Full-field electroretinography, required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. Early childhood-onset obesity, primarily truncal with a body mass index (BMI: kg/m Progressive bilateral sensorineural hearing impairment (initially in the high-frequency range), usually diagnosed between ages one and ten years, although onset can vary Acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy Insulin resistance / type 2 diabetes mellitus (T2DM), the result of tissue resistance to the actions of insulin, usually present in childhood and manifest as elevated plasma insulin concentration and glucose intolerance. Insulin resistance ranges from hyperinsulinemia to glucose intolerance to T2DM, depending on the age of the individual. T2DM can develop in childhood or adolescence. Normal stature in childhood; short stature in adulthood Hypogonadism, non-autoimmune hypothyroidism, and female hyperandrogenism Urologic dysfunction / detrusor instability Progressive decrease in renal function Hepatic disease that is variable and ranges from elevated transaminases to steatohepatitis / nonalcoholic fatty liver disease (NAFLD). The liver and spleen may be enlarged. Extensive fibrosis, cirrhosis, portal hypertension, and liver failure have been described. Hypertriglyceridemia Hypertension Gradual thickening of subcutaneous tissues (e.g., thick ears) Alopecia Alström Syndrome Diagnostic Criteria by Age 1 Nystagmus / photophobia / impaired vision Infantile cardiomyopathy Obesity SNHL 1 Nystagmus / photophobia / impaired vision (if old enough for testing: cone dystrophy by ERG) History of infantile cardiomyopathy SNHL Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) Restrictive cardiomyopathy ↓ renal function 1 Vision (history of nystagmus in infancy/childhood, impaired vision, legal blindness, cone & rod dystrophy by ERG) SNHL Restrictive cardiomyopathy &/OR history of infantile cardiomyopathy Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) CKD Stage ≥III Adapted from CKD = chronic kidney disease; ERG = electroretinogram; SNHL = sensorineural hearing loss; T2DM = type 2 diabetes mellitus Children in these age groups should be reevaluated for the presence of major and minor criteria as they age. 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 Alström syndrome is broad, individuals with the distinctive findings described in For an introduction to multigene panels click When the diagnosis of Alström syndrome is not considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, For introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alström Syndrome See See Because approximately 10% of families with Alström syndrome have no identified Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The following have been reported: a gross deletion [ • Cone-rod dystrophy with decreased vision and secondary nystagmus and photodysphoria (light sensitivity / photophobia) usually within the first year of life. Full-field electroretinography, required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. • Early childhood-onset obesity, primarily truncal with a body mass index (BMI: kg/m • Progressive bilateral sensorineural hearing impairment (initially in the high-frequency range), usually diagnosed between ages one and ten years, although onset can vary • Acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy • Insulin resistance / type 2 diabetes mellitus (T2DM), the result of tissue resistance to the actions of insulin, usually present in childhood and manifest as elevated plasma insulin concentration and glucose intolerance. Insulin resistance ranges from hyperinsulinemia to glucose intolerance to T2DM, depending on the age of the individual. T2DM can develop in childhood or adolescence. • Normal stature in childhood; short stature in adulthood • Hypogonadism, non-autoimmune hypothyroidism, and female hyperandrogenism • Urologic dysfunction / detrusor instability • Progressive decrease in renal function • Hepatic disease that is variable and ranges from elevated transaminases to steatohepatitis / nonalcoholic fatty liver disease (NAFLD). The liver and spleen may be enlarged. Extensive fibrosis, cirrhosis, portal hypertension, and liver failure have been described. • Hypertriglyceridemia • Hypertension • Gradual thickening of subcutaneous tissues (e.g., thick ears) • Alopecia • 1 • Nystagmus / photophobia / impaired vision • Infantile cardiomyopathy • Obesity • SNHL • 1 • Nystagmus / photophobia / impaired vision (if old enough for testing: cone dystrophy by ERG) • History of infantile cardiomyopathy • SNHL • Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) • Restrictive cardiomyopathy • ↓ renal function • 1 • Vision (history of nystagmus in infancy/childhood, impaired vision, legal blindness, cone & rod dystrophy by ERG) • SNHL • Restrictive cardiomyopathy &/OR history of infantile cardiomyopathy • Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) • CKD Stage ≥III ## Suggestive Findings Alström syndrome Cone-rod dystrophy with decreased vision and secondary nystagmus and photodysphoria (light sensitivity / photophobia) usually within the first year of life. Full-field electroretinography, required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. Early childhood-onset obesity, primarily truncal with a body mass index (BMI: kg/m Progressive bilateral sensorineural hearing impairment (initially in the high-frequency range), usually diagnosed between ages one and ten years, although onset can vary Acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy Insulin resistance / type 2 diabetes mellitus (T2DM), the result of tissue resistance to the actions of insulin, usually present in childhood and manifest as elevated plasma insulin concentration and glucose intolerance. Insulin resistance ranges from hyperinsulinemia to glucose intolerance to T2DM, depending on the age of the individual. T2DM can develop in childhood or adolescence. Normal stature in childhood; short stature in adulthood Hypogonadism, non-autoimmune hypothyroidism, and female hyperandrogenism Urologic dysfunction / detrusor instability Progressive decrease in renal function Hepatic disease that is variable and ranges from elevated transaminases to steatohepatitis / nonalcoholic fatty liver disease (NAFLD). The liver and spleen may be enlarged. Extensive fibrosis, cirrhosis, portal hypertension, and liver failure have been described. Hypertriglyceridemia Hypertension Gradual thickening of subcutaneous tissues (e.g., thick ears) Alopecia • Cone-rod dystrophy with decreased vision and secondary nystagmus and photodysphoria (light sensitivity / photophobia) usually within the first year of life. Full-field electroretinography, required to establish the diagnosis of cone-rod dystrophy, is abnormal from birth, eventually with impairment of both cone and rod function. Fundus examination in the first decade may be normal or may show a pale optic disc and narrowing of the retinal vessels. • Early childhood-onset obesity, primarily truncal with a body mass index (BMI: kg/m • Progressive bilateral sensorineural hearing impairment (initially in the high-frequency range), usually diagnosed between ages one and ten years, although onset can vary • Acute infantile-onset cardiomyopathy and/or adolescent- or adult-onset restrictive cardiomyopathy • Insulin resistance / type 2 diabetes mellitus (T2DM), the result of tissue resistance to the actions of insulin, usually present in childhood and manifest as elevated plasma insulin concentration and glucose intolerance. Insulin resistance ranges from hyperinsulinemia to glucose intolerance to T2DM, depending on the age of the individual. T2DM can develop in childhood or adolescence. • Normal stature in childhood; short stature in adulthood • Hypogonadism, non-autoimmune hypothyroidism, and female hyperandrogenism • Urologic dysfunction / detrusor instability • Progressive decrease in renal function • Hepatic disease that is variable and ranges from elevated transaminases to steatohepatitis / nonalcoholic fatty liver disease (NAFLD). The liver and spleen may be enlarged. Extensive fibrosis, cirrhosis, portal hypertension, and liver failure have been described. • Hypertriglyceridemia • Hypertension • Gradual thickening of subcutaneous tissues (e.g., thick ears) • Alopecia ## Establishing the Diagnosis Alström Syndrome Diagnostic Criteria by Age 1 Nystagmus / photophobia / impaired vision Infantile cardiomyopathy Obesity SNHL 1 Nystagmus / photophobia / impaired vision (if old enough for testing: cone dystrophy by ERG) History of infantile cardiomyopathy SNHL Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) Restrictive cardiomyopathy ↓ renal function 1 Vision (history of nystagmus in infancy/childhood, impaired vision, legal blindness, cone & rod dystrophy by ERG) SNHL Restrictive cardiomyopathy &/OR history of infantile cardiomyopathy Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) CKD Stage ≥III Adapted from CKD = chronic kidney disease; ERG = electroretinogram; SNHL = sensorineural hearing loss; T2DM = type 2 diabetes mellitus Children in these age groups should be reevaluated for the presence of major and minor criteria as they age. 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 Alström syndrome is broad, individuals with the distinctive findings described in For an introduction to multigene panels click When the diagnosis of Alström syndrome is not considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, For introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alström Syndrome See See Because approximately 10% of families with Alström syndrome have no identified Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The following have been reported: a gross deletion [ • 1 • Nystagmus / photophobia / impaired vision • Infantile cardiomyopathy • Obesity • SNHL • 1 • Nystagmus / photophobia / impaired vision (if old enough for testing: cone dystrophy by ERG) • History of infantile cardiomyopathy • SNHL • Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) • Restrictive cardiomyopathy • ↓ renal function • 1 • Vision (history of nystagmus in infancy/childhood, impaired vision, legal blindness, cone & rod dystrophy by ERG) • SNHL • Restrictive cardiomyopathy &/OR history of infantile cardiomyopathy • Obesity &/OR its complications (e.g., insulin resistance, T2DM, liver steatosis, hypertriglyceridemia) • CKD Stage ≥III ## Option 1 For an introduction to multigene panels click ## Option 2 When the diagnosis of Alström syndrome is not considered because an individual has atypical phenotypic features, If exome sequencing is not diagnostic, For introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Alström Syndrome See See Because approximately 10% of families with Alström syndrome have no identified Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. The following have been reported: a gross deletion [ ## Clinical Characteristics The first clinical manifestation of Alström syndrome ( Age of Onset and Incidence of Common Features of Alström Syndrome Based on a study of 182 patients by SNHL = sensorineural hearing loss; T2DM = type 2 diabetes mellitus Given the age-dependent nature of many features of Alström syndrome, percentages are not exact and may be underestimates. Rare individuals with atypical later onset and milder retinal dystrophy are reported. The proportion of infants with Alström syndrome who develop infantile-onset cardiomyopathy is probably underestimated because some infants succumb to heart failure before the diagnosis of Alström syndrome is made. Optical coherence tomography (OCT) reveals central macular changes that are mild during early childhood but slowly progress, resulting in loss of photoreceptors and retinal pigment epithelium. Severe retinal wrinkling, intraretinal opacities, foveal contour abnormalities, optic nerve drusen, vitreoretinal separation, and hyperreflectivities in all retinal layers are observed. The severity of the macular changes on OCT correlates with vision [ In 33 individuals with Alström syndrome, the average rate of progression of hearing loss was 10-15 db/decade [ A high incidence of adhesive otitis media (glue ear) due to long-standing fluid in the middle ear can lead to an additional conductive hearing loss [ More than 40% of infants with Alström syndrome present with a transient but severe cardiomyopathy with onset between ages three weeks and four months [ About 20% of individuals with Alström syndrome develop a later-onset progressive restrictive cardiomyopathy identified between the teens and late 30s. A characteristic feature of these individuals appears to be myocardial fibrosis documented at postmortem [ Flow-limiting coronary artery disease occurs in approximately 10% but does not appear to be related to progression of myocardial fibrosis. In a small study of 12 unrelated individuals with Alström syndrome, obesity (BMI and waist circumference) decreased with age, whereas insulin resistance increased with age [ Coronary artery disease as a result of insulin resistance, diabetes, dyslipidemia, and renal failure was reported in one affected individual [ Diabetic peripheral neuropathy with risk of foot ulceration occurs rarely if at all in Alström syndrome [ Fertility in females has not been systematically studied. Although a molecular diagnosis was not confirmed, one clinical report describes two unrelated females with late presentation of the syndrome, each of whom had healthy children [ Renal ultrasonography and MRI may reveal abnormalities [ Renal biopsy often shows interstitial fibrosis, glomerular hyalinosis, and tubular atrophy but absence of histopathologic features of diabetic or reflux nephropathy [ Obstructive uropathy is rare. Liver biopsies and postmortem examination have revealed varying degrees of steatohepatitis, hepatic fibrosis, cirrhosis, chronic nonspecific active hepatitis with lymphocytic infiltration, and patchy necrosis [ A study of the burden of otosinopulmonary disease in 38 individuals with Alström syndrome revealed that recurrent otitis media was ubiquitous (92%), with 50% requiring pressure-equalization tube placement [ Scoliosis and kyphosis of varying severity (30%-70%) [ Severe flat feet ( Dental abnormalities Hypothyroidism (20%-30%) [ Hypertension, often beginning in childhood (30%) Delay in early developmental milestones in ~20% of affected individuals, most commonly in gross and fine motor skills; ~30% have a learning disability. Cognitive impairment (IQ <70) is very rare. Genotype-phenotype correlations are challenging because almost all The prevalence of Alström syndrome is difficult to estimate; it is possible that individuals with attenuated forms of Alström syndrome may be underdiagnosed [ About 950 individuals diagnosed with Alström syndrome have been identified worldwide ( Ethnically or geographically isolated populations have a higher-than-average frequency of Alström syndrome [ • Scoliosis and kyphosis of varying severity (30%-70%) [ • Severe flat feet ( • Dental abnormalities • Hypothyroidism (20%-30%) [ • Hypertension, often beginning in childhood (30%) • Delay in early developmental milestones in ~20% of affected individuals, most commonly in gross and fine motor skills; ~30% have a learning disability. Cognitive impairment (IQ <70) is very rare. ## Clinical Description The first clinical manifestation of Alström syndrome ( Age of Onset and Incidence of Common Features of Alström Syndrome Based on a study of 182 patients by SNHL = sensorineural hearing loss; T2DM = type 2 diabetes mellitus Given the age-dependent nature of many features of Alström syndrome, percentages are not exact and may be underestimates. Rare individuals with atypical later onset and milder retinal dystrophy are reported. The proportion of infants with Alström syndrome who develop infantile-onset cardiomyopathy is probably underestimated because some infants succumb to heart failure before the diagnosis of Alström syndrome is made. Optical coherence tomography (OCT) reveals central macular changes that are mild during early childhood but slowly progress, resulting in loss of photoreceptors and retinal pigment epithelium. Severe retinal wrinkling, intraretinal opacities, foveal contour abnormalities, optic nerve drusen, vitreoretinal separation, and hyperreflectivities in all retinal layers are observed. The severity of the macular changes on OCT correlates with vision [ In 33 individuals with Alström syndrome, the average rate of progression of hearing loss was 10-15 db/decade [ A high incidence of adhesive otitis media (glue ear) due to long-standing fluid in the middle ear can lead to an additional conductive hearing loss [ More than 40% of infants with Alström syndrome present with a transient but severe cardiomyopathy with onset between ages three weeks and four months [ About 20% of individuals with Alström syndrome develop a later-onset progressive restrictive cardiomyopathy identified between the teens and late 30s. A characteristic feature of these individuals appears to be myocardial fibrosis documented at postmortem [ Flow-limiting coronary artery disease occurs in approximately 10% but does not appear to be related to progression of myocardial fibrosis. In a small study of 12 unrelated individuals with Alström syndrome, obesity (BMI and waist circumference) decreased with age, whereas insulin resistance increased with age [ Coronary artery disease as a result of insulin resistance, diabetes, dyslipidemia, and renal failure was reported in one affected individual [ Diabetic peripheral neuropathy with risk of foot ulceration occurs rarely if at all in Alström syndrome [ Fertility in females has not been systematically studied. Although a molecular diagnosis was not confirmed, one clinical report describes two unrelated females with late presentation of the syndrome, each of whom had healthy children [ Renal ultrasonography and MRI may reveal abnormalities [ Renal biopsy often shows interstitial fibrosis, glomerular hyalinosis, and tubular atrophy but absence of histopathologic features of diabetic or reflux nephropathy [ Obstructive uropathy is rare. Liver biopsies and postmortem examination have revealed varying degrees of steatohepatitis, hepatic fibrosis, cirrhosis, chronic nonspecific active hepatitis with lymphocytic infiltration, and patchy necrosis [ A study of the burden of otosinopulmonary disease in 38 individuals with Alström syndrome revealed that recurrent otitis media was ubiquitous (92%), with 50% requiring pressure-equalization tube placement [ Scoliosis and kyphosis of varying severity (30%-70%) [ Severe flat feet ( Dental abnormalities Hypothyroidism (20%-30%) [ Hypertension, often beginning in childhood (30%) Delay in early developmental milestones in ~20% of affected individuals, most commonly in gross and fine motor skills; ~30% have a learning disability. Cognitive impairment (IQ <70) is very rare. • Scoliosis and kyphosis of varying severity (30%-70%) [ • Severe flat feet ( • Dental abnormalities • Hypothyroidism (20%-30%) [ • Hypertension, often beginning in childhood (30%) • Delay in early developmental milestones in ~20% of affected individuals, most commonly in gross and fine motor skills; ~30% have a learning disability. Cognitive impairment (IQ <70) is very rare. ## Genotype-Phenotype Correlations Genotype-phenotype correlations are challenging because almost all ## Prevalence The prevalence of Alström syndrome is difficult to estimate; it is possible that individuals with attenuated forms of Alström syndrome may be underdiagnosed [ About 950 individuals diagnosed with Alström syndrome have been identified worldwide ( Ethnically or geographically isolated populations have a higher-than-average frequency of Alström syndrome [ ## Genetically Related (Allelic) Disorders Currently no phenotypes other than Alström syndrome are known to be caused by biallelic ## Differential Diagnosis Polydactyly, cognitive impairment, and structural heart and genitourinary defects are not typical in Alström syndrome; these features should prompt evaluation for alternative diagnosis such as Bardet-Biedl syndrome (see Disorders to Consider in the Differential Diagnosis of Alström Syndrome Rod-cone dystrophy Central obesity Hypogonadism Renal dysfunction Older mean age of onset of visual problems in BBS (8.5 yrs in BBS vs birth - 2 yrs in AS) Polydactyly is common in BBS (not described in AS). Cognitive impairment is common in BBS (normal intelligence in most persons w/AS). Hearing problems are infrequent (~5%) in BBS. Diabetes mellitus is less frequent (5%-10%) in BBS. Infantile nystagmus Photophobia Severely ↓ visual acuity Poor or no color discrimination Only the retina is affected in ACH. Common in ACH; not reported in AS: central outer retinal atrophy/cavitation Common in AS; less common in ACH: retention of central inner retinal layers (foveal immaturity) Cardiomyopathy, obesity, SNHL, T2DM, liver disease, & renal dysfunction Retinal degeneration ↓ visual acuity Onset typically in 1st yr of life Nystagmus Photophobia Absence of other organ system involvement in LCA/EOSRD Characteristic oculo-digital sign (repeated eye rubbing, poking, & pressing of eyes) in LCA/EOSRD Dilated cardiomyopathy Renal dysfunction (in syndromic forms due to mt defect) Cardiomyopathy Sensorineural deafness Optic atrophy Pigmentary retinopathy Diabetes mellitus CNS involvement & muscle weakness may occur in mt disorders (not reported in AS). Late-childhood or adulthood presentation in mt disorders (vs AS, which usually presents in 1st yr of life) AD = autosomal dominant; AR = autosomal recessive; AS = Alström syndrome; MOI = mode of inheritance; Mat = maternal; mt = mitochondrial; SNHL = sensorineural hearing loss At least 21 genes are associated with BBS: In some families, pathogenic variants in more than one BBS-related gene may result in a clinical phenotype of BBS. However, such families are difficult to identify and by previous estimations may account for less than 10% of all BBS. To date, variants in 24 genes account for 70%-80% of individuals with LCA/EOSRD (see Mitochondrial disorders are a heterogeneous group of complex disorders that may be caused by pathogenic variants in mitochondrial DNA or nuclear DNA (see • Rod-cone dystrophy • Central obesity • Hypogonadism • Renal dysfunction • Older mean age of onset of visual problems in BBS (8.5 yrs in BBS vs birth - 2 yrs in AS) • Polydactyly is common in BBS (not described in AS). • Cognitive impairment is common in BBS (normal intelligence in most persons w/AS). • Hearing problems are infrequent (~5%) in BBS. • Diabetes mellitus is less frequent (5%-10%) in BBS. • Infantile nystagmus • Photophobia • Severely ↓ visual acuity • Poor or no color discrimination • Only the retina is affected in ACH. • Common in ACH; not reported in AS: central outer retinal atrophy/cavitation • Common in AS; less common in ACH: retention of central inner retinal layers (foveal immaturity) • Cardiomyopathy, obesity, SNHL, T2DM, liver disease, & renal dysfunction • Retinal degeneration • ↓ visual acuity • Onset typically in 1st yr of life • Nystagmus • Photophobia • Absence of other organ system involvement in LCA/EOSRD • Characteristic oculo-digital sign (repeated eye rubbing, poking, & pressing of eyes) in LCA/EOSRD • Dilated cardiomyopathy • Renal dysfunction (in syndromic forms due to mt defect) • Cardiomyopathy • Sensorineural deafness • Optic atrophy • Pigmentary retinopathy • Diabetes mellitus • CNS involvement & muscle weakness may occur in mt disorders (not reported in AS). • Late-childhood or adulthood presentation in mt disorders (vs AS, which usually presents in 1st yr of life) ## Management To establish the extent of disease and needs in an individual diagnosed with Alström syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Alström Syndrome Measure height, weight, head & waist circumference. Detailed dietary history: caloric intake & dietary components Assess daily physical activity level. Assess for obesity (check weight for height or calculate BMI). Assess for short stature, check IGF-1. Infants / young children: assess for photophobia, nystagmus, & impaired visual acuity. Older children / adults: assess for cataracts; impaired vision; perform visual field testing, electroretinography. Assess for high-frequency SNHL. Perform auditory brain stem response & otoacustic emissions. Hyperinsulinemia (check skin for acanthosis nigricans from age 5 yrs on) Pre-diabetes from age 4 yrs on (HbA1C, postprandial C-peptide & blood glucose, oral glucose tolerance test) Dyslipidemia from age 5 yrs on Assess pubertal development; check levels of FSH, LH, estrogen, & testosterone as needed. Males: evidence of delayed or arrested puberty secondary to hypogonadotropic hypogonadism &/or testicular fibrosis Females: hirsutism, polycystic ovarian syndrome, precocious puberty, irregular menses, amenorrhea Ages 3 wks to 4 mos: assess for infantile cardiomyopathy; order baseline echocardiogram. Teens to late 30s: assess for restrictive cardiomyopathy incl EKG & cardiac MRI to detect myocardial fibrosis. Assess for detrusor-urethral dyssynergia. Refer to urologist as needed. Assess fine & gross motor, speech/language, general cognitive, & vocational skills. Evaluate special considerations in school setting for those w/impaired vision & hearing Assess renal function. Refer to nephrologist as needed. Check CBC, serum electrolytes, creatinine, cystatin C, BUN Check blood pressure, 24-hr blood pressure monitoring as needed Assess for nonalcoholic fatty liver disease. Refer to hepatologist as needed. Assess for liver disease by ultrasonography, FibroScan In patients w/advanced liver disease: assess need for upper endoscopy to evaluate for esophageal varices. Use of community or Need for social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; SNHL = sensorineural hearing loss See No therapy exists to prevent the progressive organ involvement of Alström syndrome. Individuals with Alström syndrome require coordinated multidisciplinary care to formulate and coordinate management and therapeutic interventions. Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms. Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large-print reading materials while vision is still present, are crucial. Myringotomy has been helpful in individuals with recurrent otitis media. Hearing can be maximized with bilateral digital hearing aids. Cochlear implantation has benefited some patients [ Glitazones are added to further reduce insulin resistance but must be avoided in the presence of active or treated heart failure. These treatments should be discontinued when the serum creatinine concentration exceeds 200 µmol/L (2.6 mg/dL) or if cardiomyopathy is evident. Incretin analogs given subcutaneously, as in nonsyndromic T2DM, are successful in two thirds of patients in whom diabetes is suboptimally controlled on good nutrition, exercise, and metformin [ The progression to diabetes mellitus and the severity of hyperglycemia can be mitigated by lifestyle changes and reduction of severe obesity. Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/L or 1,770 mg/dL) especially if pancreatitis has occurred and diabetes is absent or well controlled [ Pancreatitis should be treated as in the general population. In order to reduce serum triglyceride levels, a 48-hour fast with intravenous saline will allow excess circulating triglyceride to be metabolized, thus resetting lipid trafficking. Subsequent healthy diet, exercise, and optimal treatment of diabetes will then sustain lower triglyceride levels [ As children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormone replacement is necessary. Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health. Thyroxine therapy should be initiated and monitored if the individual is hypothyroid. Free T4 and TSH monitoring is recommended as many people with Alström syndrome have secondary hypothyroidism. The use of enzyme ACE inhibitors is recommended if proteinuria is detected. As in the general population, intense inhibition of the renin-angiotensin-aldosterone axis with ACE inhibition, A2 blockade, and aldosterone blockade (spironolactone or eplenerone) is likely to result in hyperkalemia and potentially renal failure [ Although successful renal transplantation has occurred in increasing numbers of individuals [ If skeletal abnormalities are present, referral to an orthopedist is appropriate. Kyphoscoliosis may require surgical treatment. Characteristic stoop can be countered by exercise. Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population. Routine pediatric immunizations including annual flu shots should be given and administration of pneumococcal vaccination considered. Care must be taken during sedation or operative procedures. The combination of decreased myocardial function, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered. A study on aspects of learning from the perspective of people with Alström syndrome revealed that individuals with Alström syndrome have an image of themselves as capable people willing to learn, but in constant need of support to continue learning throughout their lives to be as independent as possible [ An overview of the current holistic approach to families of persons with Alström syndrome emphasizes the possibilities for better integration in society and attainment of educational and employment opportunities [ 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 restricted environment at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. 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 depression, anxiety, and nihilism are common in the late teens as young persons with Alström syndrome realize the severity of its effects. These issues can be addressed by a pediatric psychiatrist. A suggested plan for annual evaluations for patients with Alström syndrome may be found at Recommended Surveillance for Individuals with Alström Syndrome Every 3-6 mos in 1st 2 yrs Every 6-12 mos after age 2 yrs Annually if normal Every 3 mos if abnormal Annually if normal More frequently if abnormal Adult males: evaluate for hypogonadism; measure serum testosterone & gonadotropins. Adult females: evaluate for hyperandrogenism. All patients w/renal disease should be followed by nephrologist & have urine protein/creatinine ratio. Evaluate all patients w/CKD Stage ≥III for bone disease (PTH, calcium, phosphorus, bone density). Based on Monitoring Guidelines from Alström Syndrome International ( ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CKD = chronic kidney disease; CT = computerized tomography; GGT = gama glutamil transferase; HDL = high density lipoproteins; LDL = low density lipoproteins; LV = left ventricular; MRI = magnetic resonance imaging; PTH = parathyroid hormone; US = ultrasound Recommended frequencies shown are for stable well-controlled patients. In many patients more frequent evaluations are needed. Substances contraindicated in persons with renal, hepatic, and/or myocardial disease should be avoided. Therapy directed at one system may have adverse effects on other systems; for example, the use of glitazone therapy in diabetes mellitus is contraindicated in the presence of cardiac failure. It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with Alström syndrome in order to identify as early as possible those who would benefit from prompt evaluation for manifestations of Alström syndrome ( See A treatment trial with the antifibrotic agent PBI-4050 is currently under way [ Search • Measure height, weight, head & waist circumference. • Detailed dietary history: caloric intake & dietary components • Assess daily physical activity level. • Assess for obesity (check weight for height or calculate BMI). • Assess for short stature, check IGF-1. • Infants / young children: assess for photophobia, nystagmus, & impaired visual acuity. • Older children / adults: assess for cataracts; impaired vision; perform visual field testing, electroretinography. • Assess for high-frequency SNHL. • Perform auditory brain stem response & otoacustic emissions. • Hyperinsulinemia (check skin for acanthosis nigricans from age 5 yrs on) • Pre-diabetes from age 4 yrs on (HbA1C, postprandial C-peptide & blood glucose, oral glucose tolerance test) • Dyslipidemia from age 5 yrs on • Assess pubertal development; check levels of FSH, LH, estrogen, & testosterone as needed. • Males: evidence of delayed or arrested puberty secondary to hypogonadotropic hypogonadism &/or testicular fibrosis • Females: hirsutism, polycystic ovarian syndrome, precocious puberty, irregular menses, amenorrhea • Ages 3 wks to 4 mos: assess for infantile cardiomyopathy; order baseline echocardiogram. • Teens to late 30s: assess for restrictive cardiomyopathy incl EKG & cardiac MRI to detect myocardial fibrosis. • Assess for detrusor-urethral dyssynergia. • Refer to urologist as needed. • Assess fine & gross motor, speech/language, general cognitive, & vocational skills. • Evaluate special considerations in school setting for those w/impaired vision & hearing • Assess renal function. • Refer to nephrologist as needed. • Check CBC, serum electrolytes, creatinine, cystatin C, BUN • Check blood pressure, 24-hr blood pressure monitoring as needed • Assess for nonalcoholic fatty liver disease. • Refer to hepatologist as needed. • Assess for liver disease by ultrasonography, FibroScan • In patients w/advanced liver disease: assess need for upper endoscopy to evaluate for esophageal varices. • Use of community or • Need for social work involvement for parental support. • Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms. • Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large-print reading materials while vision is still present, are crucial. • Myringotomy has been helpful in individuals with recurrent otitis media. • Hearing can be maximized with bilateral digital hearing aids. • Cochlear implantation has benefited some patients [ • Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/L or 1,770 mg/dL) especially if pancreatitis has occurred and diabetes is absent or well controlled [ • Pancreatitis should be treated as in the general population. In order to reduce serum triglyceride levels, a 48-hour fast with intravenous saline will allow excess circulating triglyceride to be metabolized, thus resetting lipid trafficking. Subsequent healthy diet, exercise, and optimal treatment of diabetes will then sustain lower triglyceride levels [ • As children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormone replacement is necessary. • Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health. • Thyroxine therapy should be initiated and monitored if the individual is hypothyroid. Free T4 and TSH monitoring is recommended as many people with Alström syndrome have secondary hypothyroidism. • The use of enzyme ACE inhibitors is recommended if proteinuria is detected. As in the general population, intense inhibition of the renin-angiotensin-aldosterone axis with ACE inhibition, A2 blockade, and aldosterone blockade (spironolactone or eplenerone) is likely to result in hyperkalemia and potentially renal failure [ • Although successful renal transplantation has occurred in increasing numbers of individuals [ • If skeletal abnormalities are present, referral to an orthopedist is appropriate. Kyphoscoliosis may require surgical treatment. Characteristic stoop can be countered by exercise. • Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population. • Routine pediatric immunizations including annual flu shots should be given and administration of pneumococcal vaccination considered. • Care must be taken during sedation or operative procedures. The combination of decreased myocardial function, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered. • 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 restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Every 3-6 mos in 1st 2 yrs • Every 6-12 mos after age 2 yrs • Annually if normal • Every 3 mos if abnormal • Annually if normal • More frequently if abnormal • Adult males: evaluate for hypogonadism; measure serum testosterone & gonadotropins. • Adult females: evaluate for hyperandrogenism. • All patients w/renal disease should be followed by nephrologist & have urine protein/creatinine ratio. • Evaluate all patients w/CKD Stage ≥III for bone disease (PTH, calcium, phosphorus, bone density). ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Alström syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Alström Syndrome Measure height, weight, head & waist circumference. Detailed dietary history: caloric intake & dietary components Assess daily physical activity level. Assess for obesity (check weight for height or calculate BMI). Assess for short stature, check IGF-1. Infants / young children: assess for photophobia, nystagmus, & impaired visual acuity. Older children / adults: assess for cataracts; impaired vision; perform visual field testing, electroretinography. Assess for high-frequency SNHL. Perform auditory brain stem response & otoacustic emissions. Hyperinsulinemia (check skin for acanthosis nigricans from age 5 yrs on) Pre-diabetes from age 4 yrs on (HbA1C, postprandial C-peptide & blood glucose, oral glucose tolerance test) Dyslipidemia from age 5 yrs on Assess pubertal development; check levels of FSH, LH, estrogen, & testosterone as needed. Males: evidence of delayed or arrested puberty secondary to hypogonadotropic hypogonadism &/or testicular fibrosis Females: hirsutism, polycystic ovarian syndrome, precocious puberty, irregular menses, amenorrhea Ages 3 wks to 4 mos: assess for infantile cardiomyopathy; order baseline echocardiogram. Teens to late 30s: assess for restrictive cardiomyopathy incl EKG & cardiac MRI to detect myocardial fibrosis. Assess for detrusor-urethral dyssynergia. Refer to urologist as needed. Assess fine & gross motor, speech/language, general cognitive, & vocational skills. Evaluate special considerations in school setting for those w/impaired vision & hearing Assess renal function. Refer to nephrologist as needed. Check CBC, serum electrolytes, creatinine, cystatin C, BUN Check blood pressure, 24-hr blood pressure monitoring as needed Assess for nonalcoholic fatty liver disease. Refer to hepatologist as needed. Assess for liver disease by ultrasonography, FibroScan In patients w/advanced liver disease: assess need for upper endoscopy to evaluate for esophageal varices. Use of community or Need for social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; SNHL = sensorineural hearing loss See • Measure height, weight, head & waist circumference. • Detailed dietary history: caloric intake & dietary components • Assess daily physical activity level. • Assess for obesity (check weight for height or calculate BMI). • Assess for short stature, check IGF-1. • Infants / young children: assess for photophobia, nystagmus, & impaired visual acuity. • Older children / adults: assess for cataracts; impaired vision; perform visual field testing, electroretinography. • Assess for high-frequency SNHL. • Perform auditory brain stem response & otoacustic emissions. • Hyperinsulinemia (check skin for acanthosis nigricans from age 5 yrs on) • Pre-diabetes from age 4 yrs on (HbA1C, postprandial C-peptide & blood glucose, oral glucose tolerance test) • Dyslipidemia from age 5 yrs on • Assess pubertal development; check levels of FSH, LH, estrogen, & testosterone as needed. • Males: evidence of delayed or arrested puberty secondary to hypogonadotropic hypogonadism &/or testicular fibrosis • Females: hirsutism, polycystic ovarian syndrome, precocious puberty, irregular menses, amenorrhea • Ages 3 wks to 4 mos: assess for infantile cardiomyopathy; order baseline echocardiogram. • Teens to late 30s: assess for restrictive cardiomyopathy incl EKG & cardiac MRI to detect myocardial fibrosis. • Assess for detrusor-urethral dyssynergia. • Refer to urologist as needed. • Assess fine & gross motor, speech/language, general cognitive, & vocational skills. • Evaluate special considerations in school setting for those w/impaired vision & hearing • Assess renal function. • Refer to nephrologist as needed. • Check CBC, serum electrolytes, creatinine, cystatin C, BUN • Check blood pressure, 24-hr blood pressure monitoring as needed • Assess for nonalcoholic fatty liver disease. • Refer to hepatologist as needed. • Assess for liver disease by ultrasonography, FibroScan • In patients w/advanced liver disease: assess need for upper endoscopy to evaluate for esophageal varices. • Use of community or • Need for social work involvement for parental support. ## Treatment of Manifestations No therapy exists to prevent the progressive organ involvement of Alström syndrome. Individuals with Alström syndrome require coordinated multidisciplinary care to formulate and coordinate management and therapeutic interventions. Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms. Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large-print reading materials while vision is still present, are crucial. Myringotomy has been helpful in individuals with recurrent otitis media. Hearing can be maximized with bilateral digital hearing aids. Cochlear implantation has benefited some patients [ Glitazones are added to further reduce insulin resistance but must be avoided in the presence of active or treated heart failure. These treatments should be discontinued when the serum creatinine concentration exceeds 200 µmol/L (2.6 mg/dL) or if cardiomyopathy is evident. Incretin analogs given subcutaneously, as in nonsyndromic T2DM, are successful in two thirds of patients in whom diabetes is suboptimally controlled on good nutrition, exercise, and metformin [ The progression to diabetes mellitus and the severity of hyperglycemia can be mitigated by lifestyle changes and reduction of severe obesity. Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/L or 1,770 mg/dL) especially if pancreatitis has occurred and diabetes is absent or well controlled [ Pancreatitis should be treated as in the general population. In order to reduce serum triglyceride levels, a 48-hour fast with intravenous saline will allow excess circulating triglyceride to be metabolized, thus resetting lipid trafficking. Subsequent healthy diet, exercise, and optimal treatment of diabetes will then sustain lower triglyceride levels [ As children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormone replacement is necessary. Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health. Thyroxine therapy should be initiated and monitored if the individual is hypothyroid. Free T4 and TSH monitoring is recommended as many people with Alström syndrome have secondary hypothyroidism. The use of enzyme ACE inhibitors is recommended if proteinuria is detected. As in the general population, intense inhibition of the renin-angiotensin-aldosterone axis with ACE inhibition, A2 blockade, and aldosterone blockade (spironolactone or eplenerone) is likely to result in hyperkalemia and potentially renal failure [ Although successful renal transplantation has occurred in increasing numbers of individuals [ If skeletal abnormalities are present, referral to an orthopedist is appropriate. Kyphoscoliosis may require surgical treatment. Characteristic stoop can be countered by exercise. Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population. Routine pediatric immunizations including annual flu shots should be given and administration of pneumococcal vaccination considered. Care must be taken during sedation or operative procedures. The combination of decreased myocardial function, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered. A study on aspects of learning from the perspective of people with Alström syndrome revealed that individuals with Alström syndrome have an image of themselves as capable people willing to learn, but in constant need of support to continue learning throughout their lives to be as independent as possible [ An overview of the current holistic approach to families of persons with Alström syndrome emphasizes the possibilities for better integration in society and attainment of educational and employment opportunities [ 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 restricted environment at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. 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 depression, anxiety, and nihilism are common in the late teens as young persons with Alström syndrome realize the severity of its effects. These issues can be addressed by a pediatric psychiatrist. • Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms. • Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large-print reading materials while vision is still present, are crucial. • Myringotomy has been helpful in individuals with recurrent otitis media. • Hearing can be maximized with bilateral digital hearing aids. • Cochlear implantation has benefited some patients [ • Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/L or 1,770 mg/dL) especially if pancreatitis has occurred and diabetes is absent or well controlled [ • Pancreatitis should be treated as in the general population. In order to reduce serum triglyceride levels, a 48-hour fast with intravenous saline will allow excess circulating triglyceride to be metabolized, thus resetting lipid trafficking. Subsequent healthy diet, exercise, and optimal treatment of diabetes will then sustain lower triglyceride levels [ • As children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormone replacement is necessary. • Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health. • Thyroxine therapy should be initiated and monitored if the individual is hypothyroid. Free T4 and TSH monitoring is recommended as many people with Alström syndrome have secondary hypothyroidism. • The use of enzyme ACE inhibitors is recommended if proteinuria is detected. As in the general population, intense inhibition of the renin-angiotensin-aldosterone axis with ACE inhibition, A2 blockade, and aldosterone blockade (spironolactone or eplenerone) is likely to result in hyperkalemia and potentially renal failure [ • Although successful renal transplantation has occurred in increasing numbers of individuals [ • If skeletal abnormalities are present, referral to an orthopedist is appropriate. Kyphoscoliosis may require surgical treatment. Characteristic stoop can be countered by exercise. • Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population. • Routine pediatric immunizations including annual flu shots should be given and administration of pneumococcal vaccination considered. • Care must be taken during sedation or operative procedures. The combination of decreased myocardial function, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered. • 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 restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Medical Issues No therapy exists to prevent the progressive organ involvement of Alström syndrome. Individuals with Alström syndrome require coordinated multidisciplinary care to formulate and coordinate management and therapeutic interventions. Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms. Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large-print reading materials while vision is still present, are crucial. Myringotomy has been helpful in individuals with recurrent otitis media. Hearing can be maximized with bilateral digital hearing aids. Cochlear implantation has benefited some patients [ Glitazones are added to further reduce insulin resistance but must be avoided in the presence of active or treated heart failure. These treatments should be discontinued when the serum creatinine concentration exceeds 200 µmol/L (2.6 mg/dL) or if cardiomyopathy is evident. Incretin analogs given subcutaneously, as in nonsyndromic T2DM, are successful in two thirds of patients in whom diabetes is suboptimally controlled on good nutrition, exercise, and metformin [ The progression to diabetes mellitus and the severity of hyperglycemia can be mitigated by lifestyle changes and reduction of severe obesity. Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/L or 1,770 mg/dL) especially if pancreatitis has occurred and diabetes is absent or well controlled [ Pancreatitis should be treated as in the general population. In order to reduce serum triglyceride levels, a 48-hour fast with intravenous saline will allow excess circulating triglyceride to be metabolized, thus resetting lipid trafficking. Subsequent healthy diet, exercise, and optimal treatment of diabetes will then sustain lower triglyceride levels [ As children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormone replacement is necessary. Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health. Thyroxine therapy should be initiated and monitored if the individual is hypothyroid. Free T4 and TSH monitoring is recommended as many people with Alström syndrome have secondary hypothyroidism. The use of enzyme ACE inhibitors is recommended if proteinuria is detected. As in the general population, intense inhibition of the renin-angiotensin-aldosterone axis with ACE inhibition, A2 blockade, and aldosterone blockade (spironolactone or eplenerone) is likely to result in hyperkalemia and potentially renal failure [ Although successful renal transplantation has occurred in increasing numbers of individuals [ If skeletal abnormalities are present, referral to an orthopedist is appropriate. Kyphoscoliosis may require surgical treatment. Characteristic stoop can be countered by exercise. Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population. Routine pediatric immunizations including annual flu shots should be given and administration of pneumococcal vaccination considered. Care must be taken during sedation or operative procedures. The combination of decreased myocardial function, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered. • Early on when photodysphoria is significant, the use of red-orange tinted prescription lenses may reduce symptoms. • Early educational planning should be based on the certainty of blindness. Instruction in the use of Braille, mobility training, adaptive living skills, and computing skills (including voice recognition and transcription software), and the use of large-print reading materials while vision is still present, are crucial. • Myringotomy has been helpful in individuals with recurrent otitis media. • Hearing can be maximized with bilateral digital hearing aids. • Cochlear implantation has benefited some patients [ • Nicotinic acid derivatives can be helpful in long-term reduction of severe hypertriglyceridemia (>20 mmol/L or 1,770 mg/dL) especially if pancreatitis has occurred and diabetes is absent or well controlled [ • Pancreatitis should be treated as in the general population. In order to reduce serum triglyceride levels, a 48-hour fast with intravenous saline will allow excess circulating triglyceride to be metabolized, thus resetting lipid trafficking. Subsequent healthy diet, exercise, and optimal treatment of diabetes will then sustain lower triglyceride levels [ • As children approach puberty, gonadotropin and pituitary hormones should be assessed to determine if hormone replacement is necessary. • Male hypogonadism should be treated with testosterone according to local endocrine guidelines to preserve sexuality, muscle strength, and bone health. • Thyroxine therapy should be initiated and monitored if the individual is hypothyroid. Free T4 and TSH monitoring is recommended as many people with Alström syndrome have secondary hypothyroidism. • The use of enzyme ACE inhibitors is recommended if proteinuria is detected. As in the general population, intense inhibition of the renin-angiotensin-aldosterone axis with ACE inhibition, A2 blockade, and aldosterone blockade (spironolactone or eplenerone) is likely to result in hyperkalemia and potentially renal failure [ • Although successful renal transplantation has occurred in increasing numbers of individuals [ • If skeletal abnormalities are present, referral to an orthopedist is appropriate. Kyphoscoliosis may require surgical treatment. Characteristic stoop can be countered by exercise. • Reflux esophagitis, skin manifestations, orthopedic abnormalities, and neurologic manifestations should be treated as in the general population. • Routine pediatric immunizations including annual flu shots should be given and administration of pneumococcal vaccination considered. • Care must be taken during sedation or operative procedures. The combination of decreased myocardial function, pulmonary hypertension, and pulmonary fibrosis can cause sudden severe hypoxia in an affected individual following surgery or even during a minor infection. Close monitoring of cardiac status and oxygenation are necessary until the individual is fully recovered. ## Developmental Delay Management Issues A study on aspects of learning from the perspective of people with Alström syndrome revealed that individuals with Alström syndrome have an image of themselves as capable people willing to learn, but in constant need of support to continue learning throughout their lives to be as independent as possible [ An overview of the current holistic approach to families of persons with Alström syndrome emphasizes the possibilities for better integration in society and attainment of educational and employment opportunities [ 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 restricted environment at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction ## 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 depression, anxiety, and nihilism are common in the late teens as young persons with Alström syndrome realize the severity of its effects. These issues can be addressed by a pediatric psychiatrist. ## Surveillance A suggested plan for annual evaluations for patients with Alström syndrome may be found at Recommended Surveillance for Individuals with Alström Syndrome Every 3-6 mos in 1st 2 yrs Every 6-12 mos after age 2 yrs Annually if normal Every 3 mos if abnormal Annually if normal More frequently if abnormal Adult males: evaluate for hypogonadism; measure serum testosterone & gonadotropins. Adult females: evaluate for hyperandrogenism. All patients w/renal disease should be followed by nephrologist & have urine protein/creatinine ratio. Evaluate all patients w/CKD Stage ≥III for bone disease (PTH, calcium, phosphorus, bone density). Based on Monitoring Guidelines from Alström Syndrome International ( ALT = alanine aminotransferase; AP = alkaline phosphatase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; CKD = chronic kidney disease; CT = computerized tomography; GGT = gama glutamil transferase; HDL = high density lipoproteins; LDL = low density lipoproteins; LV = left ventricular; MRI = magnetic resonance imaging; PTH = parathyroid hormone; US = ultrasound Recommended frequencies shown are for stable well-controlled patients. In many patients more frequent evaluations are needed. • Every 3-6 mos in 1st 2 yrs • Every 6-12 mos after age 2 yrs • Annually if normal • Every 3 mos if abnormal • Annually if normal • More frequently if abnormal • Adult males: evaluate for hypogonadism; measure serum testosterone & gonadotropins. • Adult females: evaluate for hyperandrogenism. • All patients w/renal disease should be followed by nephrologist & have urine protein/creatinine ratio. • Evaluate all patients w/CKD Stage ≥III for bone disease (PTH, calcium, phosphorus, bone density). ## Agents/Circumstances to Avoid Substances contraindicated in persons with renal, hepatic, and/or myocardial disease should be avoided. Therapy directed at one system may have adverse effects on other systems; for example, the use of glitazone therapy in diabetes mellitus is contraindicated in the presence of cardiac failure. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an individual with Alström syndrome in order to identify as early as possible those who would benefit from prompt evaluation for manifestations of Alström syndrome ( See ## Therapies Under Investigation A treatment trial with the antifibrotic agent PBI-4050 is currently under way [ Search ## Genetic Counseling Alström syndrome 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 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 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 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 Alström syndrome 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 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 carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources 14 Whitney Farm Road Mount Desert ME 04660 4 St Kitts Close Torquay Devon TQ2 7GD United Kingdom United Kingdom • • 14 Whitney Farm Road • Mount Desert ME 04660 • • • 4 St Kitts Close • Torquay Devon TQ2 7GD • United Kingdom • • • • • • • United Kingdom • • • ## Molecular Genetics Alstrom Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Alstrom Syndrome ( Given the clinical overlap between Alström syndrome and other ciliopathies, extreme caution should be exercised in classifying ## Molecular Pathogenesis Given the clinical overlap between Alström syndrome and other ciliopathies, extreme caution should be exercised in classifying ## References ## Literature Cited ## Chapter Notes Tim Barrett, MD (2019-present)Catherine Carey, MD, FRCP; Torbay Hospital, Devon (2003-2019)Tarekegn Geberhiwot, MD (2019-present)Meral Gunay-Aygun, MD (2019-present)Ian Hopkinson, BSc (Hons), MBChB, PhD, MRCGP; University College London (2003-2010)Seamus Macdermott, MD, FRCS; Torbay Hospital, Devon (2003-2019)Jan D Marshall, MS; The Jackson Library, Bar Harbor (2003-2016)Richard B Paisey, MD, FRCP (2005-present)Rick Steeds, MD (2019-present)Denise Williams, MD (2019-present) Author Jan Marshall died September 6, 2016. 13 June 2019 (bp) Comprehensive update posted live 31 May 2012 (me) Comprehensive update posted live 8 June 2010 (me) Comprehensive update posted live 25 June 2007 (me) Comprehensive update posted live 7 February 2005 (me) Comprehensive update posted live 11 May 2004 (ih) Revision: test availability 7 February 2003 (me) Review posted live 6 June 2002 (ih) Original submission • 13 June 2019 (bp) Comprehensive update posted live • 31 May 2012 (me) Comprehensive update posted live • 8 June 2010 (me) Comprehensive update posted live • 25 June 2007 (me) Comprehensive update posted live • 7 February 2005 (me) Comprehensive update posted live • 11 May 2004 (ih) Revision: test availability • 7 February 2003 (me) Review posted live • 6 June 2002 (ih) Original submission ## Author History Tim Barrett, MD (2019-present)Catherine Carey, MD, FRCP; Torbay Hospital, Devon (2003-2019)Tarekegn Geberhiwot, MD (2019-present)Meral Gunay-Aygun, MD (2019-present)Ian Hopkinson, BSc (Hons), MBChB, PhD, MRCGP; University College London (2003-2010)Seamus Macdermott, MD, FRCS; Torbay Hospital, Devon (2003-2019)Jan D Marshall, MS; The Jackson Library, Bar Harbor (2003-2016)Richard B Paisey, MD, FRCP (2005-present)Rick Steeds, MD (2019-present)Denise Williams, MD (2019-present) Author Jan Marshall died September 6, 2016. ## Revision History 13 June 2019 (bp) Comprehensive update posted live 31 May 2012 (me) Comprehensive update posted live 8 June 2010 (me) Comprehensive update posted live 25 June 2007 (me) Comprehensive update posted live 7 February 2005 (me) Comprehensive update posted live 11 May 2004 (ih) Revision: test availability 7 February 2003 (me) Review posted live 6 June 2002 (ih) Original submission • 13 June 2019 (bp) Comprehensive update posted live • 31 May 2012 (me) Comprehensive update posted live • 8 June 2010 (me) Comprehensive update posted live • 25 June 2007 (me) Comprehensive update posted live • 7 February 2005 (me) Comprehensive update posted live • 11 May 2004 (ih) Revision: test availability • 7 February 2003 (me) Review posted live • 6 June 2002 (ih) Original submission Age range of onset of features in Alström syndrome	[ "N Akdeniz, SG Bilgili, S Aktar, S Yuca, O Calka, A Kilic, M Kosem. 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alzheimer-early	alzheimer-early	[ "EOFAD", "EOFAD", "Amyloid-beta A4 protein", "Presenilin-1", "Presenilin-2", "APP", "PSEN1", "PSEN2", "Early-Onset Familial Alzheimer Disease" ]	Early-Onset Familial Alzheimer Disease – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Thomas D Bird	Summary Alzheimer disease (AD) is characterized by adult-onset progressive dementia associated with cerebral cortical atrophy, beta-amyloid plaque formation, and intraneuronal neurofibrillary tangles. AD typically begins with subtle memory failure that becomes more severe and is eventually incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, hallucinations, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism. Familial AD (FAD) characterizes families that have more than one member with AD and usually implies multiple affected persons in more than one generation. Early-onset FAD (EOFAD) refers to families in which onset is consistently before age 60 to 65 years and often before age 55 years. EOFAD is diagnosed in families with multiple affected individuals with mean age of onset before 65 years and/or with a documented pathogenic variant in one of the genes known to be associated with EOFAD. The three clinically indistinguishable subtypes of EOFAD based on the underlying genetic mechanism are: Alzheimer disease type 1 (AD1), caused by mutation of EOFAD is inherited in an autosomal dominant manner. Most individuals with EOFAD had an affected parent; occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. Each child of an individual with EOFAD has a 50% chance of inheriting the pathogenic variant and developing EOFAD. Prenatal testing for pregnancies at increased risk for is possible if the pathogenic variant in the family is known; however, prenatal testing for adult-onset disorders is uncommon.	## Diagnosis Alzheimer disease (AD) (see Adult-onset slowly progressive dementia Absence of other causes of dementia Cerebral cortical atrophy by neuroimaging studies Beta-amyloid neuritic plaques and intraneuronal neurofibrillary tangles at post-mortem examination (see diagnostic criteria, Early-onset familial Alzheimer disease (EOFAD) is diagnosed in families that have more than one member with AD (usually multiple affected persons in more than one generation) in which the age of onset is consistently before age 60 to 65 years and often before age 55 years. Genetic Testing Used in Early-Onset Familial Alzheimer Disease See See The ability of the test method used to detect a variant that is present in the indicated gene The highest yield for identification of a pathogenic variant in Finnish population; this variant is rarely observed in other populations. 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 Testing that identifies 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 chromosomal microarray (CMA) that includes this gene/chromosome segment. Sequence analysis and scanning for pathogenic variants can have similar variant detection frequencies; however, variant detection frequencies for scanning may vary considerably among laboratories depending on the specific protocol used. In one affected individual, a When the family history is positive for early-onset AD: First perform sequence analysis of If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. In simplex cases (i.e., a single occurrence in a family) the testing strategy is similar, but the likelihood of finding a pathogenic variant is relatively low (~6% in the study by Note: Pathogenic variant detection frequency is low in persons with late-onset AD regardless of family history. Ninety percent of persons with • Adult-onset slowly progressive dementia • Absence of other causes of dementia • Cerebral cortical atrophy by neuroimaging studies • Beta-amyloid neuritic plaques and intraneuronal neurofibrillary tangles at post-mortem examination (see diagnostic criteria, • When the family history is positive for early-onset AD: • First perform sequence analysis of • If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of • Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. • First perform sequence analysis of • If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of • Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. • In simplex cases (i.e., a single occurrence in a family) the testing strategy is similar, but the likelihood of finding a pathogenic variant is relatively low (~6% in the study by • First perform sequence analysis of • If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of • Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. ## Clinical Diagnosis Alzheimer disease (AD) (see Adult-onset slowly progressive dementia Absence of other causes of dementia Cerebral cortical atrophy by neuroimaging studies Beta-amyloid neuritic plaques and intraneuronal neurofibrillary tangles at post-mortem examination (see diagnostic criteria, Early-onset familial Alzheimer disease (EOFAD) is diagnosed in families that have more than one member with AD (usually multiple affected persons in more than one generation) in which the age of onset is consistently before age 60 to 65 years and often before age 55 years. • Adult-onset slowly progressive dementia • Absence of other causes of dementia • Cerebral cortical atrophy by neuroimaging studies • Beta-amyloid neuritic plaques and intraneuronal neurofibrillary tangles at post-mortem examination (see diagnostic criteria, ## Molecular Genetic Testing Genetic Testing Used in Early-Onset Familial Alzheimer Disease See See The ability of the test method used to detect a variant that is present in the indicated gene The highest yield for identification of a pathogenic variant in Finnish population; this variant is rarely observed in other populations. 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 Testing that identifies 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 chromosomal microarray (CMA) that includes this gene/chromosome segment. Sequence analysis and scanning for pathogenic variants can have similar variant detection frequencies; however, variant detection frequencies for scanning may vary considerably among laboratories depending on the specific protocol used. In one affected individual, a ## Testing Strategy When the family history is positive for early-onset AD: First perform sequence analysis of If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. In simplex cases (i.e., a single occurrence in a family) the testing strategy is similar, but the likelihood of finding a pathogenic variant is relatively low (~6% in the study by Note: Pathogenic variant detection frequency is low in persons with late-onset AD regardless of family history. Ninety percent of persons with • When the family history is positive for early-onset AD: • First perform sequence analysis of • If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of • Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. • First perform sequence analysis of • If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of • Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. • In simplex cases (i.e., a single occurrence in a family) the testing strategy is similar, but the likelihood of finding a pathogenic variant is relatively low (~6% in the study by • First perform sequence analysis of • If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of • Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants. ## Clinical Characteristics Alzheimer disease (AD) typically begins with subtle and poorly recognized failure of memory [ The APOE e4 allele may influence age of onset [ CSF Aβ42 levels have been reported to be low in presymptomatic persons with PET scans with Pittsburgh compound-B show early amyloid deposition in the striatum in persons with The APOE e4 allele influences age of onset (see Homozygosity for the APOE e4 allele may be associated with younger age of onset (see Pathogenic variants in transmembrane loops 2, 4, and 6 of A frontotemporal type of dementia with personality and behavioral changes has been associated with the pathogenic variants Psychiatric symptoms at onset have been described in families with the pathogenic variants Deletion of exon 9 in Very early onset (mean age 30 years) with additional Lewy body pathology has been associated with the pathogenic variants Two Later-onset FAD (50s-70s) has been associated with the pathogenic variants Purkinje cell loss in the cerebellum has been reported with the The combination of cerebral hemorrhage and presenile dementia is caused by the The EOFAD has been associated with Anticipation has not been documented. Sixty-one percent of individuals with early-onset AD had a positive family history and 13% had affected individuals in three generations [ EOFAD comprises less than 3% of all AD. Some families with Volga German ancestry have a founder variant in Among families with EOFAD, 40%-80% have a pathogenic variant in • Pathogenic variants in transmembrane loops 2, 4, and 6 of • A frontotemporal type of dementia with personality and behavioral changes has been associated with the pathogenic variants • Psychiatric symptoms at onset have been described in families with the pathogenic variants • Deletion of exon 9 in • Very early onset (mean age 30 years) with additional Lewy body pathology has been associated with the pathogenic variants • Two • Later-onset FAD (50s-70s) has been associated with the pathogenic variants • Purkinje cell loss in the cerebellum has been reported with the • The combination of cerebral hemorrhage and presenile dementia is caused by the • The • EOFAD has been associated with • Sixty-one percent of individuals with early-onset AD had a positive family history and 13% had affected individuals in three generations [ • EOFAD comprises less than 3% of all AD. • Some families with Volga German ancestry have a founder variant in • Among families with EOFAD, 40%-80% have a pathogenic variant in ## Clinical Description Alzheimer disease (AD) typically begins with subtle and poorly recognized failure of memory [ The APOE e4 allele may influence age of onset [ CSF Aβ42 levels have been reported to be low in presymptomatic persons with PET scans with Pittsburgh compound-B show early amyloid deposition in the striatum in persons with The APOE e4 allele influences age of onset (see Homozygosity for the APOE e4 allele may be associated with younger age of onset (see ## Genotype-Phenotype Correlations Pathogenic variants in transmembrane loops 2, 4, and 6 of A frontotemporal type of dementia with personality and behavioral changes has been associated with the pathogenic variants Psychiatric symptoms at onset have been described in families with the pathogenic variants Deletion of exon 9 in Very early onset (mean age 30 years) with additional Lewy body pathology has been associated with the pathogenic variants Two Later-onset FAD (50s-70s) has been associated with the pathogenic variants Purkinje cell loss in the cerebellum has been reported with the The combination of cerebral hemorrhage and presenile dementia is caused by the The EOFAD has been associated with • Pathogenic variants in transmembrane loops 2, 4, and 6 of • A frontotemporal type of dementia with personality and behavioral changes has been associated with the pathogenic variants • Psychiatric symptoms at onset have been described in families with the pathogenic variants • Deletion of exon 9 in • Very early onset (mean age 30 years) with additional Lewy body pathology has been associated with the pathogenic variants • Two • Later-onset FAD (50s-70s) has been associated with the pathogenic variants • Purkinje cell loss in the cerebellum has been reported with the • The combination of cerebral hemorrhage and presenile dementia is caused by the • The • EOFAD has been associated with ## Penetrance ## Anticipation Anticipation has not been documented. ## Prevalence Sixty-one percent of individuals with early-onset AD had a positive family history and 13% had affected individuals in three generations [ EOFAD comprises less than 3% of all AD. Some families with Volga German ancestry have a founder variant in Among families with EOFAD, 40%-80% have a pathogenic variant in • Sixty-one percent of individuals with early-onset AD had a positive family history and 13% had affected individuals in three generations [ • EOFAD comprises less than 3% of all AD. • Some families with Volga German ancestry have a founder variant in • Among families with EOFAD, 40%-80% have a pathogenic variant in ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Approximately 75% of individuals with Alzheimer disease (AD) have no family history of AD and approximately 25% of individuals with AD can be divided into several genetic subgroups. Familial cases appear to have the same phenotype as nonfamilial cases both clinically and pathologically and thus are distinguished only by a positive family history (see Other genetic causes of early-onset dementia include forms of frontotemporal dementia (e.g., frontotemporal dementia with parkinsonism-17 [FTDP-17], ## Management To establish the extent of disease in an individual diagnosed with early-onset familial Alzheimer disease (EOFAD), the following evaluations are recommended if they have not already been completed: History (especially first symptoms, duration, progression). In particular, onset before age 45 years may indicate more rapid progression. Examination (especially mental status) MRI, PET. Severe cortical atrophy on MRI or marked metabolic deficits on PET imaging suggest more advanced disease. The mainstay of treatment is supportive and each symptom is managed on an individual basis [ Although the exact biochemical basis of Alzheimer disease is not well understood, it is known that deficiencies of the brain cholinergic system and of other neurotransmitters are present. Agents that increase cholinergic activity, such as tacrine cholinesterase inhibitors, are approved for treatment and show modest but variable benefit. Aricept Memantine, an NMDA receptor antagonist, has also been approved for use in AD [ Medical and behavioral management of depression, aggression, sleep disturbance, seizures, and hallucinations is required. Depression and seizures should be treated with appropriate medications. Physical and occupational therapy can be helpful to manage problems with gait and activities of daily living. Monthly surveillance to identify and manage secondary complications is indicated. Sudden changes in environment and over-sedation should be avoided. See Nonsteroidal anti-inflammatory drugs (NSAIDs), lipid-lowering agents, vitamin E, beta secretase inhibitors and β amyloid "vaccination" are being investigated as possible therapeutic agents for AD [ An amyloid vaccination immunization trial of Aβ42 in late-onset AD was stopped because encephalitis developed in 6% of the subjects [ A treatment trial of an anti-Aβ monoclonal antibody showed no significant differences when primary efficacy was analyzed [ A treatment trial with a gamma secretase inhibitor (tarenflurbil) showed no efficacy [ Retrospective studies of NSAIDs have been mixed, showing possible protective effects [ Search • History (especially first symptoms, duration, progression). In particular, onset before age 45 years may indicate more rapid progression. • Examination (especially mental status) • MRI, PET. Severe cortical atrophy on MRI or marked metabolic deficits on PET imaging suggest more advanced disease. ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with early-onset familial Alzheimer disease (EOFAD), the following evaluations are recommended if they have not already been completed: History (especially first symptoms, duration, progression). In particular, onset before age 45 years may indicate more rapid progression. Examination (especially mental status) MRI, PET. Severe cortical atrophy on MRI or marked metabolic deficits on PET imaging suggest more advanced disease. • History (especially first symptoms, duration, progression). In particular, onset before age 45 years may indicate more rapid progression. • Examination (especially mental status) • MRI, PET. Severe cortical atrophy on MRI or marked metabolic deficits on PET imaging suggest more advanced disease. ## Treatment of Manifestations The mainstay of treatment is supportive and each symptom is managed on an individual basis [ Although the exact biochemical basis of Alzheimer disease is not well understood, it is known that deficiencies of the brain cholinergic system and of other neurotransmitters are present. Agents that increase cholinergic activity, such as tacrine cholinesterase inhibitors, are approved for treatment and show modest but variable benefit. Aricept Memantine, an NMDA receptor antagonist, has also been approved for use in AD [ Medical and behavioral management of depression, aggression, sleep disturbance, seizures, and hallucinations is required. Depression and seizures should be treated with appropriate medications. Physical and occupational therapy can be helpful to manage problems with gait and activities of daily living. ## Surveillance Monthly surveillance to identify and manage secondary complications is indicated. ## Agents/Circumstances to Avoid Sudden changes in environment and over-sedation should be avoided. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Nonsteroidal anti-inflammatory drugs (NSAIDs), lipid-lowering agents, vitamin E, beta secretase inhibitors and β amyloid "vaccination" are being investigated as possible therapeutic agents for AD [ An amyloid vaccination immunization trial of Aβ42 in late-onset AD was stopped because encephalitis developed in 6% of the subjects [ A treatment trial of an anti-Aβ monoclonal antibody showed no significant differences when primary efficacy was analyzed [ A treatment trial with a gamma secretase inhibitor (tarenflurbil) showed no efficacy [ Retrospective studies of NSAIDs have been mixed, showing possible protective effects [ Search ## Genetic Counseling Early-onset familial Alzheimer disease (EOFAD) is inherited in an autosomal dominant manner. Most individuals diagnosed as having EOFAD have had an affected parent. Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. Occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. A proband with EOFAD may have the disorder as the result of a Note: Although most individuals diagnosed with EOFAD 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 reduced penetrance. The risk to sibs depends on the genetic status of the parents. If a parent of the proband was affected or had a pathogenic variant, the risk to sibs of having inherited the variant is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about 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 of developing EOFAD. Testing for the pathogenic variant in the absence of definite symptoms of the disease is considered 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 usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of EOFAD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding 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 for such testing is recommended and adequate procedures should be followed to safeguard confidentiality of test results and to ensure arrangements for long-term follow up and evaluations. In a study of 21 individuals at risk for EOFAD or Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, 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 as having EOFAD have had an affected parent. Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. • A proband with EOFAD may have the disorder as the result of a • The risk to sibs depends on the genetic status of the parents. • If a parent of the proband was affected or had a pathogenic variant, the risk to sibs of having inherited the variant is 50%. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about 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 of developing EOFAD. ## Mode of Inheritance Early-onset familial Alzheimer disease (EOFAD) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed as having EOFAD have had an affected parent. Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. Occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. A proband with EOFAD may have the disorder as the result of a Note: Although most individuals diagnosed with EOFAD 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 reduced penetrance. The risk to sibs depends on the genetic status of the parents. If a parent of the proband was affected or had a pathogenic variant, the risk to sibs of having inherited the variant is 50%. When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. • Most individuals diagnosed as having EOFAD have had an affected parent. Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. • A proband with EOFAD may have the disorder as the result of a • The risk to sibs depends on the genetic status of the parents. • If a parent of the proband was affected or had a pathogenic variant, the risk to sibs of having inherited the variant is 50%. • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about 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 of developing EOFAD. Testing for the pathogenic variant in the absence of definite symptoms of the disease is considered 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 usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of EOFAD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding 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 for such testing is recommended and adequate procedures should be followed to safeguard confidentiality of test results and to ensure arrangements for long-term follow up and evaluations. In a study of 21 individuals at risk for EOFAD or • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about 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 of developing EOFAD. ## Prenatal Testing and Preimplantation Genetic Testing Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, 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 225 North Michigan Avenue Fl 17 Chicago IL 60601-7633 PO Box 8250 Silver Spring MD 20907 31 Center Drive Building 31, Room 5C27 MSC 2292 Bethesda MD 20892 • • 225 North Michigan Avenue • Fl 17 • Chicago IL 60601-7633 • • • PO Box 8250 • Silver Spring MD 20907 • • • • • 31 Center Drive • Building 31, Room 5C27 • MSC 2292 • Bethesda MD 20892 • • • ## Molecular Genetics Early-Onset Familial Alzheimer Disease : Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Early-Onset Familial Alzheimer Disease ( Selected Variants listed in the table have been provided by the author. See Pathogenic variant associated with cerebral hemorrhagic amyloidosis of the Dutch type Selected Note on variant classification: Variants listed in the table have been provided by the author. Note on nomenclature: See See Selected Note on variant classification: Variants listed in the table have been provided by the author. Note on nomenclature: See ## References ## Published Guidelines / Consensus Statements ## Literature Cited ## Suggested Reading ## Chapter Notes 13 September 2018 (ma) Chapter retired: covered in 18 October 2012 (tb) Revision: changes in biomarkers identified in individuals with mutations associated with EOFAD 2 August 2012 (tb) Revision: additional information about 23 December 2010 (me) Comprehensive update posted live 28 April 2009 (tb) Revision: FISH testing available clinically for duplications in 2 October 2007 (me) Comprehensive update posted live 26 April 2007 (tb) Revision: sequence analysis for AD1 (APP mutations) clinically available 12 February 2007 (tb) Revision: clinical testing for APP mutations no longer available 19 September 2005 (me) Comprehensive update posted live 15 September 2003 (tb) Revision: clinical testing for APP available 7 August 2003 (me) Comprehensive update posted live 20 June 2001 (ca) Comprehensive update posted live 24 September 1999 (pb) Review posted live Spring 1996 (tb) Original submission • 13 September 2018 (ma) Chapter retired: covered in • 18 October 2012 (tb) Revision: changes in biomarkers identified in individuals with mutations associated with EOFAD • 2 August 2012 (tb) Revision: additional information about • 23 December 2010 (me) Comprehensive update posted live • 28 April 2009 (tb) Revision: FISH testing available clinically for duplications in • 2 October 2007 (me) Comprehensive update posted live • 26 April 2007 (tb) Revision: sequence analysis for AD1 (APP mutations) clinically available • 12 February 2007 (tb) Revision: clinical testing for APP mutations no longer available • 19 September 2005 (me) Comprehensive update posted live • 15 September 2003 (tb) Revision: clinical testing for APP available • 7 August 2003 (me) Comprehensive update posted live • 20 June 2001 (ca) Comprehensive update posted live • 24 September 1999 (pb) Review posted live • Spring 1996 (tb) Original submission ## Revision History 13 September 2018 (ma) Chapter retired: covered in 18 October 2012 (tb) Revision: changes in biomarkers identified in individuals with mutations associated with EOFAD 2 August 2012 (tb) Revision: additional information about 23 December 2010 (me) Comprehensive update posted live 28 April 2009 (tb) Revision: FISH testing available clinically for duplications in 2 October 2007 (me) Comprehensive update posted live 26 April 2007 (tb) Revision: sequence analysis for AD1 (APP mutations) clinically available 12 February 2007 (tb) Revision: clinical testing for APP mutations no longer available 19 September 2005 (me) Comprehensive update posted live 15 September 2003 (tb) Revision: clinical testing for APP available 7 August 2003 (me) Comprehensive update posted live 20 June 2001 (ca) Comprehensive update posted live 24 September 1999 (pb) Review posted live Spring 1996 (tb) Original submission • 13 September 2018 (ma) Chapter retired: covered in • 18 October 2012 (tb) Revision: changes in biomarkers identified in individuals with mutations associated with EOFAD • 2 August 2012 (tb) Revision: additional information about • 23 December 2010 (me) Comprehensive update posted live • 28 April 2009 (tb) Revision: FISH testing available clinically for duplications in • 2 October 2007 (me) Comprehensive update posted live • 26 April 2007 (tb) Revision: sequence analysis for AD1 (APP mutations) clinically available • 12 February 2007 (tb) Revision: clinical testing for APP mutations no longer available • 19 September 2005 (me) Comprehensive update posted live • 15 September 2003 (tb) Revision: clinical testing for APP available • 7 August 2003 (me) Comprehensive update posted live • 20 June 2001 (ca) Comprehensive update posted live • 24 September 1999 (pb) Review posted live • Spring 1996 (tb) Original submission	[]	24/9/1999	23/12/2010	18/10/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
alzheimer	alzheimer	[ "Early-Onset Familial Alzheimer Disease", "Late-Onset Familial Alzheimer Disease", "Amyloid-beta precursor protein", "Apolipoprotein E", "Presenilin-1", "Presenilin-2", "APOE", "APP", "PSEN1", "PSEN2", "Alzheimer Disease", "Overview" ]	Alzheimer Disease Overview	Thomas D Bird	Summary The purpose of this overview is to: Describe the Review the genetic Provide an Inform	## Clinical Characteristics of Alzheimer Disease Alzheimer disease (AD) is characterized by dementia that typically begins with subtle and poorly recognized failure of memory (often called mild cognitive impairment or MCI) and slowly becomes more severe and, eventually, incapacitating. Other common findings include confusion, poor judgment, language disturbance, visual complaints, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur. Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years. Approximately 95% of all AD is late onset (age >60-65 years) and 5% is early onset (age <60-65 years). Establishing the diagnosis of Alzheimer disease relies on clinical-neuropathologic assessment. Neuropathologic findings of β-amyloid plaques, intraneuronal neurofibrillary tangles (containing tau protein), and amyloid angiopathy remain the gold standard for diagnosis. The plaques should stain positively with β-amyloid antibodies and negative for prion antibodies (which are diagnostic of The numbers of plaques and tangles must exceed those found in age-matched controls without dementia. Guidelines for the quantitative assessment of these changes exist [ Aggregation of alpha-synuclein in the form of Lewy bodies may also be found in neurons in the amygdala; frequently there is accumulation of TDP-43 protein [ The clinical diagnosis of AD, based on clinical signs of slowly progressive dementia and neuroimaging findings of gross cerebral cortical atrophy, is correct approximately 80%-90% of the time. Greater precision can be obtained by use of more sophisticated studies such as amyloid PET imaging, CSF concentrations of amyloid and tau, and (in the near future) tau PET imaging and plasma concentration of β amyloid [ • The plaques should stain positively with β-amyloid antibodies and negative for prion antibodies (which are diagnostic of • The numbers of plaques and tangles must exceed those found in age-matched controls without dementia. Guidelines for the quantitative assessment of these changes exist [ • Aggregation of alpha-synuclein in the form of Lewy bodies may also be found in neurons in the amygdala; frequently there is accumulation of TDP-43 protein [ ## Causes of Alzheimer Disease Causes of Alzheimer Disease ≥3 persons in a family with AD Essentially all persons with Down syndrome (trisomy 21) develop the neuropathologic hallmarks of AD after age 40 years [ Approximately 25% of all AD is familial (i.e., ≥3 persons in a family have AD) and 75% is nonfamilial (i.e., an individual with AD and no known family history of AD). Because familial AD and nonfamilial AD appear to have the same clinical and pathologic phenotypes, they can only be distinguished by family history and/or by molecular genetic testing. Investigations have supported the concept that late-onset AD (age >60-65 years) is a complex disorder that may involve multiple susceptibility genes [ While the association of the Approximately 42% of persons with AD do Of note, the Research studies have identified variants in ~20 genes that increase the risk of AD slightly (i.e., <2%). Many of these genes have a role in brain development, cytoskeletal organization, and immune function. Variants in these susceptibility genes differ from variants in genes known to cause Alzheimer disease as no variant in any of these genes "causes" AD; therefore, these genes should not be included in any diagnostic testing (see Furthermore, it should be noted that while various combinations of variants in these genes have been proposed as markers for genetic risk of developing AD (so-called "polygenic risk scores") [ The following list of susceptibility genes is based on reviews by NOTE: The See Early-onset familial AD (EOFAD) refers to AD that occurs in multiple members of a family with a mean onset usually before age 65 years. The dementia phenotype is similar to that of late-onset AD, sometimes with a long prodrome [ Early-Onset Familial Alzheimer Disease (EOFAD) Relatively rapid progression over 6-7 yrs is common. Often associated w/seizures, myoclonus, & language deficits Founder variants identified in residents of the state of Antioquia, Colombia Mean duration: 11 yrs Reduced penetrance (i.e., asymptomatic heterozygotes age >80 yrs) reported Founder variant identified in the Volga German population AD = Alzheimer disease; FTD = frontotemporal dementia Genes are in alphabetic order. It is likely that pathogenic variants in other genes causative of EOFAD will be identified because kindreds with autosomal dominant FAD with no known pathogenic variants in • Relatively rapid progression over 6-7 yrs is common. • Often associated w/seizures, myoclonus, & language deficits • Founder variants identified in residents of the state of Antioquia, Colombia • Mean duration: 11 yrs • Reduced penetrance (i.e., asymptomatic heterozygotes age >80 yrs) reported • Founder variant identified in the Volga German population ## Familial Alzheimer Disease Approximately 25% of all AD is familial (i.e., ≥3 persons in a family have AD) and 75% is nonfamilial (i.e., an individual with AD and no known family history of AD). Because familial AD and nonfamilial AD appear to have the same clinical and pathologic phenotypes, they can only be distinguished by family history and/or by molecular genetic testing. Investigations have supported the concept that late-onset AD (age >60-65 years) is a complex disorder that may involve multiple susceptibility genes [ While the association of the Approximately 42% of persons with AD do Of note, the Research studies have identified variants in ~20 genes that increase the risk of AD slightly (i.e., <2%). Many of these genes have a role in brain development, cytoskeletal organization, and immune function. Variants in these susceptibility genes differ from variants in genes known to cause Alzheimer disease as no variant in any of these genes "causes" AD; therefore, these genes should not be included in any diagnostic testing (see Furthermore, it should be noted that while various combinations of variants in these genes have been proposed as markers for genetic risk of developing AD (so-called "polygenic risk scores") [ The following list of susceptibility genes is based on reviews by NOTE: The See Early-onset familial AD (EOFAD) refers to AD that occurs in multiple members of a family with a mean onset usually before age 65 years. The dementia phenotype is similar to that of late-onset AD, sometimes with a long prodrome [ Early-Onset Familial Alzheimer Disease (EOFAD) Relatively rapid progression over 6-7 yrs is common. Often associated w/seizures, myoclonus, & language deficits Founder variants identified in residents of the state of Antioquia, Colombia Mean duration: 11 yrs Reduced penetrance (i.e., asymptomatic heterozygotes age >80 yrs) reported Founder variant identified in the Volga German population AD = Alzheimer disease; FTD = frontotemporal dementia Genes are in alphabetic order. It is likely that pathogenic variants in other genes causative of EOFAD will be identified because kindreds with autosomal dominant FAD with no known pathogenic variants in • Relatively rapid progression over 6-7 yrs is common. • Often associated w/seizures, myoclonus, & language deficits • Founder variants identified in residents of the state of Antioquia, Colombia • Mean duration: 11 yrs • Reduced penetrance (i.e., asymptomatic heterozygotes age >80 yrs) reported • Founder variant identified in the Volga German population ## Late-Onset Familial AD Investigations have supported the concept that late-onset AD (age >60-65 years) is a complex disorder that may involve multiple susceptibility genes [ While the association of the Approximately 42% of persons with AD do Of note, the ## Susceptibility Genes Research studies have identified variants in ~20 genes that increase the risk of AD slightly (i.e., <2%). Many of these genes have a role in brain development, cytoskeletal organization, and immune function. Variants in these susceptibility genes differ from variants in genes known to cause Alzheimer disease as no variant in any of these genes "causes" AD; therefore, these genes should not be included in any diagnostic testing (see Furthermore, it should be noted that while various combinations of variants in these genes have been proposed as markers for genetic risk of developing AD (so-called "polygenic risk scores") [ The following list of susceptibility genes is based on reviews by NOTE: The See ## Early-Onset Familial AD Early-onset familial AD (EOFAD) refers to AD that occurs in multiple members of a family with a mean onset usually before age 65 years. The dementia phenotype is similar to that of late-onset AD, sometimes with a long prodrome [ Early-Onset Familial Alzheimer Disease (EOFAD) Relatively rapid progression over 6-7 yrs is common. Often associated w/seizures, myoclonus, & language deficits Founder variants identified in residents of the state of Antioquia, Colombia Mean duration: 11 yrs Reduced penetrance (i.e., asymptomatic heterozygotes age >80 yrs) reported Founder variant identified in the Volga German population AD = Alzheimer disease; FTD = frontotemporal dementia Genes are in alphabetic order. It is likely that pathogenic variants in other genes causative of EOFAD will be identified because kindreds with autosomal dominant FAD with no known pathogenic variants in • Relatively rapid progression over 6-7 yrs is common. • Often associated w/seizures, myoclonus, & language deficits • Founder variants identified in residents of the state of Antioquia, Colombia • Mean duration: 11 yrs • Reduced penetrance (i.e., asymptomatic heterozygotes age >80 yrs) reported • Founder variant identified in the Volga German population ## Evaluation Strategies to Identify the Genetic Cause of Alzheimer Disease in a Proband Establishing a specific genetic cause of Alzheimer disease (AD): Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, and laboratory testing to exclude disorders included in the differential diagnosis (see The two most important indicators of a genetic form of AD are age of onset ( There is no specific age cutoff and the general rule is that in a single individual diagnosed with AD, the earlier the onset, the more likely a genetic cause. Onset before 50 years has the highest likelihood of a genetic cause and after 70 years the lowest. A positive family history (≥3 affected persons) of early-onset dementia increases the probability of a genetic cause. Because of the significant overlap in clinical manifestations and age of onset in AD, single-gene testing (i.e., sequence analysis, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended. NOTE: Some laboratories offer multigene panels for "neurodegenerative disorders." While the genes included in such panels are likely to vary significantly by laboratory, often the genes known to cause the disorders mentioned in the differential diagnosis of AD (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, and laboratory testing to exclude disorders included in the differential diagnosis (see • There is no specific age cutoff and the general rule is that in a single individual diagnosed with AD, the earlier the onset, the more likely a genetic cause. Onset before 50 years has the highest likelihood of a genetic cause and after 70 years the lowest. • A positive family history (≥3 affected persons) of early-onset dementia increases the probability of a genetic cause. ## Inform Genetic Counseling of Family Members of an Individual with Alzheimer Disease Genetic counseling for people with late-onset nonfamilial AD (i.e., an individual with AD and no known family history) and their family members must be empiric and relatively nonspecific. First-degree relatives of a person with nonfamilial AD have a cumulative lifetime risk of developing AD of approximately 15%-39%, which is typically reported as a 20%-25% risk [ Disagreement exists as to whether the age of onset of AD in a person with nonfamilial AD changes the risk to first-degree relatives. Inheritance of LOFAD (i.e., ≥3 persons in a family have AD) is thought to be multifactorial and potentially involve multiple susceptibility genes [ EOFAD in which an individual has a pathogenic variant in Most individuals diagnosed as having Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. A proband with EOFAD may have the disorder as the result of a The family history of some individuals diagnosed with EOFAD 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 (age-related) penetrance. Therefore, an apparently negative family history cannot be considered 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 was affected and/or is known to be heterozygous for an Sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for EOFAD because of the possibility of reduced (age-related) penetrance in a parent. Predictive testing for asymptomatic adults at risk for 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 EOFAD, it is appropriate to consider testing of symptomatic individuals regardless of age. A young asymptomatic female who is homozygous for the A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ See the • Most individuals diagnosed as having • Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. • Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. • A proband with EOFAD may have the disorder as the result of a • The family history of some individuals diagnosed with EOFAD 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 (age-related) penetrance. Therefore, an apparently negative family history cannot be considered confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. • If a parent of the proband was affected and/or is known to be heterozygous for an • Sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for EOFAD because of the possibility of reduced (age-related) penetrance in a parent. • Predictive testing for asymptomatic adults at risk for • 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 • • A young asymptomatic female who is homozygous for the • A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ • A young asymptomatic female who is homozygous for the • A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ • A young asymptomatic female who is homozygous for the • A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ ## Risk to Family Members – Nonfamilial Alzheimer Disease Genetic counseling for people with late-onset nonfamilial AD (i.e., an individual with AD and no known family history) and their family members must be empiric and relatively nonspecific. First-degree relatives of a person with nonfamilial AD have a cumulative lifetime risk of developing AD of approximately 15%-39%, which is typically reported as a 20%-25% risk [ Disagreement exists as to whether the age of onset of AD in a person with nonfamilial AD changes the risk to first-degree relatives. ## Risk to Family Members – Late-Onset Familial Alzheimer Disease (LOFAD) Inheritance of LOFAD (i.e., ≥3 persons in a family have AD) is thought to be multifactorial and potentially involve multiple susceptibility genes [ ## Risk to Family Members – EOFAD in which an individual has a pathogenic variant in Most individuals diagnosed as having Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. A proband with EOFAD may have the disorder as the result of a The family history of some individuals diagnosed with EOFAD 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 (age-related) penetrance. Therefore, an apparently negative family history cannot be considered 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 was affected and/or is known to be heterozygous for an Sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for EOFAD because of the possibility of reduced (age-related) penetrance in a parent. • Most individuals diagnosed as having • Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. • Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. • A proband with EOFAD may have the disorder as the result of a • The family history of some individuals diagnosed with EOFAD 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 (age-related) penetrance. Therefore, an apparently negative family history cannot be considered confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. • Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children. • Occasionally, neither parent is identified as having had AD, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. In this instance, a parent of the proband is presumed to be heterozygous for a familial AD-causing pathogenic variant associated with reduced (age-related) penetrance. • If a parent of the proband was affected and/or is known to be heterozygous for an • Sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for EOFAD because of the possibility of reduced (age-related) penetrance in a parent. ## Related Genetic Counseling Issues Predictive testing for asymptomatic adults at risk for 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 EOFAD, it is appropriate to consider testing of symptomatic individuals regardless of age. A young asymptomatic female who is homozygous for the A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ See the • Predictive testing for asymptomatic adults at risk for • 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 • • A young asymptomatic female who is homozygous for the • A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ • A young asymptomatic female who is homozygous for the • A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ • A young asymptomatic female who is homozygous for the • A young asymptomatic homozygous male has a 25%-30% risk of developing AD by age 80 years, compared with 10%-15% probability in the general male population [ ## Resources 225 North Michigan Avenue Fl 17 Chicago IL 60601-7633 PO Box 8250 Silver Spring MD 20907 31 Center Drive Building 31, Room 5C27 MSC 2292 Bethesda MD 20892 • • 225 North Michigan Avenue • Fl 17 • Chicago IL 60601-7633 • • • PO Box 8250 • Silver Spring MD 20907 • • • • • • • 31 Center Drive • Building 31, Room 5C27 • MSC 2292 • Bethesda MD 20892 • ## Chapter Notes 20 December 2018 (bp) Comprehensive update posted live 30 March 2010 (me) Comprehensive update posted live 9 May 2007 (me) Comprehensive update posted live 10 February 2005 (me) Comprehensive update posted live 29 January 2003 (me) Comprehensive update posted live 23 October 1998 (me) Overview posted live Spring 1996 (tb) Original submission • 20 December 2018 (bp) Comprehensive update posted live • 30 March 2010 (me) Comprehensive update posted live • 9 May 2007 (me) Comprehensive update posted live • 10 February 2005 (me) Comprehensive update posted live • 29 January 2003 (me) Comprehensive update posted live • 23 October 1998 (me) Overview posted live • Spring 1996 (tb) Original submission ## Revision History 20 December 2018 (bp) Comprehensive update posted live 30 March 2010 (me) Comprehensive update posted live 9 May 2007 (me) Comprehensive update posted live 10 February 2005 (me) Comprehensive update posted live 29 January 2003 (me) Comprehensive update posted live 23 October 1998 (me) Overview posted live Spring 1996 (tb) Original submission • 20 December 2018 (bp) Comprehensive update posted live • 30 March 2010 (me) Comprehensive update posted live • 9 May 2007 (me) Comprehensive update posted live • 10 February 2005 (me) Comprehensive update posted live • 29 January 2003 (me) Comprehensive update posted live • 23 October 1998 (me) Overview posted live • Spring 1996 (tb) Original submission ## References ## Literature Cited	[]	23/10/1998	20/12/2018	24/9/2015	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
amish-mcph	amish-mcph	[ "SLC25A19 Deficiency", "SLC25A19 Deficiency", "Amish Lethal Microcephaly", "Thiamine Metabolism Dysfunction Syndrome 4 (THMD-4)", "Mitochondrial thiamine pyrophosphate carrier", "SLC25A19", "SLC25A19-Related Thiamine Metabolism Dysfunction" ]		Brahim Tabarki, Farah Thabet, Majid Alfadhel	Summary Amish lethal microcephaly is characterized by severe congenital microcephaly, developmental delay, seizures, 2-oxoglutaric aciduria, and often premature death. THMD-4 is characterized by febrile illness-associated episodic encephalopathy, progressive polyneuropathy, and bilateral striatal necrosis. The diagnosis of SLC25A19 deficiency is established in a proband with suggestive findings and biallelic pathogenic variants in SLC25A19 deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Amish lethal microcephaly Thiamine metabolism dysfunction syndrome 4 (THMD-4) For synonyms and outdated names, see For other genetic causes of these phenotypes, see • Amish lethal microcephaly • Thiamine metabolism dysfunction syndrome 4 (THMD-4) ## Diagnosis Severe congenital microcephaly Developmental delay Seizures Lactic acidosis Highly elevated (≥10-fold increase) levels of acid 2-ketoglutarate on urine organic acids Acute episodic encephalopathy and weakness triggered by fever Hypotonia with developmental delay Seizures Progressive peripheral neuropathy Lactic acidosis Brain MRI shows T The diagnosis of SLC25A19 deficiency 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: Targeted analysis for the For an introduction to multigene panels click When the diagnosis of SLC25A19 deficiency has not been considered because an individual has atypical phenotypic features, 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. One large • Severe congenital microcephaly • Developmental delay • Seizures • Lactic acidosis • Highly elevated (≥10-fold increase) levels of acid 2-ketoglutarate on urine organic acids • Acute episodic encephalopathy and weakness triggered by fever • Hypotonia with developmental delay • Seizures • Progressive peripheral neuropathy • Lactic acidosis • Brain MRI shows T ## Suggestive Findings Severe congenital microcephaly Developmental delay Seizures Lactic acidosis Highly elevated (≥10-fold increase) levels of acid 2-ketoglutarate on urine organic acids Acute episodic encephalopathy and weakness triggered by fever Hypotonia with developmental delay Seizures Progressive peripheral neuropathy Lactic acidosis Brain MRI shows T • Severe congenital microcephaly • Developmental delay • Seizures • Lactic acidosis • Highly elevated (≥10-fold increase) levels of acid 2-ketoglutarate on urine organic acids • Acute episodic encephalopathy and weakness triggered by fever • Hypotonia with developmental delay • Seizures • Progressive peripheral neuropathy • Lactic acidosis • Brain MRI shows T ## Establishing the Diagnosis The diagnosis of SLC25A19 deficiency 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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Note: Targeted analysis for the For an introduction to multigene panels click When the diagnosis of SLC25A19 deficiency has not been considered because an individual has atypical phenotypic features, 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. One large ## Option 1 Note: Targeted analysis for the For an introduction to multigene panels click ## Option 2 When the diagnosis of SLC25A19 deficiency has not been considered because an individual has atypical phenotypic features, 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. One large ## Clinical Characteristics The two phenotypes observed in Amish lethal microcephaly is characterized by severe congenital microcephaly, developmental delay, seizures, 2-oxoglutaric aciduria, and often premature death. The phenotype shows little variability [ THMD-4 is characterized by febrile illness-associated episodic encephalopathy, progressive polyneuropathy, and bilateral striatal necrosis. Lack of or delayed thiamine treatment following the first acute encephalopathic episode was associated with early death or severe neurologic sequalae including dystonia, hypotonia, and developmental delay. Early supplementation with thiamine was associated with a good prognosis, with full recovery in most individuals; a few individuals had residual deficits. It is unknown whether life span in individuals with THMD-4 is abnormal. One reported individual is alive at age 18 years [ In those with other Thiamine metabolism dysfunction syndrome 4 may also be referred to as Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors from Lancaster County, Pennsylvania. At least 61 affected infants have been born to 33 nuclear families in the past 40 years. In this population, incidence is approximately one in 500 births. THMD-4 is a rare disorder, with only 16 individuals reported to date. ## Clinical Description The two phenotypes observed in Amish lethal microcephaly is characterized by severe congenital microcephaly, developmental delay, seizures, 2-oxoglutaric aciduria, and often premature death. The phenotype shows little variability [ THMD-4 is characterized by febrile illness-associated episodic encephalopathy, progressive polyneuropathy, and bilateral striatal necrosis. Lack of or delayed thiamine treatment following the first acute encephalopathic episode was associated with early death or severe neurologic sequalae including dystonia, hypotonia, and developmental delay. Early supplementation with thiamine was associated with a good prognosis, with full recovery in most individuals; a few individuals had residual deficits. It is unknown whether life span in individuals with THMD-4 is abnormal. One reported individual is alive at age 18 years [ ## Amish Lethal Microcephaly Amish lethal microcephaly is characterized by severe congenital microcephaly, developmental delay, seizures, 2-oxoglutaric aciduria, and often premature death. The phenotype shows little variability [ ## Thiamine Metabolism Dysfunction Syndrome 4 (THMD-4) THMD-4 is characterized by febrile illness-associated episodic encephalopathy, progressive polyneuropathy, and bilateral striatal necrosis. Lack of or delayed thiamine treatment following the first acute encephalopathic episode was associated with early death or severe neurologic sequalae including dystonia, hypotonia, and developmental delay. Early supplementation with thiamine was associated with a good prognosis, with full recovery in most individuals; a few individuals had residual deficits. It is unknown whether life span in individuals with THMD-4 is abnormal. One reported individual is alive at age 18 years [ ## Genotype-Phenotype Correlations In those with other ## Nomenclature Thiamine metabolism dysfunction syndrome 4 may also be referred to as ## Prevalence Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors from Lancaster County, Pennsylvania. At least 61 affected infants have been born to 33 nuclear families in the past 40 years. In this population, incidence is approximately one in 500 births. THMD-4 is a rare disorder, with only 16 individuals reported to date. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The primary microcephalies are a group of rare, phenotypically and etiologically heterogeneous disorders of brain growth characterized by (1) a head circumference two or more standard deviations (SD) below the mean at birth and three or more SD below the mean by age one year, and (2) mild-to-severe intellectual disability. Additional clinical or neuroimaging features can be associated. Most primary microcephalies are inherited in an autosomal recessive manner. To date, pathogenic variants in more than 100 genes are known to cause primary microcephaly (for review, see The degree of microcephaly is much greater in Amish lethal microcephaly than in any of these other genetically defined microcephaly syndromes. Additionally, 2-ketoglutaric aciduria is a good clue for the diagnosis of Amish lethal microcephaly, as 2-ketoglutaric aciduria has not been reported as a finding in other genetically defined microcephaly syndromes. Genes of Interest in the Differential Diagnosis of Thiamine Metabolism Dysfunction Syndrome 4 AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; XL = X-linked More than 65 organic acids are known [ The term "Leigh-like syndrome" is often used for individuals with clinical and other features that are strongly suggestive of Leigh syndrome but who do not fulfill the stringent diagnostic criteria because of atypical neuropathology (variation in the distribution or character of lesions or with the additional presence of unusual features such as extensive cortical destruction), atypical or normal neuroimaging, normal blood and cerebrospinal fluid lactate levels, or incomplete evaluation. The heterogeneous clinical presentation that occurs in Leigh syndrome is also present in Leigh-like syndromes. (See See ## Amish Lethal Microcephaly The primary microcephalies are a group of rare, phenotypically and etiologically heterogeneous disorders of brain growth characterized by (1) a head circumference two or more standard deviations (SD) below the mean at birth and three or more SD below the mean by age one year, and (2) mild-to-severe intellectual disability. Additional clinical or neuroimaging features can be associated. Most primary microcephalies are inherited in an autosomal recessive manner. To date, pathogenic variants in more than 100 genes are known to cause primary microcephaly (for review, see The degree of microcephaly is much greater in Amish lethal microcephaly than in any of these other genetically defined microcephaly syndromes. Additionally, 2-ketoglutaric aciduria is a good clue for the diagnosis of Amish lethal microcephaly, as 2-ketoglutaric aciduria has not been reported as a finding in other genetically defined microcephaly syndromes. ## Thiamine Metabolism Dysfunction Syndrome 4 Genes of Interest in the Differential Diagnosis of Thiamine Metabolism Dysfunction Syndrome 4 AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; XL = X-linked More than 65 organic acids are known [ The term "Leigh-like syndrome" is often used for individuals with clinical and other features that are strongly suggestive of Leigh syndrome but who do not fulfill the stringent diagnostic criteria because of atypical neuropathology (variation in the distribution or character of lesions or with the additional presence of unusual features such as extensive cortical destruction), atypical or normal neuroimaging, normal blood and cerebrospinal fluid lactate levels, or incomplete evaluation. The heterogeneous clinical presentation that occurs in Leigh syndrome is also present in Leigh-like syndromes. (See See ## Management No clinical practice guidelines for To establish the extent of disease in an individual diagnosed with SLC25A19 deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Neurologic eval Urine organic acids To incl brain MRI Consider EEG if seizures are a concern. Consider serum lactate & blood gas. 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. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Oral thiamine treatment (400-600 mg daily) is critical from the time of diagnosis. The dose must be increased during febrile illness, surgery, or acute decompensation (by 25%). This treatment is lifelong. It prevents metabolic decompensation and improves outcomes [ In Amish lethal microcephaly, thiamine supplementation is usually without benefit. One individual showed stabilization of his symptoms with thiamine treatment [ 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 May require admission to ICU to manage seizures & ↑ intracranial pressure. ↑ thiamine to 2x the daily dose (up to 1,500 mg daily); can administer thiamine intravenously. Standardized treatment w/ASM by experienced neurologist. The few children w/Amish lethal microcephaly who were treated responded well to phenobarbital. Many ASMs may be effective. Valproate must be avoided. Education of parents/caregivers Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls Infants w/Amish lethal microcephaly have responded to benzodiazepine anxiolytics. 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 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 To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake OT = occupational therapy; PT = physical therapy Avoidance of contact with individuals with communicable respiratory diseases is appropriate. Avoid sodium valproate as an anti-seizure medication. 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 For at-risk newborn sibs when prenatal testing was not performed, prior to genetic testing, or while it is under way, urine organic acids and pyruvate and lactate levels should be considered. Supplementation with pharmacologic doses of thiamine (vitamin B See Search • Neurologic eval • Urine organic acids • To incl brain MRI • Consider EEG if seizures are a concern. • Consider serum lactate & blood gas. • 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. • Community or • Social work involvement for parental support; • Home nursing referral. • May require admission to ICU to manage seizures & ↑ intracranial pressure. • ↑ thiamine to 2x the daily dose (up to 1,500 mg daily); can administer thiamine intravenously. • Standardized treatment w/ASM by experienced neurologist. • The few children w/Amish lethal microcephaly who were treated responded well to phenobarbital. • Many ASMs may be effective. • Valproate must be avoided. • Education of parents/caregivers • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls • Infants w/Amish lethal microcephaly have responded to benzodiazepine anxiolytics. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Evaluation Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with SLC25A19 deficiency, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Neurologic eval Urine organic acids To incl brain MRI Consider EEG if seizures are a concern. Consider serum lactate & blood gas. 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. Community or Social work involvement for parental support; Home nursing referral. MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Neurologic eval • Urine organic acids • To incl brain MRI • Consider EEG if seizures are a concern. • Consider serum lactate & blood gas. • 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. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Oral thiamine treatment (400-600 mg daily) is critical from the time of diagnosis. The dose must be increased during febrile illness, surgery, or acute decompensation (by 25%). This treatment is lifelong. It prevents metabolic decompensation and improves outcomes [ In Amish lethal microcephaly, thiamine supplementation is usually without benefit. One individual showed stabilization of his symptoms with thiamine treatment [ 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 May require admission to ICU to manage seizures & ↑ intracranial pressure. ↑ thiamine to 2x the daily dose (up to 1,500 mg daily); can administer thiamine intravenously. Standardized treatment w/ASM by experienced neurologist. The few children w/Amish lethal microcephaly who were treated responded well to phenobarbital. Many ASMs may be effective. Valproate must be avoided. Education of parents/caregivers Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls Infants w/Amish lethal microcephaly have responded to benzodiazepine anxiolytics. 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 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 • May require admission to ICU to manage seizures & ↑ intracranial pressure. • ↑ thiamine to 2x the daily dose (up to 1,500 mg daily); can administer thiamine intravenously. • Standardized treatment w/ASM by experienced neurologist. • The few children w/Amish lethal microcephaly who were treated responded well to phenobarbital. • Many ASMs may be effective. • Valproate must be avoided. • Education of parents/caregivers • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls • Infants w/Amish lethal microcephaly have responded to benzodiazepine anxiolytics. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Targeted Therapy Oral thiamine treatment (400-600 mg daily) is critical from the time of diagnosis. The dose must be increased during febrile illness, surgery, or acute decompensation (by 25%). This treatment is lifelong. It prevents metabolic decompensation and improves outcomes [ In Amish lethal microcephaly, thiamine supplementation is usually without benefit. One individual showed stabilization of his symptoms with thiamine treatment [ ## 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 May require admission to ICU to manage seizures & ↑ intracranial pressure. ↑ thiamine to 2x the daily dose (up to 1,500 mg daily); can administer thiamine intravenously. Standardized treatment w/ASM by experienced neurologist. The few children w/Amish lethal microcephaly who were treated responded well to phenobarbital. Many ASMs may be effective. Valproate must be avoided. Education of parents/caregivers Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls Infants w/Amish lethal microcephaly have responded to benzodiazepine anxiolytics. 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 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 • May require admission to ICU to manage seizures & ↑ intracranial pressure. • ↑ thiamine to 2x the daily dose (up to 1,500 mg daily); can administer thiamine intravenously. • Standardized treatment w/ASM by experienced neurologist. • The few children w/Amish lethal microcephaly who were treated responded well to phenobarbital. • Many ASMs may be effective. • Valproate must be avoided. • Education of parents/caregivers • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls • Infants w/Amish lethal microcephaly have responded to benzodiazepine anxiolytics. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## 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 Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Agents/Circumstances to Avoid Avoidance of contact with individuals with communicable respiratory diseases is appropriate. Avoid sodium valproate as an anti-seizure medication. ## 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 For at-risk newborn sibs when prenatal testing was not performed, prior to genetic testing, or while it is under way, urine organic acids and pyruvate and lactate levels should be considered. Supplementation with pharmacologic doses of thiamine (vitamin B 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, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Intrafamilial clinical variability has not been reported to date. Heterozygotes (carriers) are asymptomatic, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder. Amish lethal microcephaly is lethal before reproductive age. To date, individuals with thiamine metabolism dysfunction syndrome 4 are not known to reproduce. Carrier testing for at-risk family members requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors in Lancaster County, Pennsylvania. In this population, incidence is approximately one in 500 births (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 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, have normal urinary excretion of 2-ketoglutarate, 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 not been reported to date. • Heterozygotes (carriers) are asymptomatic, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder. • Amish lethal microcephaly is lethal before reproductive age. • To date, individuals with thiamine metabolism dysfunction syndrome 4 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 young adults who are carriers or are at risk of being carriers. • Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors in Lancaster County, Pennsylvania. In this population, incidence is approximately one in 500 births (see ## 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, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Intrafamilial clinical variability has not been reported to date. Heterozygotes (carriers) are asymptomatic, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder. Amish lethal microcephaly is lethal before reproductive age. To date, individuals with thiamine metabolism dysfunction syndrome 4 are not known to reproduce. • 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, have normal urinary excretion of 2-ketoglutarate, 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 not been reported to date. • Heterozygotes (carriers) are asymptomatic, have normal urinary excretion of 2-ketoglutarate, and are not at risk of developing the disorder. • Amish lethal microcephaly is lethal before reproductive age. • To date, individuals with thiamine metabolism dysfunction syndrome 4 are not known to reproduce. ## Carrier Detection Carrier testing for at-risk family members requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Carrier testing for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors in Lancaster County, Pennsylvania. In this population, incidence is approximately one in 500 births (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 for the reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. Amish lethal microcephaly has been found primarily in the Old Order Amish who have ancestors in Lancaster County, Pennsylvania. In this population, incidence is approximately one in 500 births (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 PO Box 5801 Bethesda MD 20824 • • • • PO Box 5801 • Bethesda MD 20824 • ## Molecular Genetics SLC25A19-Related Thiamine Metabolism Dysfunction: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SLC25A19-Related Thiamine Metabolism Dysfunction ( A bacterially expressed human SLC25A19 protein containing the Knockout mouse embryos homozygous for a null allele of Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis A bacterially expressed human SLC25A19 protein containing the Knockout mouse embryos homozygous for a null allele of Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Majid Alfadhel, MD, FCCMG (2023-present)Leslie G Biesecker, MD; National Human Genome Research Institute (2003-2023)Marjorie J Lindhurst, PhD; National Human Genome Research Institute (2003-2017)Brahim Tabarki, MD (2023-present)Farah Thabet, MD (2023-present) 30 March 2023 (sw) Comprehensive update posted live 7 December 2017 (ha) Comprehensive update posted live 16 June 2011 (me) Comprehensive update posted live 5 May 2009 (me) Comprehensive update posted 20 December 2005 (me) Comprehensive update posted live 4 September 2003 (me) Review posted live 24 June 2003 (mjl) Original submission • 30 March 2023 (sw) Comprehensive update posted live • 7 December 2017 (ha) Comprehensive update posted live • 16 June 2011 (me) Comprehensive update posted live • 5 May 2009 (me) Comprehensive update posted • 20 December 2005 (me) Comprehensive update posted live • 4 September 2003 (me) Review posted live • 24 June 2003 (mjl) Original submission ## Author History Majid Alfadhel, MD, FCCMG (2023-present)Leslie G Biesecker, MD; National Human Genome Research Institute (2003-2023)Marjorie J Lindhurst, PhD; National Human Genome Research Institute (2003-2017)Brahim Tabarki, MD (2023-present)Farah Thabet, MD (2023-present) ## Revision History 30 March 2023 (sw) Comprehensive update posted live 7 December 2017 (ha) Comprehensive update posted live 16 June 2011 (me) Comprehensive update posted live 5 May 2009 (me) Comprehensive update posted 20 December 2005 (me) Comprehensive update posted live 4 September 2003 (me) Review posted live 24 June 2003 (mjl) Original submission • 30 March 2023 (sw) Comprehensive update posted live • 7 December 2017 (ha) Comprehensive update posted live • 16 June 2011 (me) Comprehensive update posted live • 5 May 2009 (me) Comprehensive update posted • 20 December 2005 (me) Comprehensive update posted live • 4 September 2003 (me) Review posted live • 24 June 2003 (mjl) Original submission ## Key Sections in this ## References ## Literature Cited	[]	4/9/2003	30/3/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
amrf	amrf	[ "Lysosome membrane protein 2", "SCARB2", "SCARB2-Related Action Myoclonus-Renal Failure Syndrome" ]		Changrui Xiao, Haejun Ahn, Sara Kibrom, Camilo Toro	Summary The diagnosis of The supportive care for neurologic manifestations that is recommended to improve quality of life, maximize function, and reduce complications includes pharmacotherapy to reduce myoclonus; anti-seizure medication (ASM) and vagus nerve stimulation to reduce seizures; physical and occupational therapy to help maintain mobility and optimize activities of daily living; adaptive devices to help maintain/improve independence in mobility; educational support for those with cognitive decline; speech-language therapy to explore use of alternative communication methods; feeding therapy programs for those with dysphagia to improve nutrition and reduce aspiration risk. Treatment for renal involvement, under the care of a nephrologist, is typically focused on remission of proteinuria and often includes a combination of renin-angiotensin-aldosterone inhibition and immunosuppressive medications. Treatment of ESKD is supportive; while renal replacement therapy can prolong survival, it does not improve neurologic features. In addition, all women of childbearing age should be advised to take 1 mg/day of folic acid and to increase it to 4 mg/day when planning a pregnancy (ideally three months prior to conception) and during the pregnancy, in order to reduce the risk of congenital malformations that can be associated with fetal exposure to ASMs.	## Diagnosis No consensus clinical diagnostic criteria for The tremor can later involve the head, trunk, lower extremities, and sometimes tongue and voice. In the later stages of the disease, it may become masked by striking myoclonic jerks. Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); Sensorineural hearing loss. Proteinuria, the first manifestation of kidney disease, is initially mild and asymptomatic. Kidney disease can progress to nephrotic syndrome and end-stage kidney disease. Common histologic findings on kidney biopsy include tubular abnormalities and focal segmental glomerulosclerosis. In some families, renal manifestations appear first in late childhood or the early teenage years and neurologic manifestations in the late third or early fourth decade [ 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 (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions and duplications. Methods used may include a range of techniques such as 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 tremor can later involve the head, trunk, lower extremities, and sometimes tongue and voice. In the later stages of the disease, it may become masked by striking myoclonic jerks. • Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); • Sensorineural hearing loss. • Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); • Sensorineural hearing loss. • Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); • Sensorineural hearing loss. • Proteinuria, the first manifestation of kidney disease, is initially mild and asymptomatic. • Kidney disease can progress to nephrotic syndrome and end-stage kidney disease. • Common histologic findings on kidney biopsy include tubular abnormalities and focal segmental glomerulosclerosis. • In some families, renal manifestations appear first in late childhood or the early teenage years and neurologic manifestations in the late third or early fourth decade [ ## Suggestive Findings The tremor can later involve the head, trunk, lower extremities, and sometimes tongue and voice. In the later stages of the disease, it may become masked by striking myoclonic jerks. Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); Sensorineural hearing loss. Proteinuria, the first manifestation of kidney disease, is initially mild and asymptomatic. Kidney disease can progress to nephrotic syndrome and end-stage kidney disease. Common histologic findings on kidney biopsy include tubular abnormalities and focal segmental glomerulosclerosis. In some families, renal manifestations appear first in late childhood or the early teenage years and neurologic manifestations in the late third or early fourth decade [ • The tremor can later involve the head, trunk, lower extremities, and sometimes tongue and voice. In the later stages of the disease, it may become masked by striking myoclonic jerks. • Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); • Sensorineural hearing loss. • Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); • Sensorineural hearing loss. • Sensorimotor peripheral neuropathy (most often predominantly demyelinating or more rarely axonal); • Sensorineural hearing loss. • Proteinuria, the first manifestation of kidney disease, is initially mild and asymptomatic. • Kidney disease can progress to nephrotic syndrome and end-stage kidney disease. • Common histologic findings on kidney biopsy include tubular abnormalities and focal segmental glomerulosclerosis. • In some families, renal manifestations appear first in late childhood or the early teenage years and neurologic manifestations in the late third or early fourth decade [ ## 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 (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions and duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions and duplications. Methods used may include a range of techniques such as 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 age of onset varies, even within the same family. Neurologic manifestations can appear before (in one third of affected individuals), simultaneously, or after renal manifestations. In juvenile In some persons renal manifestations occur early (late childhood or early teenage years) and neurologic involvement much later (late in the third decade or early in the fourth decade) [ In three persons of Japanese descent who did not develop SRNS, neurologic manifestations appeared in the fifth or sixth decade [ The neurologic and renal manifestations progress independently. Of note, the neurologic manifestations are not the result of a metabolic encephalopathy due to renal involvement (chronic kidney disease [CKD] or ESKD) and are not improved by treatment of the renal disease by either dialysis or by kidney transplantation [ Even in the same family, the number and range of clinical manifestations and the order of their appearance can vary. Neurologic manifestations may occur first or in isolation in some family members, and renal manifestations may occur first or in isolation in other family members [ Renal manifestations can be variable even within the same family, including proteinuria, reduced creatinine clearance, CKD, or ESKD. Some individuals do not develop kidney disease [ The disease progresses relentlessly, with neurologic deterioration (especially increasing severity of myoclonus) and/or ESKD leading to death within seven to 15 years after onset. SCARB2-Related Action Myoclonus – Renal Failure Syndrome: Frequency of Select Neurologic Features With time, myoclonic jerks involve the proximal limbs. Their amplitude and frequency increase by movements of the limbs, typically by walking down stairs. Action myoclonus can also involve the trunk. Attempts at speaking and executed speech can induce myoclonus of the bulbar musculature, contributing to the dysarthria. Myoclonus can also be "negative" and characterized by a sudden cessation of postural tone that leads to postural lapses. This is particularly prominent in the standing position, where postural lapses of the antigravity muscles create a "bouncing" stance [ Action myoclonus is often the most disabling neurologic manifestation and may prevent affected individuals from performing activities of daily living such as speaking, swallowing food, or walking [ Intermittent photic stimulation may produce whole-body myoclonus with multiple spikes in the EEG record associated with slow waves. These generalized spike/polyspike-wave bursts can outlast the duration of light stimulation [ Follow up over the course of the disease shows a preserved alpha background activity at disease onset, with rare generalized or focal epileptiform discharges. Over the years, irregular slower theta and delta waves progressively intermix with the alpha waves, and the epileptic activity becomes more frequent [ Some affected individuals may be diagnosed with a predominantly demyelinating peripheral neuropathy before the onset of renal involvement [ The initial manifestation of renal disease is mild proteinuria that may progress to nephrotic syndrome and ultimately to end-stage kidney disease (ESKD). In 15 individuals with AMRF, proteinuria, which occurred in all individuals, was detected between ages nine and 30 years (mean: 20.1 years, median: 19 years); in 12 individuals progression to ESKD requiring dialysis or kidney transplant occurred within zero to eight years of diagnosis (mean: 3.8 years, median: 4.5 years) [ The renal manifestations may precede or follow the onset of neurologic findings and can be variable, even within the same family. In two sibs with molecularly confirmed In another family, proteinuria was detected in two sisters three to four years following the onset of neurologic manifestations. Both subsequently developed nephrotic syndrome (proteinuria, anasarca, and pleural effusions). One died of FSGS can be classified as primary (idiopathic), secondary (infection/inflammation, malignancy, drug related), and genetic. Individuals with genetic forms of FSGS or SRNS are unlikely to benefit from prolonged immunosuppression [ Disease onset in the fifth or sixth decade has been reported in two Japanese families to date. No data on long-term survival exists for No genotype-phenotype correlations have been observed. Of note, three individuals known to have late-onset disease were homozygous for the The title of this Familial myoclonus with renal failure Progressive myoclonus epilepsy with renal failure Epilepsy, progressive myoclonic 4 (EPM4), with or without renal failure. However, the presence or absence of renal failure represents only part of the clinical spectrum of AMRF. The term "progressive myoclonus epilepsy (PME)" covers a large group of diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration. Exact prevalence figures are not available. • Neurologic manifestations can appear before (in one third of affected individuals), simultaneously, or after renal manifestations. In juvenile • In some persons renal manifestations occur early (late childhood or early teenage years) and neurologic involvement much later (late in the third decade or early in the fourth decade) [ • In three persons of Japanese descent who did not develop SRNS, neurologic manifestations appeared in the fifth or sixth decade [ • Familial myoclonus with renal failure • Progressive myoclonus epilepsy with renal failure • Epilepsy, progressive myoclonic 4 (EPM4), with or without renal failure. However, the presence or absence of renal failure represents only part of the clinical spectrum of AMRF. ## Clinical Description The age of onset varies, even within the same family. Neurologic manifestations can appear before (in one third of affected individuals), simultaneously, or after renal manifestations. In juvenile In some persons renal manifestations occur early (late childhood or early teenage years) and neurologic involvement much later (late in the third decade or early in the fourth decade) [ In three persons of Japanese descent who did not develop SRNS, neurologic manifestations appeared in the fifth or sixth decade [ The neurologic and renal manifestations progress independently. Of note, the neurologic manifestations are not the result of a metabolic encephalopathy due to renal involvement (chronic kidney disease [CKD] or ESKD) and are not improved by treatment of the renal disease by either dialysis or by kidney transplantation [ Even in the same family, the number and range of clinical manifestations and the order of their appearance can vary. Neurologic manifestations may occur first or in isolation in some family members, and renal manifestations may occur first or in isolation in other family members [ Renal manifestations can be variable even within the same family, including proteinuria, reduced creatinine clearance, CKD, or ESKD. Some individuals do not develop kidney disease [ The disease progresses relentlessly, with neurologic deterioration (especially increasing severity of myoclonus) and/or ESKD leading to death within seven to 15 years after onset. SCARB2-Related Action Myoclonus – Renal Failure Syndrome: Frequency of Select Neurologic Features With time, myoclonic jerks involve the proximal limbs. Their amplitude and frequency increase by movements of the limbs, typically by walking down stairs. Action myoclonus can also involve the trunk. Attempts at speaking and executed speech can induce myoclonus of the bulbar musculature, contributing to the dysarthria. Myoclonus can also be "negative" and characterized by a sudden cessation of postural tone that leads to postural lapses. This is particularly prominent in the standing position, where postural lapses of the antigravity muscles create a "bouncing" stance [ Action myoclonus is often the most disabling neurologic manifestation and may prevent affected individuals from performing activities of daily living such as speaking, swallowing food, or walking [ Intermittent photic stimulation may produce whole-body myoclonus with multiple spikes in the EEG record associated with slow waves. These generalized spike/polyspike-wave bursts can outlast the duration of light stimulation [ Follow up over the course of the disease shows a preserved alpha background activity at disease onset, with rare generalized or focal epileptiform discharges. Over the years, irregular slower theta and delta waves progressively intermix with the alpha waves, and the epileptic activity becomes more frequent [ Some affected individuals may be diagnosed with a predominantly demyelinating peripheral neuropathy before the onset of renal involvement [ The initial manifestation of renal disease is mild proteinuria that may progress to nephrotic syndrome and ultimately to end-stage kidney disease (ESKD). In 15 individuals with AMRF, proteinuria, which occurred in all individuals, was detected between ages nine and 30 years (mean: 20.1 years, median: 19 years); in 12 individuals progression to ESKD requiring dialysis or kidney transplant occurred within zero to eight years of diagnosis (mean: 3.8 years, median: 4.5 years) [ The renal manifestations may precede or follow the onset of neurologic findings and can be variable, even within the same family. In two sibs with molecularly confirmed In another family, proteinuria was detected in two sisters three to four years following the onset of neurologic manifestations. Both subsequently developed nephrotic syndrome (proteinuria, anasarca, and pleural effusions). One died of FSGS can be classified as primary (idiopathic), secondary (infection/inflammation, malignancy, drug related), and genetic. Individuals with genetic forms of FSGS or SRNS are unlikely to benefit from prolonged immunosuppression [ Disease onset in the fifth or sixth decade has been reported in two Japanese families to date. No data on long-term survival exists for • Neurologic manifestations can appear before (in one third of affected individuals), simultaneously, or after renal manifestations. In juvenile • In some persons renal manifestations occur early (late childhood or early teenage years) and neurologic involvement much later (late in the third decade or early in the fourth decade) [ • In three persons of Japanese descent who did not develop SRNS, neurologic manifestations appeared in the fifth or sixth decade [ ## Neurologic Disease With time, myoclonic jerks involve the proximal limbs. Their amplitude and frequency increase by movements of the limbs, typically by walking down stairs. Action myoclonus can also involve the trunk. Attempts at speaking and executed speech can induce myoclonus of the bulbar musculature, contributing to the dysarthria. Myoclonus can also be "negative" and characterized by a sudden cessation of postural tone that leads to postural lapses. This is particularly prominent in the standing position, where postural lapses of the antigravity muscles create a "bouncing" stance [ Action myoclonus is often the most disabling neurologic manifestation and may prevent affected individuals from performing activities of daily living such as speaking, swallowing food, or walking [ Intermittent photic stimulation may produce whole-body myoclonus with multiple spikes in the EEG record associated with slow waves. These generalized spike/polyspike-wave bursts can outlast the duration of light stimulation [ Follow up over the course of the disease shows a preserved alpha background activity at disease onset, with rare generalized or focal epileptiform discharges. Over the years, irregular slower theta and delta waves progressively intermix with the alpha waves, and the epileptic activity becomes more frequent [ Some affected individuals may be diagnosed with a predominantly demyelinating peripheral neuropathy before the onset of renal involvement [ ## Renal Disease The initial manifestation of renal disease is mild proteinuria that may progress to nephrotic syndrome and ultimately to end-stage kidney disease (ESKD). In 15 individuals with AMRF, proteinuria, which occurred in all individuals, was detected between ages nine and 30 years (mean: 20.1 years, median: 19 years); in 12 individuals progression to ESKD requiring dialysis or kidney transplant occurred within zero to eight years of diagnosis (mean: 3.8 years, median: 4.5 years) [ The renal manifestations may precede or follow the onset of neurologic findings and can be variable, even within the same family. In two sibs with molecularly confirmed In another family, proteinuria was detected in two sisters three to four years following the onset of neurologic manifestations. Both subsequently developed nephrotic syndrome (proteinuria, anasarca, and pleural effusions). One died of FSGS can be classified as primary (idiopathic), secondary (infection/inflammation, malignancy, drug related), and genetic. Individuals with genetic forms of FSGS or SRNS are unlikely to benefit from prolonged immunosuppression [ ## Other Findings ## Late-Onset Disease onset in the fifth or sixth decade has been reported in two Japanese families to date. ## Prognosis No data on long-term survival exists for ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been observed. Of note, three individuals known to have late-onset disease were homozygous for the ## Nomenclature The title of this Familial myoclonus with renal failure Progressive myoclonus epilepsy with renal failure Epilepsy, progressive myoclonic 4 (EPM4), with or without renal failure. However, the presence or absence of renal failure represents only part of the clinical spectrum of AMRF. The term "progressive myoclonus epilepsy (PME)" covers a large group of diseases characterized by myoclonus, epilepsy, and progressive neurologic deterioration. • Familial myoclonus with renal failure • Progressive myoclonus epilepsy with renal failure • Epilepsy, progressive myoclonic 4 (EPM4), with or without renal failure. However, the presence or absence of renal failure represents only part of the clinical spectrum of AMRF. ## Prevalence Exact prevalence figures are not available. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis At the onset of neurologic manifestations, the differential diagnosis includes other causes of myoclonus such as: Acquired causes including toxic exposure (e.g., medication effects) and Lance-Adams syndrome; Metabolic encephalopathies; Hereditary, non-progressive neurologic conditions (see Hereditary Non-Progressive Myoclonic Disorders in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Also referred to as familial adult myoclonic epilepsy (FAME) & familial cortical myoclonic tremor associated with epilepsy (FCMTE) In individuals with a progressive myoclonic epilepsy (PME) phenotype who do not have biallelic Disorders with a Progressive Myoclonic Epilepsy Phenotype in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; DRPLA = dentatorubral-pallidoluysian atrophy; Mat = maternal; MERRF = myoclonic epilepsy with ragged red fibers; MOI = mode of inheritance; PME = progressive myoclonic epilepsy A recurrent See • Acquired causes including toxic exposure (e.g., medication effects) and Lance-Adams syndrome; • Metabolic encephalopathies; • Hereditary, non-progressive neurologic conditions (see ## Neurologic Manifestations At the onset of neurologic manifestations, the differential diagnosis includes other causes of myoclonus such as: Acquired causes including toxic exposure (e.g., medication effects) and Lance-Adams syndrome; Metabolic encephalopathies; Hereditary, non-progressive neurologic conditions (see Hereditary Non-Progressive Myoclonic Disorders in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Also referred to as familial adult myoclonic epilepsy (FAME) & familial cortical myoclonic tremor associated with epilepsy (FCMTE) In individuals with a progressive myoclonic epilepsy (PME) phenotype who do not have biallelic Disorders with a Progressive Myoclonic Epilepsy Phenotype in the Differential Diagnosis of AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; DRPLA = dentatorubral-pallidoluysian atrophy; Mat = maternal; MERRF = myoclonic epilepsy with ragged red fibers; MOI = mode of inheritance; PME = progressive myoclonic epilepsy A recurrent • Acquired causes including toxic exposure (e.g., medication effects) and Lance-Adams syndrome; • Metabolic encephalopathies; • Hereditary, non-progressive neurologic conditions (see ## Renal Manifestations See ## Management No clinical practice guidelines for the neurologic manifestations of Generally, myoclonus and seizure management follow the same guidelines as other PME syndromes [ Clinical practice recommendations have been published for the diagnosis and management of steroid-resistant nephrotic syndrome, the likely renal disease of 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 special education Serum creatinine/BUN; urine protein/creatinine; renal ultrasound exam May require kidney biopsy. 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/care-giver support; Home nursing referral. ADL = activities of daily living; BAEP = brain stem auditory evoked potentials; BARS = Brief Ataxia Rating Scale; BUN = blood urea nitrogen; ICARS = International Cooperative Ataxia Rating Scale; EMG = electromyogram; MOI = mode of inheritance; NCV = nerve conduction velocities; OT = occupational therapist/therapy; PT = physical therapist/therapy; SARA = Scale for the Assessment and Rating of Ataxia; Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Supportive care to improve quality of life, maximize function, and reduce complications of neurologic manifestations is recommended. This can include multidisciplinary care by specialists (see Supportive Treatment of Neurologic Manifestations in Individuals with 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) Adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs) Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration PEG tube in advanced cases Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. Social work involvement for parental/caregiver support Home nursing referral ADL = activities of daily living; OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy; SRNS = steroid-resistant nephrotic syndrome; SUDEP = sudden unexpected death in epilepsy The goal of treatment in FSGS is remission of proteinuria. Treatment often includes a combination of renin-angiotensin-aldosterone system inhibition and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors, mycophenolate mofetil, and rituximab. Therapy should be guided by a nephrologist. Treatment of end-stage kidney disease in The following information represents typical management recommendations for school-age individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. 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 BMI. Consult a nutritionist. High-calorie supplementation Urine protein/creatinine Nephrology follow up Measurement of blood pressure Urine protein/creatinine Serum creatinine concentration ADL = activities of daily living; BAEP = brain stem auditory evoked potentials; EMG = electromyogram; UMRS = Unified Myoclonus Rating Scale Phenytoin may aggravate neurologic symptoms or even accelerate cerebellar degeneration. Sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin), and gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures [ See Some anti-seizure medications (ASMs) can increase the risk of malformations, growth restriction, or neurodevelopmental disabilities in exposed fetuses. However, when pregnant women experience prolonged seizures, the risk of adverse fetal outcomes is increased. Therefore, it is recommended that pregnant women with a known seizure disorder continue to take ASMs and the prescribing physician follows standard measures to prevent fetopathy, including: Possible changes of medication prior to pregnancy; During pregnancy, spacing of ASMs into four doses a day or taking extended-release medications, so that the drug levels do not have significant peaks or troughs; Monitoring ASM dosages and levels during pregnancy and after delivery. In addition, all women of childbearing age should be advised to take 1 mg/day of folic acid and increase it to 4 mg/day when planning a pregnancy (ideally three months prior to conception) and during the pregnancy, in order to reduce the risk of neural tube defects and other congenital malformations that can be associated with fetal exposure to ASMs. See Substrate reduction therapy (SRT) with miglustat (600 mg daily) has been reported to improve myoclonus, epilepsy, and dysphagia [ While venglustat theoretically has a similar mechanism of action with better central nervous system penetration than miglustat, no reports of its use in Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for special education • Serum creatinine/BUN; urine protein/creatinine; renal ultrasound exam • May require kidney biopsy. • 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/care-giver support; • Home nursing referral. • 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) • Adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs) • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • PEG tube in advanced cases • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • Social work involvement for parental/caregiver support • Home nursing referral • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Monitor BMI. • Consult a nutritionist. • High-calorie supplementation • Urine protein/creatinine • Nephrology follow up • Measurement of blood pressure • Urine protein/creatinine • Serum creatinine concentration • Possible changes of medication prior to pregnancy; • During pregnancy, spacing of ASMs into four doses a day or taking extended-release medications, so that the drug levels do not have significant peaks or troughs; • Monitoring ASM dosages and levels during pregnancy and after delivery. ## 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 special education Serum creatinine/BUN; urine protein/creatinine; renal ultrasound exam May require kidney biopsy. 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/care-giver support; Home nursing referral. ADL = activities of daily living; BAEP = brain stem auditory evoked potentials; BARS = Brief Ataxia Rating Scale; BUN = blood urea nitrogen; ICARS = International Cooperative Ataxia Rating Scale; EMG = electromyogram; MOI = mode of inheritance; NCV = nerve conduction velocities; OT = occupational therapist/therapy; PT = physical therapist/therapy; SARA = Scale for the Assessment and Rating of Ataxia; Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for special education • Serum creatinine/BUN; urine protein/creatinine; renal ultrasound exam • May require kidney biopsy. • 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/care-giver support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Supportive care to improve quality of life, maximize function, and reduce complications of neurologic manifestations is recommended. This can include multidisciplinary care by specialists (see Supportive Treatment of Neurologic Manifestations in Individuals with 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) Adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs) Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration PEG tube in advanced cases Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. Social work involvement for parental/caregiver support Home nursing referral ADL = activities of daily living; OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy; SRNS = steroid-resistant nephrotic syndrome; SUDEP = sudden unexpected death in epilepsy The goal of treatment in FSGS is remission of proteinuria. Treatment often includes a combination of renin-angiotensin-aldosterone system inhibition and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors, mycophenolate mofetil, and rituximab. Therapy should be guided by a nephrologist. Treatment of end-stage kidney disease in The following information represents typical management recommendations for school-age individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • 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) • Adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs) • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • PEG tube in advanced cases • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • Social work involvement for parental/caregiver support • Home nursing referral • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Neurologic Manifestations Supportive care to improve quality of life, maximize function, and reduce complications of neurologic manifestations is recommended. This can include multidisciplinary care by specialists (see Supportive Treatment of Neurologic Manifestations in Individuals with 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) Adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs) Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) Video esophagram may help define best food consistency. Education re strategies to mitigate aspiration PEG tube in advanced cases Consider nutritional & vitamin supplementation to meet dietary needs. Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. Social work involvement for parental/caregiver support Home nursing referral ADL = activities of daily living; OT = occupational therapy; PEG = percutaneous endoscopic gastrostomy; PT = physical therapy; SRNS = steroid-resistant nephrotic syndrome; SUDEP = sudden unexpected death in epilepsy • 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) • Adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs) • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs) • Video esophagram may help define best food consistency. • Education re strategies to mitigate aspiration • PEG tube in advanced cases • Consider nutritional & vitamin supplementation to meet dietary needs. • Avoid obesity, which can exacerbate difficulties w/ambulation & mobility. • Social work involvement for parental/caregiver support • Home nursing referral ## Renal Disease The goal of treatment in FSGS is remission of proteinuria. Treatment often includes a combination of renin-angiotensin-aldosterone system inhibition and immunosuppressive medications such as glucocorticoids, calcineurin inhibitors, mycophenolate mofetil, and rituximab. Therapy should be guided by a nephrologist. Treatment of end-stage kidney disease in ## Developmental Delay / Intellectual Disability / Educational Issues The following information represents typical management recommendations for school-age individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Surveillance 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 BMI. Consult a nutritionist. High-calorie supplementation Urine protein/creatinine Nephrology follow up Measurement of blood pressure Urine protein/creatinine Serum creatinine concentration ADL = activities of daily living; BAEP = brain stem auditory evoked potentials; EMG = electromyogram; UMRS = Unified Myoclonus Rating Scale • Monitor BMI. • Consult a nutritionist. • High-calorie supplementation • Urine protein/creatinine • Nephrology follow up • Measurement of blood pressure • Urine protein/creatinine • Serum creatinine concentration ## Agents/Circumstances to Avoid Phenytoin may aggravate neurologic symptoms or even accelerate cerebellar degeneration. Sodium channel blockers (carbamazepine, oxcarbazepine), GABAergic drugs (tiagabine, vigabatrin), and gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures [ ## Evaluation of Relatives at Risk See ## Pregnancy Management Some anti-seizure medications (ASMs) can increase the risk of malformations, growth restriction, or neurodevelopmental disabilities in exposed fetuses. However, when pregnant women experience prolonged seizures, the risk of adverse fetal outcomes is increased. Therefore, it is recommended that pregnant women with a known seizure disorder continue to take ASMs and the prescribing physician follows standard measures to prevent fetopathy, including: Possible changes of medication prior to pregnancy; During pregnancy, spacing of ASMs into four doses a day or taking extended-release medications, so that the drug levels do not have significant peaks or troughs; Monitoring ASM dosages and levels during pregnancy and after delivery. In addition, all women of childbearing age should be advised to take 1 mg/day of folic acid and increase it to 4 mg/day when planning a pregnancy (ideally three months prior to conception) and during the pregnancy, in order to reduce the risk of neural tube defects and other congenital malformations that can be associated with fetal exposure to ASMs. See • Possible changes of medication prior to pregnancy; • During pregnancy, spacing of ASMs into four doses a day or taking extended-release medications, so that the drug levels do not have significant peaks or troughs; • Monitoring ASM dosages and levels during pregnancy and after delivery. ## Therapies Under Investigation Substrate reduction therapy (SRT) with miglustat (600 mg daily) has been reported to improve myoclonus, epilepsy, and dysphagia [ While venglustat theoretically has a similar mechanism of action with better central nervous system penetration than miglustat, no reports of its use in Search ## Genetic Counseling 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 The number and range of clinical manifestations and the order of their appearance can vary between affected sibs. Neurologic manifestations may occur first or in isolation in some family members, and renal manifestations may occur first or in isolation in other family members [ Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the For women who are affected 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 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 • The number and range of clinical manifestations and the order of their appearance can vary between affected sibs. Neurologic manifestations may occur first or in isolation in some family members, and renal manifestations may occur first or in isolation in other family members [ • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • For women who are affected 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 at risk of being carriers. ## Mode of Inheritance ## 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 The number and range of clinical manifestations and the order of their appearance can vary between affected sibs. Neurologic manifestations may occur first or in isolation in some family members, and renal manifestations may occur first or in isolation in other family members [ 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 • 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 • The number and range of clinical manifestations and the order of their appearance can vary between affected sibs. Neurologic manifestations may occur first or in isolation in some family members, and renal manifestations may occur first or in isolation in other family members [ • 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 For women who are affected 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 at risk of being carriers. • For women who are affected 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 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 Clinical, Genetic and Experimental Research into Hereditary Disease of the Podocyte • • • • Canada • • • • • • • • • • • • • Canada • • • • • • • • • Clinical, Genetic and Experimental Research into Hereditary Disease of the Podocyte • ## Molecular Genetics SCARB2-Related Action Myoclonus – Renal Failure Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for SCARB2-Related Action Myoclonus – Renal Failure Syndrome ( LMP2 likely also has other less well-characterized functions possibly related to cholesterol transport that may also contribute to disease pathogenesis [ Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis LMP2 likely also has other less well-characterized functions possibly related to cholesterol transport that may also contribute to disease pathogenesis [ Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Dr Changrui Xiao ( 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. Dina Amrom, MD; McGill University (2015-2023)Eva Andermann, MDCM, PhD, FCCMG; McGill University (2015-2023)Frederick Andermann, MD, FRCP(C); McGill University (2015-2023)Haejun Ahn, MD (2023-present)Sara Kibrom, MD (2023-present)Camilo Toro, MD (2023-present)Changrui Xiao, MD (2023-present) 9 February 2023 (bp) Comprehensive update posted live 17 December 2015 (me) Review posted live 25 February 2014 (da) Original submission • 9 February 2023 (bp) Comprehensive update posted live • 17 December 2015 (me) Review posted live • 25 February 2014 (da) Original submission ## Author Notes Dr Changrui Xiao ( ## 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. ## Author History Dina Amrom, MD; McGill University (2015-2023)Eva Andermann, MDCM, PhD, FCCMG; McGill University (2015-2023)Frederick Andermann, MD, FRCP(C); McGill University (2015-2023)Haejun Ahn, MD (2023-present)Sara Kibrom, MD (2023-present)Camilo Toro, MD (2023-present)Changrui Xiao, MD (2023-present) ## Revision History 9 February 2023 (bp) Comprehensive update posted live 17 December 2015 (me) Review posted live 25 February 2014 (da) Original submission • 9 February 2023 (bp) Comprehensive update posted live • 17 December 2015 (me) Review posted live • 25 February 2014 (da) Original submission ## References ## Literature Cited	[]	17/12/2015	9/2/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
androgen	androgen	[ "Testicular Feminization", "Testicular Feminization", "Complete Androgen Insensitivity Syndrome (CAIS)", "Partial Androgen Insensitivity Syndrome (PAIS)", "Mild Androgen Insensitivity Syndrome (MAIS)", "Androgen receptor", "AR", "Androgen Insensitivity Syndrome" ]	Androgen Insensitivity Syndrome	Bruce Gottlieb, Mark A Trifiro	Summary Androgen insensitivity syndrome (AIS) is typically characterized by evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility in individuals with a 46,XY karyotype. AIS represents a spectrum of defects in androgen action and can be subdivided into three broad phenotypes: Complete androgen insensitivity syndrome (CAIS), with typical female external genitalia Partial androgen insensitivity syndrome (PAIS) with predominantly female, predominantly male, or ambiguous external genitalia Mild androgen insensitivity syndrome (MAIS) with typical male external genitalia The diagnosis of AIS is established in an individual with a 46,XY karyotype who has: undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland; AND/OR a hemizygous pathogenic variant in AIS is inherited in an X-linked manner. Affected 46,XY individuals are almost always infertile. Each offspring of a female known to carry an Having a 46,XY karyotype and being affected Having a 46,XY karyotype and being unaffected Having a 46,XX karyotype and being a carrier Having a 46,XX karyotype and not being a carrier Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family is known.	Complete androgen insensitivity syndrome (CAIS) Partial androgen insensitivity syndrome (PAIS) Mild androgen insensitivity syndrome (MAIS) For synonyms and outdated names see For other genetic causes of these phenotypes see • Complete androgen insensitivity syndrome (CAIS) • Partial androgen insensitivity syndrome (PAIS) • Mild androgen insensitivity syndrome (MAIS) ## Diagnosis No formal diagnostic criteria for identifying AIS have as yet been published; large variance is seen at the molecular, biochemical, and morphologic levels due to the extreme variation in these characteristics with the various AIS phenotypes [ Androgen insensitivity syndrome (AIS) Absence of extragenital abnormalities Two nondysplastic testes Absent or rudimentary müllerian structures (i.e., fallopian tubes, uterus, and cervix) and the presence of a short vagina Undermasculinization of the external genitalia at birth Impaired spermatogenesis and/or somatic virilization (some degree of impaired virilization at puberty) Affected 46,XY individuals; Manifesting heterozygous females (46,XX). About 10% of heterozygous females have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair. Note: Absence of a family history of AIS or suggestive features of AIS does not preclude the diagnosis. Normal 46,XY karyotype Evidence of normal or increased synthesis of testosterone (T) by the testes Evidence of normal conversion of testosterone to dihydrotestosterone (DHT) Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland In CAIS, but not in PAIS: possible reduction in postnatal (0-3 months) surge in serum LH and serum T concentrations [ In the "predominantly male" phenotype ( Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun The diagnosis of AIS Undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased LH production by the pituitary gland; AND/OR A hemizygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Androgen Insensitivity Syndrome CAIS: 65%-95% PAIS: <50% MAIS: Unknown CAIS = complete androgen insensitivity syndrome; MAIS = mild androgen insensitivity syndrome; PAIS = partial androgen insensitivity 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. An informal survey of AIS databases in Canada, United States, and Great Britain showed that • Absence of extragenital abnormalities • Two nondysplastic testes • Absent or rudimentary müllerian structures (i.e., fallopian tubes, uterus, and cervix) and the presence of a short vagina • Undermasculinization of the external genitalia at birth • Impaired spermatogenesis and/or somatic virilization (some degree of impaired virilization at puberty) • Affected 46,XY individuals; • Manifesting heterozygous females (46,XX). About 10% of heterozygous females have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair. • Normal 46,XY karyotype • Evidence of normal or increased synthesis of testosterone (T) by the testes • Evidence of normal conversion of testosterone to dihydrotestosterone (DHT) • Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland • In CAIS, but not in PAIS: possible reduction in postnatal (0-3 months) surge in serum LH and serum T concentrations [ • In the "predominantly male" phenotype ( • Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ • Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun • Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ • Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun • Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ • Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun • Undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased LH production by the pituitary gland; AND/OR • A hemizygous pathogenic (or likely pathogenic) variant in • Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • CAIS: 65%-95% • PAIS: <50% • MAIS: Unknown ## Suggestive Findings Androgen insensitivity syndrome (AIS) Absence of extragenital abnormalities Two nondysplastic testes Absent or rudimentary müllerian structures (i.e., fallopian tubes, uterus, and cervix) and the presence of a short vagina Undermasculinization of the external genitalia at birth Impaired spermatogenesis and/or somatic virilization (some degree of impaired virilization at puberty) Affected 46,XY individuals; Manifesting heterozygous females (46,XX). About 10% of heterozygous females have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair. Note: Absence of a family history of AIS or suggestive features of AIS does not preclude the diagnosis. Normal 46,XY karyotype Evidence of normal or increased synthesis of testosterone (T) by the testes Evidence of normal conversion of testosterone to dihydrotestosterone (DHT) Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland In CAIS, but not in PAIS: possible reduction in postnatal (0-3 months) surge in serum LH and serum T concentrations [ In the "predominantly male" phenotype ( Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun • Absence of extragenital abnormalities • Two nondysplastic testes • Absent or rudimentary müllerian structures (i.e., fallopian tubes, uterus, and cervix) and the presence of a short vagina • Undermasculinization of the external genitalia at birth • Impaired spermatogenesis and/or somatic virilization (some degree of impaired virilization at puberty) • Affected 46,XY individuals; • Manifesting heterozygous females (46,XX). About 10% of heterozygous females have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair. • Normal 46,XY karyotype • Evidence of normal or increased synthesis of testosterone (T) by the testes • Evidence of normal conversion of testosterone to dihydrotestosterone (DHT) • Evidence of normal or increased luteinizing hormone (LH) production by the pituitary gland • In CAIS, but not in PAIS: possible reduction in postnatal (0-3 months) surge in serum LH and serum T concentrations [ • In the "predominantly male" phenotype ( • Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ • Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun • Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ • Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun • Less than normal decline of sex hormone-binding globulin in response to a standard dose of the anabolic androgen, stanozolol [ • Higher than normal levels of anti-müllerian hormone during the first year of life or after puberty has begun ## Establishing the Diagnosis The diagnosis of AIS Undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased LH production by the pituitary gland; AND/OR A hemizygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Androgen Insensitivity Syndrome CAIS: 65%-95% PAIS: <50% MAIS: Unknown CAIS = complete androgen insensitivity syndrome; MAIS = mild androgen insensitivity syndrome; PAIS = partial androgen insensitivity 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. An informal survey of AIS databases in Canada, United States, and Great Britain showed that • Undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structures, evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased LH production by the pituitary gland; AND/OR • A hemizygous pathogenic (or likely pathogenic) variant in • Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • CAIS: 65%-95% • PAIS: <50% • MAIS: Unknown ## Clinical Characteristics Androgen insensitivity syndrome (AIS) can be subdivided into three phenotypes: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS) ( Classification of AIS Phenotypes Absent OR rudimentary wolffian duct derivatives Absence or presence of epididymides &/or vas deferens Inguinal, labial, or abdominal testes Short blind-ending vagina Scant OR absent pubic &/OR axillary hair Inguinal OR labial testes Clitoromegaly & labial fusion Distinct urethral & vaginal openings OR aurogenital sinus Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum Descended OR undescended testes Perineoscrotal hypospadias OR urogenital sinus Gynecomastia (development of breasts) in puberty Simple (glandular or penile) OR severe (perineal) "isolated" hypospadias w/normal-sized penis & descended testes OR severe hypospadias w/micropenis, bifid scrotum, & either descended or undescended testes Gynecomastia in puberty Impaired spermatogenesis &/OR impaired pubertal virilization Gynecomastia in puberty Adapted from CAIS almost always runs true in families; that is, affected XY relatives usually have normal female external genitalia and seldom have any sign of external genital masculinization, such as clitoromegaly or posterior labial fusion [ MAIS almost always runs true in families. A correlation does exist among certain missense The correlation is much less clear in PAIS, in which interfamilial phenotypic variation is observed [ The Androgen Receptor Gene Mutations Database includes In some instances, the variable expressivity associated with a number of single-nucleotide variants may be attributed to somatic mosaicism rather than to the modifying influence of "background" genetic factors [ It remains to be determined whether specific missense variants can be correlated with normal or impaired spermatogenesis and with absence or presence of localized expressions of undervirilization (e.g., gynecomastia, high-pitched voice, impotence). Although specific variants associated with azoospermia have been reported [ No definitive data regarding penetrance exist, possibly because of under-ascertainment of affected individuals, particularly phenotypic but infertile males in whom The terms "testicular feminization" and androgen resistance syndrome are outdated and thus rarely used now. Standard references quote a prevalence of 2:100,000 to 5:100,000 for complete AIS (CAIS) based on estimates derived from otherwise healthy phenotypic females found to have histologically normal inguinal or abdominal testes. A survey in the Netherlands over a ten-year period based on reported cases of AIS concluded that the minimal incidence was 1:99,000 [ Partial AIS (PAIS) is at least as common as CAIS. The prevalence of mild AIS (MAIS) has not yet been determined. However, it is much less frequently reported than CAIS and PAIS [ • Absent OR rudimentary wolffian duct derivatives • Absence or presence of epididymides &/or vas deferens • Inguinal, labial, or abdominal testes • Short blind-ending vagina • Scant OR absent pubic &/OR axillary hair • Inguinal OR labial testes • Clitoromegaly & labial fusion • Distinct urethral & vaginal openings OR aurogenital sinus • Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum • Descended OR undescended testes • Perineoscrotal hypospadias OR urogenital sinus • Gynecomastia (development of breasts) in puberty • Simple (glandular or penile) OR severe (perineal) "isolated" hypospadias w/normal-sized penis & descended testes OR severe hypospadias w/micropenis, bifid scrotum, & either descended or undescended testes • Gynecomastia in puberty • Impaired spermatogenesis &/OR impaired pubertal virilization • Gynecomastia in puberty ## Clinical Description Androgen insensitivity syndrome (AIS) can be subdivided into three phenotypes: complete androgen insensitivity syndrome (CAIS), partial androgen insensitivity syndrome (PAIS), and mild androgen insensitivity syndrome (MAIS) ( Classification of AIS Phenotypes Absent OR rudimentary wolffian duct derivatives Absence or presence of epididymides &/or vas deferens Inguinal, labial, or abdominal testes Short blind-ending vagina Scant OR absent pubic &/OR axillary hair Inguinal OR labial testes Clitoromegaly & labial fusion Distinct urethral & vaginal openings OR aurogenital sinus Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum Descended OR undescended testes Perineoscrotal hypospadias OR urogenital sinus Gynecomastia (development of breasts) in puberty Simple (glandular or penile) OR severe (perineal) "isolated" hypospadias w/normal-sized penis & descended testes OR severe hypospadias w/micropenis, bifid scrotum, & either descended or undescended testes Gynecomastia in puberty Impaired spermatogenesis &/OR impaired pubertal virilization Gynecomastia in puberty Adapted from CAIS almost always runs true in families; that is, affected XY relatives usually have normal female external genitalia and seldom have any sign of external genital masculinization, such as clitoromegaly or posterior labial fusion [ MAIS almost always runs true in families. • Absent OR rudimentary wolffian duct derivatives • Absence or presence of epididymides &/or vas deferens • Inguinal, labial, or abdominal testes • Short blind-ending vagina • Scant OR absent pubic &/OR axillary hair • Inguinal OR labial testes • Clitoromegaly & labial fusion • Distinct urethral & vaginal openings OR aurogenital sinus • Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum • Descended OR undescended testes • Perineoscrotal hypospadias OR urogenital sinus • Gynecomastia (development of breasts) in puberty • Simple (glandular or penile) OR severe (perineal) "isolated" hypospadias w/normal-sized penis & descended testes OR severe hypospadias w/micropenis, bifid scrotum, & either descended or undescended testes • Gynecomastia in puberty • Impaired spermatogenesis &/OR impaired pubertal virilization • Gynecomastia in puberty ## Genotype-Phenotype Correlations A correlation does exist among certain missense The correlation is much less clear in PAIS, in which interfamilial phenotypic variation is observed [ The Androgen Receptor Gene Mutations Database includes In some instances, the variable expressivity associated with a number of single-nucleotide variants may be attributed to somatic mosaicism rather than to the modifying influence of "background" genetic factors [ It remains to be determined whether specific missense variants can be correlated with normal or impaired spermatogenesis and with absence or presence of localized expressions of undervirilization (e.g., gynecomastia, high-pitched voice, impotence). Although specific variants associated with azoospermia have been reported [ ## Penetrance No definitive data regarding penetrance exist, possibly because of under-ascertainment of affected individuals, particularly phenotypic but infertile males in whom ## Nomenclature The terms "testicular feminization" and androgen resistance syndrome are outdated and thus rarely used now. ## Prevalence Standard references quote a prevalence of 2:100,000 to 5:100,000 for complete AIS (CAIS) based on estimates derived from otherwise healthy phenotypic females found to have histologically normal inguinal or abdominal testes. A survey in the Netherlands over a ten-year period based on reported cases of AIS concluded that the minimal incidence was 1:99,000 [ Partial AIS (PAIS) is at least as common as CAIS. The prevalence of mild AIS (MAIS) has not yet been determined. However, it is much less frequently reported than CAIS and PAIS [ ## Genetically Related (Allelic) Disorders Expansion of the polymorphic CAG trinucleotide repeat within See ## Differential Diagnosis A Elevated levels of testosterone precursors caused by a partial testosterone biosynthetic defect in which compensatory serum LH concentrations stimulate a normal plasma testosterone concentration The presence of müllerian duct derivatives as a result of a testicular organogenesis defect with impaired Sertoli cell production of anti-müllerian hormone The presence of wolffian duct-derived internal male reproductive structures that differentiate in response to testosterone, suggesting 5-alpha-reductase deficiency, a partial testosterone biosynthetic defect, or PAIS. 5-alpha-reductase deficiency (OMIM A recent study has reported that some individuals with features of PAIS have been found to have biallelic pathogenic variants in Issues to consider in individuals with some, but not all, of the clinical features of AIS: Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization. Normal responsiveness to androgen after birth does not prove that it was normal before birth. That is, in utero delay in the acquisition of normal androgen biosynthesis or normal androgen sensitivity may lead to features consistent with androgen insensitivity. Subnormal sensitivity to androgen after birth may involve components of the overall androgen response system (AR-interacting proteins) beyond the androgen receptor itself. • Elevated levels of testosterone precursors caused by a partial testosterone biosynthetic defect in which compensatory serum LH concentrations stimulate a normal plasma testosterone concentration • The presence of müllerian duct derivatives as a result of a testicular organogenesis defect with impaired Sertoli cell production of anti-müllerian hormone • The presence of wolffian duct-derived internal male reproductive structures that differentiate in response to testosterone, suggesting 5-alpha-reductase deficiency, a partial testosterone biosynthetic defect, or PAIS. 5-alpha-reductase deficiency (OMIM • A recent study has reported that some individuals with features of PAIS have been found to have biallelic pathogenic variants in • Normal serum concentrations of T, DHT, and LH after birth do not prove that the concentration was normal during the critical period of fetal genital masculinization. • Normal responsiveness to androgen after birth does not prove that it was normal before birth. That is, in utero delay in the acquisition of normal androgen biosynthesis or normal androgen sensitivity may lead to features consistent with androgen insensitivity. • Subnormal sensitivity to androgen after birth may involve components of the overall androgen response system (AR-interacting proteins) beyond the androgen receptor itself. ## Management To establish the extent of disease and the needs of an individual diagnosed with androgen insensitivity syndrome, a complete evaluation by specialists in disorders of sex development (DSDs), which can include specialists in endocrinology, urology, gynecology, clinical genetics, psychology, and psychiatry [ A number of clinicians have sought to establish a consensus statement on management of DSD including AIS [ Even in CAIS this may not always be easy. Psychological counseling and use of support groups can be of benefit [ Gender identity has become a topic of increasing importance due to the possibility of changes in sex assignment over time [ Issues of sexual orientation regardless of gender phenotype have also become increasingly important to explore and discuss [ A critical consideration of any surgical intervention is the nature and timing of such intervention; thus, surgeons need to be involved with the affected individuals and pediatrician in any such decisions [ A common practice is to remove the testes after puberty when feminization of the affected individual is complete, since feminization occurs partly by testicular estrogen and partly by peripheral conversion of androgen to estrogen. The rationale for postpubertal gonadectomy is that testicular malignancy, which develops at the usual rate for cryptorchid testes, seldom occurs before puberty [ However, the issue of gonadectomy is controversial. Some have argued that the true risk for malignant transformation of the gonads is small and have suggested postpubertal gonad biopsy as opposed to removal [ In one study of 48 individuals diagnosed with either CAIS or PAIS, gonadoblastomas were observed in 9/30 (30%) of individuals with CAIS and 3/18 (16%) of individuals with PAIS, suggesting that the risk of gonadal malignancy may be greater than previously reported; the authors suggest earlier rather than later prophylactic gonadectomy [ Vaginal dilation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length. If this method fails, new treatments of blind vagina have been proposed, including autologous buccal mucosal graft vaginoplasty and enhanced balloon vaginoplasty [ The question of how much and when to disclose the diagnosis of CAIS to an affected individual has not been resolved uniformly; however, it has become obvious that explanation of the diagnosis in an empathic setting is much preferable to systematic concealment or self-discovery of the diagnosis in an environment devoid of support from family, professionals, and other affected individuals [ The issues are similar to those discussed under CAIS, except prepubertal gonadectomy helps avoid the emotional discomfort of increasing clitoromegaly at the time of puberty. In instances in which the diagnosis of PAIS is difficult to establish because of the presence of somatic mosaicism, a change of sex assignment can result in concomitant problems [ The assignment of sex in an infant with ambiguous genitalia is a complex process that requires timely assessment by a multidisciplinary team in consultation with the family and should be resolved as early as possible. Aside from purely anatomic and surgical considerations, the choice of a male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen to try to predict potential androgen responsiveness at puberty. Furthermore, appreciable phallic growth in response to administered androgen facilitates reconstructive surgery. In instances in which maximum information is being gathered on an infant with no family history of AIS before sex is assigned, sequence analysis of It has also been reported that the length of the Based on experience with a small number of individuals, the role of long-term androgen pharmacotherapy in individuals with PAIS who are raised as males remains unclear. Response to androgen treatment may be substantial in individuals with certain missense variants in the DNA-binding domain of the androgen receptor [ Gynecomastia that develops in puberty eventually requires reduction mammoplasty. It has been reported that tamoxifen has been used for treating pubertal gynecomastia in two sibs with PAIS [ Those individuals with PAIS who are raised as females and who have gonadectomy after puberty may need combined estrogen and androgen replacement therapy, the latter to maintain libido. Men with MAIS often require reduction mammoplasty for treatment of gynecomastia. A trial of androgen pharmacotherapy is recommended to attempt to improve virilization [ The efficacy of androgen therapy in preventing manifestations such as gynecomastia is not clear. Women with CAIS have decreased bone mineral density, regardless of timing of gonadectomy [ In addition to estrogen replacement therapy, supplemental calcium and vitamin D are recommended. Regular weight-bearing exercises are encouraged to maintain bone health. Bisphosphonate therapy may be indicated for those individuals with evidence of decreased bone mineral density and/or multiple fractures. Appropriate measures include the following: Monitoring of postnatal development of genitalia that were ambiguous at birth for changes that could lead to reconsideration of the assigned sex For individuals assigned a male sex, evaluation during puberty for signs of gynecomastia In adults, monitoring of bone mineral density through DXA (dual-energy x-ray absorptiometry) scanning [ It is appropriate to evaluate the apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include karyotype in sibs who have normal external female genitalia but have not yet undergone menarche. Molecular genetic testing can be pursued next if a phenotypic female is found to have a 46,XY karyotype and if the Androgen binding assays may be considered if an See Search Apolipoprotein D (APOD) is a possible biomarker of AR function in AIS [ • Even in CAIS this may not always be easy. • Psychological counseling and use of support groups can be of benefit [ • Gender identity has become a topic of increasing importance due to the possibility of changes in sex assignment over time [ • Issues of sexual orientation regardless of gender phenotype have also become increasingly important to explore and discuss [ • In addition to estrogen replacement therapy, supplemental calcium and vitamin D are recommended. • Regular weight-bearing exercises are encouraged to maintain bone health. • Bisphosphonate therapy may be indicated for those individuals with evidence of decreased bone mineral density and/or multiple fractures. • Monitoring of postnatal development of genitalia that were ambiguous at birth for changes that could lead to reconsideration of the assigned sex • For individuals assigned a male sex, evaluation during puberty for signs of gynecomastia • In adults, monitoring of bone mineral density through DXA (dual-energy x-ray absorptiometry) scanning [ • Evaluations can include karyotype in sibs who have normal external female genitalia but have not yet undergone menarche. • Molecular genetic testing can be pursued next if a phenotypic female is found to have a 46,XY karyotype and if the • Androgen binding assays may be considered if an ## Evaluations Following Initial Diagnosis To establish the extent of disease and the needs of an individual diagnosed with androgen insensitivity syndrome, a complete evaluation by specialists in disorders of sex development (DSDs), which can include specialists in endocrinology, urology, gynecology, clinical genetics, psychology, and psychiatry [ ## Treatment of Manifestations A number of clinicians have sought to establish a consensus statement on management of DSD including AIS [ Even in CAIS this may not always be easy. Psychological counseling and use of support groups can be of benefit [ Gender identity has become a topic of increasing importance due to the possibility of changes in sex assignment over time [ Issues of sexual orientation regardless of gender phenotype have also become increasingly important to explore and discuss [ A critical consideration of any surgical intervention is the nature and timing of such intervention; thus, surgeons need to be involved with the affected individuals and pediatrician in any such decisions [ A common practice is to remove the testes after puberty when feminization of the affected individual is complete, since feminization occurs partly by testicular estrogen and partly by peripheral conversion of androgen to estrogen. The rationale for postpubertal gonadectomy is that testicular malignancy, which develops at the usual rate for cryptorchid testes, seldom occurs before puberty [ However, the issue of gonadectomy is controversial. Some have argued that the true risk for malignant transformation of the gonads is small and have suggested postpubertal gonad biopsy as opposed to removal [ In one study of 48 individuals diagnosed with either CAIS or PAIS, gonadoblastomas were observed in 9/30 (30%) of individuals with CAIS and 3/18 (16%) of individuals with PAIS, suggesting that the risk of gonadal malignancy may be greater than previously reported; the authors suggest earlier rather than later prophylactic gonadectomy [ Vaginal dilation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length. If this method fails, new treatments of blind vagina have been proposed, including autologous buccal mucosal graft vaginoplasty and enhanced balloon vaginoplasty [ The question of how much and when to disclose the diagnosis of CAIS to an affected individual has not been resolved uniformly; however, it has become obvious that explanation of the diagnosis in an empathic setting is much preferable to systematic concealment or self-discovery of the diagnosis in an environment devoid of support from family, professionals, and other affected individuals [ The issues are similar to those discussed under CAIS, except prepubertal gonadectomy helps avoid the emotional discomfort of increasing clitoromegaly at the time of puberty. In instances in which the diagnosis of PAIS is difficult to establish because of the presence of somatic mosaicism, a change of sex assignment can result in concomitant problems [ The assignment of sex in an infant with ambiguous genitalia is a complex process that requires timely assessment by a multidisciplinary team in consultation with the family and should be resolved as early as possible. Aside from purely anatomic and surgical considerations, the choice of a male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen to try to predict potential androgen responsiveness at puberty. Furthermore, appreciable phallic growth in response to administered androgen facilitates reconstructive surgery. In instances in which maximum information is being gathered on an infant with no family history of AIS before sex is assigned, sequence analysis of It has also been reported that the length of the Based on experience with a small number of individuals, the role of long-term androgen pharmacotherapy in individuals with PAIS who are raised as males remains unclear. Response to androgen treatment may be substantial in individuals with certain missense variants in the DNA-binding domain of the androgen receptor [ Gynecomastia that develops in puberty eventually requires reduction mammoplasty. It has been reported that tamoxifen has been used for treating pubertal gynecomastia in two sibs with PAIS [ Those individuals with PAIS who are raised as females and who have gonadectomy after puberty may need combined estrogen and androgen replacement therapy, the latter to maintain libido. Men with MAIS often require reduction mammoplasty for treatment of gynecomastia. A trial of androgen pharmacotherapy is recommended to attempt to improve virilization [ • Even in CAIS this may not always be easy. • Psychological counseling and use of support groups can be of benefit [ • Gender identity has become a topic of increasing importance due to the possibility of changes in sex assignment over time [ • Issues of sexual orientation regardless of gender phenotype have also become increasingly important to explore and discuss [ ## CAIS A critical consideration of any surgical intervention is the nature and timing of such intervention; thus, surgeons need to be involved with the affected individuals and pediatrician in any such decisions [ A common practice is to remove the testes after puberty when feminization of the affected individual is complete, since feminization occurs partly by testicular estrogen and partly by peripheral conversion of androgen to estrogen. The rationale for postpubertal gonadectomy is that testicular malignancy, which develops at the usual rate for cryptorchid testes, seldom occurs before puberty [ However, the issue of gonadectomy is controversial. Some have argued that the true risk for malignant transformation of the gonads is small and have suggested postpubertal gonad biopsy as opposed to removal [ In one study of 48 individuals diagnosed with either CAIS or PAIS, gonadoblastomas were observed in 9/30 (30%) of individuals with CAIS and 3/18 (16%) of individuals with PAIS, suggesting that the risk of gonadal malignancy may be greater than previously reported; the authors suggest earlier rather than later prophylactic gonadectomy [ Vaginal dilation to augment vaginal length and to avoid dyspareunia is typically the treatment of choice for those with short vaginal length. If this method fails, new treatments of blind vagina have been proposed, including autologous buccal mucosal graft vaginoplasty and enhanced balloon vaginoplasty [ The question of how much and when to disclose the diagnosis of CAIS to an affected individual has not been resolved uniformly; however, it has become obvious that explanation of the diagnosis in an empathic setting is much preferable to systematic concealment or self-discovery of the diagnosis in an environment devoid of support from family, professionals, and other affected individuals [ ## PAIS with Predominantly Female Genitalia (Incomplete AIS) The issues are similar to those discussed under CAIS, except prepubertal gonadectomy helps avoid the emotional discomfort of increasing clitoromegaly at the time of puberty. In instances in which the diagnosis of PAIS is difficult to establish because of the presence of somatic mosaicism, a change of sex assignment can result in concomitant problems [ ## PAIS with Ambiguous Genitalia or Predominantly Male Genitalia The assignment of sex in an infant with ambiguous genitalia is a complex process that requires timely assessment by a multidisciplinary team in consultation with the family and should be resolved as early as possible. Aside from purely anatomic and surgical considerations, the choice of a male sex-of-rearing demands a therapeutic trial with pharmacologic doses of androgen to try to predict potential androgen responsiveness at puberty. Furthermore, appreciable phallic growth in response to administered androgen facilitates reconstructive surgery. In instances in which maximum information is being gathered on an infant with no family history of AIS before sex is assigned, sequence analysis of It has also been reported that the length of the Based on experience with a small number of individuals, the role of long-term androgen pharmacotherapy in individuals with PAIS who are raised as males remains unclear. Response to androgen treatment may be substantial in individuals with certain missense variants in the DNA-binding domain of the androgen receptor [ Gynecomastia that develops in puberty eventually requires reduction mammoplasty. It has been reported that tamoxifen has been used for treating pubertal gynecomastia in two sibs with PAIS [ Those individuals with PAIS who are raised as females and who have gonadectomy after puberty may need combined estrogen and androgen replacement therapy, the latter to maintain libido. ## MAIS Men with MAIS often require reduction mammoplasty for treatment of gynecomastia. A trial of androgen pharmacotherapy is recommended to attempt to improve virilization [ ## Prevention of Primary Manifestations The efficacy of androgen therapy in preventing manifestations such as gynecomastia is not clear. ## Prevention of Secondary Manifestations Women with CAIS have decreased bone mineral density, regardless of timing of gonadectomy [ In addition to estrogen replacement therapy, supplemental calcium and vitamin D are recommended. Regular weight-bearing exercises are encouraged to maintain bone health. Bisphosphonate therapy may be indicated for those individuals with evidence of decreased bone mineral density and/or multiple fractures. • In addition to estrogen replacement therapy, supplemental calcium and vitamin D are recommended. • Regular weight-bearing exercises are encouraged to maintain bone health. • Bisphosphonate therapy may be indicated for those individuals with evidence of decreased bone mineral density and/or multiple fractures. ## Surveillance Appropriate measures include the following: Monitoring of postnatal development of genitalia that were ambiguous at birth for changes that could lead to reconsideration of the assigned sex For individuals assigned a male sex, evaluation during puberty for signs of gynecomastia In adults, monitoring of bone mineral density through DXA (dual-energy x-ray absorptiometry) scanning [ • Monitoring of postnatal development of genitalia that were ambiguous at birth for changes that could lead to reconsideration of the assigned sex • For individuals assigned a male sex, evaluation during puberty for signs of gynecomastia • In adults, monitoring of bone mineral density through DXA (dual-energy x-ray absorptiometry) scanning [ ## Evaluation of Relatives at Risk It is appropriate to evaluate the apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. Evaluations can include karyotype in sibs who have normal external female genitalia but have not yet undergone menarche. Molecular genetic testing can be pursued next if a phenotypic female is found to have a 46,XY karyotype and if the Androgen binding assays may be considered if an See • Evaluations can include karyotype in sibs who have normal external female genitalia but have not yet undergone menarche. • Molecular genetic testing can be pursued next if a phenotypic female is found to have a 46,XY karyotype and if the • Androgen binding assays may be considered if an ## Therapies Under Investigation Search ## Other Apolipoprotein D (APOD) is a possible biomarker of AR function in AIS [ ## Genetic Counseling Androgen insensitivity syndrome (AIS) is inherited in an X-linked manner. The father of a proband will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. If the proband is the only affected family member (i.e., a simplex case) several possibilities exist regarding the carrier status of the mother: The mother is heterozygous for an The mother has germline mosaicism or somatic and germline mosaicism for an The mother is not a carrier and the pathogenic variant occurred If the mother of the proband has an Sibs with a 46,XY karyotype who inherit the Sibs with a 46,XX karyotype who inherit the If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Each offspring of a female known to be a carrier of an Having a 46,XY karyotype and being affected Having a 46,XY karyotype and being unaffected Having a 46,XX karyotype and being a carrier Having a 46,XX karyotype and not being a carrier The phenotype of offspring with a 46,XY karyotype and CAIS or MAIS tends to be fairly predictable. The genital phenotype of individuals with PAIS within a family is generally consistent; however, a wide range of phenotypic variability is seen among families who share the same PAIS pathogenic variant, making it difficult to predict the phenotype in a simplex case. Female carriers may be identified through one or a combination of the following: Note: Inability to detect a pathogenic variant in See Management, Of particular interest is a case report of an individual with CAIS with male gender identity [ An additional ethical and possibly legal issue is the genetic testing of other family members for AIS. In a 1999 court decision (unrelated to AIS) chromosome findings alone were used to determine an individual's sex. Clinicians should be aware that information provided to individuals with AIS and their families (in the interest of facilitating appropriate medical care) could potentially have legal implications for such individuals/families [ The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Differences in perspective may exist among medical professionals and in 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 proband will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. • If the proband is the only affected family member (i.e., a simplex case) several possibilities exist regarding the carrier status of the mother: • The mother is heterozygous for an • The mother has germline mosaicism or somatic and germline mosaicism for an • The mother is not a carrier and the pathogenic variant occurred • The mother is heterozygous for an • The mother has germline mosaicism or somatic and germline mosaicism for an • The mother is not a carrier and the pathogenic variant occurred • The mother is heterozygous for an • The mother has germline mosaicism or somatic and germline mosaicism for an • The mother is not a carrier and the pathogenic variant occurred • If the mother of the proband has an • Sibs with a 46,XY karyotype who inherit the • Sibs with a 46,XX karyotype who inherit the • Sibs with a 46,XY karyotype who inherit the • Sibs with a 46,XX karyotype who inherit the • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Sibs with a 46,XY karyotype who inherit the • Sibs with a 46,XX karyotype who inherit the • Each offspring of a female known to be a carrier of an • Having a 46,XY karyotype and being affected • Having a 46,XY karyotype and being unaffected • Having a 46,XX karyotype and being a carrier • Having a 46,XX karyotype and not being a carrier • Having a 46,XY karyotype and being affected • Having a 46,XY karyotype and being unaffected • Having a 46,XX karyotype and being a carrier • Having a 46,XX karyotype and not being a carrier • The phenotype of offspring with a 46,XY karyotype and CAIS or MAIS tends to be fairly predictable. The genital phenotype of individuals with PAIS within a family is generally consistent; however, a wide range of phenotypic variability is seen among families who share the same PAIS pathogenic variant, making it difficult to predict the phenotype in a simplex case. • Having a 46,XY karyotype and being affected • Having a 46,XY karyotype and being unaffected • Having a 46,XX karyotype and being a carrier • Having a 46,XX karyotype and not being a carrier • Note: Inability to detect a pathogenic 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 or at risk. ## Mode of Inheritance Androgen insensitivity syndrome (AIS) is inherited in an X-linked manner. ## Risk to Family Members The father of a proband will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. If the proband is the only affected family member (i.e., a simplex case) several possibilities exist regarding the carrier status of the mother: The mother is heterozygous for an The mother has germline mosaicism or somatic and germline mosaicism for an The mother is not a carrier and the pathogenic variant occurred If the mother of the proband has an Sibs with a 46,XY karyotype who inherit the Sibs with a 46,XX karyotype who inherit the If the proband represents a simplex case (i.e., a single occurrence in a family) and if the Each offspring of a female known to be a carrier of an Having a 46,XY karyotype and being affected Having a 46,XY karyotype and being unaffected Having a 46,XX karyotype and being a carrier Having a 46,XX karyotype and not being a carrier The phenotype of offspring with a 46,XY karyotype and CAIS or MAIS tends to be fairly predictable. The genital phenotype of individuals with PAIS within a family is generally consistent; however, a wide range of phenotypic variability is seen among families who share the same PAIS pathogenic variant, making it difficult to predict the phenotype in a simplex case. • The father of a proband will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote (carrier). If a woman has more than one affected child and the pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism. • If the proband is the only affected family member (i.e., a simplex case) several possibilities exist regarding the carrier status of the mother: • The mother is heterozygous for an • The mother has germline mosaicism or somatic and germline mosaicism for an • The mother is not a carrier and the pathogenic variant occurred • The mother is heterozygous for an • The mother has germline mosaicism or somatic and germline mosaicism for an • The mother is not a carrier and the pathogenic variant occurred • The mother is heterozygous for an • The mother has germline mosaicism or somatic and germline mosaicism for an • The mother is not a carrier and the pathogenic variant occurred • If the mother of the proband has an • Sibs with a 46,XY karyotype who inherit the • Sibs with a 46,XX karyotype who inherit the • Sibs with a 46,XY karyotype who inherit the • Sibs with a 46,XX karyotype who inherit the • If the proband represents a simplex case (i.e., a single occurrence in a family) and if the • Sibs with a 46,XY karyotype who inherit the • Sibs with a 46,XX karyotype who inherit the • Each offspring of a female known to be a carrier of an • Having a 46,XY karyotype and being affected • Having a 46,XY karyotype and being unaffected • Having a 46,XX karyotype and being a carrier • Having a 46,XX karyotype and not being a carrier • Having a 46,XY karyotype and being affected • Having a 46,XY karyotype and being unaffected • Having a 46,XX karyotype and being a carrier • Having a 46,XX karyotype and not being a carrier • The phenotype of offspring with a 46,XY karyotype and CAIS or MAIS tends to be fairly predictable. The genital phenotype of individuals with PAIS within a family is generally consistent; however, a wide range of phenotypic variability is seen among families who share the same PAIS pathogenic variant, making it difficult to predict the phenotype in a simplex case. • Having a 46,XY karyotype and being affected • Having a 46,XY karyotype and being unaffected • Having a 46,XX karyotype and being a carrier • Having a 46,XX karyotype and not being a carrier ## Heterozygote (Carrier) Detection Female carriers may be identified through one or a combination of the following: Note: Inability to detect a pathogenic variant in • Note: Inability to detect a pathogenic variant in • ## Related Genetic Counseling Issues See Management, Of particular interest is a case report of an individual with CAIS with male gender identity [ An additional ethical and possibly legal issue is the genetic testing of other family members for AIS. In a 1999 court decision (unrelated to AIS) chromosome findings alone were used to determine an individual's sex. Clinicians should be aware that information provided to individuals with AIS and their families (in the interest of facilitating appropriate medical care) could potentially have legal implications for such individuals/families [ The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and in 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 3239 South Brisbane Queensland 4101 Australia The Lady Davis Institute for Medical Research Montreal Quebec Canada Rohnert Park CA 94928 • • PO Box 3239 • South Brisbane Queensland 4101 • Australia • • • The Lady Davis Institute for Medical Research • Montreal Quebec • Canada • • • Rohnert Park CA 94928 • • • • • ## Molecular Genetics Androgen Insensitivity Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Androgen Insensitivity Syndrome ( For a detailed summary of gene and protein information, see Coincidentally, two major species of Note: The Single-nucleotide variants in exon 1 are relatively uncommon; the majority of variants are either nonsense or small deletions or insertions that result in a frameshift; thus, they almost always cause CAIS; PAIS is seldom the result of exon 1 variants [ A relatively small number of Expansion of the trinucleotide repeat tract (CAG) Two forms of the androgen receptor protein (A and B) are produced by the alternative splice forms of The androgen receptor is a well-defined transcriptional regulatory factor. Once activated by binding to androgen, it collaborates with other co-regulatory proteins (some involve DNA binding, others do not) to achieve control over the rate of transcription of an androgen target gene that is under the influence of a nearby promoter. A large number of AR-associated proteins have now been identified [ The effect of specific variants on the functionality of the androgen receptor has been studied using molecular dynamic modeling based on the x-ray crystal structure [ Prostate cancer Male breast cancer Laryngeal cancer Liver cancer Testicular cancer Bladder cancer [ • Prostate cancer • Male breast cancer • Laryngeal cancer • Liver cancer • Testicular cancer • Bladder cancer [ ## Chapter Notes Lenore K Beitel, PhD (2004-2017) Bruce Gottlieb, PhD (2004-present) Leonard Pinsky, MD, FACMG; McGill University (1999-2004) Mark A Trifiro, MD (1999-present) 11 May 2017 (ma) Comprehensive update posted live 10 July 2014 (me) Comprehensive update posted live 6 October 2011 (me) Comprehensive update posted live 24 May 2007 (cd) Revision: deletion/duplication analysis available on a clinical basis 19 September 2006 (me) Comprehensive update posted live 8 April 2004 (me) Comprehensive update posted live 12 December 2002 (lp) Revision: Testing 19 November 2001 (me) Comprehensive update posted live 24 March 1999 (pb) Review posted live 1998 (lp/mt) Original submission • 11 May 2017 (ma) Comprehensive update posted live • 10 July 2014 (me) Comprehensive update posted live • 6 October 2011 (me) Comprehensive update posted live • 24 May 2007 (cd) Revision: deletion/duplication analysis available on a clinical basis • 19 September 2006 (me) Comprehensive update posted live • 8 April 2004 (me) Comprehensive update posted live • 12 December 2002 (lp) Revision: Testing • 19 November 2001 (me) Comprehensive update posted live • 24 March 1999 (pb) Review posted live • 1998 (lp/mt) Original submission ## Author History Lenore K Beitel, PhD (2004-2017) Bruce Gottlieb, PhD (2004-present) Leonard Pinsky, MD, FACMG; McGill University (1999-2004) Mark A Trifiro, MD (1999-present) ## Revision History 11 May 2017 (ma) Comprehensive update posted live 10 July 2014 (me) Comprehensive update posted live 6 October 2011 (me) Comprehensive update posted live 24 May 2007 (cd) Revision: deletion/duplication analysis available on a clinical basis 19 September 2006 (me) Comprehensive update posted live 8 April 2004 (me) Comprehensive update posted live 12 December 2002 (lp) Revision: Testing 19 November 2001 (me) Comprehensive update posted live 24 March 1999 (pb) Review posted live 1998 (lp/mt) Original submission • 11 May 2017 (ma) Comprehensive update posted live • 10 July 2014 (me) Comprehensive update posted live • 6 October 2011 (me) Comprehensive update posted live • 24 May 2007 (cd) Revision: deletion/duplication analysis available on a clinical basis • 19 September 2006 (me) Comprehensive update posted live • 8 April 2004 (me) Comprehensive update posted live • 12 December 2002 (lp) Revision: Testing • 19 November 2001 (me) Comprehensive update posted live • 24 March 1999 (pb) Review posted live • 1998 (lp/mt) Original submission ## References Diamond M, Beh HG. Changes in the management of children with intersex conditions. Available Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Consensus in guidelines for evaluation of DSD by the Texas Children’s Hospital multidisciplinary gender medicine team. Available Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannapoulou K, MacDougall J. Androgen insensitivity syndrome. Available Pasterski V, Prentice P, Hughes IA. Impact of the consensus statement and the new DSD classification system. Available Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Available • Diamond M, Beh HG. Changes in the management of children with intersex conditions. Available • Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Consensus in guidelines for evaluation of DSD by the Texas Children’s Hospital multidisciplinary gender medicine team. Available • Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannapoulou K, MacDougall J. Androgen insensitivity syndrome. Available • Pasterski V, Prentice P, Hughes IA. Impact of the consensus statement and the new DSD classification system. Available • Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Available ## Published Guidelines / Consensus Statements Diamond M, Beh HG. Changes in the management of children with intersex conditions. Available Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Consensus in guidelines for evaluation of DSD by the Texas Children’s Hospital multidisciplinary gender medicine team. Available Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannapoulou K, MacDougall J. Androgen insensitivity syndrome. Available Pasterski V, Prentice P, Hughes IA. Impact of the consensus statement and the new DSD classification system. Available Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Available • Diamond M, Beh HG. Changes in the management of children with intersex conditions. Available • Douglas G, Axelrad ME, Brandt ML, Crabtree E, Dietrich JE, French S, Gunn S, Karaviti L, Lopez ME, Macias CG, McCullough LB, Suresh D, Sutton VR. Consensus in guidelines for evaluation of DSD by the Texas Children’s Hospital multidisciplinary gender medicine team. Available • Hughes IA, Davies JD, Bunch TI, Pasterski V, Mastroyannapoulou K, MacDougall J. Androgen insensitivity syndrome. Available • Pasterski V, Prentice P, Hughes IA. Impact of the consensus statement and the new DSD classification system. Available • Wiesemann C, Ude-Koeller S, Sinnecker GH, Thyen U. Ethical principles and recommendations for the medical management of differences of sex development (DSD)/intersex in children and adolescents. Available ## Literature Cited	[ "M Appari, R Werner, L Wunsch, G Cario, J Demeter, O Hiort, F Rieppe, JD Brooks, PM Holterhus. Apolipoprotein D (APOD) is a putative biomarker of androgen receptor function in androgen insensitivity syndrome.. J Mol Med 2009;87:623-32", "D Becker, LM Wain, YH Chong, SJ Gosai, NK Henderson, J Milburn, V Stott, BJ Wheeler. 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angelman	angelman	[ "Ubiquitin-protein ligase E3A", "UBE3A", "Angelman Syndrome" ]	Angelman Syndrome	Aditi I Dagli, Jennifer Mathews, Charles A Williams	Summary Angelman syndrome (AS) is characterized by severe developmental delay or intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. The diagnosis of AS is established in a proband who meets the consensus clinical diagnostic criteria and/or who has findings on molecular genetic testing that suggest 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	## Diagnosis Consensus criteria for the clinical diagnosis of Angelman syndrome (AS) have been developed in conjunction with the Scientific Advisory Committee of the US Angelman Syndrome Foundation [ AS Normal prenatal and birth history, normal head circumference at birth, no major birth defects Delayed attainment of developmental milestones by age six to 12 months, eventually classified as severe, without loss of skills Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs Behavioral uniqueness including any combination of frequent laughter/smiling, apparent happy demeanor, excitability (often with hand-flapping movements), and hypermotoric behavior Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years Seizures, usually starting before age three years Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves Craniofacial features including flat occiput, occipital groove, wide mouth, widely spaced teeth, protruding tongue, prognathia (See Feeding problems and/or hypotonia during infancy, tongue thrusting, suck/swallowing disorders, frequent drooling, excessive chewing/mouthing behaviors Strabismus Hypopigmented skin, light hair and eye color compared to family members; seen only in those with a 15q11.2-q13 deletion Hyperactive lower-extremity deep-tendon reflexes Uplifted, flexed arm position especially during ambulation Wide-based gait with pronated or valgus-positioned ankles Increased sensitivity to heat Abnormal sleep-wake cycles and diminished need for sleep Attraction to and fascination with water; fascination with crinkly items such as certain papers and plastics Abnormal food-related behaviors Obesity (in the older child; more common in those who do not have a 15q11.2-q13 deletion) Scoliosis Constipation Deletion of the 15q11.2-q13 genomic region (detected by chromosomal microarray or other methods) is suggestive of AS but not, in and of itself, diagnostic. Metabolic, hematologic, and chemical laboratory profiles are normal. Brain imaging shows structurally normal brain by MRI or CT, although mild cortical atrophy or dysmyelination may be observed. The clinical diagnosis of AS can be Abnormal methylation at 15q11.2-q13 due to one of the following: Deletion of the maternally inherited 15q11.2-q13 region (which includes Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 An imprinting defect of the maternal chromosome 15q11.2-q13 region A pathogenic variant in the maternally derived Note: Most commercially available DNA methylation analysis tests cannot distinguish between AS resulting from a 15q11.2-q13 deletion, UPD, or an imprinting defect. Further testing is required to identify the underlying molecular mechanism (see If DNA methylation analysis is normal: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click * Fewer than 1% of individuals with AS have a cytogenetically visible chromosome 15 rearrangement (i.e., translocation or inversion) involving 15q11.2-q13. Molecular Genetic Testing Used in Angelman Syndrome CMA = chromosomal microarray analysis; del/dup = deletion/duplication; IC = imprinting center; MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; UPD = uniparental disomy See About 10% of individuals with the presumptive clinical diagnosis of AS have normal results for all testing methods described in this table [ Individuals with AS caused by a 5- to 7-Mb deletion of 15q11.2-q13, uniparental disomy (UPD), or an imprinting defect have only an unmethylated (i.e., "paternal") contribution (i.e., an abnormal parent-specific DNA methylation imprint). DNA methylation analysis will not distinguish the genetic mechanism. More than 90% of imprinting defects are thought to be epigenetic pathogenic variants occurring during maternal oogenesis or in early embryogenesis [ FISH analysis with the CMA has a slightly higher sensitivity for 15q11.2-q13 deletions than FISH and will provide detailed information regarding size of the deletion. CMA also can identify deletions and duplications in other regions of the genome. SNP-based chromosomal microarray can identify UPD, but not UPD due to heterodisomy. UPD is detected using polymorphic DNA markers, which requires a DNA sample from the affected individual and both parents. Gene-targeted deletion/duplication analysis detects deletions or duplications in intragenic or other targeted regions. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, MLPA, and a gene-targeted microarray designed to detect single-exon deletions or duplications. Although 3% of all individuals with AS have imprinting center defects, <10% will have detectable small deletions in the imprinting center. Sequence analysis detects variants that are benign, likely benign, of uncertain significance (VUS), 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. Since CMA usually detects large 15q11.2-q13 deletions, but in rare instances has detected Possible explanations for the failure to detect AS-causing genetic abnormalities in approximately 10% of individuals with clinically diagnosed AS: Incorrect clinical diagnosis Undetected pathogenic variants in the regulatory region(s) of Other unidentified mechanisms or gene(s) involved in • Normal prenatal and birth history, normal head circumference at birth, no major birth defects • Delayed attainment of developmental milestones by age six to 12 months, eventually classified as severe, without loss of skills • Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills • Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs • Behavioral uniqueness including any combination of frequent laughter/smiling, apparent happy demeanor, excitability (often with hand-flapping movements), and hypermotoric behavior • Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years • Seizures, usually starting before age three years • Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves • Craniofacial features including flat occiput, occipital groove, wide mouth, widely spaced teeth, protruding tongue, prognathia (See • Feeding problems and/or hypotonia during infancy, tongue thrusting, suck/swallowing disorders, frequent drooling, excessive chewing/mouthing behaviors • Strabismus • Hypopigmented skin, light hair and eye color compared to family members; seen only in those with a 15q11.2-q13 deletion • Hyperactive lower-extremity deep-tendon reflexes • Uplifted, flexed arm position especially during ambulation • Wide-based gait with pronated or valgus-positioned ankles • Increased sensitivity to heat • Abnormal sleep-wake cycles and diminished need for sleep • Attraction to and fascination with water; fascination with crinkly items such as certain papers and plastics • Abnormal food-related behaviors • Obesity (in the older child; more common in those who do not have a 15q11.2-q13 deletion) • Scoliosis • Constipation • Abnormal methylation at 15q11.2-q13 due to one of the following: • Deletion of the maternally inherited 15q11.2-q13 region (which includes • Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 • An imprinting defect of the maternal chromosome 15q11.2-q13 region • Deletion of the maternally inherited 15q11.2-q13 region (which includes • Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 • An imprinting defect of the maternal chromosome 15q11.2-q13 region • A pathogenic variant in the maternally derived • Deletion of the maternally inherited 15q11.2-q13 region (which includes • Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 • An imprinting defect of the maternal chromosome 15q11.2-q13 region • Note: Most commercially available DNA methylation analysis tests cannot distinguish between AS resulting from a 15q11.2-q13 deletion, UPD, or an imprinting defect. Further testing is required to identify the underlying molecular mechanism (see • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • Incorrect clinical diagnosis • Undetected pathogenic variants in the regulatory region(s) of • Other unidentified mechanisms or gene(s) involved in ## Suggestive Findings AS Normal prenatal and birth history, normal head circumference at birth, no major birth defects Delayed attainment of developmental milestones by age six to 12 months, eventually classified as severe, without loss of skills Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs Behavioral uniqueness including any combination of frequent laughter/smiling, apparent happy demeanor, excitability (often with hand-flapping movements), and hypermotoric behavior Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years Seizures, usually starting before age three years Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves Craniofacial features including flat occiput, occipital groove, wide mouth, widely spaced teeth, protruding tongue, prognathia (See Feeding problems and/or hypotonia during infancy, tongue thrusting, suck/swallowing disorders, frequent drooling, excessive chewing/mouthing behaviors Strabismus Hypopigmented skin, light hair and eye color compared to family members; seen only in those with a 15q11.2-q13 deletion Hyperactive lower-extremity deep-tendon reflexes Uplifted, flexed arm position especially during ambulation Wide-based gait with pronated or valgus-positioned ankles Increased sensitivity to heat Abnormal sleep-wake cycles and diminished need for sleep Attraction to and fascination with water; fascination with crinkly items such as certain papers and plastics Abnormal food-related behaviors Obesity (in the older child; more common in those who do not have a 15q11.2-q13 deletion) Scoliosis Constipation Deletion of the 15q11.2-q13 genomic region (detected by chromosomal microarray or other methods) is suggestive of AS but not, in and of itself, diagnostic. Metabolic, hematologic, and chemical laboratory profiles are normal. Brain imaging shows structurally normal brain by MRI or CT, although mild cortical atrophy or dysmyelination may be observed. • Normal prenatal and birth history, normal head circumference at birth, no major birth defects • Delayed attainment of developmental milestones by age six to 12 months, eventually classified as severe, without loss of skills • Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills • Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs • Behavioral uniqueness including any combination of frequent laughter/smiling, apparent happy demeanor, excitability (often with hand-flapping movements), and hypermotoric behavior • Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years • Seizures, usually starting before age three years • Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves • Craniofacial features including flat occiput, occipital groove, wide mouth, widely spaced teeth, protruding tongue, prognathia (See • Feeding problems and/or hypotonia during infancy, tongue thrusting, suck/swallowing disorders, frequent drooling, excessive chewing/mouthing behaviors • Strabismus • Hypopigmented skin, light hair and eye color compared to family members; seen only in those with a 15q11.2-q13 deletion • Hyperactive lower-extremity deep-tendon reflexes • Uplifted, flexed arm position especially during ambulation • Wide-based gait with pronated or valgus-positioned ankles • Increased sensitivity to heat • Abnormal sleep-wake cycles and diminished need for sleep • Attraction to and fascination with water; fascination with crinkly items such as certain papers and plastics • Abnormal food-related behaviors • Obesity (in the older child; more common in those who do not have a 15q11.2-q13 deletion) • Scoliosis • Constipation ## Clinical Normal prenatal and birth history, normal head circumference at birth, no major birth defects Delayed attainment of developmental milestones by age six to 12 months, eventually classified as severe, without loss of skills Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs Behavioral uniqueness including any combination of frequent laughter/smiling, apparent happy demeanor, excitability (often with hand-flapping movements), and hypermotoric behavior • Normal prenatal and birth history, normal head circumference at birth, no major birth defects • Delayed attainment of developmental milestones by age six to 12 months, eventually classified as severe, without loss of skills • Speech impairment, with minimal to no use of words; receptive language skills and nonverbal communication skills higher than expressive language skills • Movement or balance disorder, usually ataxia of gait and/or tremulous movement of the limbs • Behavioral uniqueness including any combination of frequent laughter/smiling, apparent happy demeanor, excitability (often with hand-flapping movements), and hypermotoric behavior ## Clinical criteria that help establish the diagnosis [ Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years Seizures, usually starting before age three years Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves Craniofacial features including flat occiput, occipital groove, wide mouth, widely spaced teeth, protruding tongue, prognathia (See Feeding problems and/or hypotonia during infancy, tongue thrusting, suck/swallowing disorders, frequent drooling, excessive chewing/mouthing behaviors Strabismus Hypopigmented skin, light hair and eye color compared to family members; seen only in those with a 15q11.2-q13 deletion Hyperactive lower-extremity deep-tendon reflexes Uplifted, flexed arm position especially during ambulation Wide-based gait with pronated or valgus-positioned ankles Increased sensitivity to heat Abnormal sleep-wake cycles and diminished need for sleep Attraction to and fascination with water; fascination with crinkly items such as certain papers and plastics Abnormal food-related behaviors Obesity (in the older child; more common in those who do not have a 15q11.2-q13 deletion) Scoliosis Constipation • Delayed or disproportionately slow growth in head circumference, usually resulting in absolute or relative microcephaly by age two years • Seizures, usually starting before age three years • Abnormal EEG, with a characteristic pattern of large-amplitude slow-spike waves • Craniofacial features including flat occiput, occipital groove, wide mouth, widely spaced teeth, protruding tongue, prognathia (See • Feeding problems and/or hypotonia during infancy, tongue thrusting, suck/swallowing disorders, frequent drooling, excessive chewing/mouthing behaviors • Strabismus • Hypopigmented skin, light hair and eye color compared to family members; seen only in those with a 15q11.2-q13 deletion • Hyperactive lower-extremity deep-tendon reflexes • Uplifted, flexed arm position especially during ambulation • Wide-based gait with pronated or valgus-positioned ankles • Increased sensitivity to heat • Abnormal sleep-wake cycles and diminished need for sleep • Attraction to and fascination with water; fascination with crinkly items such as certain papers and plastics • Abnormal food-related behaviors • Obesity (in the older child; more common in those who do not have a 15q11.2-q13 deletion) • Scoliosis • Constipation ## Laboratory Deletion of the 15q11.2-q13 genomic region (detected by chromosomal microarray or other methods) is suggestive of AS but not, in and of itself, diagnostic. Metabolic, hematologic, and chemical laboratory profiles are normal. ## Radiographic Brain imaging shows structurally normal brain by MRI or CT, although mild cortical atrophy or dysmyelination may be observed. ## Establishing the Diagnosis The clinical diagnosis of AS can be Abnormal methylation at 15q11.2-q13 due to one of the following: Deletion of the maternally inherited 15q11.2-q13 region (which includes Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 An imprinting defect of the maternal chromosome 15q11.2-q13 region A pathogenic variant in the maternally derived Note: Most commercially available DNA methylation analysis tests cannot distinguish between AS resulting from a 15q11.2-q13 deletion, UPD, or an imprinting defect. Further testing is required to identify the underlying molecular mechanism (see If DNA methylation analysis is normal: For an introduction to multigene panels click For an introduction to comprehensive genomic testing click * Fewer than 1% of individuals with AS have a cytogenetically visible chromosome 15 rearrangement (i.e., translocation or inversion) involving 15q11.2-q13. Molecular Genetic Testing Used in Angelman Syndrome CMA = chromosomal microarray analysis; del/dup = deletion/duplication; IC = imprinting center; MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; UPD = uniparental disomy See About 10% of individuals with the presumptive clinical diagnosis of AS have normal results for all testing methods described in this table [ Individuals with AS caused by a 5- to 7-Mb deletion of 15q11.2-q13, uniparental disomy (UPD), or an imprinting defect have only an unmethylated (i.e., "paternal") contribution (i.e., an abnormal parent-specific DNA methylation imprint). DNA methylation analysis will not distinguish the genetic mechanism. More than 90% of imprinting defects are thought to be epigenetic pathogenic variants occurring during maternal oogenesis or in early embryogenesis [ FISH analysis with the CMA has a slightly higher sensitivity for 15q11.2-q13 deletions than FISH and will provide detailed information regarding size of the deletion. CMA also can identify deletions and duplications in other regions of the genome. SNP-based chromosomal microarray can identify UPD, but not UPD due to heterodisomy. UPD is detected using polymorphic DNA markers, which requires a DNA sample from the affected individual and both parents. Gene-targeted deletion/duplication analysis detects deletions or duplications in intragenic or other targeted regions. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, MLPA, and a gene-targeted microarray designed to detect single-exon deletions or duplications. Although 3% of all individuals with AS have imprinting center defects, <10% will have detectable small deletions in the imprinting center. Sequence analysis detects variants that are benign, likely benign, of uncertain significance (VUS), 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. Since CMA usually detects large 15q11.2-q13 deletions, but in rare instances has detected Possible explanations for the failure to detect AS-causing genetic abnormalities in approximately 10% of individuals with clinically diagnosed AS: Incorrect clinical diagnosis Undetected pathogenic variants in the regulatory region(s) of Other unidentified mechanisms or gene(s) involved in • Abnormal methylation at 15q11.2-q13 due to one of the following: • Deletion of the maternally inherited 15q11.2-q13 region (which includes • Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 • An imprinting defect of the maternal chromosome 15q11.2-q13 region • Deletion of the maternally inherited 15q11.2-q13 region (which includes • Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 • An imprinting defect of the maternal chromosome 15q11.2-q13 region • A pathogenic variant in the maternally derived • Deletion of the maternally inherited 15q11.2-q13 region (which includes • Uniparental disomy (UPD) of the paternal chromosome region 15q11.2-q13 • An imprinting defect of the maternal chromosome 15q11.2-q13 region • Note: Most commercially available DNA methylation analysis tests cannot distinguish between AS resulting from a 15q11.2-q13 deletion, UPD, or an imprinting defect. Further testing is required to identify the underlying molecular mechanism (see • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • Incorrect clinical diagnosis • Undetected pathogenic variants in the regulatory region(s) of • Other unidentified mechanisms or gene(s) involved in ## Clinical Characteristics Angelman syndrome (AS) is characterized by severe developmental delay and intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. Angelman Syndrome: Frequency of Select Features GI = gastrointestinal Normal occipital frontal circumference should not exclude AS diagnosis. Seizure types can be quite varied; the most common are myoclonic, atonic, generalized tonic-clonic, and atypical absence [ Brain MRI may show mild atrophy and mild dysmyelination, but no structural lesions [ Certain behaviors may suggest a diagnosis of autism spectrum disorder (e.g., fascination with water and crinkly items such as certain papers and plastics, increased sensitivity to heat, abnormal food-related behaviors) but social engagement is typically good. Stereotypic behaviors such as lining up of toys or fascination with spinning objects or flashing lights rarely occur. Some individuals with AS have good response to ABA (applied behavior analysis) therapy [ The behavior profile generally continues into the adult years. Particularly challenging in teenage and adult years include frustration in communicating wants and preferences, seeking sensory stimulation and social attention, and avoidance of undesired situations [ AS may first be suspected in a toddler because of delayed gross motor milestones and hypotonia. Mildly impaired children may walk fairly normally or have minimal toe-walking or prancing gait, at times accompanied by leaning forward. Being placed in a standing position can result in anxiety or rigidity. The average age of walking is between 2.5 and six years [ Frequently voluntary movements appear irregular. On the mild end they can present as slight jerkiness to uncoordinated coarse movements on the severe end of the spectrum. These movements can prevent reaching for objects, feeding, and walking. Failure to achieve independent walking may be a result of instability resulting from tremor, epilepsy, vision issues, abnormal muscle tone, or balance problems. Ten percent of children are nonambulatory [ Appropriate and consistent use of one or two words is rare. Babies and young infants have decreased cooing and babbling. At age ten to 18 months, a single word such as "mama" may develop but is often used indiscriminately. In a survey of 47 individuals, 39% spoke up to four words but it was unclear if these words were used with purpose [ Seizures and significant hyperactivity can impede early communication development including eye contact. Most older children and adults with AS are able to communicate by pointing and reaching, using gestures, pointing to body parts, and by using communication boards. Effective fluent use of sign language does not occur [ Gastroesophageal reflux disease (GERD) occurs in 45%-65% of individuals with AS, resulting in poor weight gain and emesis in infants [ Vomiting is not uncommon and can be either cyclic or intermittent. Cyclic vomiting appears to be more common in individuals with a 15q11.2-q13 deletion or uniparental disomy (UPD). Vomiting (unrelated to illness or food allergies) can be due to a variety of factors including anxiety and behavior issues, side effects of medication, and constipation [ Hyperphagia and problematic food-related behaviors are seen in all genetic subtypes with a prevalence of 20%-50% [ Constipation is common and can occur at any age. Symptoms include hard or infrequent stools, poor or worsening appetite, vomiting, and stomach pain. Appropriate and timely management is important, as constipation can result in behavioral changes, weight loss, poor sleep quality, and increased seizures [ Although the tongue is normal in shape and size, about 30%-50% have persistent tongue protrusion. For some individuals, the problem persists into adulthood. Drooling can lead to skin irritation and aspiration, but is generally not associated with significant complications. Surgical or medication treatments (e.g., surgical reimplantation of the salivary ducts or use of local scopolamine patches) are generally not effective. Treatment is usually conservative including bibs and sometimes occupational therapy [ Astigmatism is the most common refractive error. Keratoconus can occur and may be secondary to persistent eye rubbing or gouging behaviors or other causes. Additional ocular findings include myopia, hyperopia, nystagmus, optic nerve atrophy or optic disk pallor, retinochoroidal atrophy, ptosis, and amblyopia [ All molecular causes of AS lead to a similar phenotype of severe-to-profound intellectual disability, movement disorder, characteristic behaviors, and severe limitations in speech and language. However, some phenotypic differences correlate with genotype [ The 5- to 7-Mb 15q11.2-q13 deletion results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, hypotonia, feeding difficulties), and language impairment. These individuals also have lower body mass index compared to individuals with UPD or an imprinting defect. It is unclear if individuals with larger deletions (e.g., BP1-BP3 [class I; ISCA-37404] break points) can be clinically distinguished from those with BP2-BP3 (class II; ISCA-37478) break points (see Individuals with Individuals who are mosaic for nondeletion imprinting defects (~20% of those with an imprinting defect) have the most advanced speech abilities [ Individuals with a 15q11.2-q13 deletion including The population prevalence of AS is estimated at 1:12,000-1:24,000 [ • The 5- to 7-Mb 15q11.2-q13 deletion results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, hypotonia, feeding difficulties), and language impairment. These individuals also have lower body mass index compared to individuals with UPD or an imprinting defect. It is unclear if individuals with larger deletions (e.g., BP1-BP3 [class I; ISCA-37404] break points) can be clinically distinguished from those with BP2-BP3 (class II; ISCA-37478) break points (see • Individuals with • Individuals who are mosaic for nondeletion imprinting defects (~20% of those with an imprinting defect) have the most advanced speech abilities [ • Individuals with a 15q11.2-q13 deletion including ## Clinical Description Angelman syndrome (AS) is characterized by severe developmental delay and intellectual disability, severe speech impairment, gait ataxia and/or tremulousness of the limbs, and a unique behavior with an apparent happy demeanor that includes frequent laughing, smiling, and excitability. Microcephaly and seizures are also common. Developmental delays are first noted at around age six months; however, the unique clinical features of AS do not become manifest until after age one year. Angelman Syndrome: Frequency of Select Features GI = gastrointestinal Normal occipital frontal circumference should not exclude AS diagnosis. Seizure types can be quite varied; the most common are myoclonic, atonic, generalized tonic-clonic, and atypical absence [ Brain MRI may show mild atrophy and mild dysmyelination, but no structural lesions [ Certain behaviors may suggest a diagnosis of autism spectrum disorder (e.g., fascination with water and crinkly items such as certain papers and plastics, increased sensitivity to heat, abnormal food-related behaviors) but social engagement is typically good. Stereotypic behaviors such as lining up of toys or fascination with spinning objects or flashing lights rarely occur. Some individuals with AS have good response to ABA (applied behavior analysis) therapy [ The behavior profile generally continues into the adult years. Particularly challenging in teenage and adult years include frustration in communicating wants and preferences, seeking sensory stimulation and social attention, and avoidance of undesired situations [ AS may first be suspected in a toddler because of delayed gross motor milestones and hypotonia. Mildly impaired children may walk fairly normally or have minimal toe-walking or prancing gait, at times accompanied by leaning forward. Being placed in a standing position can result in anxiety or rigidity. The average age of walking is between 2.5 and six years [ Frequently voluntary movements appear irregular. On the mild end they can present as slight jerkiness to uncoordinated coarse movements on the severe end of the spectrum. These movements can prevent reaching for objects, feeding, and walking. Failure to achieve independent walking may be a result of instability resulting from tremor, epilepsy, vision issues, abnormal muscle tone, or balance problems. Ten percent of children are nonambulatory [ Appropriate and consistent use of one or two words is rare. Babies and young infants have decreased cooing and babbling. At age ten to 18 months, a single word such as "mama" may develop but is often used indiscriminately. In a survey of 47 individuals, 39% spoke up to four words but it was unclear if these words were used with purpose [ Seizures and significant hyperactivity can impede early communication development including eye contact. Most older children and adults with AS are able to communicate by pointing and reaching, using gestures, pointing to body parts, and by using communication boards. Effective fluent use of sign language does not occur [ Gastroesophageal reflux disease (GERD) occurs in 45%-65% of individuals with AS, resulting in poor weight gain and emesis in infants [ Vomiting is not uncommon and can be either cyclic or intermittent. Cyclic vomiting appears to be more common in individuals with a 15q11.2-q13 deletion or uniparental disomy (UPD). Vomiting (unrelated to illness or food allergies) can be due to a variety of factors including anxiety and behavior issues, side effects of medication, and constipation [ Hyperphagia and problematic food-related behaviors are seen in all genetic subtypes with a prevalence of 20%-50% [ Constipation is common and can occur at any age. Symptoms include hard or infrequent stools, poor or worsening appetite, vomiting, and stomach pain. Appropriate and timely management is important, as constipation can result in behavioral changes, weight loss, poor sleep quality, and increased seizures [ Although the tongue is normal in shape and size, about 30%-50% have persistent tongue protrusion. For some individuals, the problem persists into adulthood. Drooling can lead to skin irritation and aspiration, but is generally not associated with significant complications. Surgical or medication treatments (e.g., surgical reimplantation of the salivary ducts or use of local scopolamine patches) are generally not effective. Treatment is usually conservative including bibs and sometimes occupational therapy [ Astigmatism is the most common refractive error. Keratoconus can occur and may be secondary to persistent eye rubbing or gouging behaviors or other causes. Additional ocular findings include myopia, hyperopia, nystagmus, optic nerve atrophy or optic disk pallor, retinochoroidal atrophy, ptosis, and amblyopia [ ## Genotype-Phenotype Correlations All molecular causes of AS lead to a similar phenotype of severe-to-profound intellectual disability, movement disorder, characteristic behaviors, and severe limitations in speech and language. However, some phenotypic differences correlate with genotype [ The 5- to 7-Mb 15q11.2-q13 deletion results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, hypotonia, feeding difficulties), and language impairment. These individuals also have lower body mass index compared to individuals with UPD or an imprinting defect. It is unclear if individuals with larger deletions (e.g., BP1-BP3 [class I; ISCA-37404] break points) can be clinically distinguished from those with BP2-BP3 (class II; ISCA-37478) break points (see Individuals with Individuals who are mosaic for nondeletion imprinting defects (~20% of those with an imprinting defect) have the most advanced speech abilities [ Individuals with a 15q11.2-q13 deletion including • The 5- to 7-Mb 15q11.2-q13 deletion results in the most severe phenotype with microcephaly, seizures, motor difficulties (e.g., ataxia, hypotonia, feeding difficulties), and language impairment. These individuals also have lower body mass index compared to individuals with UPD or an imprinting defect. It is unclear if individuals with larger deletions (e.g., BP1-BP3 [class I; ISCA-37404] break points) can be clinically distinguished from those with BP2-BP3 (class II; ISCA-37478) break points (see • Individuals with • Individuals who are mosaic for nondeletion imprinting defects (~20% of those with an imprinting defect) have the most advanced speech abilities [ • Individuals with a 15q11.2-q13 deletion including ## Penetrance ## Prevalence The population prevalence of AS is estimated at 1:12,000-1:24,000 [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Infants with Angelman syndrome (AS) commonly present with nonspecific psychomotor delay and/or seizures; therefore, the differential diagnosis is broad and nonspecific, encompassing such entities as cerebral palsy, static encephalopathy, or mitochondrial encephalomyopathy. The tremulousness and jerky limb movements seen in most infants with AS may help distinguish AS from these conditions. AS-mimicking conditions have been reviewed [ Genes of Interest in the Differential Diagnosis of Angelman Syndrome AD = autosomal dominant; AR = autosomal recessive; AS = Angelman syndrome; BMI = body mass index; DD = developmental delay; GERD = gastroesophageal reflux disease; ID = intellectual disability; MOI = mode of inheritance; MTHFR = methylenetetrahydrofolate reductase; XL = X-linked Craniofacial features are an important aspect for the diagnosis of PTHS, but may be less obvious in infancy. In many cases, the prominence of the nose and lower face may be the earliest clue to PTHS in an infant with developmental concern. Widely spaced eyes, broad eyebrows with a medial flare, low-hanging columella, prominent or pointed chin, open-mouth expression, and uplifted earlobes with a central depression Some ## Management No clinical practice guidelines for Angelman syndrome (AS) have been published. To establish the extent of disease and needs in an individual diagnosed with AS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Angelman Syndrome Motor, adaptive, cognitive, & nonverbal language ability Language ability & need for special communication devices Eval for early intervention / special education Screening for behavior concerns incl sleep disturbances Gross motor & fine motor skills Scoliosis & gait impairment (e.g., extent of foot pronation or ankle subluxation; tight Achilles tendons) & extent of hypotonia Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Need for orthopedic referral Community or Social work involvement for parental support; Home nursing referral. 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 Angelman Syndrome Single medication use is preferred, but seizure breakthrough is common. Some w/uncontrollable seizures have benefited from a ketogenic or low-glycemic diet. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Treat NCSE. Treat NEM. Provide rescue medication. Educate parents/caregivers. Accommodation by the family & provision of a safe environment Children w/AS w/excessive hypermotoric behaviors need an accommodating classroom space Most children do not receive drug therapy for hyperactivity, but some may benefit from use of stimulant medications (e.g., Ritalin Typically resistant to behavior therapies OT may help improve fine-motor & oral-motor control. Unstable or nonambulatory children may benefit from PT. Special adaptive chairs or positioners may be required, esp for extremely ataxic children. Speech therapy is essential & should focus on nonverbal methods of communication. Use of augmentative communication aids (e.g., picture cards, communication boards) at the earliest appropriate time Attempts to teach signing should begin as soon as child is sufficiently attentive. Upright positioning Motility drugs Thoraco-lumbar jackets as needed Those w/severe curvature may benefit from surgical rod stabilization ASM = anti-seizure medication; NCSE = nonconvulsive status epilepticus; NEM = nonepileptic myoclonus; OT = occupational therapy; PT = physical therapy Anticonvulsants most commonly used in the initial approach to treatment include clobazam, levetiracetam, lamotrigine, and clonazepam, based on clinical survey use [ Diazepam can be useful in outpatient treatment of NCSE [ NEM can be difficult to treat; levetiracetam, clobazam, and clonazepam have been used [ Individuals with AS and seizure history should have availability of rescue medications for emergency treatment of prolonged seizures, including rectal diazepam gel or intranasal midazolam or diazepam [ Recommended Surveillance for Individuals with Angelman Syndrome Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, movement disorders. Monitor developmental progress & educational needs. Speech assessment Measurement of growth parameters Eval of nutritional status Eval of older children for obesity OT = occupational therapy; PT = physical therapy Children with AS are at risk for medication overtreatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled. The behavioral phenotype of AS includes hyperexcitability, hypermotoric behaviors, and deficits in social communication. These limitations place affected individuals at risk for social disruptions. On occasion, the use of risperidone (Risperdal See Clinical trials involving oral administration of folate, vitamin B Search • Motor, adaptive, cognitive, & nonverbal language ability • Language ability & need for special communication devices • Eval for early intervention / special education • Screening for behavior concerns incl sleep disturbances • Gross motor & fine motor skills • Scoliosis & gait impairment (e.g., extent of foot pronation or ankle subluxation; tight Achilles tendons) & extent of hypotonia • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Need for orthopedic referral • Community or • Social work involvement for parental support; • Home nursing referral. • Single medication use is preferred, but seizure breakthrough is common. • Some w/uncontrollable seizures have benefited from a ketogenic or low-glycemic diet. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Treat NCSE. • Treat NEM. • Provide rescue medication. • Educate parents/caregivers. • Accommodation by the family & provision of a safe environment • Children w/AS w/excessive hypermotoric behaviors need an accommodating classroom space • Most children do not receive drug therapy for hyperactivity, but some may benefit from use of stimulant medications (e.g., Ritalin • Typically resistant to behavior therapies • OT may help improve fine-motor & oral-motor control. • Unstable or nonambulatory children may benefit from PT. • Special adaptive chairs or positioners may be required, esp for extremely ataxic children. • Speech therapy is essential & should focus on nonverbal methods of communication. • Use of augmentative communication aids (e.g., picture cards, communication boards) at the earliest appropriate time • Attempts to teach signing should begin as soon as child is sufficiently attentive. • Upright positioning • Motility drugs • Thoraco-lumbar jackets as needed • Those w/severe curvature may benefit from surgical rod stabilization • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, movement disorders. • Monitor developmental progress & educational needs. • Speech assessment • Measurement of growth parameters • Eval of nutritional status • Eval of older children for obesity • Children with AS are at risk for medication overtreatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled. • The behavioral phenotype of AS includes hyperexcitability, hypermotoric behaviors, and deficits in social communication. These limitations place affected individuals at risk for social disruptions. On occasion, the use of risperidone (Risperdal ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with AS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Angelman Syndrome Motor, adaptive, cognitive, & nonverbal language ability Language ability & need for special communication devices Eval for early intervention / special education Screening for behavior concerns incl sleep disturbances Gross motor & fine motor skills Scoliosis & gait impairment (e.g., extent of foot pronation or ankle subluxation; tight Achilles tendons) & extent of hypotonia Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Need for orthopedic referral Community or Social work involvement for parental support; Home nursing referral. 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) • Motor, adaptive, cognitive, & nonverbal language ability • Language ability & need for special communication devices • Eval for early intervention / special education • Screening for behavior concerns incl sleep disturbances • Gross motor & fine motor skills • Scoliosis & gait impairment (e.g., extent of foot pronation or ankle subluxation; tight Achilles tendons) & extent of hypotonia • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Need for orthopedic referral • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Angelman Syndrome Single medication use is preferred, but seizure breakthrough is common. Some w/uncontrollable seizures have benefited from a ketogenic or low-glycemic diet. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Treat NCSE. Treat NEM. Provide rescue medication. Educate parents/caregivers. Accommodation by the family & provision of a safe environment Children w/AS w/excessive hypermotoric behaviors need an accommodating classroom space Most children do not receive drug therapy for hyperactivity, but some may benefit from use of stimulant medications (e.g., Ritalin Typically resistant to behavior therapies OT may help improve fine-motor & oral-motor control. Unstable or nonambulatory children may benefit from PT. Special adaptive chairs or positioners may be required, esp for extremely ataxic children. Speech therapy is essential & should focus on nonverbal methods of communication. Use of augmentative communication aids (e.g., picture cards, communication boards) at the earliest appropriate time Attempts to teach signing should begin as soon as child is sufficiently attentive. Upright positioning Motility drugs Thoraco-lumbar jackets as needed Those w/severe curvature may benefit from surgical rod stabilization ASM = anti-seizure medication; NCSE = nonconvulsive status epilepticus; NEM = nonepileptic myoclonus; OT = occupational therapy; PT = physical therapy Anticonvulsants most commonly used in the initial approach to treatment include clobazam, levetiracetam, lamotrigine, and clonazepam, based on clinical survey use [ Diazepam can be useful in outpatient treatment of NCSE [ NEM can be difficult to treat; levetiracetam, clobazam, and clonazepam have been used [ Individuals with AS and seizure history should have availability of rescue medications for emergency treatment of prolonged seizures, including rectal diazepam gel or intranasal midazolam or diazepam [ • Single medication use is preferred, but seizure breakthrough is common. • Some w/uncontrollable seizures have benefited from a ketogenic or low-glycemic diet. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Treat NCSE. • Treat NEM. • Provide rescue medication. • Educate parents/caregivers. • Accommodation by the family & provision of a safe environment • Children w/AS w/excessive hypermotoric behaviors need an accommodating classroom space • Most children do not receive drug therapy for hyperactivity, but some may benefit from use of stimulant medications (e.g., Ritalin • Typically resistant to behavior therapies • OT may help improve fine-motor & oral-motor control. • Unstable or nonambulatory children may benefit from PT. • Special adaptive chairs or positioners may be required, esp for extremely ataxic children. • Speech therapy is essential & should focus on nonverbal methods of communication. • Use of augmentative communication aids (e.g., picture cards, communication boards) at the earliest appropriate time • Attempts to teach signing should begin as soon as child is sufficiently attentive. • Upright positioning • Motility drugs • Thoraco-lumbar jackets as needed • Those w/severe curvature may benefit from surgical rod stabilization ## Surveillance Recommended Surveillance for Individuals with Angelman Syndrome Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures, changes in tone, movement disorders. Monitor developmental progress & educational needs. Speech assessment Measurement of growth parameters Eval of nutritional status Eval of older children for obesity OT = occupational therapy; PT = physical therapy • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl seizures, changes in tone, movement disorders. • Monitor developmental progress & educational needs. • Speech assessment • Measurement of growth parameters • Eval of nutritional status • Eval of older children for obesity ## Agents/Circumstances to Avoid Children with AS are at risk for medication overtreatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled. The behavioral phenotype of AS includes hyperexcitability, hypermotoric behaviors, and deficits in social communication. These limitations place affected individuals at risk for social disruptions. On occasion, the use of risperidone (Risperdal • Children with AS are at risk for medication overtreatment because their movement abnormalities can be mistaken for seizures and because EEG abnormalities can persist even when seizures are controlled. • The behavioral phenotype of AS includes hyperexcitability, hypermotoric behaviors, and deficits in social communication. These limitations place affected individuals at risk for social disruptions. On occasion, the use of risperidone (Risperdal ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Clinical trials involving oral administration of folate, vitamin B Search ## Genetic Counseling Individuals with Angelman syndrome (AS) typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a If the proband does not have a 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. Once the underlying genetic mechanism has been established in the proband, the genetic status of the parents can be assessed. Recommendations for parental testing (based on the genetic mechanism in the proband) and corresponding recurrence risks to sibs are summarized in Risks to Sibs of a Proband with Angelman Syndrome by Genetic Mechanism and Parental Genetic Status <1% if maternal chromosome studies are normal Possibly as high as 50% if the mother has a chromosome rearrangement <1% if both parents have normal chromosome analyses Approaches 100% if father has a 15;15 Robertsonian translocation <1% if the IC deletion is not identified in maternal leukocyte DNA 50% if the mother is heterozygous for the IC deletion 50% if the mother is heterozygous for the <1% if the IC = imprinting center; NA = not applicable; UPD = uniparental disomy Based on terminology by Maternal germline mosaicism for large 15q11.2-q13 deletions has been reported [ Risk figure is based on the lack of recurrence among all known cases of UPD in AS with normal chromosomes, the experience with UPD in other disorders, & theoretic consideration regarding the mechanism of UPD. Theoretically, the mother could have germline mosaicism for the imprinting center deletion; to the authors' knowledge, this has not yet been reported. There is a single report of a pair of sibs with AS who had a 1-1.5-Mb inversion separating the two imprinting center elements, but no imprinting center deletion [ Maternal somatic/germline mosaicism for a If a If a proband's mother is heterozygous for a known imprinting center deletion or The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having children with AS. Prenatal testing and preimplantation genetic testing for high-risk pregnancies require prior identification of the underlying genetic mechanism in the proband. DNA methylation analysis (for 5- to 7-Mb deletion of 15q11.2-q13, UPD, and imprinting center defects) on fetal cells obtained by CVS is theoretically possible. However, the few clinical laboratories doing prenatal testing using DNA methylation analysis prefer to use amniocytes because of the relative hypomethylation of cells derived from the placenta. FISH analysis, imprinting center deletion analysis, and sequence analysis of Prenatal testing should be undertaken only after the genetic mechanism in the index case has been established and the couple has been counseled regarding recurrence risk, as the risks and the type of molecular genetic testing used vary according to the type of molecular defect in the proband (see Parents with normal chromosomes who have had one child with AS caused by either 15q11.2-q13 deletion or UPD have a low recurrence risk but may be offered prenatal testing for reassurance. Parents who have had one child with AS caused by a Prenatal testing for an inherited translocation involving chromosome 15 is relevant because of the increased recurrence risk. FISH analysis and parent-of-origin (DNA methylation and/or polymorphism) studies should be considered if an inherited translocation involving chromosome 15 is present. • If the proband does not have a • 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. • If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ • If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. • 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. • If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ • If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. • Once the underlying genetic mechanism has been established in the proband, the genetic status of the parents can be assessed. • Recommendations for parental testing (based on the genetic mechanism in the proband) and corresponding recurrence risks to sibs are summarized in • 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. • If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ • If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. • <1% if maternal chromosome studies are normal • Possibly as high as 50% if the mother has a chromosome rearrangement • <1% if both parents have normal chromosome analyses • Approaches 100% if father has a 15;15 Robertsonian translocation • <1% if the IC deletion is not identified in maternal leukocyte DNA • 50% if the mother is heterozygous for the IC deletion • 50% if the mother is heterozygous for the • <1% if the • If a • If a proband's mother is heterozygous for a known imprinting center deletion or • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having children with AS. • Parents with normal chromosomes who have had one child with AS caused by either 15q11.2-q13 deletion or UPD have a low recurrence risk but may be offered prenatal testing for reassurance. • Parents who have had one child with AS caused by a • Prenatal testing for an inherited translocation involving chromosome 15 is relevant because of the increased recurrence risk. FISH analysis and parent-of-origin (DNA methylation and/or polymorphism) studies should be considered if an inherited translocation involving chromosome 15 is present. ## Mode of Inheritance Individuals with Angelman syndrome (AS) typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a ## Risk to Family Members If the proband does not have a 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. Once the underlying genetic mechanism has been established in the proband, the genetic status of the parents can be assessed. Recommendations for parental testing (based on the genetic mechanism in the proband) and corresponding recurrence risks to sibs are summarized in Risks to Sibs of a Proband with Angelman Syndrome by Genetic Mechanism and Parental Genetic Status <1% if maternal chromosome studies are normal Possibly as high as 50% if the mother has a chromosome rearrangement <1% if both parents have normal chromosome analyses Approaches 100% if father has a 15;15 Robertsonian translocation <1% if the IC deletion is not identified in maternal leukocyte DNA 50% if the mother is heterozygous for the IC deletion 50% if the mother is heterozygous for the <1% if the IC = imprinting center; NA = not applicable; UPD = uniparental disomy Based on terminology by Maternal germline mosaicism for large 15q11.2-q13 deletions has been reported [ Risk figure is based on the lack of recurrence among all known cases of UPD in AS with normal chromosomes, the experience with UPD in other disorders, & theoretic consideration regarding the mechanism of UPD. Theoretically, the mother could have germline mosaicism for the imprinting center deletion; to the authors' knowledge, this has not yet been reported. There is a single report of a pair of sibs with AS who had a 1-1.5-Mb inversion separating the two imprinting center elements, but no imprinting center deletion [ Maternal somatic/germline mosaicism for a If a If a proband's mother is heterozygous for a known imprinting center deletion or • If the proband does not have a • 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. • If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ • If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. • 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. • If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ • If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. • Once the underlying genetic mechanism has been established in the proband, the genetic status of the parents can be assessed. • Recommendations for parental testing (based on the genetic mechanism in the proband) and corresponding recurrence risks to sibs are summarized in • 15q11.2-q13 deletion analysis (by chromosomal microarray or other methods) should be performed first. • If a 15q11.2-q13 deletion is not detected and the microarray (or other method used to detect copy number variants) does not identify segmental or whole-chromosome isodisomy, analysis of DNA polymorphisms on chromosome 15 can be used to rule out a whole-chromosome heterodisomy (to the authors' knowledge, this type of heterodisomy has not been reported in AS, although it is relatively common in Prader-Willi syndrome [ • If UPD is not detected, the presumption is that an imprinting defect is present; additional studies can then determine if there is a deletion in the imprinting center. • <1% if maternal chromosome studies are normal • Possibly as high as 50% if the mother has a chromosome rearrangement • <1% if both parents have normal chromosome analyses • Approaches 100% if father has a 15;15 Robertsonian translocation • <1% if the IC deletion is not identified in maternal leukocyte DNA • 50% if the mother is heterozygous for the IC deletion • 50% if the mother is heterozygous for the • <1% if the • If a • If a proband's mother is heterozygous for a known imprinting center deletion or ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having children with AS. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are at risk of having children with AS. ## Prenatal Testing and Preimplantation Genetic Testing Prenatal testing and preimplantation genetic testing for high-risk pregnancies require prior identification of the underlying genetic mechanism in the proband. DNA methylation analysis (for 5- to 7-Mb deletion of 15q11.2-q13, UPD, and imprinting center defects) on fetal cells obtained by CVS is theoretically possible. However, the few clinical laboratories doing prenatal testing using DNA methylation analysis prefer to use amniocytes because of the relative hypomethylation of cells derived from the placenta. FISH analysis, imprinting center deletion analysis, and sequence analysis of Prenatal testing should be undertaken only after the genetic mechanism in the index case has been established and the couple has been counseled regarding recurrence risk, as the risks and the type of molecular genetic testing used vary according to the type of molecular defect in the proband (see Parents with normal chromosomes who have had one child with AS caused by either 15q11.2-q13 deletion or UPD have a low recurrence risk but may be offered prenatal testing for reassurance. Parents who have had one child with AS caused by a Prenatal testing for an inherited translocation involving chromosome 15 is relevant because of the increased recurrence risk. FISH analysis and parent-of-origin (DNA methylation and/or polymorphism) studies should be considered if an inherited translocation involving chromosome 15 is present. • Parents with normal chromosomes who have had one child with AS caused by either 15q11.2-q13 deletion or UPD have a low recurrence risk but may be offered prenatal testing for reassurance. • Parents who have had one child with AS caused by a • Prenatal testing for an inherited translocation involving chromosome 15 is relevant because of the increased recurrence risk. FISH analysis and parent-of-origin (DNA methylation and/or polymorphism) studies should be considered if an inherited translocation involving chromosome 15 is present. ## Other ## Resources 4255 Westbrook Drive Suite 219 Aurora IL 60504 PO Box 608 Downers Grove IL 60515 • • 4255 Westbrook Drive • Suite 219 • Aurora IL 60504 • • • PO Box 608 • Downers Grove IL 60515 • • • • • • • • • • • ## Molecular Genetics Angelman Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Angelman Syndrome ( The cardinal features of Angelman syndrome result from deficient expression or function of the maternally inherited Disruption of Note: Microdeletions that flank the typical deletion region and include areas between BP1 and BP2 [ A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ Mapping these imprinting center deletions (as well as mapping the imprinting center deletions that are associated with PWS) has delineated two small regions of deletion overlap (SRO) that define two critical elements in the imprinting center, the AS-SRO and the PWS-SRO [ • Note: Microdeletions that flank the typical deletion region and include areas between BP1 and BP2 [ • A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ • A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ • A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ • A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ • Mapping these imprinting center deletions (as well as mapping the imprinting center deletions that are associated with PWS) has delineated two small regions of deletion overlap (SRO) that define two critical elements in the imprinting center, the AS-SRO and the PWS-SRO [ • A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ • A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ ## Molecular Pathogenesis The cardinal features of Angelman syndrome result from deficient expression or function of the maternally inherited Disruption of Note: Microdeletions that flank the typical deletion region and include areas between BP1 and BP2 [ A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ Mapping these imprinting center deletions (as well as mapping the imprinting center deletions that are associated with PWS) has delineated two small regions of deletion overlap (SRO) that define two critical elements in the imprinting center, the AS-SRO and the PWS-SRO [ • Note: Microdeletions that flank the typical deletion region and include areas between BP1 and BP2 [ • A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ • A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ • A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ • A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ • Mapping these imprinting center deletions (as well as mapping the imprinting center deletions that are associated with PWS) has delineated two small regions of deletion overlap (SRO) that define two critical elements in the imprinting center, the AS-SRO and the PWS-SRO [ • A proportion of mothers who have a child with AS due to a 15q11.1-q13 deletion have been found to have inversions in the 15q11.2-q13 region [ • A kindred in which two individuals had deletions (one deletion causing PWS and the other causing AS) has been previously reported to be associated with an inherited inverted intrachromosomal insertion of 15q11.2-q13 [ ## Chapter Notes Adati I Dagli, MD (2008-present)Hui-Ja Dong; University of Florida College of Medicine (2003-2005)Daniel J Driscoll, PhD, MD; University of Florida College of Medicine (1998-2011)Amy C Lossie, PhD; University of Florida College of Medicine (1998-2003)Jennifer Mathews, MS, CGC (2015-present)Charles A Williams, MD (1998-present) 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines 22 April 2021 (sw) Comprehensive update posted live 14 May 2015 (me) Comprehensive update posted live 16 June 2011 (me) Comprehensive update posted live 5 September 2008 (me) Comprehensive update posted live 8 November 2005 (me) Comprehensive update posted live 29 July 2003 (me) Comprehensive update posted live 21 November 2000 (me) Comprehensive update posted live 15 September 1998 (pb) Review posted live April 1998 (cw) Original submission • 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines • 22 April 2021 (sw) Comprehensive update posted live • 14 May 2015 (me) Comprehensive update posted live • 16 June 2011 (me) Comprehensive update posted live • 5 September 2008 (me) Comprehensive update posted live • 8 November 2005 (me) Comprehensive update posted live • 29 July 2003 (me) Comprehensive update posted live • 21 November 2000 (me) Comprehensive update posted live • 15 September 1998 (pb) Review posted live • April 1998 (cw) Original submission ## Author History Adati I Dagli, MD (2008-present)Hui-Ja Dong; University of Florida College of Medicine (2003-2005)Daniel J Driscoll, PhD, MD; University of Florida College of Medicine (1998-2011)Amy C Lossie, PhD; University of Florida College of Medicine (1998-2003)Jennifer Mathews, MS, CGC (2015-present)Charles A Williams, MD (1998-present) ## Revision History 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines 22 April 2021 (sw) Comprehensive update posted live 14 May 2015 (me) Comprehensive update posted live 16 June 2011 (me) Comprehensive update posted live 5 September 2008 (me) Comprehensive update posted live 8 November 2005 (me) Comprehensive update posted live 29 July 2003 (me) Comprehensive update posted live 21 November 2000 (me) Comprehensive update posted live 15 September 1998 (pb) Review posted live April 1998 (cw) Original submission • 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines • 22 April 2021 (sw) Comprehensive update posted live • 14 May 2015 (me) Comprehensive update posted live • 16 June 2011 (me) Comprehensive update posted live • 5 September 2008 (me) Comprehensive update posted live • 8 November 2005 (me) Comprehensive update posted live • 29 July 2003 (me) Comprehensive update posted live • 21 November 2000 (me) Comprehensive update posted live • 15 September 1998 (pb) Review posted live • April 1998 (cw) 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. Available Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140:413-18. • 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. Available • Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140:413-18. ## 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. Available Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140:413-18. • 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. Available • Williams CA, Beaudet AL, Clayton-Smith J, Knoll JH, Kyllerman M, Laan LA, Magenis RE, Moncla A, Schinzel AA, Summers JA, Wagstaff J. Angelman syndrome 2005: updated consensus for diagnostic criteria. Am J Med Genet A. 2006;140:413-18. ## Literature Cited Individuals depicted have a genetically confirmed diagnosis of Angelman syndrome. Happy expression and an unstable gait accompanied by uplifted arms are commonly observed. At times, the facial appearance can suggest the diagnosis, but usually facial features are not distinctive. Schematic drawing of chromosome region 15q11.2-q13 indicating the breakpoint regions BP1-BP6. Low copy repeat elements are located within these breakpoint regions (see The pedigree illustrates imprinting inheritance in Angelman syndrome (AS). Inheritance of a deleterious	[]	15/9/1998	22/4/2021	1/5/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aniridia	aniridia	[ "Wilms Tumor-Aniridia-Genital Anomalies-Retardation (WAGR) Syndrome", "Isolated Aniridia", "Paired box protein Pax-6", "PAX6", "PAX6-Related Aniridia" ]		Mariya Moosajee, Melanie Hingorani, Anthony T Moore	Summary The diagnosis of Isolated aniridia (i.e., without systemic involvement) and a heterozygous Aniridia and one or more additional findings of WAGR syndrome and a deletion of Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner. When the	Isolated aniridia • Isolated aniridia ## Diagnosis Aniridia. Complete or partial iris hypoplasia best seen on slit lamp examination. Iris translucency or abnormal architecture and pupillary abnormalities may also be seen. Reduced visual acuity secondary to: Absence of or reduction in the normal foveal architecture (usually [not always] observed) Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) Early-onset nystagmus (usually apparent by age 6 weeks) Microphthalmia and ocular coloboma (iris, chorioretinal, and/or optic disc) Note: Iris fluorescein angiography may identify subtle iris hypoplasia but is rarely used clinically. Wilms tumor (also known as nephroblastoma), a childhood kidney malignancy. Of children with WAGR who develop Wilms tumor, 90% do so by age four years and 98% by age seven years (see Genitourinary abnormalities. In males: cryptorchidism, hypospadias, ambiguous genitalia; in females: normal external female genitalia, but uterine abnormalities (heart-shaped bicornate uterus) and streak ovaries. In males and females: end-stage kidney disease, ureteric abnormalities, and gonadoblastoma. Intellectual disability and/or behavior abnormalities including depression, anxiety, ADHD, obsessive-compulsive disorder, and autism. Childhood-onset obesity and pancreatitis The diagnosis of Note: Deletions telomeric to A heterozygous variant in the ultraconserved MLPA detected a 0.6-Mb deletion downstream of Coverage of these regions on chromosomal or gene-targeted arrays will vary [ A deletion of Note: Reported deletions include the recurrent 11p13 deletion (see One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. Molecular genetic testing can establish the molecular basis of aniridia, and thus distinguish between isolated aniridia (no increased risk for Wilms tumor) and WAGR (markedly increased risk for Wilms tumor). In the following scenarios molecular genetic testing approaches are based on the individual's age, clinical findings, family history, and testing methods available. Perform chromosomal microarray (CMA) (which may use array-based comparative genomic hybridization [aCGH] and/or a SNP genotyping array) to identify a contiguous-gene deletion that includes If a deletion involving Perform sequence analysis of If a Perform If no 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, C-terminal extension (CTE) variants and splice site variants and small 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 one individual a heterozygous single-nucleotide variant in the ultraconserved Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. GRCh37/hg19 chr11:31,803,509-32,510,988: Genomic coordinates represent the minimum deletion size associated with the 11p13 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. Standardized clinical annotation and interpretation for genomic variants from the Chromosome microarray analysis (CMA) using oligonucleotide arrays (i.e., array comparative genomic hybridization) and/or SNP genotyping arrays. CMA designs in current clinical use target the 11p13 region. FISH is not appropriate as a diagnostic method for an individual in whom the 11p13 deletion syndrome was not detected by CMA designed to target this region. FISH, qPCR, or other quantitative methods of targeted deletion analysis can be used to identify the 11p13 deletion in at-risk relatives of the proband to help determine recurrence risk (see • Aniridia. Complete or partial iris hypoplasia best seen on slit lamp examination. Iris translucency or abnormal architecture and pupillary abnormalities may also be seen. • Reduced visual acuity secondary to: • Absence of or reduction in the normal foveal architecture (usually [not always] observed) • Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) • Absence of or reduction in the normal foveal architecture (usually [not always] observed) • Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) • Early-onset nystagmus (usually apparent by age 6 weeks) • Microphthalmia and ocular coloboma (iris, chorioretinal, and/or optic disc) • Absence of or reduction in the normal foveal architecture (usually [not always] observed) • Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) • Note: Iris fluorescein angiography may identify subtle iris hypoplasia but is rarely used clinically. • Wilms tumor (also known as nephroblastoma), a childhood kidney malignancy. Of children with WAGR who develop Wilms tumor, 90% do so by age four years and 98% by age seven years (see • Genitourinary abnormalities. In males: cryptorchidism, hypospadias, ambiguous genitalia; in females: normal external female genitalia, but uterine abnormalities (heart-shaped bicornate uterus) and streak ovaries. In males and females: end-stage kidney disease, ureteric abnormalities, and gonadoblastoma. • Intellectual disability and/or behavior abnormalities including depression, anxiety, ADHD, obsessive-compulsive disorder, and autism. • Childhood-onset obesity and pancreatitis • Note: Deletions telomeric to • A heterozygous variant in the ultraconserved • MLPA detected a 0.6-Mb deletion downstream of • Coverage of these regions on chromosomal or gene-targeted arrays will vary [ • A heterozygous variant in the ultraconserved • MLPA detected a 0.6-Mb deletion downstream of • A deletion of • Note: Reported deletions include the recurrent 11p13 deletion (see • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. • Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. • A deletion of • Note: Reported deletions include the recurrent 11p13 deletion (see • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. • Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. • A heterozygous variant in the ultraconserved • MLPA detected a 0.6-Mb deletion downstream of • A deletion of • Note: Reported deletions include the recurrent 11p13 deletion (see • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. • Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. • Perform chromosomal microarray (CMA) (which may use array-based comparative genomic hybridization [aCGH] and/or a SNP genotyping array) to identify a contiguous-gene deletion that includes • If a deletion involving • Perform sequence analysis of • If a • Perform • If no ## Suggestive Findings Aniridia. Complete or partial iris hypoplasia best seen on slit lamp examination. Iris translucency or abnormal architecture and pupillary abnormalities may also be seen. Reduced visual acuity secondary to: Absence of or reduction in the normal foveal architecture (usually [not always] observed) Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) Early-onset nystagmus (usually apparent by age 6 weeks) Microphthalmia and ocular coloboma (iris, chorioretinal, and/or optic disc) Note: Iris fluorescein angiography may identify subtle iris hypoplasia but is rarely used clinically. Wilms tumor (also known as nephroblastoma), a childhood kidney malignancy. Of children with WAGR who develop Wilms tumor, 90% do so by age four years and 98% by age seven years (see Genitourinary abnormalities. In males: cryptorchidism, hypospadias, ambiguous genitalia; in females: normal external female genitalia, but uterine abnormalities (heart-shaped bicornate uterus) and streak ovaries. In males and females: end-stage kidney disease, ureteric abnormalities, and gonadoblastoma. Intellectual disability and/or behavior abnormalities including depression, anxiety, ADHD, obsessive-compulsive disorder, and autism. Childhood-onset obesity and pancreatitis • Aniridia. Complete or partial iris hypoplasia best seen on slit lamp examination. Iris translucency or abnormal architecture and pupillary abnormalities may also be seen. • Reduced visual acuity secondary to: • Absence of or reduction in the normal foveal architecture (usually [not always] observed) • Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) • Absence of or reduction in the normal foveal architecture (usually [not always] observed) • Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) • Early-onset nystagmus (usually apparent by age 6 weeks) • Microphthalmia and ocular coloboma (iris, chorioretinal, and/or optic disc) • Absence of or reduction in the normal foveal architecture (usually [not always] observed) • Optic nerve abnormalities (e.g., optic nerve hypoplasia or coloboma) • Note: Iris fluorescein angiography may identify subtle iris hypoplasia but is rarely used clinically. • Wilms tumor (also known as nephroblastoma), a childhood kidney malignancy. Of children with WAGR who develop Wilms tumor, 90% do so by age four years and 98% by age seven years (see • Genitourinary abnormalities. In males: cryptorchidism, hypospadias, ambiguous genitalia; in females: normal external female genitalia, but uterine abnormalities (heart-shaped bicornate uterus) and streak ovaries. In males and females: end-stage kidney disease, ureteric abnormalities, and gonadoblastoma. • Intellectual disability and/or behavior abnormalities including depression, anxiety, ADHD, obsessive-compulsive disorder, and autism. • Childhood-onset obesity and pancreatitis ## Establishing the Diagnosis The diagnosis of Note: Deletions telomeric to A heterozygous variant in the ultraconserved MLPA detected a 0.6-Mb deletion downstream of Coverage of these regions on chromosomal or gene-targeted arrays will vary [ A deletion of Note: Reported deletions include the recurrent 11p13 deletion (see One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. Molecular genetic testing can establish the molecular basis of aniridia, and thus distinguish between isolated aniridia (no increased risk for Wilms tumor) and WAGR (markedly increased risk for Wilms tumor). In the following scenarios molecular genetic testing approaches are based on the individual's age, clinical findings, family history, and testing methods available. Perform chromosomal microarray (CMA) (which may use array-based comparative genomic hybridization [aCGH] and/or a SNP genotyping array) to identify a contiguous-gene deletion that includes If a deletion involving Perform sequence analysis of If a Perform If no 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, C-terminal extension (CTE) variants and splice site variants and small 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 one individual a heterozygous single-nucleotide variant in the ultraconserved Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. GRCh37/hg19 chr11:31,803,509-32,510,988: Genomic coordinates represent the minimum deletion size associated with the 11p13 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. Standardized clinical annotation and interpretation for genomic variants from the Chromosome microarray analysis (CMA) using oligonucleotide arrays (i.e., array comparative genomic hybridization) and/or SNP genotyping arrays. CMA designs in current clinical use target the 11p13 region. FISH is not appropriate as a diagnostic method for an individual in whom the 11p13 deletion syndrome was not detected by CMA designed to target this region. FISH, qPCR, or other quantitative methods of targeted deletion analysis can be used to identify the 11p13 deletion in at-risk relatives of the proband to help determine recurrence risk (see • Note: Deletions telomeric to • A heterozygous variant in the ultraconserved • MLPA detected a 0.6-Mb deletion downstream of • Coverage of these regions on chromosomal or gene-targeted arrays will vary [ • A heterozygous variant in the ultraconserved • MLPA detected a 0.6-Mb deletion downstream of • A deletion of • Note: Reported deletions include the recurrent 11p13 deletion (see • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. • Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. • A deletion of • Note: Reported deletions include the recurrent 11p13 deletion (see • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. • Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. • A heterozygous variant in the ultraconserved • MLPA detected a 0.6-Mb deletion downstream of • A deletion of • Note: Reported deletions include the recurrent 11p13 deletion (see • One or more additional findings of WAGR syndrome found on physical examination in individuals with aniridia. • Note: If the child has not had genetic testing, the clinical diagnosis of WAGR syndrome usually cannot be established or ruled out until a child has passed through the age of risk for Wilms tumor, intellectual disability, and behavior abnormalities. • Perform chromosomal microarray (CMA) (which may use array-based comparative genomic hybridization [aCGH] and/or a SNP genotyping array) to identify a contiguous-gene deletion that includes • If a deletion involving • Perform sequence analysis of • If a • Perform • If no ## Scenario 1 Perform chromosomal microarray (CMA) (which may use array-based comparative genomic hybridization [aCGH] and/or a SNP genotyping array) to identify a contiguous-gene deletion that includes If a deletion involving Perform sequence analysis of If a • Perform chromosomal microarray (CMA) (which may use array-based comparative genomic hybridization [aCGH] and/or a SNP genotyping array) to identify a contiguous-gene deletion that includes • If a deletion involving • Perform sequence analysis of • If a ## Scenario 2 Perform If no • Perform • If no ## Scenario 3 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, C-terminal extension (CTE) variants and splice site variants and small 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 one individual a heterozygous single-nucleotide variant in the ultraconserved Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. GRCh37/hg19 chr11:31,803,509-32,510,988: Genomic coordinates represent the minimum deletion size associated with the 11p13 recurrent deletion as designated by ClinGen. Deletion coordinates may vary slightly based on array design used by the testing laboratory. Note that the size of the deletion as calculated from these genomic positions may differ from the expected deletion size due to the presence of segmental duplications near breakpoints. Standardized clinical annotation and interpretation for genomic variants from the Chromosome microarray analysis (CMA) using oligonucleotide arrays (i.e., array comparative genomic hybridization) and/or SNP genotyping arrays. CMA designs in current clinical use target the 11p13 region. FISH is not appropriate as a diagnostic method for an individual in whom the 11p13 deletion syndrome was not detected by CMA designed to target this region. FISH, qPCR, or other quantitative methods of targeted deletion analysis can be used to identify the 11p13 deletion in at-risk relatives of the proband to help determine recurrence risk (see ## Clinical Characteristics Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure, lens, fovea, and optic nerve. The phenotype is variable between and within families; however, affected individuals usually show little variability between the two eyes. Individuals with aniridia characteristically show nystagmus, impaired visual acuity (usually 20/100 - 20/200), and foveal hypoplasia. Milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur [ The reduction in visual acuity is primarily caused by foveal hypoplasia, but cataracts, glaucoma, and corneal opacification are responsible for progressive visual failure. Most children with aniridia present at birth with an obvious iris or pupillary abnormality or in infancy with nystagmus (usually apparent by age 6 weeks). Congenital glaucoma rarely occurs in aniridia; in such cases, a large corneal diameter and corneal edema may be the presenting findings. Despite their many ocular issues, most individuals with aniridia can retain useful vision with appropriate ophthalmologic management. Individuals with molecularly confirmed deletions of 11p13 involving Wilms tumor, also known as a nephroblastoma, is a childhood kidney malignancy. Associated features include abdominal pain, fever, anemia, hematuria, and hypertension in up to 30% of affected children. See The risk of later end-stage kidney disease (ESKD) is significant, relating to Wilms tumor and its surgery, focal segmental glomerulosclerosis, and occasionally kidney malformation. The rate of ESKD is 36% with unilateral Wilms tumor and 90% with bilateral Wilms tumor. Approximately 25% of individuals with WAGR syndrome have proteinuria ranging from minimal to overt nephritic syndrome [ Intellectual disability (defined as IQ <74) is seen in 70% of individuals with WAGR syndrome; other individuals with WAGR syndrome can have normal intellect without behavioral issues. Behavioral abnormalities include attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. C-terminal extension (CTE) pathogenic variants, which generate a longer protein product, are associated with a moderately severe aniridic phenotype with poor vision, keratopathy, and cataracts; however, individuals with CTE pathogenic variants are less likely to have glaucoma and are more likely to have preservation of iris tissue than individuals who have pathogenic null variants [ Isolated aniridia has almost complete penetrance. Aniridia in WAGR also has almost complete penetrance. The risk of Wilms tumor is up to 77%. The prevalence of aniridia is 1:40,000 to 1:100,000. No racial or sexual differences are recognized. The prevalence of WAGR syndrome is approximately 1:500,000. • Intellectual disability (defined as IQ <74) is seen in 70% of individuals with WAGR syndrome; other individuals with WAGR syndrome can have normal intellect without behavioral issues. • Behavioral abnormalities include attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. ## Clinical Description Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure, lens, fovea, and optic nerve. The phenotype is variable between and within families; however, affected individuals usually show little variability between the two eyes. Individuals with aniridia characteristically show nystagmus, impaired visual acuity (usually 20/100 - 20/200), and foveal hypoplasia. Milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur [ The reduction in visual acuity is primarily caused by foveal hypoplasia, but cataracts, glaucoma, and corneal opacification are responsible for progressive visual failure. Most children with aniridia present at birth with an obvious iris or pupillary abnormality or in infancy with nystagmus (usually apparent by age 6 weeks). Congenital glaucoma rarely occurs in aniridia; in such cases, a large corneal diameter and corneal edema may be the presenting findings. Despite their many ocular issues, most individuals with aniridia can retain useful vision with appropriate ophthalmologic management. Individuals with molecularly confirmed deletions of 11p13 involving Wilms tumor, also known as a nephroblastoma, is a childhood kidney malignancy. Associated features include abdominal pain, fever, anemia, hematuria, and hypertension in up to 30% of affected children. See The risk of later end-stage kidney disease (ESKD) is significant, relating to Wilms tumor and its surgery, focal segmental glomerulosclerosis, and occasionally kidney malformation. The rate of ESKD is 36% with unilateral Wilms tumor and 90% with bilateral Wilms tumor. Approximately 25% of individuals with WAGR syndrome have proteinuria ranging from minimal to overt nephritic syndrome [ Intellectual disability (defined as IQ <74) is seen in 70% of individuals with WAGR syndrome; other individuals with WAGR syndrome can have normal intellect without behavioral issues. Behavioral abnormalities include attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. • Intellectual disability (defined as IQ <74) is seen in 70% of individuals with WAGR syndrome; other individuals with WAGR syndrome can have normal intellect without behavioral issues. • Behavioral abnormalities include attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. ## Aniridia Aniridia is a pan ocular disorder affecting the cornea, iris, intraocular pressure, lens, fovea, and optic nerve. The phenotype is variable between and within families; however, affected individuals usually show little variability between the two eyes. Individuals with aniridia characteristically show nystagmus, impaired visual acuity (usually 20/100 - 20/200), and foveal hypoplasia. Milder forms of aniridia with subtle iris architecture changes, good vision, and normal foveal structure do occur [ The reduction in visual acuity is primarily caused by foveal hypoplasia, but cataracts, glaucoma, and corneal opacification are responsible for progressive visual failure. Most children with aniridia present at birth with an obvious iris or pupillary abnormality or in infancy with nystagmus (usually apparent by age 6 weeks). Congenital glaucoma rarely occurs in aniridia; in such cases, a large corneal diameter and corneal edema may be the presenting findings. Despite their many ocular issues, most individuals with aniridia can retain useful vision with appropriate ophthalmologic management. ## WAGR Syndrome Individuals with molecularly confirmed deletions of 11p13 involving Wilms tumor, also known as a nephroblastoma, is a childhood kidney malignancy. Associated features include abdominal pain, fever, anemia, hematuria, and hypertension in up to 30% of affected children. See The risk of later end-stage kidney disease (ESKD) is significant, relating to Wilms tumor and its surgery, focal segmental glomerulosclerosis, and occasionally kidney malformation. The rate of ESKD is 36% with unilateral Wilms tumor and 90% with bilateral Wilms tumor. Approximately 25% of individuals with WAGR syndrome have proteinuria ranging from minimal to overt nephritic syndrome [ Intellectual disability (defined as IQ <74) is seen in 70% of individuals with WAGR syndrome; other individuals with WAGR syndrome can have normal intellect without behavioral issues. Behavioral abnormalities include attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. • Intellectual disability (defined as IQ <74) is seen in 70% of individuals with WAGR syndrome; other individuals with WAGR syndrome can have normal intellect without behavioral issues. • Behavioral abnormalities include attention-deficit/hyperactivity disorder, autism spectrum disorder, anxiety, depression, and obsessive-compulsive disorder. ## Genotype-Phenotype Correlations C-terminal extension (CTE) pathogenic variants, which generate a longer protein product, are associated with a moderately severe aniridic phenotype with poor vision, keratopathy, and cataracts; however, individuals with CTE pathogenic variants are less likely to have glaucoma and are more likely to have preservation of iris tissue than individuals who have pathogenic null variants [ ## Penetrance Isolated aniridia has almost complete penetrance. Aniridia in WAGR also has almost complete penetrance. The risk of Wilms tumor is up to 77%. ## Prevalence The prevalence of aniridia is 1:40,000 to 1:100,000. No racial or sexual differences are recognized. The prevalence of WAGR syndrome is approximately 1:500,000. ## Genetically Related (Allelic) Disorders Other Autosomal Dominant Ocular Phenotypes Caused by From ## Differential Diagnosis Heterozygous pathogenic variants in the following genes are included in the differential diagnosis of The other causes of nystagmus and poor vision in infancy (e.g., retinal dysplasia, retinal dystrophy, congenital cataracts, optic nerve hypoplasia, congenital infections) lack the iris changes seen in aniridia. Causes of partial or complete absence of iris tissue in adults include trauma, prior ocular surgery, and the iridocorneal endothelial syndromes. The age at onset, medical history, and absence of other ocular features in aniridia should prevent diagnostic confusion with aniridia. ## Individuals with Aniridia and No Identifiable Heterozygous pathogenic variants in the following genes are included in the differential diagnosis of The other causes of nystagmus and poor vision in infancy (e.g., retinal dysplasia, retinal dystrophy, congenital cataracts, optic nerve hypoplasia, congenital infections) lack the iris changes seen in aniridia. Causes of partial or complete absence of iris tissue in adults include trauma, prior ocular surgery, and the iridocorneal endothelial syndromes. The age at onset, medical history, and absence of other ocular features in aniridia should prevent diagnostic confusion with aniridia. ## Management To establish the extent of disease and needs in an individual diagnosed with aniridia (whether isolated or part of Evaluation of visual acuity (not easily performed in infants) and documentation of the degree of iris tissue deficiency, and the presence of foveal and optic nerve hypoplasia in order to predict future visual function. Evaluation for the degree of involvement of the cornea and lens and measurement of intraocular pressure, as they are potentially treatable causes of further visual reduction; however, treatable changes may not appear until later in life. Consultation with a clinical geneticist and/or genetic counselor To establish the extent of disease and needs in an individual diagnosed with WAGR syndrome, the following are recommended: Evaluation by a pediatrician to assess growth and feeding Evaluation for Evaluation by a urologist for urogenital abnormalities Developmental assessment Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production. Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted, or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film. Occlusion therapy in childhood for anisometropic amblyopia or strabismic amblyopia Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age Advice and help with schooling Social support Note: Corrective surgery for strabismus can be undertaken to improve alignment and appearance but will not result in improved visual function. Children rarely require surgery (lensectomy). In adults, phacoemulsification and intraocular lens implantation can improve visual function if the cataract is severe. Note: (1) A significant number of individuals with aniridia have poor zonular stability, which increases the risk for intraoperative complications and influences the choice of surgical technique and options for intraocular lens (IOL) implantation [ Glaucoma is usually initially treated with topical anti-glaucoma medication. Surgery is reserved for eyes that do not respond to medical therapy: Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ Note: (1) Glaucoma presenting in infancy is more difficult to treat. Medical treatment is generally ineffective and surgery is required. Goniotomy and trabeculotomy have a low success rate, but trabeculectomy with or without antimetabolites is often successful [ Ocular surface disease can be treated medically using lubricants, mucolytics, and punctal occlusion, which may help slow the progression of sight-threatening corneal changes. Note: Drops without preservatives are often required to avoid preservative-related ocular surface toxicity. When corneal opacification causes significant visual reduction, penetrating keratoplasty (PK) may be considered; however, in the presence of the significant limbal stem cell deficiency observed in aniridia, PK alone has a poor prognosis [ Limbal stem cell transplantation alone, preceding or concurrent with keratoplasty, may be undertaken but requires an allograft as both eyes are usually affected. This may take the form of a cultured stem cell sheet or a limbal tissue transplant [ Special educational support including extra or different teaching resources and a specialized educational setting, specialist teachers of the visually impaired, educational psychologists, and formal statements of educational needs; Involvement of a pediatrician and sometimes a pediatric psychiatrist. 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. 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. Measurement of intraocular pressure; Optic disc examination; Visual field assessment when possible. Note: Assessment of the optic disc and visual field may be difficult in the presence of media opacities and nystagmus. Optic disc photography is a useful method of monitoring optic disc changes. Developmental progress and educational needs require regular monitoring. Provide behavioral assessment for anxiety, ADHD, and aggressive or self-injurious behavior as needed. It has been suggested that intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy [ Early clarification of the genetic status of infants who are offspring or sibs of an individual with See Ongoing research is investigating the role and success of limbal stem cell transplantation and ocular mucous membrane cell transplantation for keratopathies associated with limbal stem cell failure, including aniridia [ A Phase II randomized, double-masked, placebo-controlled study of ataluren in individuals with aniridia caused by pathogenic nonsense variants in Search • Evaluation of visual acuity (not easily performed in infants) and documentation of the degree of iris tissue deficiency, and the presence of foveal and optic nerve hypoplasia in order to predict future visual function. • Evaluation for the degree of involvement of the cornea and lens and measurement of intraocular pressure, as they are potentially treatable causes of further visual reduction; however, treatable changes may not appear until later in life. • Consultation with a clinical geneticist and/or genetic counselor • Evaluation by a pediatrician to assess growth and feeding • Evaluation for • Evaluation by a urologist for urogenital abnormalities • Developmental assessment • Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production. • Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted, or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film. • Occlusion therapy in childhood for anisometropic amblyopia or strabismic amblyopia • Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age • Advice and help with schooling • Social support • Children rarely require surgery (lensectomy). • In adults, phacoemulsification and intraocular lens implantation can improve visual function if the cataract is severe. • Glaucoma is usually initially treated with topical anti-glaucoma medication. • Surgery is reserved for eyes that do not respond to medical therapy: • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ • Ocular surface disease can be treated medically using lubricants, mucolytics, and punctal occlusion, which may help slow the progression of sight-threatening corneal changes. Note: Drops without preservatives are often required to avoid preservative-related ocular surface toxicity. • When corneal opacification causes significant visual reduction, penetrating keratoplasty (PK) may be considered; however, in the presence of the significant limbal stem cell deficiency observed in aniridia, PK alone has a poor prognosis [ • Limbal stem cell transplantation alone, preceding or concurrent with keratoplasty, may be undertaken but requires an allograft as both eyes are usually affected. This may take the form of a cultured stem cell sheet or a limbal tissue transplant [ • Special educational support including extra or different teaching resources and a specialized educational setting, specialist teachers of the visually impaired, educational psychologists, and formal statements of educational needs; • Involvement of a pediatrician and sometimes a pediatric psychiatrist. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Measurement of intraocular pressure; • Optic disc examination; • Visual field assessment when possible. ## Evaluation Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with aniridia (whether isolated or part of Evaluation of visual acuity (not easily performed in infants) and documentation of the degree of iris tissue deficiency, and the presence of foveal and optic nerve hypoplasia in order to predict future visual function. Evaluation for the degree of involvement of the cornea and lens and measurement of intraocular pressure, as they are potentially treatable causes of further visual reduction; however, treatable changes may not appear until later in life. Consultation with a clinical geneticist and/or genetic counselor To establish the extent of disease and needs in an individual diagnosed with WAGR syndrome, the following are recommended: Evaluation by a pediatrician to assess growth and feeding Evaluation for Evaluation by a urologist for urogenital abnormalities Developmental assessment • Evaluation of visual acuity (not easily performed in infants) and documentation of the degree of iris tissue deficiency, and the presence of foveal and optic nerve hypoplasia in order to predict future visual function. • Evaluation for the degree of involvement of the cornea and lens and measurement of intraocular pressure, as they are potentially treatable causes of further visual reduction; however, treatable changes may not appear until later in life. • Consultation with a clinical geneticist and/or genetic counselor • Evaluation by a pediatrician to assess growth and feeding • Evaluation for • Evaluation by a urologist for urogenital abnormalities • Developmental assessment ## Treatment of Manifestations Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production. Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted, or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film. Occlusion therapy in childhood for anisometropic amblyopia or strabismic amblyopia Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age Advice and help with schooling Social support Note: Corrective surgery for strabismus can be undertaken to improve alignment and appearance but will not result in improved visual function. Children rarely require surgery (lensectomy). In adults, phacoemulsification and intraocular lens implantation can improve visual function if the cataract is severe. Note: (1) A significant number of individuals with aniridia have poor zonular stability, which increases the risk for intraoperative complications and influences the choice of surgical technique and options for intraocular lens (IOL) implantation [ Glaucoma is usually initially treated with topical anti-glaucoma medication. Surgery is reserved for eyes that do not respond to medical therapy: Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ Note: (1) Glaucoma presenting in infancy is more difficult to treat. Medical treatment is generally ineffective and surgery is required. Goniotomy and trabeculotomy have a low success rate, but trabeculectomy with or without antimetabolites is often successful [ Ocular surface disease can be treated medically using lubricants, mucolytics, and punctal occlusion, which may help slow the progression of sight-threatening corneal changes. Note: Drops without preservatives are often required to avoid preservative-related ocular surface toxicity. When corneal opacification causes significant visual reduction, penetrating keratoplasty (PK) may be considered; however, in the presence of the significant limbal stem cell deficiency observed in aniridia, PK alone has a poor prognosis [ Limbal stem cell transplantation alone, preceding or concurrent with keratoplasty, may be undertaken but requires an allograft as both eyes are usually affected. This may take the form of a cultured stem cell sheet or a limbal tissue transplant [ Special educational support including extra or different teaching resources and a specialized educational setting, specialist teachers of the visually impaired, educational psychologists, and formal statements of educational needs; Involvement of a pediatrician and sometimes a pediatric psychiatrist. 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. 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. • Regular eye examinations and correction of refractive errors. Refractive errors range from high myopia through emmetropia to high hypermetropia. Spectacle correction of refractive errors is usually recommended as use of contact lenses can be difficult in the presence of keratopathy and reduced tear production. • Tinted or photochromic lenses to reduce light sensitivity associated with the large pupillary aperture. Colored, tinted, or artificial pupil contact lenses may reduce light sensitivity or restore a more normal appearance to the eye but, as above, may be difficult to wear because of a poor ocular surface and tear film. • Occlusion therapy in childhood for anisometropic amblyopia or strabismic amblyopia • Optical low-vision aids and other devices such as closed-circuit television systems to help adults and children of school age • Advice and help with schooling • Social support • Children rarely require surgery (lensectomy). • In adults, phacoemulsification and intraocular lens implantation can improve visual function if the cataract is severe. • Glaucoma is usually initially treated with topical anti-glaucoma medication. • Surgery is reserved for eyes that do not respond to medical therapy: • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ • Trabeculectomy with or without antimetabolites (e.g., 5-fluorouracil, mitomycin C) is often used but is associated with a higher risk of treatment failure than that seen in individuals with primary glaucoma who undergo the same treatment. • Drainage tube surgery (with or without antimetabolites) or cyclodiode laser treatment may be necessary in refractory cases; however, this treatment is increasingly being undertaken as a primary procedure [ • Ocular surface disease can be treated medically using lubricants, mucolytics, and punctal occlusion, which may help slow the progression of sight-threatening corneal changes. Note: Drops without preservatives are often required to avoid preservative-related ocular surface toxicity. • When corneal opacification causes significant visual reduction, penetrating keratoplasty (PK) may be considered; however, in the presence of the significant limbal stem cell deficiency observed in aniridia, PK alone has a poor prognosis [ • Limbal stem cell transplantation alone, preceding or concurrent with keratoplasty, may be undertaken but requires an allograft as both eyes are usually affected. This may take the form of a cultured stem cell sheet or a limbal tissue transplant [ • Special educational support including extra or different teaching resources and a specialized educational setting, specialist teachers of the visually impaired, educational psychologists, and formal statements of educational needs; • Involvement of a pediatrician and sometimes a pediatric psychiatrist. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## 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. ## 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 Measurement of intraocular pressure; Optic disc examination; Visual field assessment when possible. Note: Assessment of the optic disc and visual field may be difficult in the presence of media opacities and nystagmus. Optic disc photography is a useful method of monitoring optic disc changes. Developmental progress and educational needs require regular monitoring. Provide behavioral assessment for anxiety, ADHD, and aggressive or self-injurious behavior as needed. • Measurement of intraocular pressure; • Optic disc examination; • Visual field assessment when possible. ## Aniridia Measurement of intraocular pressure; Optic disc examination; Visual field assessment when possible. Note: Assessment of the optic disc and visual field may be difficult in the presence of media opacities and nystagmus. Optic disc photography is a useful method of monitoring optic disc changes. • Measurement of intraocular pressure; • Optic disc examination; • Visual field assessment when possible. ## WAGR Syndrome Developmental progress and educational needs require regular monitoring. Provide behavioral assessment for anxiety, ADHD, and aggressive or self-injurious behavior as needed. ## Agents/Circumstances to Avoid It has been suggested that intraocular surgery may increase the likelihood of (or exacerbate existing) keratopathy [ ## Evaluation of Relatives at Risk Early clarification of the genetic status of infants who are offspring or sibs of an individual with See ## Therapies Under Investigation Ongoing research is investigating the role and success of limbal stem cell transplantation and ocular mucous membrane cell transplantation for keratopathies associated with limbal stem cell failure, including aniridia [ A Phase II randomized, double-masked, placebo-controlled study of ataluren in individuals with aniridia caused by pathogenic nonsense variants in Search ## Genetic Counseling Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner. Approximately 70% of individuals diagnosed with isolated aniridia have an affected parent (i.e., familial aniridia) [ Approximately 30% of affected individuals have no family history of aniridia (i.e., simplex aniridia) and have the disorder as a 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 isolated aniridia may appear to be negative because of failure to recognize the disorder in family members (severity of the phenotype may vary greatly among family members). 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 isolated aniridia or has an identifiable When the parents are clinically unaffected, the risk to the sibs of a proband is low. If the Note: In rare instances of mosaicism 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 have isolated aniridia and to parents of affected individuals. Prenatal and preimplantation genetic testing are possible if: A A deletion of 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 70% of individuals diagnosed with isolated aniridia have an affected parent (i.e., familial aniridia) [ • Approximately 30% of affected individuals have no family history of aniridia (i.e., simplex aniridia) and have the disorder as a 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 isolated aniridia may appear to be negative because of failure to recognize the disorder in family members (severity of the phenotype may vary greatly among family members). 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 isolated aniridia or has an identifiable • When the parents are clinically unaffected, the risk to the sibs of a proband is 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 have isolated aniridia and to parents of affected individuals. • A • A deletion of ## Mode of Inheritance Isolated aniridia and WAGR syndrome are inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 70% of individuals diagnosed with isolated aniridia have an affected parent (i.e., familial aniridia) [ Approximately 30% of affected individuals have no family history of aniridia (i.e., simplex aniridia) and have the disorder as a 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 isolated aniridia may appear to be negative because of failure to recognize the disorder in family members (severity of the phenotype may vary greatly among family members). 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 isolated aniridia or has an identifiable When the parents are clinically unaffected, the risk to the sibs of a proband is low. If the Note: In rare instances of mosaicism for the • Approximately 70% of individuals diagnosed with isolated aniridia have an affected parent (i.e., familial aniridia) [ • Approximately 30% of affected individuals have no family history of aniridia (i.e., simplex aniridia) and have the disorder as a 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 isolated aniridia may appear to be negative because of failure to recognize the disorder in family members (severity of the phenotype may vary greatly among family members). 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 isolated aniridia or has an identifiable • When the parents are clinically unaffected, the risk to the sibs of a proband is low. • If the ## Isolated Aniridia Approximately 70% of individuals diagnosed with isolated aniridia have an affected parent (i.e., familial aniridia) [ Approximately 30% of affected individuals have no family history of aniridia (i.e., simplex aniridia) and have the disorder as a 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 isolated aniridia may appear to be negative because of failure to recognize the disorder in family members (severity of the phenotype may vary greatly among family members). 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 isolated aniridia or has an identifiable When the parents are clinically unaffected, the risk to the sibs of a proband is low. If the Note: In rare instances of mosaicism for the • Approximately 70% of individuals diagnosed with isolated aniridia have an affected parent (i.e., familial aniridia) [ • Approximately 30% of affected individuals have no family history of aniridia (i.e., simplex aniridia) and have the disorder as a 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 isolated aniridia may appear to be negative because of failure to recognize the disorder in family members (severity of the phenotype may vary greatly among family members). 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 isolated aniridia or has an identifiable • When the parents are clinically unaffected, the risk to the sibs of a proband is low. • If the ## WAGR Syndrome ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have isolated aniridia and 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 young adults who have isolated aniridia and to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Prenatal and preimplantation genetic testing are possible if: A A deletion of Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • A • A deletion of ## Resources United Kingdom • • • • United Kingdom • • • ## Molecular Genetics PAX6-Related Aniridia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for PAX6-Related Aniridia ( Approximately 60% are intragenic loss-of-function variants that introduce a premature termination codon and (occasionally) variants of up- or downstream regulatory sequences. This is generally associated with more severe disease including a high incidence of complications [ Approximately 25% are missense variants that have been detected in less severe forms of aniridia, and that may code for nearly complete loss of protein function, or are associated with other ocular phenotypes such as isolated foveal hypoplasia [ A small percentage are C-terminal extension (CTE) variants (e.g., variants in the stop codon that extend the protein), such as Four CpG dinucleotides in exons 8, 9, 10, and 11 are the most common sites for pathogenic variants, accounting for 21% of all reported pathogenic variants [ Many pathogenic variants have been reported in Of the Of the approximately 30 known pathogenic variants for non-aniridia eye disorders, 69% are missense variants [ Reduction of expression of alternatively spliced PAX6 protein isoforms can also cause an altered or less severe phenotype [ Variants listed in the table have been provided by the authors. PAX6 protein is thought to act as the major controller of ocular development during embryogenesis by effects on cellular proliferation, differentiation, migration, and adhesion; several target genes have been identified [ Various isoforms of PAX6 protein are derived through alternative splicing (PAX6-ex12, PAX6-5a,6', PAX6-5a). The ratios of these isoforms may be critical to normal ocular development [ • Approximately 60% are intragenic loss-of-function variants that introduce a premature termination codon and (occasionally) variants of up- or downstream regulatory sequences. This is generally associated with more severe disease including a high incidence of complications [ • Approximately 25% are missense variants that have been detected in less severe forms of aniridia, and that may code for nearly complete loss of protein function, or are associated with other ocular phenotypes such as isolated foveal hypoplasia [ • A small percentage are C-terminal extension (CTE) variants (e.g., variants in the stop codon that extend the protein), such as • Of the • Of the approximately 30 known pathogenic variants for non-aniridia eye disorders, 69% are missense variants [ ## Molecular Pathogenesis Approximately 60% are intragenic loss-of-function variants that introduce a premature termination codon and (occasionally) variants of up- or downstream regulatory sequences. This is generally associated with more severe disease including a high incidence of complications [ Approximately 25% are missense variants that have been detected in less severe forms of aniridia, and that may code for nearly complete loss of protein function, or are associated with other ocular phenotypes such as isolated foveal hypoplasia [ A small percentage are C-terminal extension (CTE) variants (e.g., variants in the stop codon that extend the protein), such as Four CpG dinucleotides in exons 8, 9, 10, and 11 are the most common sites for pathogenic variants, accounting for 21% of all reported pathogenic variants [ Many pathogenic variants have been reported in Of the Of the approximately 30 known pathogenic variants for non-aniridia eye disorders, 69% are missense variants [ Reduction of expression of alternatively spliced PAX6 protein isoforms can also cause an altered or less severe phenotype [ Variants listed in the table have been provided by the authors. PAX6 protein is thought to act as the major controller of ocular development during embryogenesis by effects on cellular proliferation, differentiation, migration, and adhesion; several target genes have been identified [ Various isoforms of PAX6 protein are derived through alternative splicing (PAX6-ex12, PAX6-5a,6', PAX6-5a). The ratios of these isoforms may be critical to normal ocular development [ • Approximately 60% are intragenic loss-of-function variants that introduce a premature termination codon and (occasionally) variants of up- or downstream regulatory sequences. This is generally associated with more severe disease including a high incidence of complications [ • Approximately 25% are missense variants that have been detected in less severe forms of aniridia, and that may code for nearly complete loss of protein function, or are associated with other ocular phenotypes such as isolated foveal hypoplasia [ • A small percentage are C-terminal extension (CTE) variants (e.g., variants in the stop codon that extend the protein), such as • Of the • Of the approximately 30 known pathogenic variants for non-aniridia eye disorders, 69% are missense variants [ ## Chapter Notes 18 October 2018 (bp) Comprehensive update posted live 14 November 2013 (me) Comprehensive update posted live 12 July 2008 (me) Comprehensive update posted live 15 July 2005 (me) Comprehensive update posted live 20 May 2003 (me) Review posted live 2 September 2002 (am) Original submission • 18 October 2018 (bp) Comprehensive update posted live • 14 November 2013 (me) Comprehensive update posted live • 12 July 2008 (me) Comprehensive update posted live • 15 July 2005 (me) Comprehensive update posted live • 20 May 2003 (me) Review posted live • 2 September 2002 (am) Original submission ## Revision History 18 October 2018 (bp) Comprehensive update posted live 14 November 2013 (me) Comprehensive update posted live 12 July 2008 (me) Comprehensive update posted live 15 July 2005 (me) Comprehensive update posted live 20 May 2003 (me) Review posted live 2 September 2002 (am) Original submission • 18 October 2018 (bp) Comprehensive update posted live • 14 November 2013 (me) Comprehensive update posted live • 12 July 2008 (me) Comprehensive update posted live • 15 July 2005 (me) Comprehensive update posted live • 20 May 2003 (me) Review posted live • 2 September 2002 (am) Original submission ## References ## Literature Cited	[]	20/5/2003	18/10/2018		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ankrd17-nds	ankrd17-nds	[ "Chopra-Amiel-Gordon Syndrome (CAGS)", "Chopra-Amiel-Gordon Syndrome (CAGS)", "Ankyrin repeat domain-containing protein 17", "ANKRD17", "ANKRD17-Related Neurodevelopmental Syndrome" ]		Abigail Sveden, Christopher T Gordon, Jeanne Amiel, Maya Chopra	Summary The diagnosis of	## Diagnosis Developmental delay particularly affecting speech Intellectual disability of variable severity Neurodevelopmental and behavioral disorders including autism spectrum disorder and attention-deficit/hyperactivity disorder Ophthalmologic abnormalities (refractive errors and strabismus) Growth deficiency (postnatal short stature and poor weight gain) accompanied by feeding difficulties Recurrent infections without identified immune deficiency Gait and/or balance disturbances Epilepsy, most commonly focal seizures with secondary generalization Dysmorphic craniofacial features (triangular face shape, high anterior hairline, deep-set and/or almond-shaped eyes with periorbital fullness, low-set ears, thick nasal alae and flared nostrils, full cheeks, thin vermilion of the upper lip, Pierre Robin sequence) Genitourinary anomalies including unilateral renal agenesis 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Author, personal communications [2022] • Developmental delay particularly affecting speech • Intellectual disability of variable severity • Neurodevelopmental and behavioral disorders including autism spectrum disorder and attention-deficit/hyperactivity disorder • Ophthalmologic abnormalities (refractive errors and strabismus) • Growth deficiency (postnatal short stature and poor weight gain) accompanied by feeding difficulties • Recurrent infections without identified immune deficiency • Gait and/or balance disturbances • Epilepsy, most commonly focal seizures with secondary generalization • Dysmorphic craniofacial features (triangular face shape, high anterior hairline, deep-set and/or almond-shaped eyes with periorbital fullness, low-set ears, thick nasal alae and flared nostrils, full cheeks, thin vermilion of the upper lip, Pierre Robin sequence) • Genitourinary anomalies including unilateral renal agenesis ## Suggestive Findings Developmental delay particularly affecting speech Intellectual disability of variable severity Neurodevelopmental and behavioral disorders including autism spectrum disorder and attention-deficit/hyperactivity disorder Ophthalmologic abnormalities (refractive errors and strabismus) Growth deficiency (postnatal short stature and poor weight gain) accompanied by feeding difficulties Recurrent infections without identified immune deficiency Gait and/or balance disturbances Epilepsy, most commonly focal seizures with secondary generalization Dysmorphic craniofacial features (triangular face shape, high anterior hairline, deep-set and/or almond-shaped eyes with periorbital fullness, low-set ears, thick nasal alae and flared nostrils, full cheeks, thin vermilion of the upper lip, Pierre Robin sequence) Genitourinary anomalies including unilateral renal agenesis • Developmental delay particularly affecting speech • Intellectual disability of variable severity • Neurodevelopmental and behavioral disorders including autism spectrum disorder and attention-deficit/hyperactivity disorder • Ophthalmologic abnormalities (refractive errors and strabismus) • Growth deficiency (postnatal short stature and poor weight gain) accompanied by feeding difficulties • Recurrent infections without identified immune deficiency • Gait and/or balance disturbances • Epilepsy, most commonly focal seizures with secondary generalization • Dysmorphic craniofacial features (triangular face shape, high anterior hairline, deep-set and/or almond-shaped eyes with periorbital fullness, low-set ears, thick nasal alae and flared nostrils, full cheeks, thin vermilion of the upper lip, Pierre Robin sequence) • Genitourinary anomalies including unilateral renal agenesis ## 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 Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Author, personal communications [2022] ## Clinical Characteristics The most common clinical manifestations of To date, 33 individuals with a pathogenic variant in Select Features of The domain of speech is particularly affected in this disorder. Speech delay has been reported in nearly all individuals with Motor delay is also common, with an average age of walking of two years (range: 9 months to 4 years). The trajectory of fine motor and social development is not completely understood at this time. Developmental regression has been reported in one individual; however, this was thought to be secondary to poorly controlled epilepsy. Gait and balance abnormalities have been described in some individuals, in particular a wide-based or ataxic gait. No correlation between gait and neuroimaging abnormalities has been found. A subset of individuals manifest abnormalities in tone, including both hypotonia (typically truncal) and hypertonia with or without spasticity (typically distal). The most common seizure type is focal seizures with secondary generalization. Other seizure types include Lennox-Gastaut epilepsy, tonic seizures with head deviation, myoclonic epilepsy, tonic-clonic epilepsy, and absence seizures. Efficacy of anti-seizure medications is variable, with refractory epilepsy in a minority of individuals. Microcephaly and, less commonly, macrocephaly have also been observed in affected individuals. Joint hypermobility has been reported in one third of affected individuals. In most individuals, hypermobility was generalized. Minor digital anomalies have been described, including brachydactyly, fifth digit clinodactyly, and prominent fingertip pads. Scoliosis has been reported in three individuals. No genotype-phenotype correlations have been identified. Individuals with pathogenic missense variants are clinically indistinguishable from those with truncating variants. Based on current literature, penetrance is believed to be complete with variable expressivity. The title of this The prevalence of this rare genetic disorder is unknown. To date, 33 individuals with • Gait and balance abnormalities have been described in some individuals, in particular a wide-based or ataxic gait. No correlation between gait and neuroimaging abnormalities has been found. • A subset of individuals manifest abnormalities in tone, including both hypotonia (typically truncal) and hypertonia with or without spasticity (typically distal). • Joint hypermobility has been reported in one third of affected individuals. In most individuals, hypermobility was generalized. • Minor digital anomalies have been described, including brachydactyly, fifth digit clinodactyly, and prominent fingertip pads. • Scoliosis has been reported in three individuals. ## Clinical Description The most common clinical manifestations of To date, 33 individuals with a pathogenic variant in Select Features of The domain of speech is particularly affected in this disorder. Speech delay has been reported in nearly all individuals with Motor delay is also common, with an average age of walking of two years (range: 9 months to 4 years). The trajectory of fine motor and social development is not completely understood at this time. Developmental regression has been reported in one individual; however, this was thought to be secondary to poorly controlled epilepsy. Gait and balance abnormalities have been described in some individuals, in particular a wide-based or ataxic gait. No correlation between gait and neuroimaging abnormalities has been found. A subset of individuals manifest abnormalities in tone, including both hypotonia (typically truncal) and hypertonia with or without spasticity (typically distal). The most common seizure type is focal seizures with secondary generalization. Other seizure types include Lennox-Gastaut epilepsy, tonic seizures with head deviation, myoclonic epilepsy, tonic-clonic epilepsy, and absence seizures. Efficacy of anti-seizure medications is variable, with refractory epilepsy in a minority of individuals. Microcephaly and, less commonly, macrocephaly have also been observed in affected individuals. Joint hypermobility has been reported in one third of affected individuals. In most individuals, hypermobility was generalized. Minor digital anomalies have been described, including brachydactyly, fifth digit clinodactyly, and prominent fingertip pads. Scoliosis has been reported in three individuals. • Gait and balance abnormalities have been described in some individuals, in particular a wide-based or ataxic gait. No correlation between gait and neuroimaging abnormalities has been found. • A subset of individuals manifest abnormalities in tone, including both hypotonia (typically truncal) and hypertonia with or without spasticity (typically distal). • Joint hypermobility has been reported in one third of affected individuals. In most individuals, hypermobility was generalized. • Minor digital anomalies have been described, including brachydactyly, fifth digit clinodactyly, and prominent fingertip pads. • Scoliosis has been reported in three individuals. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. Individuals with pathogenic missense variants are clinically indistinguishable from those with truncating variants. ## Penetrance Based on current literature, penetrance is believed to be complete with variable expressivity. ## Nomenclature The title of this ## Prevalence The prevalence of this rare genetic disorder is unknown. To date, 33 individuals with ## Genetically Related (Allelic) Disorders 4q13.3 contiguous microdeletions encompassing ## Differential Diagnosis Many of the features of ## 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. EEG To incl eval of nutritional status Consider eval for gastrostomy tube placement in persons w/inadequate caloric intake. Assess for recurrent infections. Low threshold for immunologist referral Gross motor & fine motor skills Gait & balance Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Scoliosis Assess for growth deficiency. Consider measurement of thyroid function, serum & urine calcium; monitor for history of suggestive hypoglycemia symptoms. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Treatment of Manifestations in Individuals with 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, particularly low caloric intake. Routine immunizations Referral to immunologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Measurement of growth parameters Eval of nutritional status & safety of oral intake Physical medicine, OT/PT assessment of mobility, self-help skills Clinical eval for scoliosis ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy See To date, there has been one affected individual in the literature who had a pregnancy [ See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Consider brain MRI. • EEG • To incl eval of nutritional status • Consider eval for gastrostomy tube placement in persons w/inadequate caloric intake. • Assess for recurrent infections. • Low threshold for immunologist referral • Gross motor & fine motor skills • Gait & balance • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Scoliosis • Assess for growth deficiency. • Consider measurement of thyroid function, serum & urine calcium; monitor for history of suggestive hypoglycemia symptoms. • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues, particularly low caloric intake. • Routine immunizations • Referral to immunologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Physical medicine, OT/PT assessment of mobility, self-help skills • Clinical eval for scoliosis ## 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. EEG To incl eval of nutritional status Consider eval for gastrostomy tube placement in persons w/inadequate caloric intake. Assess for recurrent infections. Low threshold for immunologist referral Gross motor & fine motor skills Gait & balance Mobility, ADL, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Scoliosis Assess for growth deficiency. Consider measurement of thyroid function, serum & urine calcium; monitor for history of suggestive hypoglycemia symptoms. 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 • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Consider brain MRI. • EEG • To incl eval of nutritional status • Consider eval for gastrostomy tube placement in persons w/inadequate caloric intake. • Assess for recurrent infections. • Low threshold for immunologist referral • Gross motor & fine motor skills • Gait & balance • Mobility, ADL, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Scoliosis • Assess for growth deficiency. • Consider measurement of thyroid function, serum & urine calcium; monitor for history of suggestive hypoglycemia symptoms. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Treatment of Manifestations in Individuals with 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, particularly low caloric intake. Routine immunizations Referral to immunologist Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • 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, particularly low caloric intake. • Routine immunizations • Referral to immunologist • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Social/Behavioral Concerns 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. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Measurement of growth parameters Eval of nutritional status & safety of oral intake Physical medicine, OT/PT assessment of mobility, self-help skills Clinical eval for scoliosis 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, & movement disorders. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Physical medicine, OT/PT assessment of mobility, self-help skills • Clinical eval for scoliosis ## Evaluation of Relatives at Risk See ## Pregnancy Management To date, there has been one affected individual in the literature who had a pregnancy [ See ## Therapies Under Investigation Search ## Genetic Counseling Most probands reported to date with Rarely, individuals diagnosed with In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an Transmission of an Molecular genetic testing is recommended for the parents of the proband regardless of family history to confirm parental 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 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. • Most probands reported to date with • Rarely, individuals diagnosed with • In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an • Transmission of an • In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an • Transmission of an • Molecular genetic testing is recommended for the parents of the proband regardless of family history to confirm parental 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 • In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an • Transmission of 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 • If a parent of the proband 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 Most probands reported to date with Rarely, individuals diagnosed with In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an Transmission of an Molecular genetic testing is recommended for the parents of the proband regardless of family history to confirm parental 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 known to have the If the If the parents have not been tested for the • Most probands reported to date with • Rarely, individuals diagnosed with • In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an • Transmission of an • In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an • Transmission of an • Molecular genetic testing is recommended for the parents of the proband regardless of family history to confirm parental 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 • In one family, a heterozygous mother with borderline intellectual disability, anxiety, depression, and short stature transmitted an • Transmission of 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 • If a parent of the proband 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 Principal Investigator: Maya Chopra MBBS FRACP • • • • • • • Principal Investigator: Maya Chopra MBBS FRACP • ## Molecular Genetics ANKRD17-Related Neurodevelopmental Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ANKRD17-Related Neurodevelopmental Syndrome ( Ankyrin repeat domain-containing protein 17 (ANKRD17) belongs to a group of proteins characterized by the presence of the ankyrin repeat motif [ There is in vitro evidence for the role of ANKRD17 in cell cycle progression through cyclin E/CDK2 [ A role for ANKRD17 in antibacterial and antiviral immunity has also been proposed, via the NOD1/NOD2 [ The precise mechanism by which • There is in vitro evidence for the role of ANKRD17 in cell cycle progression through cyclin E/CDK2 [ • A role for ANKRD17 in antibacterial and antiviral immunity has also been proposed, via the NOD1/NOD2 [ ## Molecular Pathogenesis Ankyrin repeat domain-containing protein 17 (ANKRD17) belongs to a group of proteins characterized by the presence of the ankyrin repeat motif [ There is in vitro evidence for the role of ANKRD17 in cell cycle progression through cyclin E/CDK2 [ A role for ANKRD17 in antibacterial and antiviral immunity has also been proposed, via the NOD1/NOD2 [ The precise mechanism by which • There is in vitro evidence for the role of ANKRD17 in cell cycle progression through cyclin E/CDK2 [ • A role for ANKRD17 in antibacterial and antiviral immunity has also been proposed, via the NOD1/NOD2 [ ## Chapter Notes Maya Chopra Rosamund Stone Zander Translational Neuroscience Center The authors acknowledge the patients, families, and clinicians who have contributed to the understanding of this disorder. 22 December 2022 (sw) Review posted live 17 October 2022 (mc) Original submission • 22 December 2022 (sw) Review posted live • 17 October 2022 (mc) Original submission ## Author Notes Maya Chopra Rosamund Stone Zander Translational Neuroscience Center ## Acknowledgments The authors acknowledge the patients, families, and clinicians who have contributed to the understanding of this disorder. ## Revision History 22 December 2022 (sw) Review posted live 17 October 2022 (mc) Original submission • 22 December 2022 (sw) Review posted live • 17 October 2022 (mc) Original submission ## References ## Literature Cited Dysmorphic facial features of Reproduced with permission from	[ "LG Biesecker, MP Adam, FS Alkuraya, AR Amemiya, MJ Bamshad, AE Beck, JT Bennett, LM Bird, JC Carey, B Chung, RD Clark, TC Cox, C Curry, MBP Dinulos, WB Dobyns, PF Giampietro, KM Girisha, IA Glass, JM Graham, KW Gripp, CR Haldeman-Englert, BD Hall, AM Innes, JM Kalish, KM Keppler-Noreuil, K Kosaki, BA Kozel, GM Mirzaa, JJ Mulvihill, MJM Nowaczyk, RA Pagon, K Retterer, AF Rope, PA Sanchez-Lara, LH Seaver, JT Shieh, AM Slavotinek, AK Sobering, CA Stevens, DA Stevenson, TY Tan, WH Tan, AC Tsai, DD Weaver, MS Williams, E Zackai, YA Zarate. A dyadic approach to the delineation of diagnostic entities in clinical genomics.. Am J Hum Genet. 2021;108:8-15", "M Chopra, M McEntagart, J Clayton-Smith, K Platzer, A Shukla, KM Girisha, A Kaur, P Kaur, R Pfundt, H Veenstra-Knol, GMS Mancini, G Cappuccio, N Brunetti-Pierri, F Kortüm, M Hempel, J Denecke, A Lehman. CAUSES Study, Kleefstra T, Stuurman KE, Wilke M, Thompson ML, Bebin EM, Bijlsma EK, Hoffer MJV, Peeters-Scholte C, Slavotinek A, Weiss WA, Yip T, Hodoglugil U, Whittle A, diMonda J, Neira J, Yang S, Kirby A, Pinz H, Lechner R, Sleutels F, Helbig I, McKeown S, Helbig K, Willaert R, Juusola J, Semotok J, Hadonou M, Short J; Genomics England Research Consortium, Yachelevich N, Lala S, Fernández-Jaen A, Pelayo JP, Klöckner C, Kamphausen SB, Abou Jamra R, Arelin M, Innes AM, Niskakoski A, Amin S, Williams M, Evans J, Smithson S, Smedley D, de Burca A, Kini U, Delatycki MB, Gallacher L, Yeung A, Pais L, Field M, Martin E, Charles P, Courtin T, Keren B, Iascone M, Cereda A, Poke G, Abadie V, Chalouhi C, Parthasarathy P, Halliday BJ, Robertson SP, Lyonnet S, Amiel J, Gordon CT. Heterozygous ANKRD17 loss-of-function variants cause a syndrome with intellectual disability, speech delay, and dysmorphism.. Am J Hum Genet. 2021;108:1138-50", "M Deng, F Li, B Ballif, S Li, X Chen, L Guo, X. Ye. Identification and functional analysis of a novel cyclin E/Cdk2 substrate Ankrd17.. J Biol Chem. 2009;284:7875-88", "J Li, A Mahajan, M-D Tsai. Ankyrin repeat: a unique motif mediating protein-protein interactions.. Biochemistry. 2006;45:15168-78", "Ž Maldžienė, E Vaitėnienė, B Aleksiūnienė, A Utkus, E. Preikšaitienė. A case report of familial 4q13.3 microdeletion in three individuals with syndromic intellectual disability.. BMC Med Genomics. 2020;13:63", "M Menning, T. Kufer. A role for the Ankyrin repeat containing protein Ankrd17 in Nod1- and Nod2-mediated inflammatory responses.. FEBS Letters. 2013;587:2137-42", "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", "AK Sarma, N Khandker, L Kurczewski, GM Brophy. Medical management of epileptic seizures: challenges and solutions.. Neuropsychiatr Dis Treat. 2016;12:467-85", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD. Hum Genet. 2020;139:1197-207", "Y Wang, X Tong, G Li, J Li, M Deng, X. Ye. Ankrd17 positively regulates RIG-I-like receptor (RLR)-mediated immune signaling: Innate immunity.. Eur. J. Immunol. 2012;42:1304-15" ]	22/12/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ankrd26	ankrd26	[ "Thrombocytopenia 2 (THC2)", "Thrombocytopenia 2 (THC2)", "Ankyrin repeat domain-containing protein 26", "ANKRD26", "ANKRD26-Related Thrombocytopenia" ]		Juliana Perez Botero, Stefanie N Dugan, Matthew W Anderson	Summary The diagnosis of	## Diagnosis Lifelong mild-to-moderate thrombocytopenia (<150 x 10 Normal platelet size (mean platelet volume [fL] per reference interval of automated instrument) Absent or minimal bleeding tendency Family history of thrombocytopenia with an autosomal dominant pattern of inheritance Personal or family history of myeloid neoplasms at a young age Previous or suspected diagnosis of immune thrombocytopenia (ITP) without improvement on immunosuppressive treatment Absence of features suggesting syndromic association The diagnosis of Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Must include sequencing of 5'UTR, which has a significant number of the known pathogenic variants 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. • Lifelong mild-to-moderate thrombocytopenia (<150 x 10 • Normal platelet size (mean platelet volume [fL] per reference interval of automated instrument) • Absent or minimal bleeding tendency • Family history of thrombocytopenia with an autosomal dominant pattern of inheritance • Personal or family history of myeloid neoplasms at a young age • Previous or suspected diagnosis of immune thrombocytopenia (ITP) without improvement on immunosuppressive treatment • Absence of features suggesting syndromic association • For an introduction to multigene panels click ## Suggestive Findings Lifelong mild-to-moderate thrombocytopenia (<150 x 10 Normal platelet size (mean platelet volume [fL] per reference interval of automated instrument) Absent or minimal bleeding tendency Family history of thrombocytopenia with an autosomal dominant pattern of inheritance Personal or family history of myeloid neoplasms at a young age Previous or suspected diagnosis of immune thrombocytopenia (ITP) without improvement on immunosuppressive treatment Absence of features suggesting syndromic association • Lifelong mild-to-moderate thrombocytopenia (<150 x 10 • Normal platelet size (mean platelet volume [fL] per reference interval of automated instrument) • Absent or minimal bleeding tendency • Family history of thrombocytopenia with an autosomal dominant pattern of inheritance • Personal or family history of myeloid neoplasms at a young age • Previous or suspected diagnosis of immune thrombocytopenia (ITP) without improvement on immunosuppressive treatment • Absence of features suggesting syndromic association ## Establishing the Diagnosis The diagnosis of Molecular genetic testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Must include sequencing of 5'UTR, which has a significant number of the known pathogenic variants Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • For an introduction to multigene panels click ## Clinical Characteristics Individuals with Mild to moderate thrombocytopenia (50 to 150 x 10 Platelet size is normal by automated method (mean platelet volume) or microscopic analysis. Platelets have normal granularity on light microscopy. Individuals can have erythrocytosis, with some presenting with hemoglobin as high as 18.5 g/dL. Some individuals have presented with leukocytosis. No consistent genotype-phenotype correlations are known. Penetrance for thrombocytopenia is complete in individuals with an The prevalence for this rare disorder is unknown. Fewer than 200 affected individuals have been reported. However, in one large cohort, • Mild to moderate thrombocytopenia (50 to 150 x 10 • Platelet size is normal by automated method (mean platelet volume) or microscopic analysis. • Platelets have normal granularity on light microscopy. • Individuals can have erythrocytosis, with some presenting with hemoglobin as high as 18.5 g/dL. • Some individuals have presented with leukocytosis. ## Clinical Description Individuals with Mild to moderate thrombocytopenia (50 to 150 x 10 Platelet size is normal by automated method (mean platelet volume) or microscopic analysis. Platelets have normal granularity on light microscopy. Individuals can have erythrocytosis, with some presenting with hemoglobin as high as 18.5 g/dL. Some individuals have presented with leukocytosis. • Mild to moderate thrombocytopenia (50 to 150 x 10 • Platelet size is normal by automated method (mean platelet volume) or microscopic analysis. • Platelets have normal granularity on light microscopy. • Individuals can have erythrocytosis, with some presenting with hemoglobin as high as 18.5 g/dL. • Some individuals have presented with leukocytosis. ## Genotype-Phenotype Correlations No consistent genotype-phenotype correlations are known. ## Penetrance Penetrance for thrombocytopenia is complete in individuals with an ## Prevalence The prevalence for this rare disorder is unknown. Fewer than 200 affected individuals have been reported. However, in one large cohort, ## Genetically Related (Allelic) Disorders Recent evidence suggests that germline heterozygous pathogenic variants leading to N-terminal truncated ANKRD26 isoforms may predispose to myeloid neoplasms by the same gain-of-function mechanisms as pathogenic variants in the 5'UTR region. Interestingly, these individuals may present without thrombocytopenia [ ## Differential Diagnosis Due to the clinical and genetic heterogeneity and low incidence of inherited platelet disorders, the diagnosis is challenging, and sometimes inherited platelet disorders are misdiagnosed as idiopathic thrombocytopenic purpura (immune thrombocytopenia; ITP). Complex diagnostic algorithms have been proposed [ Disorders to Consider in the Differential Diagnosis of Can have normal platelet counts More bleeding due to platelet storage pool disorder (dense granule deficiency) Can have red cell macrocytosis & neutropenia Predisposes to lymphoid malignancy Sporadic Family history negative Prior platelet count normal Responds to immunosuppressive treatments Does not predispose to malignancy AD = autosomal dominant; MOI = mode of inheritance; NA = not applicable; RT = related thrombocytopenia • Can have normal platelet counts • More bleeding due to platelet storage pool disorder (dense granule deficiency) • Can have red cell macrocytosis & neutropenia • Predisposes to lymphoid malignancy • Sporadic • Family history negative • Prior platelet count normal • Responds to immunosuppressive treatments • Does not predispose to malignancy ## Management To establish the extent of disease and needs in an individual diagnosed with Clinical evaluation by a hematologist and a complete blood count including peripheral smear review for early detection of myeloid neoplasms Consideration of bone marrow aspirate and biopsy at initial evaluation to exclude hematologic malignancies if there are other cytopenias, or abnormalities in: Mean corpuscular volume Cell morphology Leukocyte differential Consultation with a clinical geneticist and/or genetic counselor Most individuals are asymptomatic and undergo observation and surveillance. When bleeding is present or a major surgical procedure is required, adjunct hemostatic agents such as antifibrinolytics or desmopressin can be given. Platelet transfusions are reserved for severe bleeding or procedures with a high bleeding risk [ Thrombopoietin analogs have been used selectively for short periods of time (preoperative). The long-term safety has not been established [ Once a myeloid neoplasm has been diagnosed, careful consideration of stem cell transplant eligibility and pre-transplant therapies should be undertaken. This is best accomplished at a large academic institution with experience in the management of individuals with germline predisposition syndromes [ Surveillance for early detection of myeloid neoplasms is indicated in all individuals with If a myeloid neoplasm that requires allogeneic stem cell transplantation develops and a related donor is being considered, a donor who does not have the It is appropriate to consider clarifying the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by evaluation of the platelet count and molecular genetic testing of the See Platelet counts and bleeding complications should be monitored during pregnancy. While the thrombocytopenia itself (particularly if mild) is unlikely to affect the pregnancy, low platelet counts can limit the ability to receive epidural analgesia or neuroaxial anesthesia. Strategies to increase platelet count (transfusion) can be considered on an individual basis in consultation with the anesthesiologist. Search • Clinical evaluation by a hematologist and a complete blood count including peripheral smear review for early detection of myeloid neoplasms • Consideration of bone marrow aspirate and biopsy at initial evaluation to exclude hematologic malignancies if there are other cytopenias, or abnormalities in: • Mean corpuscular volume • Cell morphology • Leukocyte differential • Mean corpuscular volume • Cell morphology • Leukocyte differential • Consultation with a clinical geneticist and/or genetic counselor • Mean corpuscular volume • Cell morphology • Leukocyte differential ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Clinical evaluation by a hematologist and a complete blood count including peripheral smear review for early detection of myeloid neoplasms Consideration of bone marrow aspirate and biopsy at initial evaluation to exclude hematologic malignancies if there are other cytopenias, or abnormalities in: Mean corpuscular volume Cell morphology Leukocyte differential Consultation with a clinical geneticist and/or genetic counselor • Clinical evaluation by a hematologist and a complete blood count including peripheral smear review for early detection of myeloid neoplasms • Consideration of bone marrow aspirate and biopsy at initial evaluation to exclude hematologic malignancies if there are other cytopenias, or abnormalities in: • Mean corpuscular volume • Cell morphology • Leukocyte differential • Mean corpuscular volume • Cell morphology • Leukocyte differential • Consultation with a clinical geneticist and/or genetic counselor • Mean corpuscular volume • Cell morphology • Leukocyte differential ## Treatment of Manifestations Most individuals are asymptomatic and undergo observation and surveillance. When bleeding is present or a major surgical procedure is required, adjunct hemostatic agents such as antifibrinolytics or desmopressin can be given. Platelet transfusions are reserved for severe bleeding or procedures with a high bleeding risk [ Thrombopoietin analogs have been used selectively for short periods of time (preoperative). The long-term safety has not been established [ ## Prevention of Secondary Complications Once a myeloid neoplasm has been diagnosed, careful consideration of stem cell transplant eligibility and pre-transplant therapies should be undertaken. This is best accomplished at a large academic institution with experience in the management of individuals with germline predisposition syndromes [ ## Surveillance Surveillance for early detection of myeloid neoplasms is indicated in all individuals with ## Agents/Circumstances to Avoid If a myeloid neoplasm that requires allogeneic stem cell transplantation develops and a related donor is being considered, a donor who does not have the ## Evaluation of Relatives at Risk It is appropriate to consider clarifying the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by evaluation of the platelet count and molecular genetic testing of the See ## Pregnancy Management Platelet counts and bleeding complications should be monitored during pregnancy. While the thrombocytopenia itself (particularly if mild) is unlikely to affect the pregnancy, low platelet counts can limit the ability to receive epidural analgesia or neuroaxial anesthesia. Strategies to increase platelet count (transfusion) can be considered on an individual basis in consultation with the anesthesiologist. ## Therapies Under Investigation Search ## Genetic Counseling To date, all individuals diagnosed with Some individuals diagnosed with Molecular genetic testing is recommended for the parents of a proband with a pathogenic variant. 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 If a parent of the proband is affected, the risk to the sibs is 50%. Although penetrance of thrombocytopenia is complete, intrafamilial variability in the degree of thrombocytopenia and transient increase in platelet counts during inflammatory events may occur, making molecular genetic testing more accurate than assessment of thrombocytopenia for diagnosis of affected relatives. If the parents of the proband have been tested for the If the If the parents have not been tested for the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • To date, all individuals diagnosed with • Some individuals diagnosed with • Molecular genetic testing is recommended for the parents of a proband with a pathogenic variant. • 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 • If a parent of the proband is affected, the risk to the sibs is 50%. Although penetrance of thrombocytopenia is complete, intrafamilial variability in the degree of thrombocytopenia and transient increase in platelet counts during inflammatory events may occur, making molecular genetic testing more accurate than assessment of thrombocytopenia for diagnosis of affected relatives. • If the parents of the proband have been tested 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 ## Risk to Family Members To date, all individuals diagnosed with Some individuals diagnosed with Molecular genetic testing is recommended for the parents of a proband with a pathogenic variant. 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 If a parent of the proband is affected, the risk to the sibs is 50%. Although penetrance of thrombocytopenia is complete, intrafamilial variability in the degree of thrombocytopenia and transient increase in platelet counts during inflammatory events may occur, making molecular genetic testing more accurate than assessment of thrombocytopenia for diagnosis of affected relatives. If the parents of the proband have been tested for the If the If the parents have not been tested for the • To date, all individuals diagnosed with • Some individuals diagnosed with • Molecular genetic testing is recommended for the parents of a proband with a pathogenic variant. • 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 • If a parent of the proband is affected, the risk to the sibs is 50%. Although penetrance of thrombocytopenia is complete, intrafamilial variability in the degree of thrombocytopenia and transient increase in platelet counts during inflammatory events may occur, making molecular genetic testing more accurate than assessment of thrombocytopenia for diagnosis of affected relatives. • If the parents of the proband have been tested for the • If the • If the parents have not been tested for the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 • • • • ## Molecular Genetics ANKRD26-Related Thrombocytopenia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ANKRD26-Related Thrombocytopenia ( ## Molecular Pathogenesis ## References ## Literature Cited ## Chapter Notes Juliana Perez Botero, Stefanie N Dugan, and Matthew W Anderson are part of a multidisciplinary clinical laboratory genetics team that analyzes and interprets results of molecular testing of patients with non-malignant hematologic disorders in the context of the clinical phenotype. From a research standpoint, they focus on generating data to increase the robustness of the phenotype-genotype correlation for specific non-malignant hematologic disorders and generate algorithms for time- and cost-effective molecular diagnosis. Website: 21 June 2018 (sw) Review posted live 12 January 2018 (jpb) Original submission • 21 June 2018 (sw) Review posted live • 12 January 2018 (jpb) Original submission ## Author Notes Juliana Perez Botero, Stefanie N Dugan, and Matthew W Anderson are part of a multidisciplinary clinical laboratory genetics team that analyzes and interprets results of molecular testing of patients with non-malignant hematologic disorders in the context of the clinical phenotype. From a research standpoint, they focus on generating data to increase the robustness of the phenotype-genotype correlation for specific non-malignant hematologic disorders and generate algorithms for time- and cost-effective molecular diagnosis. Website: ## Revision History 21 June 2018 (sw) Review posted live 12 January 2018 (jpb) Original submission • 21 June 2018 (sw) Review posted live • 12 January 2018 (jpb) Original submission	[ "SA Al Daama, YH Housawi, W Dridi, M Sager, FG Otieno, C Hou, L Vasquez, C Kim, L Tian, P Sleiman, H Hakonarson. A missense mutation in ANKRD26 segregates with thrombocytopenia.. Blood. 2013;122:461-2", "M Averina, H Jensvoll, H Strand, M. Sovershaev. A novel ANKRD26 gene variant causing inherited thrombocytopenia in a family of Finnish origin: another brick in the wall?. Thromb Res. 2017;151:41-3", "DV Babushok, M Bessler, TS Olson. Genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia in children and young adults.. Leuk Lymphoma. 2016;57:520-36", "A Balduini, H Raslova, CA Di Baduo, M Donada, M Ballmaier, M Germeshausen, CL Balduini. Clinic, pathogenic mechanisms and drug testing of two inherited thrombocytopenias, ANKRD26-related thrombocytopenia and MYH9-related diseases.. Eur J Med Genet. 2018;61:715-22", "CL Balduini, A Pecci, P Noris. Diagnosis and management of inherited thrombocytopenias.. Semin Thromb Hemost. 2013a;39:161-71", "CL Balduini, A Savoia, M Seri. Inherited thrombocytopenias frequently diagnosed in adults.. J Thromb Haemost. 2013b;11:1006-19", "D Bluteau, A Balduini, N Balayn, M Currao, P Nurden, C Deswarte, G Leverger, P Noris, S Perrotta, E Solary, W Vainchenker, N Debili, R Favier, H. Raslova. Thrombocytopenia-associated mutations in the ANKRD26 regulatory region induce MAPK hyperactivation.. J Clin Invest. 2014;124:580-91", "S Ferrari, AM Lombardi, MC Putti, A Bertomoro, I Cortella, I Barzon, A Girolami, F Fabris. Spectrum of 5'UTR mutations in ANKRD26 gene in patients with inherited thrombocytopenia: c.-140C>G mutation is more frequent than expected.. Platelets. 2017;28:621-4", "M Fiore, N Saut, MC Alessi, JF Viallard. Successful use of eltrombopag for surgical preparation in a patient with ANKRD26-related thrombocytopenia.. Platelets. 2016;27:828-9", "LA Godley. Inherited predisposition to acute myeloid leukemia.. Semin Hematol. 2014;51:306-21", "Y Lee, T Ise, D Ha, A Saint Fleur, Y Hahn, X Liu, S Nagata, B Lee, T Bera, I Pastan. Evolution and expression of chimeric POTE-activ genes in the human genome.. Proc Natl Acad Sci. 2006;103:17885", "C Marconi, I Canobbio, V Bozzi, T Pippucci, G Simonetti, F Melazzini, S Angori, G Martinelli, G Saglio, M Torti, I Pastan, M Seri, A. Pecci. 5'UTR point substitutions and N-terminal truncating mutations of ANKRD26 in acute myeloid leukemia.. J Hematol Oncol. 2017;10:18", "R Marquez, A Hantel, R Lorenz, B Neistadt, J Wong, JE Churpek, NA Mardini, I Shaukat, S Gurbuxani, JL Miller, LA Godley. A new family with a germline ANKRD26 mutation and predisposition to myeloid malignancies.. Leuk Lymphoma. 2014;55:2945-6", "P Noris, R Favier, MC Alessi, AE Geddis, S Kunishima, PG Heller, P Giordano, KY Niederhoffer, JB Bussel, GM Podda, N Vianelli, R Kersseboom, A Pecci, C Gnan, C Marconi, A Auvrignon, W Cohen, JC Yu, A Iguchi, A Miller Imahiyerobo, F Boehlen, D Ghalloussi, D De Rocco, P Magini, E Civaschi, G Biino, M Seri, A Savoia, CL Balduini. ANKRD26-related thrombocytopenia and myeloid malignancies.. Blood. 2013;122:1987-9", "P Noris, S Perrotta, M Seri, A Pecci, C Gnan, G Loffredo, N Pujol-Moix, M Zecca, F Scognamiglio, D De Rocco, F Punzo, F Melazzini, S Scianguetta, M Casale, C Marconi, T Pippucci, G Amendola, LD Notarangelo, C Klersy, E Civaschi, CL Balduini, A Savoia. Mutations in ANKRD26 are responsible for a frequent form of inherited thrombocytopenia: analysis of 78 patients from 21 families.. Blood. 2011;117:6673-80", "M Ouchi-Uchiyama, Y Sasahara, A Kikuchi, K Goi, T Nakane, M Ikeno, Y Noguchi, N Uike, Y Miyajima, K Matsubara, K Koh, K Sugita, M Imaizumi, S Kure. Analyses of genetic and clinical parameters for screening patients with inherited thrombocytopenia with small or normal-sized platelets.. Pediatr Blood Cancer. 2015;62:2082-8", "A. Pecci. Pathogenesis and management of inherited thrombocytopenias: rationale for the use of thrombopoietin-receptor agonists.. Int J Hematol. 2013;98:34-47", "J Perez Botero, TP Ho, WJ Hogan, S Kenderian, N Gangat, A Tefferi, RS Abraham, P Nguyen, JL Oliveira, R He, D Chen, D Viswanatha, V Rodriguez, SP Khan, MM Patnaik. Clinical spectrum and clonal evolution in germline syndromes with predisposition to myeloid neoplasms.. Br J Haematol. 2018;182:141-5", "J Perez Botero, JL Oliveira, D Chen, KK Reichard, DS Viswanatha, PL Nguyen, RK Pruthi, J Majerus, P Gada, N Gangat, A Tefferi, MM Patnaik. ASXL1 mutated chronic myelomonocytic leukemia in a patient with familial thrombocytopenia secondary to germline mutation in ANKRD26.. Blood Cancer J. 2015;5", "R Rahbari, A Wuster, SJ Lindsay, RJ Hardwick, LB Alexandrov, SA Turki, A Dominiczak, A Morris, D Porteous, B Smith, MR Stratton. UK10K Consortium, Hurles ME. Timing, rates and spectra of human germline mutation.. Nat Genet. 2016;48:126-33" ]	21/6/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ano5-md	ano5-md	[ "Anoctaminopathy", "Anoctaminopathy", "Miyoshi Muscular Dystrophy 3 (MMD3)", "Limb-Girdle Muscular Dystrophy R12 Anoctamin-5-Related (LGMD-R12)", "Anoctamin-5", "ANO5", "ANO5-Related Muscle Disease" ]		Johanna Palmio, Sini Penttilä, Manu Jokela	Summary The spectrum of The diagnosis of	Limb-girdle muscular dystrophy R12 anoctamin-5-related (LGMD-R12) Miyoshi muscular dystrophy 3 (MMD3) For synonyms and outdated names see • Limb-girdle muscular dystrophy R12 anoctamin-5-related (LGMD-R12) • Miyoshi muscular dystrophy 3 (MMD3) ## Diagnosis No consensus clinical diagnostic criteria for Asymmetric muscle weakness and atrophy, especially in the thigh muscles, with late adult onset (mean onset: age 35 years) Calf distal myopathy of early adult onset (mean onset: age 30 years) Exercise-induced myalgia 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 The most common pathogenic variants in northern European populations are Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Asymmetric muscle weakness and atrophy, especially in the thigh muscles, with late adult onset (mean onset: age 35 years) • Calf distal myopathy of early adult onset (mean onset: age 30 years) • Exercise-induced myalgia ## Suggestive Findings Asymmetric muscle weakness and atrophy, especially in the thigh muscles, with late adult onset (mean onset: age 35 years) Calf distal myopathy of early adult onset (mean onset: age 30 years) Exercise-induced myalgia • Asymmetric muscle weakness and atrophy, especially in the thigh muscles, with late adult onset (mean onset: age 35 years) • Calf distal myopathy of early adult onset (mean onset: age 30 years) • Exercise-induced myalgia ## 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 The most common pathogenic variants in northern European populations are Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click The most common pathogenic variants in northern European populations are Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 spectrum of In MMD3, calf hypertrophy and exercise myalgia can occur before apparent weakness and later calf atrophy. Clinical manifestations can be mild or subjectively nonexistent even with clear changes observed on muscle imaging. Individuals with distal onset may have proximal lower limb weakness in the later stages of the disease. Distal upper limb weakness has not been reported. Muscle weakness and atrophy are frequently asymmetric (see Persistent hyperCKemia does not seem to cause secondary adverse effects. Only limited genotype-phenotype correlations have been identified. Individuals with biallelic loss-of-function variants have been reported to use walking aids at a significantly earlier age than individuals with pathogenic variants that are expected to lead to partial or reduced function. Individuals homozygous for LGMD-R12 was previously referred to as LGMD2L [ MMD3 may also be referred to as non-dysferlin Miyoshi muscular dystrophy. The most frequent ## Clinical Description The spectrum of In MMD3, calf hypertrophy and exercise myalgia can occur before apparent weakness and later calf atrophy. Clinical manifestations can be mild or subjectively nonexistent even with clear changes observed on muscle imaging. Individuals with distal onset may have proximal lower limb weakness in the later stages of the disease. Distal upper limb weakness has not been reported. Muscle weakness and atrophy are frequently asymmetric (see Persistent hyperCKemia does not seem to cause secondary adverse effects. ## Genotype-Phenotype Correlations Only limited genotype-phenotype correlations have been identified. Individuals with biallelic loss-of-function variants have been reported to use walking aids at a significantly earlier age than individuals with pathogenic variants that are expected to lead to partial or reduced function. Individuals homozygous for ## Nomenclature LGMD-R12 was previously referred to as LGMD2L [ MMD3 may also be referred to as non-dysferlin Miyoshi muscular dystrophy. ## Prevalence The most frequent ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Genes Associated with Calf-Predominant Distal Myopathies in the Differential Diagnosis of Miyoshi Muscular Dystrophy 3 AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; MOI = mode of inheritance Miyoshi myopathy 1 is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. ## Management No clinical practice guidelines for To establish the extent of disease and needs of an individual diagnosed with MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) No definitive treatments for the limb-girdle muscular dystrophies exist. Management is tailored to each individual and each specific subtype. Weight control to avoid obesity Physical therapy to promote mobility & prevent contractures Mechanical aids to help ambulation & mobility To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Heavy muscle force training of weak muscles should be avoided, as very high plasma CK concentration has been measured after strenuous exercise [ The use of statins, which can induce muscle pain and worsen muscle weakness, should be avoided. If absolutely necessary for the health of the individual, statin use requires extra monitoring of clinical status, especially at the beginning of treatment. See Search • Weight control to avoid obesity • Physical therapy to promote mobility & prevent contractures • Mechanical aids to help ambulation & mobility ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) ## Treatment of Manifestations No definitive treatments for the limb-girdle muscular dystrophies exist. Management is tailored to each individual and each specific subtype. Weight control to avoid obesity Physical therapy to promote mobility & prevent contractures Mechanical aids to help ambulation & mobility • Weight control to avoid obesity • Physical therapy to promote mobility & prevent contractures • Mechanical aids to help ambulation & mobility ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in ## Agents/Circumstances to Avoid Heavy muscle force training of weak muscles should be avoided, as very high plasma CK concentration has been measured after strenuous exercise [ The use of statins, which can induce muscle pain and worsen muscle weakness, should be avoided. If absolutely necessary for the health of the individual, statin use requires extra monitoring of clinical status, especially at the beginning of treatment. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected individual 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. Heterozygous parents of an individual with If both parents are known to be heterozygous for an Individuals with the same pathogenic variants can develop different phenotypes even within the same family, including limb-girdle muscular dystrophy R12 anoctamin-5-related (LGMD-R12), Miyoshi muscular dystrophy 3 (MMD3), and asymptomatic hyperCKemia. Females tend to have milder disease manifestations than males with the same Heterozygous sibs of an individual with 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 should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for 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. • Heterozygous parents of an individual with • 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 with the same pathogenic variants can develop different phenotypes even within the same family, including limb-girdle muscular dystrophy R12 anoctamin-5-related (LGMD-R12), Miyoshi muscular dystrophy 3 (MMD3), and asymptomatic hyperCKemia. Females tend to have milder disease manifestations than males with the same • Heterozygous sibs 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. • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with ## Mode of Inheritance ## Risk to Family Members The parents of an affected individual 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. Heterozygous parents of an individual with If both parents are known to be heterozygous for an Individuals with the same pathogenic variants can develop different phenotypes even within the same family, including limb-girdle muscular dystrophy R12 anoctamin-5-related (LGMD-R12), Miyoshi muscular dystrophy 3 (MMD3), and asymptomatic hyperCKemia. Females tend to have milder disease manifestations than males with the same Heterozygous sibs of an individual with • The parents of an affected individual 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. • Heterozygous parents of an individual with • 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 with the same pathogenic variants can develop different phenotypes even within the same family, including limb-girdle muscular dystrophy R12 anoctamin-5-related (LGMD-R12), Miyoshi muscular dystrophy 3 (MMD3), and asymptomatic hyperCKemia. Females tend to have milder disease manifestations than males with the same • Heterozygous sibs of an individual with ## 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 should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected 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. • Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources Canada United Kingdom • • • • • • Canada • • • United Kingdom • ## Molecular Genetics ANO5-Related Muscle Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ANO5-Related Muscle Disease ( A Western blotting method has been developed to detect endogenous anoctamin-5 in membrane fractions extracted from human muscle biopsies. This method can be used to quantify the anoctamin-5 protein and evaluate the pathogenicity of novel ClinGen variant interpretation guidelines are available; see Variants listed in the table have been provided by the authors. • A Western blotting method has been developed to detect endogenous anoctamin-5 in membrane fractions extracted from human muscle biopsies. This method can be used to quantify the anoctamin-5 protein and evaluate the pathogenicity of novel • ClinGen variant interpretation guidelines are available; see ## Molecular Pathogenesis A Western blotting method has been developed to detect endogenous anoctamin-5 in membrane fractions extracted from human muscle biopsies. This method can be used to quantify the anoctamin-5 protein and evaluate the pathogenicity of novel ClinGen variant interpretation guidelines are available; see Variants listed in the table have been provided by the authors. • A Western blotting method has been developed to detect endogenous anoctamin-5 in membrane fractions extracted from human muscle biopsies. This method can be used to quantify the anoctamin-5 protein and evaluate the pathogenicity of novel • ClinGen variant interpretation guidelines are available; see ## Chapter Notes Manu Jokela, MD, PhD (2025-present)Johanna Palmio, MD, PhD (2012-present)Sini Penttilä, PhD (2012-present)Bjarne Udd, MD, PhD; University Hospital Tampere, Finland (2012-2025)Anna Vihola, PhD; Fimlab Laboratories (2019-2025) 15 May 2025 (sw) Comprehensive update posted live 22 August 2019 (ha) Comprehensive update posted live 29 November 2012 (me) Review posted live 19 July 2012 (sp) Original submission • 15 May 2025 (sw) Comprehensive update posted live • 22 August 2019 (ha) Comprehensive update posted live • 29 November 2012 (me) Review posted live • 19 July 2012 (sp) Original submission ## Author History Manu Jokela, MD, PhD (2025-present)Johanna Palmio, MD, PhD (2012-present)Sini Penttilä, PhD (2012-present)Bjarne Udd, MD, PhD; University Hospital Tampere, Finland (2012-2025)Anna Vihola, PhD; Fimlab Laboratories (2019-2025) ## Revision History 15 May 2025 (sw) Comprehensive update posted live 22 August 2019 (ha) Comprehensive update posted live 29 November 2012 (me) Review posted live 19 July 2012 (sp) Original submission • 15 May 2025 (sw) Comprehensive update posted live • 22 August 2019 (ha) Comprehensive update posted live • 29 November 2012 (me) Review posted live • 19 July 2012 (sp) Original submission ## References ## Literature Cited MR images of right (R) and left (L) upper (A) and lower (B) legs in an individual with A. Fatty degenerative changes in posterior thigh muscles in the left vastus medialis and intermedius muscles (L) B. Fatty degenerative changes in the medial gastrocnemius (left [L] greater than right [R]) and in the left soleus muscle Asymmetric atrophy of the muscles of the left calf in an individual with	[]	29/11/2012	15/5/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
anophthalmia-ov	anophthalmia-ov	[ "BCL-6 corepressor", "Beta-crystallin A4", "Bone morphogenetic protein 4", "Chromodomain-helicase-DNA-binding protein 7", "Cytochrome c-type heme lyase", "Forkhead box protein E3", "Growth/differentiation factor 6", "Homeobox expressed in ES cells 1", "Homeobox protein OTX2", "N-alpha-acetyltransferase 10", "Nance-Horan syndrome protein", "NF-kappa-B essential modulator", "Paired box protein Pax-6", "Peroxidasin homolog", "Protein-serine O-palmitoleoyltransferase porcupine", "Receptor for retinol uptake STRA6", "Retinal homeobox protein Rx", "Retinoic acid receptor beta", "Sonic hedgehog protein", "SPARC-related modular calcium-binding protein 1", "Transcription factor AP-2-alpha", "Transcription factor SOX-2", "Visual system homeobox 2", "BCOR", "BMP4", "CHD7", "CRYBA4", "FOXE3", "GDF6", "HCCS", "HESX1", "IKBKG", "NAA10", "NHS", "OTX2", "PAX6", "PORCN", "PXDN", "RARB", "RAX", "SHH", "SMOC1", "SOX2", "STRA6", "TFAP2A", "VSX2", "Microphthalmia/Anophthalmia/Coloboma Spectrum", "Overview" ]	Microphthalmia/Anophthalmia/Coloboma Spectrum – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Tanya Bardakjian, Avery Weiss, Adele Schneider	Summary Microphthalmia refers to a globe with a total axial length that is at least two standard deviations below the mean for age. Anophthalmia refers to complete absence of the globe in the presence of ocular adnexa (eyelids, conjunctiva, and lacrimal apparatus). Coloboma refers to the ocular malformations that result from failure of closure of the optic fissure. Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the iris to appear keyhole-shaped. Microphthalmia, anophthalmia, and coloboma may be unilateral or bilateral; when bilateral they may occur in any combination. Molecular genetic testing (which can include sequence analysis, gene-targeted deletion/duplication analysis, and chromosome microarray analysis [CMA]) can identify a genetic cause in 80% of individuals with bilateral anophthalmia/severe microphthalmia and in up to 20% of all individuals with an ocular malformation in the MAC spectrum. When an inherited or Children with reduced vision may benefit from visual aids and other visual resources as well as early intervention to help optimize psychomotor development, educational endeavors, life skills, and mobility. Protection of the healthy eye in those with unilateral involvement is recommended.	## Definition For an adult eye, the lower 2.5% confidence limit for the TAL is approximately 21.0 mm. In children (in whom postnatal ocular growth continues into adolescence) the lower 2.5% confidence limit must be derived from a normative plot of TAL versus age [ Length of the Neonatal and Adult Eye Total axial length (TAL) is the axial distance (in mm) from the corneal apex to the back of the globe. Anterior segment length (ASL) is the axial distance (in mm) from the cornea to the back of the lens. Posterior segment length (PSL) is the axial distance (in mm) from the back of the lens to the back of the globe. In microphthalmic eyes, measurements of ASL and PSL indicate that ASL is within or below the normal range, whereas PSL is uniformly at least two standard deviations below the mean for age [ Most postnatal growth of the eye occurs in the first three years of life, particularly during the first year. Growth of the posterior segment accounts for 60% of the prenatal and more than 90% of the postnatal increase in TAL. Although TAL is reduced at birth, the microphthalmic eye can grow by a variable amount in the postnatal period depending on the severity of the underlying malformation. Classification of microphthalmia is according to the anatomic appearance of the globe and severity of axial length reduction. Severe microphthalmia refers to a globe that is severely reduced in size, with a corneal diameter <4 mm and a TAL <10 mm at birth or <12 mm after age one year. Although the globe is inconspicuous on clinical examination, CT or MRI reveals remnants of ocular tissue, an optic nerve, and extraocular muscles. Without orbital imaging studies, severe microphthalmia can be mistaken for anophthalmia; thus, the term "clinical anophthalmia" is often interchangeably used for severe microphthalmia. Chorioretinal coloboma refers to coloboma of the retina and choroid. Iris coloboma causes the pupil to be "keyhole" shaped. Other abnormalities of the eye that can be seen with coloboma include: Sclerocornea: opacity and vascularization of portions of the normally transparent cornea which, as a result, resembles sclera Cataract: opacity of the lens Retinal dysplasia: histologic findings associated with developmental loss of structural and functional cellular components of the retina Each of these three malformations may be unilateral or bilateral; when bilateral they may occur in any combination. For example: Colobomatous malformations may occur in any combination within an eye or between eyes of the same individual. Colobomatous malformations may occur with or without microphthalmia. Colobomatous malformations in one eye may be accompanied by microphthalmia or anophthalmia in the fellow eye. Anophthalmia may be bilateral or unilateral with or without colobomatous malformation of the fellow eye. The diagnosis of MAC is based on the following: Gross inspection looking for evidence of a cornea/globe and palpation of the orbit to obtain an estimate of globe size Measurement of corneal diameter, which normally ranges from 9.0 to 10.5 mm in neonates and 10.5 to 12.0 mm in adults A-scan ultrasonography to measure total axial length and anterior and posterior segment lengths B-scan ultrasonography to evaluate the internal structures of the globe CT scan or MRI of the brain and orbits to evaluate the size and internal structures of the globe, presence of optic nerve and extraocular muscles, and brain anatomy Microphthalmia needs to be distinguished from mild microcornea with a normal-sized globe. Anophthalmia needs to be distinguished from severe microphthalmia, cryptophthalmos, and cystic eye. Cryptophthalmos ("hidden eye") refers to abnormal fusion of the entire eyelid margin with absence of eyelashes, resulting in a continuous sheet of skin extending from the forehead to the cheek. Failure of eyelid separation can be associated with maldevelopment of the underlying cornea and microphthalmia. Cryptophthalmos is usually bilateral and occurs in association with other multiple malformations collectively referred to as Fraser syndrome (OMIM Cystic eye refers to a cyst of neuroglial tissue that lacks normal ocular structures. At birth, the cyst may be small, the palpebral fissures narrow, and orbital volume reduced, suggesting anophthalmia. Postnatal expansion of the cyst can lead to distention of the cyst with bulging behind the eyelids. Orbital imaging shows an intraorbital cyst with attached extraocular muscles but no optic nerve. Cystic eye should be distinguished from the cyst associated with colobomatous microphthalmia. • For an adult eye, the lower 2.5% confidence limit for the TAL is approximately 21.0 mm. • In children (in whom postnatal ocular growth continues into adolescence) the lower 2.5% confidence limit must be derived from a normative plot of TAL versus age [ • Sclerocornea: opacity and vascularization of portions of the normally transparent cornea which, as a result, resembles sclera • Cataract: opacity of the lens • Retinal dysplasia: histologic findings associated with developmental loss of structural and functional cellular components of the retina • Colobomatous malformations may occur in any combination within an eye or between eyes of the same individual. • Colobomatous malformations may occur with or without microphthalmia. • Colobomatous malformations in one eye may be accompanied by microphthalmia or anophthalmia in the fellow eye. • Anophthalmia may be bilateral or unilateral with or without colobomatous malformation of the fellow eye. • Gross inspection looking for evidence of a cornea/globe and palpation of the orbit to obtain an estimate of globe size • Measurement of corneal diameter, which normally ranges from 9.0 to 10.5 mm in neonates and 10.5 to 12.0 mm in adults • A-scan ultrasonography to measure total axial length and anterior and posterior segment lengths • B-scan ultrasonography to evaluate the internal structures of the globe • CT scan or MRI of the brain and orbits to evaluate the size and internal structures of the globe, presence of optic nerve and extraocular muscles, and brain anatomy • Cryptophthalmos ("hidden eye") refers to abnormal fusion of the entire eyelid margin with absence of eyelashes, resulting in a continuous sheet of skin extending from the forehead to the cheek. Failure of eyelid separation can be associated with maldevelopment of the underlying cornea and microphthalmia. Cryptophthalmos is usually bilateral and occurs in association with other multiple malformations collectively referred to as Fraser syndrome (OMIM • Cystic eye refers to a cyst of neuroglial tissue that lacks normal ocular structures. At birth, the cyst may be small, the palpebral fissures narrow, and orbital volume reduced, suggesting anophthalmia. Postnatal expansion of the cyst can lead to distention of the cyst with bulging behind the eyelids. Orbital imaging shows an intraorbital cyst with attached extraocular muscles but no optic nerve. Cystic eye should be distinguished from the cyst associated with colobomatous microphthalmia. ## Establishing the Diagnosis of MAC Spectrum The diagnosis of MAC is based on the following: Gross inspection looking for evidence of a cornea/globe and palpation of the orbit to obtain an estimate of globe size Measurement of corneal diameter, which normally ranges from 9.0 to 10.5 mm in neonates and 10.5 to 12.0 mm in adults A-scan ultrasonography to measure total axial length and anterior and posterior segment lengths B-scan ultrasonography to evaluate the internal structures of the globe CT scan or MRI of the brain and orbits to evaluate the size and internal structures of the globe, presence of optic nerve and extraocular muscles, and brain anatomy • Gross inspection looking for evidence of a cornea/globe and palpation of the orbit to obtain an estimate of globe size • Measurement of corneal diameter, which normally ranges from 9.0 to 10.5 mm in neonates and 10.5 to 12.0 mm in adults • A-scan ultrasonography to measure total axial length and anterior and posterior segment lengths • B-scan ultrasonography to evaluate the internal structures of the globe • CT scan or MRI of the brain and orbits to evaluate the size and internal structures of the globe, presence of optic nerve and extraocular muscles, and brain anatomy ## Differential Diagnosis of MAC Spectrum Microphthalmia needs to be distinguished from mild microcornea with a normal-sized globe. Anophthalmia needs to be distinguished from severe microphthalmia, cryptophthalmos, and cystic eye. Cryptophthalmos ("hidden eye") refers to abnormal fusion of the entire eyelid margin with absence of eyelashes, resulting in a continuous sheet of skin extending from the forehead to the cheek. Failure of eyelid separation can be associated with maldevelopment of the underlying cornea and microphthalmia. Cryptophthalmos is usually bilateral and occurs in association with other multiple malformations collectively referred to as Fraser syndrome (OMIM Cystic eye refers to a cyst of neuroglial tissue that lacks normal ocular structures. At birth, the cyst may be small, the palpebral fissures narrow, and orbital volume reduced, suggesting anophthalmia. Postnatal expansion of the cyst can lead to distention of the cyst with bulging behind the eyelids. Orbital imaging shows an intraorbital cyst with attached extraocular muscles but no optic nerve. Cystic eye should be distinguished from the cyst associated with colobomatous microphthalmia. • Cryptophthalmos ("hidden eye") refers to abnormal fusion of the entire eyelid margin with absence of eyelashes, resulting in a continuous sheet of skin extending from the forehead to the cheek. Failure of eyelid separation can be associated with maldevelopment of the underlying cornea and microphthalmia. Cryptophthalmos is usually bilateral and occurs in association with other multiple malformations collectively referred to as Fraser syndrome (OMIM • Cystic eye refers to a cyst of neuroglial tissue that lacks normal ocular structures. At birth, the cyst may be small, the palpebral fissures narrow, and orbital volume reduced, suggesting anophthalmia. Postnatal expansion of the cyst can lead to distention of the cyst with bulging behind the eyelids. Orbital imaging shows an intraorbital cyst with attached extraocular muscles but no optic nerve. Cystic eye should be distinguished from the cyst associated with colobomatous microphthalmia. ## Causes Recent studies indicate that molecular genetic testing that includes sequence analysis, gene-targeted deletion/duplication analysis, and chromosome microarray analysis (CMA) can identify a genetic cause in: 80% of individuals with bilateral anophthalmia/severe microphthalmia [ Up to 20% of all individuals with an ocular malformation in the microphthalmia, anophthalmia, coloboma (MAC) spectrum (in which the laterality and severity of MAC can vary). Chromosome abnormalities can be identified in an estimated 25%-30% of individuals with MAC ( Common Chromosome Abnormalities Associated with Microphthalmia/Anophthalmia/Coloboma (MAC) Spectrum Trisomy 9 mosaicism Trisomy 13 Trisomy 18 4p- (Wolf-Hirschhorn syndrome) Deletion 7p15.1-p21.1 13q-, ring 13 Deletion 14q22.1-q23.2 18q- Deletion 3q26 (includes Duplication 3q syndrome (3q21-ter dup) Duplication 4p syndrome Duplication 10q syndrome Based on Single-gene causes of MAC spectrum that account for 1% or more of anophthalmia/microphthalmia/coloboma are listed in Of note, the co-occurrence of any of the ocular findings within the MAC spectrum may be unilateral or bilateral and may be in any combination within an eye (e.g., chorioretinal coloboma and/or iris coloboma ± microphthalmia) or between eyes of the same individual (e.g., colobomatous malformation in one eye and anophthalmia in the fellow eye). Molecular Genetics of Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum: Most Common Genetic Causes Pathogenic variants of any one of the genes included in this table account for ≥1% of anophthalmia/microphthalmia/coloboma (MAC). MOI = mode of inheritance AS = anterior segment dysgenesis; RD = retinal dysplasia ASD = autism spectrum disorders; DD = developmental delays; EA±TEF = esophageal atresia with or without tracheoesophageal fistula; FTT = failure to thrive; ID = intellectual disability; SNHL = sensorineural hearing loss Genes that cause ≥2% of MAC are listed from most frequent to least frequent genetic cause; they are followed in alphabetic order by genes that cause 1% of MAC. Ocular features in addition to the typical findings in the MAC spectrum Author [personal observation] Heterozygous Can also be caused by mutation of Molecular Genetics of Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum: Less Common Genetic Causes Pathogenic variants in any one of the genes listed in this table are reported in only a few families (i.e., <1% of anophthalmia/microphthalmia/coloboma (MAC). MOI = mode of inheritance RD = retinal dysplasia ACC = absence of the corpus callosum; ASD = autism spectrum disorders; CL/P = cleft lip/palate; DD = developmental delays; EA±TEF = esophageal atresia with or without tracheoesophageal fistula; FTT = failure to thrive; ID = intellectual disability; SNHL = sensorineural hearing loss Genes are listed in alphabetic order. Ocular features in addition to the typical findings in the MAC spectrum • 80% of individuals with bilateral anophthalmia/severe microphthalmia [ • Up to 20% of all individuals with an ocular malformation in the microphthalmia, anophthalmia, coloboma (MAC) spectrum (in which the laterality and severity of MAC can vary). • Trisomy 9 mosaicism • Trisomy 13 • Trisomy 18 • 4p- (Wolf-Hirschhorn syndrome) • Deletion 7p15.1-p21.1 • 13q-, ring 13 • Deletion 14q22.1-q23.2 • 18q- • Deletion 3q26 (includes • Duplication 3q syndrome (3q21-ter dup) • Duplication 4p syndrome • Duplication 10q syndrome ## Chromosome Abnormalities Chromosome abnormalities can be identified in an estimated 25%-30% of individuals with MAC ( Common Chromosome Abnormalities Associated with Microphthalmia/Anophthalmia/Coloboma (MAC) Spectrum Trisomy 9 mosaicism Trisomy 13 Trisomy 18 4p- (Wolf-Hirschhorn syndrome) Deletion 7p15.1-p21.1 13q-, ring 13 Deletion 14q22.1-q23.2 18q- Deletion 3q26 (includes Duplication 3q syndrome (3q21-ter dup) Duplication 4p syndrome Duplication 10q syndrome Based on • Trisomy 9 mosaicism • Trisomy 13 • Trisomy 18 • 4p- (Wolf-Hirschhorn syndrome) • Deletion 7p15.1-p21.1 • 13q-, ring 13 • Deletion 14q22.1-q23.2 • 18q- • Deletion 3q26 (includes • Duplication 3q syndrome (3q21-ter dup) • Duplication 4p syndrome • Duplication 10q syndrome ## Single-Gene Disorders Single-gene causes of MAC spectrum that account for 1% or more of anophthalmia/microphthalmia/coloboma are listed in Of note, the co-occurrence of any of the ocular findings within the MAC spectrum may be unilateral or bilateral and may be in any combination within an eye (e.g., chorioretinal coloboma and/or iris coloboma ± microphthalmia) or between eyes of the same individual (e.g., colobomatous malformation in one eye and anophthalmia in the fellow eye). Molecular Genetics of Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum: Most Common Genetic Causes Pathogenic variants of any one of the genes included in this table account for ≥1% of anophthalmia/microphthalmia/coloboma (MAC). MOI = mode of inheritance AS = anterior segment dysgenesis; RD = retinal dysplasia ASD = autism spectrum disorders; DD = developmental delays; EA±TEF = esophageal atresia with or without tracheoesophageal fistula; FTT = failure to thrive; ID = intellectual disability; SNHL = sensorineural hearing loss Genes that cause ≥2% of MAC are listed from most frequent to least frequent genetic cause; they are followed in alphabetic order by genes that cause 1% of MAC. Ocular features in addition to the typical findings in the MAC spectrum Author [personal observation] Heterozygous Can also be caused by mutation of Molecular Genetics of Anophthalmia/Microphthalmia/Coloboma (MAC) Spectrum: Less Common Genetic Causes Pathogenic variants in any one of the genes listed in this table are reported in only a few families (i.e., <1% of anophthalmia/microphthalmia/coloboma (MAC). MOI = mode of inheritance RD = retinal dysplasia ACC = absence of the corpus callosum; ASD = autism spectrum disorders; CL/P = cleft lip/palate; DD = developmental delays; EA±TEF = esophageal atresia with or without tracheoesophageal fistula; FTT = failure to thrive; ID = intellectual disability; SNHL = sensorineural hearing loss Genes are listed in alphabetic order. Ocular features in addition to the typical findings in the MAC spectrum ## Evaluation Strategy Establishing the specific genetic cause of microphthalmia/anophthalmia/coloboma (MAC) spectrum in a given individual usually involves the following: Ultrasound examination of the orbits MRI of the brain and orbits (or CT scan if unable to obtain an MRI) Endocrine evaluation Dental evaluation in older child Echocardiogram Renal ultrasound examination For an introduction to multigene panels click For an introduction to comprehensive genomic testing click If no diagnosis is established after the initial set of examinations and tests, reevaluation within two years is recommended. • • Ultrasound examination of the orbits • MRI of the brain and orbits (or CT scan if unable to obtain an MRI) • Ultrasound examination of the orbits • MRI of the brain and orbits (or CT scan if unable to obtain an MRI) • Endocrine evaluation • Dental evaluation in older child • Echocardiogram • Renal ultrasound examination • Endocrine evaluation • Dental evaluation in older child • Echocardiogram • Renal ultrasound examination • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click • If no diagnosis is established after the initial set of examinations and tests, reevaluation within two years is recommended. • Ultrasound examination of the orbits • MRI of the brain and orbits (or CT scan if unable to obtain an MRI) • Endocrine evaluation • Dental evaluation in older child • Echocardiogram • Renal ultrasound examination • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Genetic Counseling When an inherited or If the genetic/genomic cause If the genetic/genomic cause Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ • If the genetic/genomic cause • If the genetic/genomic cause • Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ • Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ • MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ • Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ • Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ • MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ • Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ • Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ • MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ ## Related Genetic Counseling Issues ## Prenatal Testing If the genetic/genomic cause If the genetic/genomic cause Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ • If the genetic/genomic cause • If the genetic/genomic cause • Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ • Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ • MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ • Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ • Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ • MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ • Transvaginal ultrasound examination may identify the eyes from 12 weeks' gestation onward [ • Three-dimensional and four-dimensional ultrasound examination may be used in some centers to detect complex malformations of the face, including anophthalmia/microphthalmia [ • MRI may be a useful adjunct to ultrasound examination in detection of anophthalmia [ ## Resources c/o Center for Developmental Medicine and Genetics 5501 Old York Road Genetics, Levy 2 West Philadelphia PA 19141 31 Center Drive MSC 2510 Bethesda MD 20892-2510 200 East Wells Street (at Jernigan Place) Baltimore MD 21230 • • c/o Center for Developmental Medicine and Genetics • 5501 Old York Road • Genetics, Levy 2 West • Philadelphia PA 19141 • • • 31 Center Drive • MSC 2510 • Bethesda MD 20892-2510 • • • 200 East Wells Street • (at Jernigan Place) • Baltimore MD 21230 • • • ## Management Prosthetic intervention is appropriate in severe microphthalmia and anophthalmia. In many infants, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit using conformers of progressively increasing size. In some instances, conformers do not adequately expand the orbit, especially horizontally, causing an "hour glass" deformity. An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months (when postnatal growth of the orbit can be assessed) and before the age that orbital dimensions are fixed (after which extensive orbital reconstruction may be required). Surgical options include placement of orbital implants of fixed dimensions at one or more surgeries; placement of expandable implants (silicone balloon, hydrophilic polymers); or use of a dermis-fat graft, which has the capability of post-surgical growth. Children with reduced vision may benefit from visual aids and other visual resources as well as early intervention to help optimize psychomotor development, educational endeavors, life skills, and mobility. Protection of the healthy eye in those with unilateral involvement is recommended. • In many infants, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit using conformers of progressively increasing size. In some instances, conformers do not adequately expand the orbit, especially horizontally, causing an "hour glass" deformity. • An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months (when postnatal growth of the orbit can be assessed) and before the age that orbital dimensions are fixed (after which extensive orbital reconstruction may be required). ## Treatment of MAC Spectrum Prosthetic intervention is appropriate in severe microphthalmia and anophthalmia. In many infants, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit using conformers of progressively increasing size. In some instances, conformers do not adequately expand the orbit, especially horizontally, causing an "hour glass" deformity. An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months (when postnatal growth of the orbit can be assessed) and before the age that orbital dimensions are fixed (after which extensive orbital reconstruction may be required). Surgical options include placement of orbital implants of fixed dimensions at one or more surgeries; placement of expandable implants (silicone balloon, hydrophilic polymers); or use of a dermis-fat graft, which has the capability of post-surgical growth. Children with reduced vision may benefit from visual aids and other visual resources as well as early intervention to help optimize psychomotor development, educational endeavors, life skills, and mobility. Protection of the healthy eye in those with unilateral involvement is recommended. • In many infants, an ocularist can start shortly after birth to expand the palpebral fissures, conjunctival cul-de-sac, and orbit using conformers of progressively increasing size. In some instances, conformers do not adequately expand the orbit, especially horizontally, causing an "hour glass" deformity. • An oculoplastic surgeon can help determine the most suitable options for surgical intervention after age six months (when postnatal growth of the orbit can be assessed) and before the age that orbital dimensions are fixed (after which extensive orbital reconstruction may be required). ## References ## Literature Cited ## Chapter Notes 7 November 2019 (ma) Chapter retired: outdated 9 July 2015 (me) Comprehensive update posted live – title change 15 February 2007 (cd) Revision: testing for mutations in 26 May 2006 (me) Comprehensive update posted live 29 January 2004 (me) Overview posted live 7 March 2003 (as) Original submission • 7 November 2019 (ma) Chapter retired: outdated • 9 July 2015 (me) Comprehensive update posted live – title change • 15 February 2007 (cd) Revision: testing for mutations in • 26 May 2006 (me) Comprehensive update posted live • 29 January 2004 (me) Overview posted live • 7 March 2003 (as) Original submission ## Revision History 7 November 2019 (ma) Chapter retired: outdated 9 July 2015 (me) Comprehensive update posted live – title change 15 February 2007 (cd) Revision: testing for mutations in 26 May 2006 (me) Comprehensive update posted live 29 January 2004 (me) Overview posted live 7 March 2003 (as) Original submission • 7 November 2019 (ma) Chapter retired: outdated • 9 July 2015 (me) Comprehensive update posted live – title change • 15 February 2007 (cd) Revision: testing for mutations in • 26 May 2006 (me) Comprehensive update posted live • 29 January 2004 (me) Overview posted live • 7 March 2003 (as) Original submission	[ "E Araujo Júnior, TE Kawanami, LM Nardozza, HJ Milani, PS Oliveira, AF Moron. Prenatal diagnosis of bilateral anophthalmia by 3D \"reverse face\" view ultrasound and magnetic resonance imaging.. Taiwan J Obstet Gynecol. 2012;51:616-9", "N Chassaing, A Causse, A Vigouroux, A Delahaye, JL Alessandri, O Boespflug-Tanguy, O Boute-Benejean, H Dollfus, B Duban-Bedu, B Gilbert-Dussardier, F Giuliano, M Gonzales, M Holder-Espinasse, B Isidor, ML Jacquemont, D Lacombe, D Martin-Coignard, M Mathieu-Dramard, S Odent, O Picone, L Pinson, C Quelin, S Sigaudy, A Toutain, C Thauvin-Robinet, J Kaplan, P Calvas. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet 2014;86:326-34", "CP Chen, KG Wang, JK Huang, TY Chang, YH Lin, DT Chin, CY Tzen, W Wang. Prenatal diagnosis of otocephaly with microphthalmia/anophthalmia using ultrasound and magnetic resonance imaging.. Ultrasound Obstet Gynecol. 2003;22:214-5", "A Choi, R Lao, P Ling-Fung Tang, E Wan, W Mayer, T Bardakjian, GM Shaw, PY Kwok, A Schneider, A Slavotinek. Novel mutations in PXDN cause microphthalmia and anterior segment dysgenesis.. Eur J Hum Genet. 2015;23:337-41", "RA Gordon, PB Donzis. Refractive development of the human eye.. Arch Ophthalmol. 1985;103:785-9", "L Islam, D Kelberman, L Williamson, N Lewis, MB Glindzicz, KK Nischal, JC Sowden. Functional analysis of FOXE3 mutations causing dominant and recessive ocular anterior segment disease.. Hum Mutat. 2015;36:296-300", "NL Jimenez, J Flannick, M Yahyavi, J Li, T Bardakjian, L Tonkin, A Schneider, EH Sherr, AM Slavotinek. Targeted 'next-generation' sequencing in anophthalmia and microphthalmia patients confirms SOX2, OTX2 and FOXE3 mutations.. BMC Med Genet. 2011;12:172", "K Khan, A Rudkin, DA Parry, KP Burdon, M McKibbin, CV Logan, ZI Abdelhamed, JS Muecke, N Fernandez-Fuentes, KJ Laurie, M Shires, R Fogarty, IM Carr, JA Poulter, JE Morgan, MD Mohamed, H Jafri, Y Raashid, N Meng, H Piseth, C Toomes, RJ Casson, GR Taylor, M Hammerton, E Sheridan, CA Johnson, CF Inglehearn, JE Craig, M Ali. Homozygous mutations in PXDN cause congenital cataract, corneal opacity, and developmental glaucoma.. Am J Hum Genet. 2011;89:464-73", "A Lee, J Deutinger, G. Bernaschek. Three dimensional ultrasound: abnormalities of the fetal face in surface and volume rendering mode.. Br J Obstet Gynaecol. 1995;102:302-6", "R Mashiach, D Vardimon, B Kaplan, J Shalev, I Meizner. Early sonographic detection of recurrent fetal eye anomalies.. Ultrasound Obstet Gynecol. 2004;24:640-3", "S Minić, M Obradović, I Kovacević, D Trpinac. Ocular anomalies in incontinentia pigmenti: literature review and meta-analysis.. Srp Arh Celok Lek. 2010;138:408-13", "LM Reis, R Tyler, A Schneider, T Bardakjian, E Semina. Examination of SOX2 in variable ocular conditions identified a recurrent deletion in microphthalmia and lack of mutations in other phenotypes.. Mol Vis. 2010;16:768-73", "KF Schilter, A Schneider, T Bardakjian, JF Soucy, RC Tyler, LM Reis, EV Semina. OTX2 microphthalmia syndrome: four novel mutations and delineation of a phenotype.. Clin Genet 2011;79:158-68", "AM Slavotinek. Eye development genes and known syndromes.. Mol Genet Metab. 2011;104:448-56", "AS Verma, DR Fitzpatrick. Anophthalmia and microphthalmia.. Orphanet J Rare Dis. 2007;2:47", "AH Weiss, BG Kousseff, EA Ross, J Longbottom. Simple microphthalmos.. Arch Ophthalmol. 1989;107:1625-30", "KA Williamson, DR FitzPatrick. The genetic architecture of microphthalmia, anophthalmia and coloboma.. Eur J Med Genet. 2014;57:369-80", "HS Wong, S Parker, J Tait, KC Pringle. Antenatal diagnosis of anophthalmia by three-dimensional ultrasound: a novel application of the reverse face view.. Ultrasound Obstet Gynecol. 2008;32:103-5" ]	29/1/2004	9/7/2015	15/2/2007	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ao2	ao2	[ "Sulfate transporter", "SLC26A2", "SLC26A2-Related Atelosteogenesis" ]		Andrea Superti-Furga, Sheila Unger	Summary Clinical features of The diagnosis of	## Diagnosis Rhizomelic limb shortening with normal-sized skull Hitchhiker thumbs Small chest Protuberant abdomen Cleft palate Distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia) Other usual findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. Normal-sized skull with disproportionately short skeleton Platyspondyly, hypodysplastic vertebrae, and cervical kyphosis. Ossification of the upper thoracic vertebrae and coronal clefts of the lumbar and lower thoracic vertebrae may be incomplete. Hypoplastic ilia with flat acetabulum. The pubic bones are often unossified. Shortened long bones with metaphyseal flaring. The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic; the femur is distally rounded; the radius and tibia are typically bowed. Note: (1) A distally pointed, triangular humerus had led Characteristic hand findings of sulfate transporter-related dysplasia: Hitchhiker thumb with ulnar deviation of the fingers (characteristic of Gap between the first and second toe (characteristic of Hypoplasia of the first metacarpal bone (also present in Paucity of sulfated proteoglycans in cartilage matrix [ Abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity Some chondrocytes appear surrounded by lamellar material forming concentric rings that are in some cases indistinguishable from the collagen rings typical of The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous ossification shows no abnormalities. 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 clinical and radiographic findings described in When the phenotypic and radiographic findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by perinatal-lethal skeletal dysplasia, 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. • Rhizomelic limb shortening with normal-sized skull • Hitchhiker thumbs • Small chest • Protuberant abdomen • Cleft palate • Distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia) • Normal-sized skull with disproportionately short skeleton • Platyspondyly, hypodysplastic vertebrae, and cervical kyphosis. Ossification of the upper thoracic vertebrae and coronal clefts of the lumbar and lower thoracic vertebrae may be incomplete. • Hypoplastic ilia with flat acetabulum. The pubic bones are often unossified. • Shortened long bones with metaphyseal flaring. The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic; the femur is distally rounded; the radius and tibia are typically bowed. • Note: (1) A distally pointed, triangular humerus had led • Characteristic hand findings of sulfate transporter-related dysplasia: • Hitchhiker thumb with ulnar deviation of the fingers (characteristic of • Gap between the first and second toe (characteristic of • Hypoplasia of the first metacarpal bone (also present in • Hitchhiker thumb with ulnar deviation of the fingers (characteristic of • Gap between the first and second toe (characteristic of • Hypoplasia of the first metacarpal bone (also present in • Hitchhiker thumb with ulnar deviation of the fingers (characteristic of • Gap between the first and second toe (characteristic of • Hypoplasia of the first metacarpal bone (also present in • Paucity of sulfated proteoglycans in cartilage matrix [ • Abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity • Some chondrocytes appear surrounded by lamellar material forming concentric rings that are in some cases indistinguishable from the collagen rings typical of • The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. • These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous ossification shows no abnormalities. • For an introduction to multigene panels click ## Suggestive Findings Rhizomelic limb shortening with normal-sized skull Hitchhiker thumbs Small chest Protuberant abdomen Cleft palate Distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia) Other usual findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot. Normal-sized skull with disproportionately short skeleton Platyspondyly, hypodysplastic vertebrae, and cervical kyphosis. Ossification of the upper thoracic vertebrae and coronal clefts of the lumbar and lower thoracic vertebrae may be incomplete. Hypoplastic ilia with flat acetabulum. The pubic bones are often unossified. Shortened long bones with metaphyseal flaring. The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic; the femur is distally rounded; the radius and tibia are typically bowed. Note: (1) A distally pointed, triangular humerus had led Characteristic hand findings of sulfate transporter-related dysplasia: Hitchhiker thumb with ulnar deviation of the fingers (characteristic of Gap between the first and second toe (characteristic of Hypoplasia of the first metacarpal bone (also present in Paucity of sulfated proteoglycans in cartilage matrix [ Abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity Some chondrocytes appear surrounded by lamellar material forming concentric rings that are in some cases indistinguishable from the collagen rings typical of The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous ossification shows no abnormalities. • Rhizomelic limb shortening with normal-sized skull • Hitchhiker thumbs • Small chest • Protuberant abdomen • Cleft palate • Distinctive facial features (midface retrusion, depressed nasal bridge, epicanthus, micrognathia) • Normal-sized skull with disproportionately short skeleton • Platyspondyly, hypodysplastic vertebrae, and cervical kyphosis. Ossification of the upper thoracic vertebrae and coronal clefts of the lumbar and lower thoracic vertebrae may be incomplete. • Hypoplastic ilia with flat acetabulum. The pubic bones are often unossified. • Shortened long bones with metaphyseal flaring. The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic; the femur is distally rounded; the radius and tibia are typically bowed. • Note: (1) A distally pointed, triangular humerus had led • Characteristic hand findings of sulfate transporter-related dysplasia: • Hitchhiker thumb with ulnar deviation of the fingers (characteristic of • Gap between the first and second toe (characteristic of • Hypoplasia of the first metacarpal bone (also present in • Hitchhiker thumb with ulnar deviation of the fingers (characteristic of • Gap between the first and second toe (characteristic of • Hypoplasia of the first metacarpal bone (also present in • Hitchhiker thumb with ulnar deviation of the fingers (characteristic of • Gap between the first and second toe (characteristic of • Hypoplasia of the first metacarpal bone (also present in • Paucity of sulfated proteoglycans in cartilage matrix [ • Abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity • Some chondrocytes appear surrounded by lamellar material forming concentric rings that are in some cases indistinguishable from the collagen rings typical of • The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. • These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous ossification shows no abnormalities. ## 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 clinical and radiographic findings described in When the phenotypic and radiographic findings suggest the diagnosis of For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by perinatal-lethal skeletal dysplasia, 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. • For an introduction to multigene panels click ## Option 1 When the phenotypic and radiographic 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 perinatal-lethal skeletal dysplasia, 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 To date, only a handful of individuals with The diagnosis of Newborns with Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype [ Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with the more severe phenotype of The combination of a severe pathogenic variant (predicting stop codons or structural variants in transmembrane domains) with a pathogenic variant located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene results in the less severe phenotypes, i.e., The pathogenic variant The pathogenic variant Pathogenic variants p.Cys653Ser and c.-26+2T>C are the third-most common variants (8% of alleles for each). Together with p.Arg178Ter, The pathogenic variant p.Cys653Ser results in Another pathogenic variant specific to the Finnish population is Most other pathogenic variants are rare. The same pathogenic variants found in some individuals who have the The name "atelosteogenesis" was coined by No data on the prevalence of • Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with the more severe phenotype of • The combination of a severe pathogenic variant (predicting stop codons or structural variants in transmembrane domains) with a pathogenic variant located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene results in the less severe phenotypes, i.e., • Together with p.Arg178Ter, • The pathogenic variant p.Cys653Ser results in ## Clinical Description To date, only a handful of individuals with The diagnosis of Newborns with ## Genotype-Phenotype Correlations Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype [ Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with the more severe phenotype of The combination of a severe pathogenic variant (predicting stop codons or structural variants in transmembrane domains) with a pathogenic variant located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene results in the less severe phenotypes, i.e., The pathogenic variant The pathogenic variant Pathogenic variants p.Cys653Ser and c.-26+2T>C are the third-most common variants (8% of alleles for each). Together with p.Arg178Ter, The pathogenic variant p.Cys653Ser results in Another pathogenic variant specific to the Finnish population is Most other pathogenic variants are rare. The same pathogenic variants found in some individuals who have the • Homozygosity or compound heterozygosity for pathogenic variants predicting stop codons or structural variants in transmembrane domains of the sulfate transporter are associated with the more severe phenotype of • The combination of a severe pathogenic variant (predicting stop codons or structural variants in transmembrane domains) with a pathogenic variant located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene results in the less severe phenotypes, i.e., • Together with p.Arg178Ter, • The pathogenic variant p.Cys653Ser results in ## Nomenclature The name "atelosteogenesis" was coined by ## Prevalence No data on the prevalence of ## Genetically Related (Allelic) Disorders Three other phenotypes (all with an autosomal recessive mode of inheritance) – Characterized by severe hypoplasia/dysplasia of spine, rib cage, & extremities, w/relatively preserved cranium Among most severe skeletal disorders in humans; invariably lethal in perinatal period. The radiologic differentiation of Histopathology is similar in Histopathology is very similar in • Characterized by severe hypoplasia/dysplasia of spine, rib cage, & extremities, w/relatively preserved cranium • Among most severe skeletal disorders in humans; invariably lethal in perinatal period. • The radiologic differentiation of • Histopathology is similar in • Histopathology is very similar in ## Differential Diagnosis The differentiation of Genes of Interest in the Differential Diagnosis of Hitchhiker thumb & gap between toes are not present in Absence of fibula may suggest Humerus may be completely absent in Thoracic hypoplasia is more significant. There may be trident pelvis. Typical "telephone receiver" femur is visible on x-ray in TD. Cloverleaf skull is common in TD type II. AD = autosomal dominant; AO1 = atelosteogenesis type 1; AR = autosomal recessive; MOI = mode of inheritance See OMIM • Hitchhiker thumb & gap between toes are not present in • Absence of fibula may suggest • Humerus may be completely absent in • Thoracic hypoplasia is more significant. • There may be trident pelvis. • Typical "telephone receiver" femur is visible on x-ray in TD. • Cloverleaf skull is common in TD type II. ## Management There is no specific treatment available. Decisions regarding supportive therapy versus palliative treatment depend on the degree of respiratory compromise at birth. To establish the extent of disease in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse For long-term survivors, care should include surgical repair of cleft palate. Utility of surgery for club feet is unclear as this is quite complicated and the results limited. Physiotherapy is useful for retaining range of motion. See Search ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse ## Treatment of Manifestations For long-term survivors, care should include surgical repair of cleft palate. Utility of surgery for club feet is unclear as this is quite complicated and the results limited. Physiotherapy is useful for retaining range of motion. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. 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. If one parent is known to be heterozygous for an 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • 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. • If one parent is known to be heterozygous for an ## Mode of Inheritance ## Risk to Family Members The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • 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 have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and have normal stature. No evidence suggests that carriers are at increased risk of developing degenerative joint disease. ## Carrier Detection ## 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 If one parent is known to be heterozygous for an 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 one parent is known to be heterozygous for an ## Resources • • • • • • • • • ## Molecular Genetics Atelosteogenesis Type 2: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Atelosteogenesis Type 2 ( Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans, which are either not sulfated or insufficiently sulfated [ Loss of SLC26A2 sulfate transporter activity is associated with several skeletal disorders (see Notable Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( Variant designation that does not conform to current naming conventions See ## Molecular Pathogenesis Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans, which are either not sulfated or insufficiently sulfated [ Loss of SLC26A2 sulfate transporter activity is associated with several skeletal disorders (see Notable Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants. GeneReviews follows the standard naming conventions of the Human Genome Variation Society ( Variant designation that does not conform to current naming conventions See ## Chapter Notes Diana Ballhausen, MD; Lausanne University Hospital (2002-2020)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2020)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2020)Andrea Superti-Furga, MD (2002-present)Sheila Unger, MD, FRCPC (2020-present) 16 March 2023 (sw) Revision: chapter title updated to " 24 September 2020 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 1 October 2009 (me) Comprehensive update posted live 28 December 2006 (me) Comprehensive update posted live 21 July 2004 (me) Comprehensive update posted live 30 August 2002 (me) Review posted live 1 March 2002 (lb) Original submission • 16 March 2023 (sw) Revision: chapter title updated to " • 24 September 2020 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 1 October 2009 (me) Comprehensive update posted live • 28 December 2006 (me) Comprehensive update posted live • 21 July 2004 (me) Comprehensive update posted live • 30 August 2002 (me) Review posted live • 1 March 2002 (lb) Original submission ## Author History Diana Ballhausen, MD; Lausanne University Hospital (2002-2020)Luisa Bonafé, MD, PhD; Lausanne University Hospital (2002-2020)Lauréane Mittaz-Crettol, PhD; Lausanne University Hospital (2002-2020)Andrea Superti-Furga, MD (2002-present)Sheila Unger, MD, FRCPC (2020-present) ## Revision History 16 March 2023 (sw) Revision: chapter title updated to " 24 September 2020 (sw) Comprehensive update posted live 23 January 2014 (me) Comprehensive update posted live 1 October 2009 (me) Comprehensive update posted live 28 December 2006 (me) Comprehensive update posted live 21 July 2004 (me) Comprehensive update posted live 30 August 2002 (me) Review posted live 1 March 2002 (lb) Original submission • 16 March 2023 (sw) Revision: chapter title updated to " • 24 September 2020 (sw) Comprehensive update posted live • 23 January 2014 (me) Comprehensive update posted live • 1 October 2009 (me) Comprehensive update posted live • 28 December 2006 (me) Comprehensive update posted live • 21 July 2004 (me) Comprehensive update posted live • 30 August 2002 (me) Review posted live • 1 March 2002 (lb) Original submission ## References ## Literature Cited	[]	30/8/2002	24/9/2020	16/3/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aoa	aoa	[ "AOA1", "AOA1", "Aprataxin", "APTX", "Ataxia with Oculomotor Apraxia Type 1" ]	Ataxia with Oculomotor Apraxia Type 1 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY	Paula Coutinho, Clara Barbot, Paula Coutinho	Summary Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed. The diagnosis of AOA1 is based on clinical findings (including family history) and exclusion of the diagnosis of ataxia-telangiectasia. Cerebellar atrophy is visible on MRI in all affected individuals. EMG reveals axonal neuropathy in 100% of individuals with AOA1. AOA1 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 neither affected nor a carrier. Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible if both pathogenic variants in a family have been identified.	## Diagnosis Diagnosis of ataxia with oculomotor apraxia type 1 (AOA1) should be suspected in individuals with the following combination of clinical features and test results. • Cerebellar ataxia, oculomotor apraxia, and areflexia followed by signs of severe peripheral neuropathy • Childhood onset • Slow progression leading to severe motor handicap • Long survival [ • Absence of extraneurologic findings common in • Family history consistent with autosomal recessive inheritance • • • o o o o The diagnosis of AOA1 is established in a proband with the detection of biallelic pathogenic variants in For an introduction to multigene panels click Molecular Genetic Testing Used in AOA1 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 All Portuguese families with AOA1 share the same pathogenic variant ( 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. Deletion of the entire gene Scanning for pathogenic variants identified variants diagnostic for either AOA1 or AOA2 in only 20 of the 43 (46.5%) individuals with the ataxia with oculomotor apraxia phenotype. In other words, almost half of Portuguese families with AOA do not appear to have AOA1 or AOA2 using scanning for pathogenic variants; thus, pathogenic variants in other genes or pathogenic variants not detectable by this test method (e.g., exon or whole-gene deletions) may be causative [ ## Suggestive Findings Diagnosis of ataxia with oculomotor apraxia type 1 (AOA1) should be suspected in individuals with the following combination of clinical features and test results. • Cerebellar ataxia, oculomotor apraxia, and areflexia followed by signs of severe peripheral neuropathy • Childhood onset • Slow progression leading to severe motor handicap • Long survival [ • Absence of extraneurologic findings common in • Family history consistent with autosomal recessive inheritance • • • o o o o ## Establishing the Diagnosis The diagnosis of AOA1 is established in a proband with the detection of biallelic pathogenic variants in For an introduction to multigene panels click Molecular Genetic Testing Used in AOA1 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 All Portuguese families with AOA1 share the same pathogenic variant ( 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. Deletion of the entire gene Scanning for pathogenic variants identified variants diagnostic for either AOA1 or AOA2 in only 20 of the 43 (46.5%) individuals with the ataxia with oculomotor apraxia phenotype. In other words, almost half of Portuguese families with AOA do not appear to have AOA1 or AOA2 using scanning for pathogenic variants; thus, pathogenic variants in other genes or pathogenic variants not detectable by this test method (e.g., exon or whole-gene deletions) may be causative [ ## Clinical Characteristics Ataxia is the main cause of disability in ataxia with oculomotor apraxia type 1 in the first stages of the disease. Later, peripheral axonal motor neuropathy dominates the clinical picture. After initial normal motor development, all individuals develop cerebellar ataxia. The first manifestations of AOA1 are slowly progressive gait imbalance followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Blinking is exaggerated in most individuals. Ocular movements on command are usually slightly limited; the eyes stop before reaching extreme positions of gaze. These slow eye movements appear equally on lateral and vertical gaze. When the head is immobilized, movement of the eyes is impossible. Oculocephalic reflexes are spared until advanced stages of the disease. When standing and turning their heads, affected individuals lose their balance and tend to move the whole body to compensate. Ocular pursuit movements remain normal during the first years after the appearance of oculomotor apraxia. Later, oculomotor apraxia is followed by progressive external ophthalmoplegia (beginning with upward gaze). Hands and feet are short and atrophic. Vibration and postural sense are impaired only in older individuals with very long disease duration. Pain and light touch sensation are preserved. Cognitive impairment was reported in several families of different ethnic origins who had a range of variant types, including nonsense, frameshift, splice site, and missense [ • The • The presence of severe cognitive impairment in Two compound heterozygotes for the The pathogenic variant In two Italian adults, homozygous The pathogenic missense variant To the authors' knowledge, no correlation exists between a specific pathogenic variant and the affected individual's survival. In Japan, AOA1 is called early-onset ataxia with oculomotor apraxia and hypoalbuminemia [ Through a systematic population-based survey of hereditary ataxias being conducted in Portugal since 1993 [ In Japan, AOA1 appears to be the most frequent cause of autosomal recessive ataxia [ Affected individuals with pathogenic variants in ## Clinical Description Ataxia is the main cause of disability in ataxia with oculomotor apraxia type 1 in the first stages of the disease. Later, peripheral axonal motor neuropathy dominates the clinical picture. After initial normal motor development, all individuals develop cerebellar ataxia. The first manifestations of AOA1 are slowly progressive gait imbalance followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Blinking is exaggerated in most individuals. Ocular movements on command are usually slightly limited; the eyes stop before reaching extreme positions of gaze. These slow eye movements appear equally on lateral and vertical gaze. When the head is immobilized, movement of the eyes is impossible. Oculocephalic reflexes are spared until advanced stages of the disease. When standing and turning their heads, affected individuals lose their balance and tend to move the whole body to compensate. Ocular pursuit movements remain normal during the first years after the appearance of oculomotor apraxia. Later, oculomotor apraxia is followed by progressive external ophthalmoplegia (beginning with upward gaze). Hands and feet are short and atrophic. Vibration and postural sense are impaired only in older individuals with very long disease duration. Pain and light touch sensation are preserved. ## Genotype-Phenotype Correlations Cognitive impairment was reported in several families of different ethnic origins who had a range of variant types, including nonsense, frameshift, splice site, and missense [ • The • The presence of severe cognitive impairment in Two compound heterozygotes for the The pathogenic variant In two Italian adults, homozygous The pathogenic missense variant To the authors' knowledge, no correlation exists between a specific pathogenic variant and the affected individual's survival. ## Nomenclature In Japan, AOA1 is called early-onset ataxia with oculomotor apraxia and hypoalbuminemia [ ## Prevalence Through a systematic population-based survey of hereditary ataxias being conducted in Portugal since 1993 [ In Japan, AOA1 appears to be the most frequent cause of autosomal recessive ataxia [ Affected individuals with pathogenic variants in ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The diagnosis of AOA1 is ruled out whenever the clinical picture includes non-progressive ataxia, microcephaly, or seizures. The differential diagnosis varies by age group. AOA2 is associated with pathogenic variants of Comparison of AOA1, AOA2, AOA3 and AOA4 • When oculomotor apraxia is present, • • • • Peripheral neuropathy with areflexia and See also ## Management To establish the extent of disease and needs in an individual diagnosed with ataxia with oculomotor apraxia type 1 (AOA1), the following evaluations are recommended: • Examination of cognitive function • Examination of cranial nerve function • Extended neurologic examination of the limbs: initial inspection, tone, strength testing, reflexes, coordination, sensory testing • Ophthalmologic examination • Consultation with a clinical geneticist and/or genetic counselor Physical therapy may be helpful, particularly for disabilities resulting from peripheral neuropathy. A wheelchair is usually necessary for mobility by age 15-20 years. Educational support should be provided to compensate for difficulties in speaking (dysarthria), in reading (oculomotor apraxia), and in writing (upper-limb ataxia and weakness). High-protein diet to restore serum albumin concentration is indicated to prevent edema secondary to hypoalbuminemia. Low-cholesterol diet is advised. Routine visits to the neurologist are appropriate. See Search ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ataxia with oculomotor apraxia type 1 (AOA1), the following evaluations are recommended: • Examination of cognitive function • Examination of cranial nerve function • Extended neurologic examination of the limbs: initial inspection, tone, strength testing, reflexes, coordination, sensory testing • Ophthalmologic examination • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Physical therapy may be helpful, particularly for disabilities resulting from peripheral neuropathy. A wheelchair is usually necessary for mobility by age 15-20 years. Educational support should be provided to compensate for difficulties in speaking (dysarthria), in reading (oculomotor apraxia), and in writing (upper-limb ataxia and weakness). ## Prevention of Secondary Complications High-protein diet to restore serum albumin concentration is indicated to prevent edema secondary to hypoalbuminemia. Low-cholesterol diet is advised. ## Surveillance Routine visits to the neurologist are appropriate. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling AOA1 is inherited in an autosomal recessive manner. • Both parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of the sib being a carrier of an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. • 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 ## Mode of Inheritance AOA1 is inherited in an autosomal recessive manner. ## Risk to Family Members • Both parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Once an at-risk sib is known to be unaffected, the risk of the sib being a carrier of an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk family members is possible if the pathogenic variants in the family have been identified. ## 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. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources Rua 25 de Abril n.º 82 Castro Marim 8950-122 Portugal United Kingdom Sanford Research • • Rua 25 de Abril n.º 82 • Castro Marim 8950-122 • Portugal • • • United Kingdom • • • • • Sanford Research • ## Molecular Genetics Ataxia with Oculomotor Apraxia Type 1: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ataxia with Oculomotor Apraxia Type 1 ( Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Reference sequences are those of the long isoform: • The PANT domain (PNKP-AOA1 N-terminal domain), also known as putative forkhead-associated (FHA) domain [ • The HIT domain (middle domain), defined by the HIT motif, for nucleotide binding and hydrolysis. Members of the HIT super family (histidine triad) of nucleotide hydrolases/transferases [ o The Hint (histidine triad nucleotide binding)-related proteins, binding nucleotides and displaying adenosine 5'-monophosphoramidase activity [ o The Fhit (fragile histidine triad)-related proteins, cleaving diadenosine tetraphosphate (Ap • The C-terminal domain, containing a divergent zinc-finger motif [ The presence of these three domains has suggested that aprataxin is a nuclear protein with a role in DNA repair, reminiscent of the function of the protein defective in Several in vitro and in vivo studies have shown that aprataxin (long isoform) interacts with Even when in vitro and in vivo studies show that aprataxin interacts with XRCC4, AOA1 cell lines exhibit neither radio-resistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of ataxia-telangiectasia [ ## Molecular Pathogenesis Selected Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Reference sequences are those of the long isoform: • The PANT domain (PNKP-AOA1 N-terminal domain), also known as putative forkhead-associated (FHA) domain [ • The HIT domain (middle domain), defined by the HIT motif, for nucleotide binding and hydrolysis. Members of the HIT super family (histidine triad) of nucleotide hydrolases/transferases [ o The Hint (histidine triad nucleotide binding)-related proteins, binding nucleotides and displaying adenosine 5'-monophosphoramidase activity [ o The Fhit (fragile histidine triad)-related proteins, cleaving diadenosine tetraphosphate (Ap • The C-terminal domain, containing a divergent zinc-finger motif [ The presence of these three domains has suggested that aprataxin is a nuclear protein with a role in DNA repair, reminiscent of the function of the protein defective in Several in vitro and in vivo studies have shown that aprataxin (long isoform) interacts with Even when in vitro and in vivo studies show that aprataxin interacts with XRCC4, AOA1 cell lines exhibit neither radio-resistant DNA synthesis nor a reduced ability to phosphorylate downstream targets of ATM following DNA damage, suggesting that AOA1 lacks the cell cycle checkpoint defects that are characteristic of ataxia-telangiectasia [ ## Chapter Notes The authors wish to express their gratitude to all patients and families for their collaboration and support, as well as to all the physicians involved in the clinical study of the families. Genetic studies were supported by funds from the Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science) and the Portuguese Ministry of Health (projects STRDA/C/SAU/277/92, PECS/C/SAU/219/95, POCI/SAU-ESP/59114/04). Paula Coutinho, MD, PhD (2002-present)Clara Barbot MD, PhD (2002-present)Maria-Céu Moreira da Silva, MS, PhD; CNRS/INSERM/Université Louis-Pasteur (2002-2010)Michel Koenig, MD, PhD; CNRS/INSERM/Université Louis-Pasteur (2002-2010) • 2 May 2024 (ma) Chapter retired: outdated • 19 March 2015 (me) Comprehensive update posted live • 22 June 2010 (me) Comprehensive update posted live • 5 June 2006 (me) Comprehensive update posted live • 25 May 2004 (me) Comprehensive update posted live • 28 January 2004 (pc) Revision: change in test availability • 11 June 2002 (me) Review posted live • 8 November 2001 (pc) Original submission ## Acknowledgments The authors wish to express their gratitude to all patients and families for their collaboration and support, as well as to all the physicians involved in the clinical study of the families. Genetic studies were supported by funds from the Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science) and the Portuguese Ministry of Health (projects STRDA/C/SAU/277/92, PECS/C/SAU/219/95, POCI/SAU-ESP/59114/04). ## Author History Paula Coutinho, MD, PhD (2002-present)Clara Barbot MD, PhD (2002-present)Maria-Céu Moreira da Silva, MS, PhD; CNRS/INSERM/Université Louis-Pasteur (2002-2010)Michel Koenig, MD, PhD; CNRS/INSERM/Université Louis-Pasteur (2002-2010) ## Revision History • 2 May 2024 (ma) Chapter retired: outdated • 19 March 2015 (me) Comprehensive update posted live • 22 June 2010 (me) Comprehensive update posted live • 5 June 2006 (me) Comprehensive update posted live • 25 May 2004 (me) Comprehensive update posted live • 28 January 2004 (pc) Revision: change in test availability • 11 June 2002 (me) Review posted live • 8 November 2001 (pc) Original submission ## References ## Literature Cited	[]	11/6/2002	19/3/2015	28/1/2004	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aoa2	aoa2	[ "AOA2", "AOA2", "Probable helicase senataxin", "SETX", "Ataxia with Oculomotor Apraxia Type 2" ]	Ataxia with Oculomotor Apraxia Type 2	Maria-Ceu Moreira, Michel Koenig	Summary Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset of ataxia between age three and 30 years after initial normal development, axonal sensorimotor neuropathy, oculomotor apraxia, cerebellar atrophy, and elevated serum concentration of alpha-fetoprotein (AFP). The diagnosis of AOA2 is based on clinical, laboratory, and radiographic features; family history; and exclusion of the diagnosis of ataxia-telangiectasia, AOA1, and AOA4. Identification of biallelic pathogenic variants in AOA2 is inherited in an autosomal recessive manner. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants in the family have been identified.	## Diagnosis Ataxia with oculomotor apraxia type 2 (AOA2) Cerebellar ataxia Absent or diminished tendon reflexes and later a peripheral axonal sensorimotor neuropathy (>90% of individuals) Oculomotor apraxia (~51% of individuals) Pyramidal signs (Plantar response is either flexor or neutral.) Dystonic posture of the hands, choreic movements, head or postural tremor Onset between age three and 30 years Slow progression Absence of cardiac involvement, cancer predisposition, and immunodeficiency; rare or absent telangiectasia Absence of severe intellectual disability / cognitive regression Family history consistent with autosomal recessive inheritance Note: Normal serum AFP concentration is highly variable, varies over time, and in individuals with AOA2 is lower than that usually observed in individuals with Increased serum creatine kinase (CK) concentration in some affected individuals The diagnosis of AOA2 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 AOA2 is broad, individuals with the distinctive features described in When the phenotypic and laboratory findings suggest the diagnosis of AOA2 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 ataxia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ataxia with Oculomotor Apraxia Type 2 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. Detailed in • Cerebellar ataxia • Absent or diminished tendon reflexes and later a peripheral axonal sensorimotor neuropathy (>90% of individuals) • Oculomotor apraxia (~51% of individuals) • Pyramidal signs (Plantar response is either flexor or neutral.) • Dystonic posture of the hands, choreic movements, head or postural tremor • Onset between age three and 30 years • Slow progression • Absence of cardiac involvement, cancer predisposition, and immunodeficiency; rare or absent telangiectasia • Absence of severe intellectual disability / cognitive regression • Family history consistent with autosomal recessive inheritance • Note: Normal serum AFP concentration is highly variable, varies over time, and in individuals with AOA2 is lower than that usually observed in individuals with • Increased serum creatine kinase (CK) concentration in some affected individuals • For an introduction to multigene panels click ## Suggestive Findings Ataxia with oculomotor apraxia type 2 (AOA2) Cerebellar ataxia Absent or diminished tendon reflexes and later a peripheral axonal sensorimotor neuropathy (>90% of individuals) Oculomotor apraxia (~51% of individuals) Pyramidal signs (Plantar response is either flexor or neutral.) Dystonic posture of the hands, choreic movements, head or postural tremor Onset between age three and 30 years Slow progression Absence of cardiac involvement, cancer predisposition, and immunodeficiency; rare or absent telangiectasia Absence of severe intellectual disability / cognitive regression Family history consistent with autosomal recessive inheritance Note: Normal serum AFP concentration is highly variable, varies over time, and in individuals with AOA2 is lower than that usually observed in individuals with Increased serum creatine kinase (CK) concentration in some affected individuals • Cerebellar ataxia • Absent or diminished tendon reflexes and later a peripheral axonal sensorimotor neuropathy (>90% of individuals) • Oculomotor apraxia (~51% of individuals) • Pyramidal signs (Plantar response is either flexor or neutral.) • Dystonic posture of the hands, choreic movements, head or postural tremor • Onset between age three and 30 years • Slow progression • Absence of cardiac involvement, cancer predisposition, and immunodeficiency; rare or absent telangiectasia • Absence of severe intellectual disability / cognitive regression • Family history consistent with autosomal recessive inheritance • Note: Normal serum AFP concentration is highly variable, varies over time, and in individuals with AOA2 is lower than that usually observed in individuals with • Increased serum creatine kinase (CK) concentration in some affected individuals ## Establishing the Diagnosis The diagnosis of AOA2 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 AOA2 is broad, individuals with the distinctive features described in When the phenotypic and laboratory findings suggest the diagnosis of AOA2 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 ataxia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ataxia with Oculomotor Apraxia Type 2 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. Detailed in • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of AOA2 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 ataxia, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ataxia with Oculomotor Apraxia Type 2 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. Detailed in ## Clinical Characteristics Ataxia is the first sign of ataxia with oculomotor apraxia type 2 (AOA2) and is the major cause of disability early in the disease course. Later, peripheral sensorimotor neuropathy, particularly of the lower limbs, plays a significant role in disease progression. Saccadic pursuit, gaze-evoked nystagmus, poor horizontal optokinetic nystagmus, and square-wave jerks have also been observed in several individuals [ In an Algerian study, 37% of affected individuals presented with convergent strabismus [ Rarely, involuntary movements have been reported as a prominent presenting sign of AOA2, although they are accompanied by ataxia in almost all individuals. Two individuals had upper limb dystonia as an initial sign. Two sibs presented with prominent chorea of the trunk and face. One individual had isolated head tremor as the initial sign at age nine years [ Pyramidal signs were found in 20.5% of individuals with AOA2 [ Postmortem brain examination in an Italian individual age 79 years who died of heart failure revealed reduction in the overall size of the brain, including atrophy of the cerebellar folia and marked widening of the sulci [ A study of 90 individuals with AOA2 found that pathogenic missense variants in the helicase domain caused less severe AOA2 phenotypes than missense variants outside of this domain, or deletions, or truncating variants of AOA2 was first known as "ataxia with later onset and high level of alpha-fetoprotein." The prevalence of A study of 102 individuals with suspected autosomal recessive cerebellar ataxia from Eastern Europe (95 from Alsace, in eastern France) reported seven individuals with AOA2 (6.9%). AOA2 prevalence in Alsace was inferred to be slightly less than 1:400,000 [ ## Clinical Description Ataxia is the first sign of ataxia with oculomotor apraxia type 2 (AOA2) and is the major cause of disability early in the disease course. Later, peripheral sensorimotor neuropathy, particularly of the lower limbs, plays a significant role in disease progression. Saccadic pursuit, gaze-evoked nystagmus, poor horizontal optokinetic nystagmus, and square-wave jerks have also been observed in several individuals [ In an Algerian study, 37% of affected individuals presented with convergent strabismus [ Rarely, involuntary movements have been reported as a prominent presenting sign of AOA2, although they are accompanied by ataxia in almost all individuals. Two individuals had upper limb dystonia as an initial sign. Two sibs presented with prominent chorea of the trunk and face. One individual had isolated head tremor as the initial sign at age nine years [ Pyramidal signs were found in 20.5% of individuals with AOA2 [ Postmortem brain examination in an Italian individual age 79 years who died of heart failure revealed reduction in the overall size of the brain, including atrophy of the cerebellar folia and marked widening of the sulci [ ## Genotype-Phenotype Correlations A study of 90 individuals with AOA2 found that pathogenic missense variants in the helicase domain caused less severe AOA2 phenotypes than missense variants outside of this domain, or deletions, or truncating variants of ## Nomenclature AOA2 was first known as "ataxia with later onset and high level of alpha-fetoprotein." ## Prevalence The prevalence of A study of 102 individuals with suspected autosomal recessive cerebellar ataxia from Eastern Europe (95 from Alsace, in eastern France) reported seven individuals with AOA2 (6.9%). AOA2 prevalence in Alsace was inferred to be slightly less than 1:400,000 [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Ataxia with oculomotor apraxia type 1 (AOA1; OMIM Ataxia with oculomotor apraxia type 4 (AOA4) (OMIM When oculomotor apraxia and/or high serum concentrations of alpha-fetoprotein are present, • Ataxia with oculomotor apraxia type 1 (AOA1; OMIM • Ataxia with oculomotor apraxia type 4 (AOA4) (OMIM • When oculomotor apraxia and/or high serum concentrations of alpha-fetoprotein are present, ## Management To establish the extent of disease and needs in an individual diagnosed with oculomotor apraxia type 2 (AOA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Neurologic examination including assessment of cranial nerve function, gait and limb ataxia, coordination, tone, strength, reflexes, and sensory perception Ophthalmologic examination Physical therapy and occupational therapy assessment of strength and balance Assessment of cognitive function Serum cholesterol Consultation with a clinical geneticist and/or genetic counselor Serum alpha-fetoprotein (AFP) concentration, if not evaluated previously Physical therapy may be helpful, particularly for disabilities resulting from peripheral neuropathy. A wheelchair is usually necessary for mobility by age 30 years. Educational support (e.g., use of a computer with speech recognition and special keyboard for typing) should be provided to compensate for difficulties in reading (caused by oculomotor apraxia) and in writing (caused by upper-limb ataxia). A low-cholesterol diet is advised to reduce the risk of adverse health effects of hypercholesterolemia Routine visits to the attending neurologist are indicated. Ophthalmologic surveillance is recommended. Cholesterol level should be monitored regularly. See Search • Neurologic examination including assessment of cranial nerve function, gait and limb ataxia, coordination, tone, strength, reflexes, and sensory perception • Ophthalmologic examination • Physical therapy and occupational therapy assessment of strength and balance • Assessment of cognitive function • Serum cholesterol • Consultation with a clinical geneticist and/or genetic counselor • Serum alpha-fetoprotein (AFP) concentration, if not evaluated previously ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with oculomotor apraxia type 2 (AOA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Neurologic examination including assessment of cranial nerve function, gait and limb ataxia, coordination, tone, strength, reflexes, and sensory perception Ophthalmologic examination Physical therapy and occupational therapy assessment of strength and balance Assessment of cognitive function Serum cholesterol Consultation with a clinical geneticist and/or genetic counselor Serum alpha-fetoprotein (AFP) concentration, if not evaluated previously • Neurologic examination including assessment of cranial nerve function, gait and limb ataxia, coordination, tone, strength, reflexes, and sensory perception • Ophthalmologic examination • Physical therapy and occupational therapy assessment of strength and balance • Assessment of cognitive function • Serum cholesterol • Consultation with a clinical geneticist and/or genetic counselor • Serum alpha-fetoprotein (AFP) concentration, if not evaluated previously ## Treatment of Manifestations Physical therapy may be helpful, particularly for disabilities resulting from peripheral neuropathy. A wheelchair is usually necessary for mobility by age 30 years. Educational support (e.g., use of a computer with speech recognition and special keyboard for typing) should be provided to compensate for difficulties in reading (caused by oculomotor apraxia) and in writing (caused by upper-limb ataxia). ## Prevention of Secondary Complications A low-cholesterol diet is advised to reduce the risk of adverse health effects of hypercholesterolemia ## Surveillance Routine visits to the attending neurologist are indicated. Ophthalmologic surveillance is recommended. Cholesterol level should be monitored regularly. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Ataxia with oculomotor apraxia type 2 (AOA2) 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Mode of Inheritance Ataxia with oculomotor apraxia type 2 (AOA2) 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 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 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 Sanford Research • • United Kingdom • • • • • Sanford Research • ## Molecular Genetics Ataxia with Oculomotor Apraxia Type 2: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ataxia with Oculomotor Apraxia Type 2 ( Variants listed in the table have been provided by the authors. Because investigating the roles of senataxin in human and model organisms is an active area of research, the authors direct the reader to both recent reviews [ ## Chapter Notes The authors wish to thank all patients and their families for their collaboration, as well as all the physicians involved in the clinical study of the families. Genetic studies were supported by funds from the Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science), the Portuguese Ministry of Health (projects STRDA/C/SAU/277/92 and PECS/C/SAU/219/95), the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpitaux Universitaires de Strasbourg (PHRC regional), and the GIS-Maladies Rares (SPATAX Research Network. Grant 4MR12FA004DS). MCM had a post-graduate fellowship SFRH/BPD/11502/2002 from Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science). 12 July 2018 (sw) Comprehensive update posted live 8 December 2011 (me) Comprehensive update posted live 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for 5 March 2007 (me) Comprehensive update posted live 31 May 2005 (mcm) Revision: Sequence analysis clinically available 15 November 2004 (me) Review posted live 23 June 2004 (mcm) Original submission • 12 July 2018 (sw) Comprehensive update posted live • 8 December 2011 (me) Comprehensive update posted live • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for • 5 March 2007 (me) Comprehensive update posted live • 31 May 2005 (mcm) Revision: Sequence analysis clinically available • 15 November 2004 (me) Review posted live • 23 June 2004 (mcm) Original submission ## Acknowledgments The authors wish to thank all patients and their families for their collaboration, as well as all the physicians involved in the clinical study of the families. Genetic studies were supported by funds from the Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science), the Portuguese Ministry of Health (projects STRDA/C/SAU/277/92 and PECS/C/SAU/219/95), the Institut National de la Santé et de la Recherche Médicale, the Centre National de la Recherche Scientifique, the Hôpitaux Universitaires de Strasbourg (PHRC regional), and the GIS-Maladies Rares (SPATAX Research Network. Grant 4MR12FA004DS). MCM had a post-graduate fellowship SFRH/BPD/11502/2002 from Fundação para a Ciência e a Tecnologia (Portuguese Ministry of Science). ## Revision History 12 July 2018 (sw) Comprehensive update posted live 8 December 2011 (me) Comprehensive update posted live 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for 5 March 2007 (me) Comprehensive update posted live 31 May 2005 (mcm) Revision: Sequence analysis clinically available 15 November 2004 (me) Review posted live 23 June 2004 (mcm) Original submission • 12 July 2018 (sw) Comprehensive update posted live • 8 December 2011 (me) Comprehensive update posted live • 24 March 2009 (cd) Revision: deletion/duplication analysis available clinically for • 5 March 2007 (me) Comprehensive update posted live • 31 May 2005 (mcm) Revision: Sequence analysis clinically available • 15 November 2004 (me) Review posted live • 23 June 2004 (mcm) Original submission ## References ## Literature Cited	[]	15/11/2004	12/7/2018	24/3/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ap4-def	ap4-def	[ "Adaptor Protein Complex 4 Deficiency (AP-4 Deficiency)", "AP-4-Associated HSP", "AP-4 Deficiency Syndrome", "Adaptor Protein Complex 4 Deficiency (AP-4 Deficiency)", "AP-4-Associated HSP", "AP-4 Deficiency Syndrome", "AP-4 Associated Hereditary Spastic Paraplegia", "AP-4 complex subunit beta-1", "AP-4 complex subunit epsilon-1", "AP-4 complex subunit mu-1", "AP-4 complex subunit sigma-1", "AP4B1", "AP4E1", "AP4M1", "AP4S1", "AP-4-Associated Hereditary Spastic Paraplegia" ]	AP-4-Associated Hereditary Spastic Paraplegia	Julian Alecu, Luca Schierbaum, Darius Ebrahimi-Fakhari	Summary AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged febrile seizures. As the disease progresses, older children have intellectual disability that is usually moderate to severe; most affected individuals communicate nonverbally. Neurobehavioral/psychiatric manifestations (e.g., impulsivity, hyperactivity, and inattention) are common. Hypotonia transitions to progressive lower-extremity weakness and spasticity, accompanied by pyramidal signs such as plantar extension, ankle clonus, and hyperreflexia. Although some children achieve independent ambulation, most eventually lose this ability and rely on mobility aids or wheelchairs. In adolescence or early adulthood, spasticity may affect the upper extremities in some individuals but is generally less severe and not significantly disabling. Complications in some individuals include contractures, foot deformities, and bladder and bowel dysfunction. Dysphagia may emerge in advanced stages of the disease. The diagnosis of AP-4-HSP is established in a proband with suggestive findings and biallelic pathogenic variants in AP-4-HSP is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No consensus clinical diagnostic criteria for AP-4-associated hereditary spastic paraplegia (AP-4-HSP) have been published. AP-4-HSP Progressive spastic paraparesis typically with onset between ages 4 and 6 years Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development Hypotonia in infancy (usually mild) Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) Seizures, including frequent febrile seizures Urinary and stool incontinence Foot deformities (most commonly clubfoot) Episodes of stereotypic laughter Short stature Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity Extrapyramidal manifestations, including dystonia and ataxia Thinning or absence of the anterior commissure Thinning of the corpus callosum (with prominent thinning of the posterior parts) Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration Global cerebral volume reduction Ears of the grizzly bear sign [for examples see Delayed myelination Bilateral peri-sylvian polymicrogyria Bilateral malrotation of the hippocampi Ears of the lynx sign [for examples see Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ The diagnosis of AP-4-HSP 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 Frameshift variants are the most common pathogenic variants in Overall, the majority of pathogenic variants in For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in AP-4-Associated Hereditary Spastic Paraplegia AP-4-HSP = AP-4-associated hereditary spastic paraplegia Genes are listed in alphabetic order. See Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP) ( 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. • • Progressive spastic paraparesis typically with onset between ages 4 and 6 years • Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development • Hypotonia in infancy (usually mild) • Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) • Seizures, including frequent febrile seizures • Urinary and stool incontinence • Progressive spastic paraparesis typically with onset between ages 4 and 6 years • Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development • Hypotonia in infancy (usually mild) • Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) • Seizures, including frequent febrile seizures • Urinary and stool incontinence • • Foot deformities (most commonly clubfoot) • Episodes of stereotypic laughter • Short stature • Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity • Extrapyramidal manifestations, including dystonia and ataxia • Foot deformities (most commonly clubfoot) • Episodes of stereotypic laughter • Short stature • Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity • Extrapyramidal manifestations, including dystonia and ataxia • Progressive spastic paraparesis typically with onset between ages 4 and 6 years • Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development • Hypotonia in infancy (usually mild) • Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) • Seizures, including frequent febrile seizures • Urinary and stool incontinence • Foot deformities (most commonly clubfoot) • Episodes of stereotypic laughter • Short stature • Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity • Extrapyramidal manifestations, including dystonia and ataxia • • Thinning or absence of the anterior commissure • Thinning of the corpus callosum (with prominent thinning of the posterior parts) • Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration • Global cerebral volume reduction • Ears of the grizzly bear sign [for examples see • Thinning or absence of the anterior commissure • Thinning of the corpus callosum (with prominent thinning of the posterior parts) • Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration • Global cerebral volume reduction • Ears of the grizzly bear sign [for examples see • • Delayed myelination • Bilateral peri-sylvian polymicrogyria • Bilateral malrotation of the hippocampi • Ears of the lynx sign [for examples see • Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ • Delayed myelination • Bilateral peri-sylvian polymicrogyria • Bilateral malrotation of the hippocampi • Ears of the lynx sign [for examples see • Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ • Thinning or absence of the anterior commissure • Thinning of the corpus callosum (with prominent thinning of the posterior parts) • Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration • Global cerebral volume reduction • Ears of the grizzly bear sign [for examples see • Delayed myelination • Bilateral peri-sylvian polymicrogyria • Bilateral malrotation of the hippocampi • Ears of the lynx sign [for examples see • Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ ## Suggestive Findings AP-4-HSP Progressive spastic paraparesis typically with onset between ages 4 and 6 years Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development Hypotonia in infancy (usually mild) Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) Seizures, including frequent febrile seizures Urinary and stool incontinence Foot deformities (most commonly clubfoot) Episodes of stereotypic laughter Short stature Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity Extrapyramidal manifestations, including dystonia and ataxia Thinning or absence of the anterior commissure Thinning of the corpus callosum (with prominent thinning of the posterior parts) Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration Global cerebral volume reduction Ears of the grizzly bear sign [for examples see Delayed myelination Bilateral peri-sylvian polymicrogyria Bilateral malrotation of the hippocampi Ears of the lynx sign [for examples see Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ • • Progressive spastic paraparesis typically with onset between ages 4 and 6 years • Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development • Hypotonia in infancy (usually mild) • Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) • Seizures, including frequent febrile seizures • Urinary and stool incontinence • Progressive spastic paraparesis typically with onset between ages 4 and 6 years • Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development • Hypotonia in infancy (usually mild) • Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) • Seizures, including frequent febrile seizures • Urinary and stool incontinence • • Foot deformities (most commonly clubfoot) • Episodes of stereotypic laughter • Short stature • Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity • Extrapyramidal manifestations, including dystonia and ataxia • Foot deformities (most commonly clubfoot) • Episodes of stereotypic laughter • Short stature • Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity • Extrapyramidal manifestations, including dystonia and ataxia • Progressive spastic paraparesis typically with onset between ages 4 and 6 years • Early-onset global developmental delay, including delayed motor milestones, failure to achieve or loss of independent ambulation, and impaired or absent speech development • Hypotonia in infancy (usually mild) • Postnatal microcephaly (usually 2-3 standard deviations below the mean for age and sex) • Seizures, including frequent febrile seizures • Urinary and stool incontinence • Foot deformities (most commonly clubfoot) • Episodes of stereotypic laughter • Short stature • Neurobehavioral/psychiatric manifestations, including short attention span, overactivity, and impulsivity • Extrapyramidal manifestations, including dystonia and ataxia • • Thinning or absence of the anterior commissure • Thinning of the corpus callosum (with prominent thinning of the posterior parts) • Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration • Global cerebral volume reduction • Ears of the grizzly bear sign [for examples see • Thinning or absence of the anterior commissure • Thinning of the corpus callosum (with prominent thinning of the posterior parts) • Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration • Global cerebral volume reduction • Ears of the grizzly bear sign [for examples see • • Delayed myelination • Bilateral peri-sylvian polymicrogyria • Bilateral malrotation of the hippocampi • Ears of the lynx sign [for examples see • Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ • Delayed myelination • Bilateral peri-sylvian polymicrogyria • Bilateral malrotation of the hippocampi • Ears of the lynx sign [for examples see • Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ • Thinning or absence of the anterior commissure • Thinning of the corpus callosum (with prominent thinning of the posterior parts) • Nonspecific volume reduction of the periventricular white matter, usually with enlargement of the lateral ventricles in colpocephaly configuration • Global cerebral volume reduction • Ears of the grizzly bear sign [for examples see • Delayed myelination • Bilateral peri-sylvian polymicrogyria • Bilateral malrotation of the hippocampi • Ears of the lynx sign [for examples see • Findings suggestive of iron deposition in the globus pallidus and substantia nigra have been identified in six individuals to date [ ## Establishing the Diagnosis The diagnosis of AP-4-HSP 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 Frameshift variants are the most common pathogenic variants in Overall, the majority of pathogenic variants in For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in AP-4-Associated Hereditary Spastic Paraplegia AP-4-HSP = AP-4-associated hereditary spastic paraplegia Genes are listed in alphabetic order. See Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP) ( 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. ## Option 1 For an introduction to multigene panels click ## Option 2 Frameshift variants are the most common pathogenic variants in Overall, the majority of pathogenic variants in For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in AP-4-Associated Hereditary Spastic Paraplegia AP-4-HSP = AP-4-associated hereditary spastic paraplegia Genes are listed in alphabetic order. See Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP) ( 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. ## Clinical Characteristics AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged febrile seizures. As the disease progresses, hypotonia transitions to progressive lower-extremity weakness and spasticity, accompanied by pyramidal signs such as plantar extension, ankle clonus, and hyperreflexia. Although some children achieve independent ambulation, most eventually lose this ability and rely on mobility aids or wheelchairs. In adolescence or early adulthood, spasticity may affect the upper extremities in some individuals but is generally less severe and not significantly disabling. Complications include contractures, foot deformities, and bladder and bowel dysfunction. Dysphagia may emerge in advanced stages of the disease. Dystonia is a prominent extrapyramidal manifestation in early childhood in some, and cerebellar features may become more apparent in later stages. Behavioral manifestations such as impulsivity, hyperactivity, and inattention are frequently observed. To date, uncomplicated hereditary spastic paraplegia, a pure spastic paraparesis without other neurologic manifestations, has not been reported in individuals with AP-4-HSP. This summary integrates findings from 156 individuals across 101 families [ Onset of progressive spastic paraparesis typically occurs between ages four and six years (85%, 256/301). In children younger than age four years, lower limb spasticity is present in 60% (47/78). In children age four years and older, lower limb spasticity is present in 96% (216/226). Pyramidal signs, such as hyperreflexia in the lower extremities, ankle clonus, and a positive Babinski sign, are often evident in early childhood. Spasticity initially manifests in the ankles, often accompanied by in-toeing, and progressively moves proximally, further impairing ambulation. Over time, most children with AP-4-HSP require mobility aids or transition to full-time wheelchair use. Sitting (median age: 12 months; Q1-Q3: 9-18 months) Crawling (median age: 18 months; Q1-Q3: 12.3-24 months) Standing unsupported (median age: 24 months; Q1-Q3: 18-36 months) Walking with support (median age: 25 months; Q1-Q3: 20-36 months) About 45% (110/243) of individuals achieve independent walking (median age: 30 months; Q1-Q3: 24-36 months), a skill that is often lost as the disease progresses. About 70% (94/134) of affected individuals, including individuals with and without epilepsy, have seizures in the setting of fever. In general, seizures become less frequent with age and are often well controlled with standard anti-seizure medications (ASMs). Children with developmental brain malformations, such as polymicrogyria, often require continued treatment with ASMs and may develop medically refractory epilepsy. Short attention span (33%, 100/301); Overactivity (12%, 35/301); Impulsivity (12%, 37/301). AP-4-HSP is caused by biallelic loss-of-function variants in one of the four genes that encode subunits of the adaptor protein complex 4 (AP-4): β4, ε, μ4, and σ4. Because loss of any one subunit renders the entire complex nonfunctional, biallelic loss-of-function variants in any one of the four genes cause the same molecular defect – loss of AP-4 function – and the same phenotype. No genotype-phenotype correlations have been reported for any of the four genes known to cause AP-4-HSP ( Other designations used to refer to AP-4-HSP are listed in AP-4-Associated Hereditary Spastic Paraplegia: Nomenclature Hereditary spastic paraplegia type 47 Spastic paraplegia type 47 (SPG47) Hereditary spastic paraplegia type 50 Spastic paraplegia type 50 (SPG50) Hereditary spastic paraplegia type 51 Spastic paraplegia type 51 (SPG51) Hereditary spastic paraplegia type 52 Spastic paraplegia type 52 (SPG52) Genetic loci for hereditary spastic paraplegia are designated "SPG" (for " Recommendations for the nomenclature of genetic movement disorders, including AP-4-HSP, have been published [ AP-4-HSP is rare. To date, more than 300 individuals with AP-4-HSP are known; 311 have been included in the Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP) ( Families with AP-4-HSP have been reported from North America, South America Europe, the Middle East, China, and the Indian subcontinent [D Ebrahimi-Fakhari, unpublished data]. About half of individuals with AP-4-HSP have consanguineous parents (46%, 142/311) [D Ebrahimi-Fakhari, unpublished data]. Previously reported consanguinity rates were higher likely due to ascertainment bias, as initial reports were focused on families from countries with high rates of consanguinity [ • Onset of progressive spastic paraparesis typically occurs between ages four and six years (85%, 256/301). • In children younger than age four years, lower limb spasticity is present in 60% (47/78). • In children age four years and older, lower limb spasticity is present in 96% (216/226). • Sitting (median age: 12 months; Q1-Q3: 9-18 months) • Crawling (median age: 18 months; Q1-Q3: 12.3-24 months) • Standing unsupported (median age: 24 months; Q1-Q3: 18-36 months) • Walking with support (median age: 25 months; Q1-Q3: 20-36 months) • Short attention span (33%, 100/301); • Overactivity (12%, 35/301); • Impulsivity (12%, 37/301). • Short attention span (33%, 100/301); • Overactivity (12%, 35/301); • Impulsivity (12%, 37/301). • Short attention span (33%, 100/301); • Overactivity (12%, 35/301); • Impulsivity (12%, 37/301). • Hereditary spastic paraplegia type 47 • Spastic paraplegia type 47 (SPG47) • Hereditary spastic paraplegia type 50 • Spastic paraplegia type 50 (SPG50) • Hereditary spastic paraplegia type 51 • Spastic paraplegia type 51 (SPG51) • Hereditary spastic paraplegia type 52 • Spastic paraplegia type 52 (SPG52) ## Clinical Description AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is a childhood-onset and complex form of hereditary spastic paraplegia. Spastic paraparesis is a universal feature in affected individuals. Manifestations typically begin before age one year, with infants presenting with hypotonia, mild postnatal microcephaly, and delayed developmental milestones. Seizures are common in early childhood, often starting as prolonged febrile seizures. As the disease progresses, hypotonia transitions to progressive lower-extremity weakness and spasticity, accompanied by pyramidal signs such as plantar extension, ankle clonus, and hyperreflexia. Although some children achieve independent ambulation, most eventually lose this ability and rely on mobility aids or wheelchairs. In adolescence or early adulthood, spasticity may affect the upper extremities in some individuals but is generally less severe and not significantly disabling. Complications include contractures, foot deformities, and bladder and bowel dysfunction. Dysphagia may emerge in advanced stages of the disease. Dystonia is a prominent extrapyramidal manifestation in early childhood in some, and cerebellar features may become more apparent in later stages. Behavioral manifestations such as impulsivity, hyperactivity, and inattention are frequently observed. To date, uncomplicated hereditary spastic paraplegia, a pure spastic paraparesis without other neurologic manifestations, has not been reported in individuals with AP-4-HSP. This summary integrates findings from 156 individuals across 101 families [ Onset of progressive spastic paraparesis typically occurs between ages four and six years (85%, 256/301). In children younger than age four years, lower limb spasticity is present in 60% (47/78). In children age four years and older, lower limb spasticity is present in 96% (216/226). Pyramidal signs, such as hyperreflexia in the lower extremities, ankle clonus, and a positive Babinski sign, are often evident in early childhood. Spasticity initially manifests in the ankles, often accompanied by in-toeing, and progressively moves proximally, further impairing ambulation. Over time, most children with AP-4-HSP require mobility aids or transition to full-time wheelchair use. Sitting (median age: 12 months; Q1-Q3: 9-18 months) Crawling (median age: 18 months; Q1-Q3: 12.3-24 months) Standing unsupported (median age: 24 months; Q1-Q3: 18-36 months) Walking with support (median age: 25 months; Q1-Q3: 20-36 months) About 45% (110/243) of individuals achieve independent walking (median age: 30 months; Q1-Q3: 24-36 months), a skill that is often lost as the disease progresses. About 70% (94/134) of affected individuals, including individuals with and without epilepsy, have seizures in the setting of fever. In general, seizures become less frequent with age and are often well controlled with standard anti-seizure medications (ASMs). Children with developmental brain malformations, such as polymicrogyria, often require continued treatment with ASMs and may develop medically refractory epilepsy. Short attention span (33%, 100/301); Overactivity (12%, 35/301); Impulsivity (12%, 37/301). • Onset of progressive spastic paraparesis typically occurs between ages four and six years (85%, 256/301). • In children younger than age four years, lower limb spasticity is present in 60% (47/78). • In children age four years and older, lower limb spasticity is present in 96% (216/226). • Sitting (median age: 12 months; Q1-Q3: 9-18 months) • Crawling (median age: 18 months; Q1-Q3: 12.3-24 months) • Standing unsupported (median age: 24 months; Q1-Q3: 18-36 months) • Walking with support (median age: 25 months; Q1-Q3: 20-36 months) • Short attention span (33%, 100/301); • Overactivity (12%, 35/301); • Impulsivity (12%, 37/301). • Short attention span (33%, 100/301); • Overactivity (12%, 35/301); • Impulsivity (12%, 37/301). • Short attention span (33%, 100/301); • Overactivity (12%, 35/301); • Impulsivity (12%, 37/301). ## Phenotype Correlations by Gene AP-4-HSP is caused by biallelic loss-of-function variants in one of the four genes that encode subunits of the adaptor protein complex 4 (AP-4): β4, ε, μ4, and σ4. Because loss of any one subunit renders the entire complex nonfunctional, biallelic loss-of-function variants in any one of the four genes cause the same molecular defect – loss of AP-4 function – and the same phenotype. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been reported for any of the four genes known to cause AP-4-HSP ( ## Nomenclature Other designations used to refer to AP-4-HSP are listed in AP-4-Associated Hereditary Spastic Paraplegia: Nomenclature Hereditary spastic paraplegia type 47 Spastic paraplegia type 47 (SPG47) Hereditary spastic paraplegia type 50 Spastic paraplegia type 50 (SPG50) Hereditary spastic paraplegia type 51 Spastic paraplegia type 51 (SPG51) Hereditary spastic paraplegia type 52 Spastic paraplegia type 52 (SPG52) Genetic loci for hereditary spastic paraplegia are designated "SPG" (for " Recommendations for the nomenclature of genetic movement disorders, including AP-4-HSP, have been published [ • Hereditary spastic paraplegia type 47 • Spastic paraplegia type 47 (SPG47) • Hereditary spastic paraplegia type 50 • Spastic paraplegia type 50 (SPG50) • Hereditary spastic paraplegia type 51 • Spastic paraplegia type 51 (SPG51) • Hereditary spastic paraplegia type 52 • Spastic paraplegia type 52 (SPG52) ## Prevalence AP-4-HSP is rare. To date, more than 300 individuals with AP-4-HSP are known; 311 have been included in the Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia (HSP) ( Families with AP-4-HSP have been reported from North America, South America Europe, the Middle East, China, and the Indian subcontinent [D Ebrahimi-Fakhari, unpublished data]. About half of individuals with AP-4-HSP have consanguineous parents (46%, 142/311) [D Ebrahimi-Fakhari, unpublished data]. Previously reported consanguinity rates were higher likely due to ascertainment bias, as initial reports were focused on families from countries with high rates of consanguinity [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Heterozygous variants in ## Differential Diagnosis Many of the initial manifestations of AP-4-associated hereditary spastic paraplegia (AP-4-HSP) are nonspecific and may resemble other disorders characterized by spasticity, developmental delay / intellectual disability, and a thin corpus callosum. Children with AP-4-HSP are often diagnosed with cerebral palsy before genetic testing is obtained. Genetic Disorders in the Differential Diagnosis of AP-4-Associated Hereditary Spastic Paraplegia Central visual impairment Cerebellar hypoplasia/atrophy Optic atrophy Motor sensory neuropathy Later onset Brain iron accumulation is more common in SPG35. Congenital cataracts Hearing loss Neuropathy Later onset Distal amyotrophy Pigmentary retinopathy Ataxia Parkinsonism Ears of the lynx sign on MRI is more common in SPG11 Onset in young adulthood Cerebellar signs Autonomic sensory neuropathy Apneas / chronic respiratory disease Dysmorphism Later onset Pigmentary retinopathy Neuropathy Parkinsonism AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; SPG = spastic paraplegia; XL = X-linked Genetic loci for hereditary spastic paraplegia are designated "SPG" (for " • Central visual impairment • Cerebellar hypoplasia/atrophy • Optic atrophy • Motor sensory neuropathy • Later onset • Brain iron accumulation is more common in SPG35. • Congenital cataracts • Hearing loss • Neuropathy • Later onset • Distal amyotrophy • Pigmentary retinopathy • Ataxia • Parkinsonism • Ears of the lynx sign on MRI is more common in SPG11 • Onset in young adulthood • Cerebellar signs • Autonomic sensory neuropathy • Apneas / chronic respiratory disease • Dysmorphism • Later onset • Pigmentary retinopathy • Neuropathy • Parkinsonism ## Management No clinical practice guidelines for AP-4-associated hereditary spastic paraplegia (AP-4-HSP) 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 AP-4-HSP, the evaluations summarized in AP-4-Associated Hereditary Spastic Paraplegia: Recommended Evaluations Following Initial Diagnosis Muscle tone (hypotonia, spasticity, pyramidal signs) Possible seizures To incl motor, adaptive, & cognitive 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. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; AP-4-HSP = AP-4-associated hereditary spastic paraplegia; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) At present, no treatment prevents, halts, or reverses the progression of the neurologic manifestations of AP-4-HSP. 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 AP-4-Associated Hereditary Spastic Paraplegia: Treatment of Manifestations PT Antispastic medications Botulinum toxin injections Intrathecal baclofen pump Surgical treatment Progression of contractures, scoliosis, & foot deformities may be delayed w/regular PT & antispastic medications. Consider need for durable medical equipment &/or positioning devices (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Nutritional supplementation Gastrostomy tube placement Referral to nutritionist Gastrostomy feeding ↓ aspiration risk, provides reliable route for medication, & can improve nutritional status. Minimize aspiration risk. Pulmonary toilet Aspiration, pulmonary infections, restrictive lung disease can be secondary to scoliosis & spasticity. Referral to pulmonologist Anticholinergic drugs Botulinum toxin injections Surgery Mgmt of secretions Gastrostomy tube feeding Stool softeners, prokinetics, osmotic agents, or laxatives as needed Proton pump inhibitors, histamine receptor antagonists, or antacids as needed Consideration of fundoplication in refractory cases PT &/or referral to orthopedic surgeon for contractures & scoliosis PT, ankle-foot orthoses, &/or referral to orthopedic surgeon for foot deformities Ensure appropriate social work involvement to connect families w/local resources & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; 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. 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. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Affected individuals should be evaluated periodically (i.e., every 6-12 months) by their multidisciplinary care team that includes a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and speech-language pathologist to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations. AP-4-Associated Hereditary Spastic Paraplegia: Recommended Surveillance Evaluate for aspiration risk & nutritional status. Monitor for constipation & bowel dysfunction. PT/OT eval; assess for contractures, scoliosis, & foot deformities. Hip/spine radiographs Monitor & treat spasticity. Monitor those w/seizures as clinically indicated. OT = occupational therapy; PT = physical therapy See Several disease-modifying therapies for AP-4-HSP are currently under development, including AAV9-based gene replacement therapies and small molecule screens. For A similar strategy for Furthermore, a cell-based phenotypic high-throughput screen has identified small molecules capable of restoring protein trafficking in AP-4-deficient cells, including neurons derived from patient-derived induced pluripotent stem cells [ See Search • Muscle tone (hypotonia, spasticity, pyramidal signs) • Possible seizures • To incl motor, adaptive, & cognitive • 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. • Community or • Social work involvement for parental support • Home nursing referral • PT • Antispastic medications • Botulinum toxin injections • Intrathecal baclofen pump • Surgical treatment • Progression of contractures, scoliosis, & foot deformities may be delayed w/regular PT & antispastic medications. • Consider need for durable medical equipment &/or positioning devices (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Nutritional supplementation • Gastrostomy tube placement • Referral to nutritionist • Gastrostomy feeding ↓ aspiration risk, provides reliable route for medication, & can improve nutritional status. • Minimize aspiration risk. • Pulmonary toilet • Aspiration, pulmonary infections, restrictive lung disease can be secondary to scoliosis & spasticity. • Referral to pulmonologist • Anticholinergic drugs • Botulinum toxin injections • Surgery • Mgmt of secretions • Gastrostomy tube feeding • Stool softeners, prokinetics, osmotic agents, or laxatives as needed • Proton pump inhibitors, histamine receptor antagonists, or antacids as needed • Consideration of fundoplication in refractory cases • PT &/or referral to orthopedic surgeon for contractures & scoliosis • PT, ankle-foot orthoses, &/or referral to orthopedic surgeon for foot deformities • Ensure appropriate social work involvement to connect families w/local resources & 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. • Evaluate for aspiration risk & nutritional status. • Monitor for constipation & bowel dysfunction. • PT/OT eval; assess for contractures, scoliosis, & foot deformities. • Hip/spine radiographs • Monitor & treat spasticity. • Monitor those w/seizures as clinically indicated. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with AP-4-HSP, the evaluations summarized in AP-4-Associated Hereditary Spastic Paraplegia: Recommended Evaluations Following Initial Diagnosis Muscle tone (hypotonia, spasticity, pyramidal signs) Possible seizures To incl motor, adaptive, & cognitive 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. Community or Social work involvement for parental support Home nursing referral ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; AP-4-HSP = AP-4-associated hereditary spastic paraplegia; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Muscle tone (hypotonia, spasticity, pyramidal signs) • Possible seizures • To incl motor, adaptive, & cognitive • 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. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations At present, no treatment prevents, halts, or reverses the progression of the neurologic manifestations of AP-4-HSP. 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 AP-4-Associated Hereditary Spastic Paraplegia: Treatment of Manifestations PT Antispastic medications Botulinum toxin injections Intrathecal baclofen pump Surgical treatment Progression of contractures, scoliosis, & foot deformities may be delayed w/regular PT & antispastic medications. Consider need for durable medical equipment &/or positioning devices (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Nutritional supplementation Gastrostomy tube placement Referral to nutritionist Gastrostomy feeding ↓ aspiration risk, provides reliable route for medication, & can improve nutritional status. Minimize aspiration risk. Pulmonary toilet Aspiration, pulmonary infections, restrictive lung disease can be secondary to scoliosis & spasticity. Referral to pulmonologist Anticholinergic drugs Botulinum toxin injections Surgery Mgmt of secretions Gastrostomy tube feeding Stool softeners, prokinetics, osmotic agents, or laxatives as needed Proton pump inhibitors, histamine receptor antagonists, or antacids as needed Consideration of fundoplication in refractory cases PT &/or referral to orthopedic surgeon for contractures & scoliosis PT, ankle-foot orthoses, &/or referral to orthopedic surgeon for foot deformities Ensure appropriate social work involvement to connect families w/local resources & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ASM = anti-seizure medication; GERD = gastroesophageal reflux disease; 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. 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. • PT • Antispastic medications • Botulinum toxin injections • Intrathecal baclofen pump • Surgical treatment • Progression of contractures, scoliosis, & foot deformities may be delayed w/regular PT & antispastic medications. • Consider need for durable medical equipment &/or positioning devices (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Nutritional supplementation • Gastrostomy tube placement • Referral to nutritionist • Gastrostomy feeding ↓ aspiration risk, provides reliable route for medication, & can improve nutritional status. • Minimize aspiration risk. • Pulmonary toilet • Aspiration, pulmonary infections, restrictive lung disease can be secondary to scoliosis & spasticity. • Referral to pulmonologist • Anticholinergic drugs • Botulinum toxin injections • Surgery • Mgmt of secretions • Gastrostomy tube feeding • Stool softeners, prokinetics, osmotic agents, or laxatives as needed • Proton pump inhibitors, histamine receptor antagonists, or antacids as needed • Consideration of fundoplication in refractory cases • PT &/or referral to orthopedic surgeon for contractures & scoliosis • PT, ankle-foot orthoses, &/or referral to orthopedic surgeon for foot deformities • Ensure appropriate social work involvement to connect families w/local resources & 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. ## 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 To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Affected individuals should be evaluated periodically (i.e., every 6-12 months) by their multidisciplinary care team that includes a neurologist, clinical geneticist, developmental specialist, orthopedic surgeon/physiatrist, physical therapist, occupational therapist, and speech-language pathologist to assess disease progression, maximize ambulation and communication skills, and reduce other manifestations. AP-4-Associated Hereditary Spastic Paraplegia: Recommended Surveillance Evaluate for aspiration risk & nutritional status. Monitor for constipation & bowel dysfunction. PT/OT eval; assess for contractures, scoliosis, & foot deformities. Hip/spine radiographs Monitor & treat spasticity. Monitor those w/seizures as clinically indicated. OT = occupational therapy; PT = physical therapy • Evaluate for aspiration risk & nutritional status. • Monitor for constipation & bowel dysfunction. • PT/OT eval; assess for contractures, scoliosis, & foot deformities. • Hip/spine radiographs • Monitor & treat spasticity. • Monitor those w/seizures as clinically indicated. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Several disease-modifying therapies for AP-4-HSP are currently under development, including AAV9-based gene replacement therapies and small molecule screens. For A similar strategy for Furthermore, a cell-based phenotypic high-throughput screen has identified small molecules capable of restoring protein trafficking in AP-4-deficient cells, including neurons derived from patient-derived induced pluripotent stem cells [ See Search ## Genetic Counseling AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is inherited in an autosomal recessive manner. The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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. It is appropriate to offer AP-4-HSP molecular genetic testing to reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive AP-4-HSP, particularly if consanguinity is likely. About 50% of individuals with AP-4-HSP are from consanguineous families [ 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 • 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. • It is appropriate to offer AP-4-HSP molecular genetic testing to reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive AP-4-HSP, particularly if consanguinity is likely. About 50% of individuals with AP-4-HSP are from consanguineous families [ ## Mode of Inheritance AP-4-associated hereditary spastic paraplegia (AP-4-HSP) 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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. It is appropriate to offer AP-4-HSP molecular genetic testing to reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive AP-4-HSP, particularly if consanguinity is likely. About 50% of individuals with AP-4-HSP are from consanguineous 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 carriers or are at risk of being carriers. • It is appropriate to offer AP-4-HSP molecular genetic testing to reproductive partners of individuals known to be heterozygous for a pathogenic variant associated with autosomal recessive AP-4-HSP, particularly if consanguinity is likely. About 50% of individuals with AP-4-HSP are from consanguineous families [ ## 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 Australia Tom Wahlig Stiftung Germany • • • • • • Australia • • • • • • • Tom Wahlig Stiftung • Germany • ## Molecular Genetics AP-4-Associated Hereditary Spastic Paraplegia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for AP-4-Associated Hereditary Spastic Paraplegia ( The adaptor protein complex 4 (AP-4) comprises the subunits β4, ε, μ4, and σ4, which are encoded by the genes AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is caused by biallelic pathogenic variants in any one of these four genes, as reduction or loss of the mutated subunit reduces the cellular level of the other three subunits, resulting in their degradation by the cell when they are no longer able to be incorporated into a stable complex [ AP-4 is part of the well-conserved adaptor protein complexes (APs) family and is associated with the cytosolic side of membranes to identify cargo proteins, and subsequently form vesicle coats that facilitate the budding and transport of vesicles from donor organelles. By recognizing distinct cargo and targeting specific cellular compartments, APs play a crucial role in enabling eukaryotic cells to effectively sort, transport, and recycle proteins along organized intracellular pathways [ ## Molecular Pathogenesis The adaptor protein complex 4 (AP-4) comprises the subunits β4, ε, μ4, and σ4, which are encoded by the genes AP-4-associated hereditary spastic paraplegia (AP-4-HSP) is caused by biallelic pathogenic variants in any one of these four genes, as reduction or loss of the mutated subunit reduces the cellular level of the other three subunits, resulting in their degradation by the cell when they are no longer able to be incorporated into a stable complex [ AP-4 is part of the well-conserved adaptor protein complexes (APs) family and is associated with the cytosolic side of membranes to identify cargo proteins, and subsequently form vesicle coats that facilitate the budding and transport of vesicles from donor organelles. By recognizing distinct cargo and targeting specific cellular compartments, APs play a crucial role in enabling eukaryotic cells to effectively sort, transport, and recycle proteins along organized intracellular pathways [ ## Chapter Notes The Boston Children's Hospital Hereditary Spastic Paraplegia Research Program is actively involved in clinical research regarding individuals with AP-4-related HSP. The team would be happy to communicate with persons who have any questions regarding diagnosis of AP-4-HSP or other considerations. Contact: Phone: 1-617-355-6388 Email: To assess the pathogenicity of variants of uncertain significance in any of the four AP-4 subunit genes, high-throughput imaging of subcellular ATG9A distribution in patient-derived cells has been utilized as a diagnostic functional assay on a research basis [ The Spastic Paraplegia Centers of Excellence Research Network (SP-CERN) may serve as an additional resource. Phone: 1-617-355-6388 Email: Web page: The Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq) ( The authors are grateful to their patients and their families for endorsing and supporting their research on AP-4-HSP. The authors also acknowledge grant funding from the CureAP-4 Foundation and the Spastic Paraplegia Foundation. Julian Alecu, MD, PhD (2025-current)Robert Behne; Boston Children's Hospital (2018-2025)Alexandra K Davies, PhD; University of Cambridge (2018-2025)Darius Ebrahimi-Fakhari, MD, PhD (2018-current)Jennifer Hirst, PhD; University of Cambridge (2018-2025)Luca Schierbaum, MD, PhD (2025-current) 6 February 2025 (bp) Comprehensive update posted live 13 December 2018 (bp) Review posted live 21 June 2018 (def) Original submission • Phone: 1-617-355-6388 • Email: • Phone: 1-617-355-6388 • Email: • Web page: • 6 February 2025 (bp) Comprehensive update posted live • 13 December 2018 (bp) Review posted live • 21 June 2018 (def) Original submission ## Author Notes The Boston Children's Hospital Hereditary Spastic Paraplegia Research Program is actively involved in clinical research regarding individuals with AP-4-related HSP. The team would be happy to communicate with persons who have any questions regarding diagnosis of AP-4-HSP or other considerations. Contact: Phone: 1-617-355-6388 Email: To assess the pathogenicity of variants of uncertain significance in any of the four AP-4 subunit genes, high-throughput imaging of subcellular ATG9A distribution in patient-derived cells has been utilized as a diagnostic functional assay on a research basis [ The Spastic Paraplegia Centers of Excellence Research Network (SP-CERN) may serve as an additional resource. Phone: 1-617-355-6388 Email: Web page: The Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq) ( • Phone: 1-617-355-6388 • Email: • Phone: 1-617-355-6388 • Email: • Web page: ## Acknowledgments The authors are grateful to their patients and their families for endorsing and supporting their research on AP-4-HSP. The authors also acknowledge grant funding from the CureAP-4 Foundation and the Spastic Paraplegia Foundation. ## Author History Julian Alecu, MD, PhD (2025-current)Robert Behne; Boston Children's Hospital (2018-2025)Alexandra K Davies, PhD; University of Cambridge (2018-2025)Darius Ebrahimi-Fakhari, MD, PhD (2018-current)Jennifer Hirst, PhD; University of Cambridge (2018-2025)Luca Schierbaum, MD, PhD (2025-current) ## Revision History 6 February 2025 (bp) Comprehensive update posted live 13 December 2018 (bp) Review posted live 21 June 2018 (def) Original submission • 6 February 2025 (bp) Comprehensive update posted live • 13 December 2018 (bp) Review posted live • 21 June 2018 (def) Original submission ## References ## Literature Cited	[]	13/12/2018	6/2/2025		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
apbd	apbd	[ "1,4-alpha-glucan-branching enzyme", "GBE1", "GBE1-Adult Polyglucosan Body Disease" ]		H Orhan Akman, Alexander Lossos, Or Kakhlon	Summary Most individuals with classic The diagnosis of Once the	## Diagnosis Onset age ≥40 years Progressive neurogenic bladder Gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement Sensory loss predominantly in the distal lower extremities Mild difficulties in cognition (often executive dysfunction) A history of infantile liver disease [ Paraventricular, subcortical, and deep white matter slowly progressive changes that may include involvement of the upper pons, superior cerebellar peduncles, dentate nuclei, and anterior medulla (including the olives) often extending to the level of the cervical-medullary junction [ Cerebral, cerebellar, and spinal cord slowly progressive atrophy The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click 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 Data derived from the subscription-based professional view of Human Gene Mutation Database [ Note: Although almost all variants associated with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Intragenic deletions, such as those reported by • Onset age ≥40 years • Progressive neurogenic bladder • Gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement • Sensory loss predominantly in the distal lower extremities • Mild difficulties in cognition (often executive dysfunction) • A history of infantile liver disease [ • Paraventricular, subcortical, and deep white matter slowly progressive changes that may include involvement of the upper pons, superior cerebellar peduncles, dentate nuclei, and anterior medulla (including the olives) often extending to the level of the cervical-medullary junction [ • Cerebral, cerebellar, and spinal cord slowly progressive atrophy ## Suggestive Findings Onset age ≥40 years Progressive neurogenic bladder Gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement Sensory loss predominantly in the distal lower extremities Mild difficulties in cognition (often executive dysfunction) A history of infantile liver disease [ Paraventricular, subcortical, and deep white matter slowly progressive changes that may include involvement of the upper pons, superior cerebellar peduncles, dentate nuclei, and anterior medulla (including the olives) often extending to the level of the cervical-medullary junction [ Cerebral, cerebellar, and spinal cord slowly progressive atrophy • Onset age ≥40 years • Progressive neurogenic bladder • Gait difficulties (i.e., spasticity and weakness) from mixed upper and lower motor neuron involvement • Sensory loss predominantly in the distal lower extremities • Mild difficulties in cognition (often executive dysfunction) • A history of infantile liver disease [ • Paraventricular, subcortical, and deep white matter slowly progressive changes that may include involvement of the upper pons, superior cerebellar peduncles, dentate nuclei, and anterior medulla (including the olives) often extending to the level of the cervical-medullary junction [ • Cerebral, cerebellar, and spinal cord slowly progressive atrophy ## Establishing the Diagnosis The diagnosis of Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of For an introduction to multigene panels click 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 Data derived from the subscription-based professional view of Human Gene Mutation Database [ Note: Although almost all variants associated with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Intragenic deletions, such as those reported by ## 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 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 [ Note: Although almost all variants associated with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Intragenic deletions, such as those reported by ## Clinical Characteristics Most individuals with More than 160 individuals of Ashkenazi and non-Ashkenazi Jewish heritage have been reported [ Select Features of Classic Based on In their review of 50 individuals with An "intermediate form" of 1,4-alpha-glucan-branching enzyme (GBE) deficiency in two individuals of non-Ashkenazi Jewish heritage was associated with residual GBE activity – a history of infantile hepatomegaly and increased glycogen on liver biopsy that resolved spontaneously (in one individual) and a family history of severe infantile liver disease (in the other individual), and acute onset of neurologic manifestations in their 30s and 40s (about one decade earlier than typical APBD) followed by a relapsing-remitting course of acute neurologic deficits (mimicking multiple sclerosis) with subsequent neurologic impairment [ Specialized autonomic testing (thermoregulatory sweat tests and autonomic reflex testing) shows sudomotor sweating abnormalities often with specific spinal cord level identified. Nerve conduction velocity and electromyogram reveal an axonal lumbosacral polyradiculoneuropathy. Sural nerve biopsy reveals characteristic polyglucosans within nerve sheaths. The extent and characteristics of the identified polyglucosans typically distinguish them from the rare polyglucosans found in normal older individuals [ Muscle. Diastase-resistant, periodic acid-Schiff (PAS)-positive material is characteristic. No clear correlation of clinical severity and More than 160 individuals with The carrier frequency for • Specialized autonomic testing (thermoregulatory sweat tests and autonomic reflex testing) shows sudomotor sweating abnormalities often with specific spinal cord level identified. • Nerve conduction velocity and electromyogram reveal an axonal lumbosacral polyradiculoneuropathy. • Sural nerve biopsy reveals characteristic polyglucosans within nerve sheaths. The extent and characteristics of the identified polyglucosans typically distinguish them from the rare polyglucosans found in normal older individuals [ • Muscle. Diastase-resistant, periodic acid-Schiff (PAS)-positive material is characteristic. ## Clinical Description Most individuals with More than 160 individuals of Ashkenazi and non-Ashkenazi Jewish heritage have been reported [ Select Features of Classic Based on In their review of 50 individuals with An "intermediate form" of 1,4-alpha-glucan-branching enzyme (GBE) deficiency in two individuals of non-Ashkenazi Jewish heritage was associated with residual GBE activity – a history of infantile hepatomegaly and increased glycogen on liver biopsy that resolved spontaneously (in one individual) and a family history of severe infantile liver disease (in the other individual), and acute onset of neurologic manifestations in their 30s and 40s (about one decade earlier than typical APBD) followed by a relapsing-remitting course of acute neurologic deficits (mimicking multiple sclerosis) with subsequent neurologic impairment [ Specialized autonomic testing (thermoregulatory sweat tests and autonomic reflex testing) shows sudomotor sweating abnormalities often with specific spinal cord level identified. Nerve conduction velocity and electromyogram reveal an axonal lumbosacral polyradiculoneuropathy. Sural nerve biopsy reveals characteristic polyglucosans within nerve sheaths. The extent and characteristics of the identified polyglucosans typically distinguish them from the rare polyglucosans found in normal older individuals [ Muscle. Diastase-resistant, periodic acid-Schiff (PAS)-positive material is characteristic. • Specialized autonomic testing (thermoregulatory sweat tests and autonomic reflex testing) shows sudomotor sweating abnormalities often with specific spinal cord level identified. • Nerve conduction velocity and electromyogram reveal an axonal lumbosacral polyradiculoneuropathy. • Sural nerve biopsy reveals characteristic polyglucosans within nerve sheaths. The extent and characteristics of the identified polyglucosans typically distinguish them from the rare polyglucosans found in normal older individuals [ • Muscle. Diastase-resistant, periodic acid-Schiff (PAS)-positive material is characteristic. ## Classic ## Atypical In their review of 50 individuals with An "intermediate form" of 1,4-alpha-glucan-branching enzyme (GBE) deficiency in two individuals of non-Ashkenazi Jewish heritage was associated with residual GBE activity – a history of infantile hepatomegaly and increased glycogen on liver biopsy that resolved spontaneously (in one individual) and a family history of severe infantile liver disease (in the other individual), and acute onset of neurologic manifestations in their 30s and 40s (about one decade earlier than typical APBD) followed by a relapsing-remitting course of acute neurologic deficits (mimicking multiple sclerosis) with subsequent neurologic impairment [ ## Other Specialized autonomic testing (thermoregulatory sweat tests and autonomic reflex testing) shows sudomotor sweating abnormalities often with specific spinal cord level identified. Nerve conduction velocity and electromyogram reveal an axonal lumbosacral polyradiculoneuropathy. Sural nerve biopsy reveals characteristic polyglucosans within nerve sheaths. The extent and characteristics of the identified polyglucosans typically distinguish them from the rare polyglucosans found in normal older individuals [ Muscle. Diastase-resistant, periodic acid-Schiff (PAS)-positive material is characteristic. • Specialized autonomic testing (thermoregulatory sweat tests and autonomic reflex testing) shows sudomotor sweating abnormalities often with specific spinal cord level identified. • Nerve conduction velocity and electromyogram reveal an axonal lumbosacral polyradiculoneuropathy. • Sural nerve biopsy reveals characteristic polyglucosans within nerve sheaths. The extent and characteristics of the identified polyglucosans typically distinguish them from the rare polyglucosans found in normal older individuals [ • Muscle. Diastase-resistant, periodic acid-Schiff (PAS)-positive material is characteristic. ## Genotype-Phenotype Correlations No clear correlation of clinical severity and ## Prevalence More than 160 individuals with The carrier frequency for ## Genetically Related (Allelic) Disorders The only other disorder known to be associated with biallelic pathogenic variants in GBE enzyme activity is typically undetectable or minimally detectable; Multiple homozygous or compound heterozygous The phenotype associated with GSD IV spans a spectrum that includes the following forms (subtypes) based on age of presentation, clinical manifestations, and severity: • GBE enzyme activity is typically undetectable or minimally detectable; • Multiple homozygous or compound heterozygous ## Differential Diagnosis Delay in diagnosis of Other disorders that may present similarly to Other genes associated with polyglucosans are summarized in Other Genes Associated with Accumulation of Polyglucosan Bodies AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance Based on Polyglucosan bodies also occur in double athetosis (Bielschowsky bodies) and normal older persons (corpora amylacea). ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Obtain history for stroke-like episodes. Assess for UMN (spasticity) & LMN involvement (weakness & sensory loss). Brain & spine MRI (if not obtained at time of diagnosis) to exclude other causes of gait spasticity & neurogenic bladder Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores Need for adaptive devices Footwear needs PT needs Small motor function (hands, feet, face, fingers, toes) ADL Referral to urologist Consider urodynamic eval & imaging of urinary tract & kidneys. Use of community or Need for social work involvement for care-giver support; Need for home nursing referral. ADL = activities of daily living; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Optimally, care is provided by a multidisciplinary team that includes specialists in physical medicine rehabilitation, urology, and behavioral neurology or psychology (i.e., behavioralists) (see Treatment of Manifestations in Individuals with Stretching exercises to ↑ flexibility, ↓ spasticity, & maintain or ↑ joint range of motion & prevent joint contractures Aerobic exercise to ↑ cardiovascular fitness & to maintain & ↑ muscle strength, coordination, & balance Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL Transfers (e.g., from bed to wheelchair, wheelchair to car) Training on how to fall to ↓ risk of injury To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming To assist w/household modifications to meet special needs ADL = activities of daily living; OT = occupational therapy; PT = physical therapy; UTI = urinary tract infection Recommended Surveillance for Individuals with Neurologic assessment for progression of UMN & LMN signs Monitor for development of new manifestations. LMN = lower motor neuron; OT = occupational therapy/therapist; PT = physical therapy/therapist; UMN = upper motor neuron See Clinical trials involve use of guaiacol [ Search • Obtain history for stroke-like episodes. • Assess for UMN (spasticity) & LMN involvement (weakness & sensory loss). • Brain & spine MRI (if not obtained at time of diagnosis) to exclude other causes of gait spasticity & neurogenic bladder • Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores • Need for adaptive devices • Footwear needs • PT needs • Small motor function (hands, feet, face, fingers, toes) • ADL • Referral to urologist • Consider urodynamic eval & imaging of urinary tract & kidneys. • Use of community or • Need for social work involvement for care-giver support; • Need for home nursing referral. • Stretching exercises to ↑ flexibility, ↓ spasticity, & maintain or ↑ joint range of motion & prevent joint contractures • Aerobic exercise to ↑ cardiovascular fitness & to maintain & ↑ muscle strength, coordination, & balance • Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL • Transfers (e.g., from bed to wheelchair, wheelchair to car) • Training on how to fall to ↓ risk of injury • To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming • To assist w/household modifications to meet special needs • Neurologic assessment for progression of UMN & LMN signs • Monitor for development of new manifestations. ## 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 Obtain history for stroke-like episodes. Assess for UMN (spasticity) & LMN involvement (weakness & sensory loss). Brain & spine MRI (if not obtained at time of diagnosis) to exclude other causes of gait spasticity & neurogenic bladder Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores Need for adaptive devices Footwear needs PT needs Small motor function (hands, feet, face, fingers, toes) ADL Referral to urologist Consider urodynamic eval & imaging of urinary tract & kidneys. Use of community or Need for social work involvement for care-giver support; Need for home nursing referral. ADL = activities of daily living; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UMN = upper motor neuron Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Obtain history for stroke-like episodes. • Assess for UMN (spasticity) & LMN involvement (weakness & sensory loss). • Brain & spine MRI (if not obtained at time of diagnosis) to exclude other causes of gait spasticity & neurogenic bladder • Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores • Need for adaptive devices • Footwear needs • PT needs • Small motor function (hands, feet, face, fingers, toes) • ADL • Referral to urologist • Consider urodynamic eval & imaging of urinary tract & kidneys. • Use of community or • Need for social work involvement for care-giver support; • Need for home nursing referral. ## Treatment of Manifestations Optimally, care is provided by a multidisciplinary team that includes specialists in physical medicine rehabilitation, urology, and behavioral neurology or psychology (i.e., behavioralists) (see Treatment of Manifestations in Individuals with Stretching exercises to ↑ flexibility, ↓ spasticity, & maintain or ↑ joint range of motion & prevent joint contractures Aerobic exercise to ↑ cardiovascular fitness & to maintain & ↑ muscle strength, coordination, & balance Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL Transfers (e.g., from bed to wheelchair, wheelchair to car) Training on how to fall to ↓ risk of injury To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming To assist w/household modifications to meet special needs ADL = activities of daily living; OT = occupational therapy; PT = physical therapy; UTI = urinary tract infection • Stretching exercises to ↑ flexibility, ↓ spasticity, & maintain or ↑ joint range of motion & prevent joint contractures • Aerobic exercise to ↑ cardiovascular fitness & to maintain & ↑ muscle strength, coordination, & balance • Strengthening exercises to improve posture, walking, arm strength to improve use of mobility aids, ADL • Transfers (e.g., from bed to wheelchair, wheelchair to car) • Training on how to fall to ↓ risk of injury • To accomplish tasks such as mobility, washing, dressing, eating, cooking, & grooming • To assist w/household modifications to meet special needs ## Surveillance Recommended Surveillance for Individuals with Neurologic assessment for progression of UMN & LMN signs Monitor for development of new manifestations. LMN = lower motor neuron; OT = occupational therapy/therapist; PT = physical therapy/therapist; UMN = upper motor neuron • Neurologic assessment for progression of UMN & LMN signs • Monitor for development of new manifestations. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Clinical trials involve use of guaiacol [ Search ## Genetic Counseling Note: The fact that some individuals reported with The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic. 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. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic. • 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. ## Mode of Inheritance Note: The fact that some individuals reported with ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a Heterozygotes (carriers) are asymptomatic. If both parents are known to be heterozygous for a Heterozygotes (carriers) are asymptomatic. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • Heterozygotes (carriers) are asymptomatic. • If both parents are known to be heterozygous for a • Heterozygotes (carriers) are asymptomatic. ## 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. • 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. ## 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 8 West 37th Street Suite 901 New York NY 10018 • • 8 West 37th Street • Suite 901 • New York NY 10018 • • • ## Molecular Genetics GBE1 Adult Polyglucosan Body Disease: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for GBE1 Adult Polyglucosan Body Disease ( The mammalian glucose storage molecule, glycogen, consists of approximately 55,000 units and yet is soluble. This solubility is achieved through branching. Glycogen synthase (GS) extends glucan chains and the 1,4-alpha-glucan-branching enzyme (GBE), encoded by GBE deficiency thus leads to poorly branched and therefore insoluble glycogen (polyglucosans), which precipitates, aggregates, and accumulates into polyglucosan bodies (PB), which, being out of solution and aggregated, cannot be degraded by glycogen phosphorylase. The amassing aggregates in neurons lead over time to axon plugging, which causes the fatal progressive axonopathic disease While GBE enzyme assay (in any tissue) is not a first-line diagnostic test for Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Molecular Pathogenesis The mammalian glucose storage molecule, glycogen, consists of approximately 55,000 units and yet is soluble. This solubility is achieved through branching. Glycogen synthase (GS) extends glucan chains and the 1,4-alpha-glucan-branching enzyme (GBE), encoded by GBE deficiency thus leads to poorly branched and therefore insoluble glycogen (polyglucosans), which precipitates, aggregates, and accumulates into polyglucosan bodies (PB), which, being out of solution and aggregated, cannot be degraded by glycogen phosphorylase. The amassing aggregates in neurons lead over time to axon plugging, which causes the fatal progressive axonopathic disease While GBE enzyme assay (in any tissue) is not a first-line diagnostic test for Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions ## Chapter Notes Dr Akman has a research laboratory at Columbia University Medical Center. He is working on the treatment of polyglucosan body diseases caused by GBE deficiency as well as RBCK1 deficiency. If you would like more information about his research or about the APBD Research Foundation, contact Dr Akman at The authors would like to thank the H Orhan Akman, PhD (2020-present)Or Kakhlon, PhD (2020-present)Christopher J Klein, MD; Mayo Clinic (2008-2020)Alexander Lossos, MD (2020-present) 17 September 2020 (bp) Comprehensive update posted live 19 December 2013 (me) Comprehensive update posted live 23 July 2009 (ck) Revision: clinical trial information 2 April 2009 (et) Review posted live 1 October 2008 (ck) Original submission • 17 September 2020 (bp) Comprehensive update posted live • 19 December 2013 (me) Comprehensive update posted live • 23 July 2009 (ck) Revision: clinical trial information • 2 April 2009 (et) Review posted live • 1 October 2008 (ck) Original submission ## Author Notes Dr Akman has a research laboratory at Columbia University Medical Center. He is working on the treatment of polyglucosan body diseases caused by GBE deficiency as well as RBCK1 deficiency. If you would like more information about his research or about the APBD Research Foundation, contact Dr Akman at ## Acknowledgments The authors would like to thank the ## Author History H Orhan Akman, PhD (2020-present)Or Kakhlon, PhD (2020-present)Christopher J Klein, MD; Mayo Clinic (2008-2020)Alexander Lossos, MD (2020-present) ## Revision History 17 September 2020 (bp) Comprehensive update posted live 19 December 2013 (me) Comprehensive update posted live 23 July 2009 (ck) Revision: clinical trial information 2 April 2009 (et) Review posted live 1 October 2008 (ck) Original submission • 17 September 2020 (bp) Comprehensive update posted live • 19 December 2013 (me) Comprehensive update posted live • 23 July 2009 (ck) Revision: clinical trial information • 2 April 2009 (et) Review posted live • 1 October 2008 (ck) Original submission ## References ## Literature Cited	[ "HO Akman, O Kakhlon, J Coku, L Peverelli, H Rosenmann, L Rozenstein-Tsalkovich, J Turnbull, V Meiner, L Chama, I Lerer, S Shpitzen, E Leitersdorf, C Paradas, M Wallace, R Schiffmann, S DiMauro, A Lossos, BA Minassian. Deep intronic GBE1 mutation in manifesting heterozygous patients with adult polyglucosan body disease.. JAMA Neurol. 2015;72:441-5", "R Alvarez, J Casas, DJ López, M Ibarguren, A Suari-Rivera, S Terés, F Guardiola-Serrano, A Lossos, X Busquets, O Kakhlon, PV Escribá. Triacylglycerol mimetics regulate membrane interactions of glycogen branching enzyme: implications for therapy.. J Lipid Res. 2017;58:1598-612", "G Cenacchi, V Papa, R Costa, V Pegoraro, R Marozzo, M Fanin, C Angelini. Update on polyglucosan storage diseases.. Virchows Arch. 2019;475:671-86", "C Bruno, OP van Diggelen, D Cassandrini, M Gimpelev, B Giuffrè, MA Donati, P Introvini, A Alegria, S Assereto, L Morandi, M Mora, E Tonoli, S Mascelli, M Traverso, E Pasquini, M Bado, L Vilarinho, G van Noort, F Mosca, S DiMauro, F Zara, C Minetti. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV).. Neurology. 2004;63:1053-8", "MA Hellmann, O Kakhlon, EH Landau, M Sadeh, N Giladi, I Schlesinger, D Kidron, O Abramsky, A Reches, Z Argov, JM Rabey, J Chapman, H Rosenmann, A Gal, J Moshe Gomori, V Meiner, A Lossos. Frequent misdiagnosis of adult polyglucosan body disease.. J Neurol. 2015;262:2346-51", "A Hussain, J Armistead, L Gushulak, C Kruck, S Pind, B Triggs-Raine, MR Natowicz. The adult polyglucosan body disease mutation GBE1 c.1076A>C occurs at high frequency in persons of Ashkenazi Jewish background.. Biochem Biophys Res Commun. 2012;426:286-8", "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", "O Kakhlon, I Ferreira, LJ Solmesky, N Khazanov, A Lossos, R Alvarez, D Yetil, S Pampou, M Weil, H Senderowitz, P Escriba, WW Yue, HO Akman. Guaiacol as a drug candidate for treating adult polyglucosan body disease.. JCI Insight. 2018;3", "CJ Klein, CJ Boes, JE Chapin, CD Lynch, NG Campeau, PJ Dyck, PJ Dyck. Adult polyglucosan body disease: case description of an expanding genetic and clinical syndrome.. Muscle Nerve 2004;29:323-8", "SC Li, WL Hwu, JL Lin, DS Bali, C Yang, SM Chu, YH Chien, HC Chou, CY Chen, WS Hsieh, PN Tsao, YT Chen, NC Lee. Association of the congenital neuromuscular form of glycogen storage disease type IV with a large deletion and recurrent frameshift mutation.. J Child Neurol. 2012;27:204-8", "A Lossos, Z Meiner, V Barash, D Soffer, I Schlesinger, O Abramsky, Z Argov, S Shpitzen, V Meiner. Adult polyglucosan body disease in Ashkenazi Jewish patients carrying the Tyr329Ser mutation in the glycogen-branching enzyme gene.. Ann Neurol 1998;44:867-72", "F Mochel, R Schiffmann, ME Steenweg, HO Akman, M Wallace, F Sedel, P Laforêt, R Levy, JM Powers, S Demeret, T Maisonobe, R Froissart, BB Da Nobrega, BL Fogel, MR Natowicz, C Lubetzki, A Durr, A Brice, H Rosenmann, V Barash, O Kakhlon, JM Gomori, MS van der Knaap, A Lossos. Adult polyglucosan body disease: natural history and key magnetic resonance imaging findings.. Ann Neurol. 2012;72:433-41", "C Paradas, HO Akman, C Ionete, H Lau, PN Riskind, DE Jones, TW Smith, M Hirano, S Dimauro. Branching enzyme deficiency: expanding the clinical spectrum.. JAMA Neurol. 2014;71:41-7", "GP Raju, HC Li, DS Bali, YT Chen, DK Urion, HG Lidov, PB Kang. A case of congenital glycogen storage disease type IV with a novel GBE1 mutation.. J Child Neurol. 2008;23:349-52", "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", "R Schiffmann, ME Wallace, D Rinaldi, I Ledoux, MP Luton, S Coleman, HO Akman, K Martin, JY Hogrel, D Blankenship, J Turner, F Mochel. A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome.. J Inherit Metab Dis. 2018;41:877-83", "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 Tasca, F Fattori, M Monforte, C Hedberg-Oldfors, M Sabatelli, B Udd, R Boldrini, E Bertini, E Ricci, A Oldfors. Start codon mutation of GYG1 causing late-onset polyglucosan body myopathy with nemaline rods.. J Neurol. 2016;263:2133-5", "SK Tay, HO Akman, WK Chung, MG Pike, F Muntoni, AP Hays, S Shanske, SJ Valberg, JR Mickelson, K Tanji, S DiMauro. Fatal infantile neuromuscular presentation of glycogen storage disease type IV.. Neuromuscul Disord. 2004;14:253-60", "M Xu, M Pinto, C Sun, JK Engelstad, P James Dyck, PJ Dyck, CJ Klein. Expanded teased nerve fibre pathological conditions in disease association.. J Neurol Neurosurg Psychiatry. 2019;90:138-40", "F Ziemssen, E Sindern, JM Schröder, YS Shin, J Zange, MW Kilimann, JP Malin, M Vorgerd. Novel missense mutations in the glycogen-branchin enzyme gene in adult polyglucosan body disease.. Ann Neurol 2000;47:536-40" ]	2/4/2009	17/9/2020	23/7/2009	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
apds	apds	[ "Activated Phosphoinositide 3-Kinase Delta (PI3Kδ) Syndrome", "APDS", "p110δ-Activating Mutation Causing Senescent T Cells, Lymphadenopathy, and Immunodeficiency Disease", "PASLI Disease", "PI3K Disease", "PASLI Disease", "Activated Phosphoinositide 3-Kinase Delta (PI3Kd) Syndrome", "APDS", "p110d-Activating Mutation Causing Senescent T Cells, Lymphadenopathy, and Immunodeficiency Disease", "PI3K Disease", "Activated PI3K Delta Syndrome Type 1 (APDS1)", "Activated PI3K Delta Syndrome Type 2 (APDS2)", "Phosphatidylinositol 3-kinase regulatory subunit alpha", "Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform", "PIK3CD", "PIK3R1", "Activated PI3K Delta Syndrome" ]	Activated PI3K Delta Syndrome	Keith Sacco, Gulbu Uzel	Summary Activated PI3K delta syndrome (APDS) is characterized by a spectrum of clinical manifestations involving the immune system leading to increased susceptibility to infections (e.g., otitis media, sinusitis, bronchitis, and pneumonia), autoimmune/autoinflammatory manifestations including autoimmune cytopenias, gastrointestinal manifestations resembling Crohn-like colitis, intussusception, and lymphoproliferation (e.g., lymphadenopathy, hepatosplenomegaly, and nodular lymphoid hyperplasia), and an increased risk of developing B-cell lymphomas and other malignancies. Short stature, growth delays, and neurodevelopmental delays are also reported. APDS type 1 (APDS1) is caused by a heterozygous pathogenic gain-of-function variant in The clinical diagnosis of APDS can be established in a proband based on suggestive clinical findings, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous pathogenic variant in APDS is an autosomal dominant disorder. Approximately 80% of individuals diagnosed with APDS have an affected parent and 20% of individuals have the disorder as the result of a	Activated PI3K delta syndrome type 1 (APDS1) Activated PI3K delta syndrome type 2 (APDS2) • Activated PI3K delta syndrome type 1 (APDS1) • Activated PI3K delta syndrome type 2 (APDS2) ## Diagnosis No consensus clinical diagnostic criteria for activated PI3K delta syndrome (APDS) have been published. APDS types 1 (APDS1) and 2 (APDS2) are characterized by a spectrum of clinical manifestations primarily involving the immune system, leading to increased susceptibility to infections, autoimmunity, and lymphoproliferation. APDS Otitis media (frequent middle ear infections that may lead to conductive hearing loss); Sinusitis (persistent sinus infections that are often difficult to treat); Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). Lymphadenopathy (often generalized and can be persistent); Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); Nodular lymphoid hyperplasia. Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. Lymphadenopathy and hepatosplenomegaly are common findings on ultrasound and computerized tomography (CT) with evidence of increased fluorodeoxyglucose uptake on positron emission tomography (PET) scans. Bronchiectasis and mosaic attenuation can be identified on CT chest imaging. The The clinical diagnosis of APDS primarily relies on a constellation of suggestive findings, including clinical manifestations, laboratory findings, and imaging results. While no consensus clinical diagnostic criteria have been universally accepted at this time, the following features are strongly indicative of APDS when combined: Recurrent sinopulmonary infections from early childhood Evidence of lymphoproliferation, such as lymphadenopathy and hepatosplenomegaly, or nodular lymphoid hyperplasia in the absence of an alternative explanation Autoimmune manifestations, particularly autoimmune cytopenias and inflammatory bowel disease-like symptoms Laboratory findings indicative of immune dysregulation, including elevated IgM levels with decreased IgG and IgA, and poor vaccine responses following T-cell-dependent immunizations (e.g. tetanus toxoid) and T-cell-independent immunizations (e.g., The molecular diagnosis of APDS A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of APDS, molecular genetic testing approaches can include use of For an introduction to multigene panels click When the diagnosis of APDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Activated PI3K Delta Syndrome Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with APDS. • Otitis media (frequent middle ear infections that may lead to conductive hearing loss); • Sinusitis (persistent sinus infections that are often difficult to treat); • Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). • Otitis media (frequent middle ear infections that may lead to conductive hearing loss); • Sinusitis (persistent sinus infections that are often difficult to treat); • Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). • Lymphadenopathy (often generalized and can be persistent); • Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); • Nodular lymphoid hyperplasia. • Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. • Lymphadenopathy (often generalized and can be persistent); • Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); • Nodular lymphoid hyperplasia. • Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. • Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); • Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and • Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); • Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and • Otitis media (frequent middle ear infections that may lead to conductive hearing loss); • Sinusitis (persistent sinus infections that are often difficult to treat); • Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). • Lymphadenopathy (often generalized and can be persistent); • Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); • Nodular lymphoid hyperplasia. • Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. • Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); • Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and • • Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. • There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. • Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). • Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. • There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. • Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). • • Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. • Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ • Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. • Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ • • T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. • A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. • T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. • A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. • Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. • There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. • Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). • Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. • Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ • T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. • A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. • Lymphadenopathy and hepatosplenomegaly are common findings on ultrasound and computerized tomography (CT) with evidence of increased fluorodeoxyglucose uptake on positron emission tomography (PET) scans. • Bronchiectasis and mosaic attenuation can be identified on CT chest imaging. • Recurrent sinopulmonary infections from early childhood • Evidence of lymphoproliferation, such as lymphadenopathy and hepatosplenomegaly, or nodular lymphoid hyperplasia in the absence of an alternative explanation • Autoimmune manifestations, particularly autoimmune cytopenias and inflammatory bowel disease-like symptoms • Laboratory findings indicative of immune dysregulation, including elevated IgM levels with decreased IgG and IgA, and poor vaccine responses following T-cell-dependent immunizations (e.g. tetanus toxoid) and T-cell-independent immunizations (e.g., • A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving • A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving ## Suggestive Findings APDS types 1 (APDS1) and 2 (APDS2) are characterized by a spectrum of clinical manifestations primarily involving the immune system, leading to increased susceptibility to infections, autoimmunity, and lymphoproliferation. APDS Otitis media (frequent middle ear infections that may lead to conductive hearing loss); Sinusitis (persistent sinus infections that are often difficult to treat); Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). Lymphadenopathy (often generalized and can be persistent); Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); Nodular lymphoid hyperplasia. Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. Lymphadenopathy and hepatosplenomegaly are common findings on ultrasound and computerized tomography (CT) with evidence of increased fluorodeoxyglucose uptake on positron emission tomography (PET) scans. Bronchiectasis and mosaic attenuation can be identified on CT chest imaging. • Otitis media (frequent middle ear infections that may lead to conductive hearing loss); • Sinusitis (persistent sinus infections that are often difficult to treat); • Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). • Otitis media (frequent middle ear infections that may lead to conductive hearing loss); • Sinusitis (persistent sinus infections that are often difficult to treat); • Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). • Lymphadenopathy (often generalized and can be persistent); • Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); • Nodular lymphoid hyperplasia. • Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. • Lymphadenopathy (often generalized and can be persistent); • Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); • Nodular lymphoid hyperplasia. • Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. • Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); • Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and • Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); • Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and • Otitis media (frequent middle ear infections that may lead to conductive hearing loss); • Sinusitis (persistent sinus infections that are often difficult to treat); • Bronchitis and pneumonia (recurrent lower respiratory tract infections that can be severe and lead to bronchiectasis). • Lymphadenopathy (often generalized and can be persistent); • Hepatosplenomegaly (due to infiltration by lymphoid cells and hypersplenism); • Nodular lymphoid hyperplasia. • Note: Nodular lymphoid hyperplasia is pathognomonic when identified in bronchial tissue and the gastrointestinal tract. • Autoimmune cytopenias (including autoimmune hemolytic anemia, immune thrombocytopenia, and autoimmune neutropenia); • Gastrointestinal manifestations (resembling Crohn-like colitis, nodular lymphoid hyperplasia of the gastrointestinal tract, and • • Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. • There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. • Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). • Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. • There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. • Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). • • Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. • Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ • Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. • Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ • • T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. • A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. • T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. • A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. • Increased levels of IgM are frequently observed, reflecting dysregulation of B-cell maturation. • There is typically a concomitant decrease in IgG and IgA levels, contributing to increased susceptibility to infections. • Classically, there is a poor response to vaccines that elicit an immune response via both a T-cell-dependent pathway (e.g., tetanus toxoid vaccine) and a T-cell-independent pathway (commonly the pneumococcal polysaccharide vaccines). • Individuals with APDS may show abnormal proportions of B-cell subsets, including reduced naïve and memory B cells and increased transitional B cells, reflecting impaired B-cell maturation. • Commonly, there is a decrease in naive CD8+ T cells with an increase in effector CD8+ T cells, and increased T follicular helper cells [ • T-cell proliferation responses specific to recall antigens (e.g., Candida and tetanus toxoid) may be diminished. • A multiplex immunoassay designed to quantitatively measure the phosphorylation levels of key proteins in the PI3K/AKT and MAPK signaling pathways specifically targets phosphorylated forms of AKT (pAKT) and ribosomal protein S6 (pS6). Individuals with APDS have increased pAKT/pS6 at baseline and after IgM and interleukin-4 stimulation compared to controls. The assay is most reliable in B cells but can be read in T cells if there is B-cell lymphopenia. • Lymphadenopathy and hepatosplenomegaly are common findings on ultrasound and computerized tomography (CT) with evidence of increased fluorodeoxyglucose uptake on positron emission tomography (PET) scans. • Bronchiectasis and mosaic attenuation can be identified on CT chest imaging. ## Establishing the Diagnosis The The clinical diagnosis of APDS primarily relies on a constellation of suggestive findings, including clinical manifestations, laboratory findings, and imaging results. While no consensus clinical diagnostic criteria have been universally accepted at this time, the following features are strongly indicative of APDS when combined: Recurrent sinopulmonary infections from early childhood Evidence of lymphoproliferation, such as lymphadenopathy and hepatosplenomegaly, or nodular lymphoid hyperplasia in the absence of an alternative explanation Autoimmune manifestations, particularly autoimmune cytopenias and inflammatory bowel disease-like symptoms Laboratory findings indicative of immune dysregulation, including elevated IgM levels with decreased IgG and IgA, and poor vaccine responses following T-cell-dependent immunizations (e.g. tetanus toxoid) and T-cell-independent immunizations (e.g., The molecular diagnosis of APDS A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of APDS, molecular genetic testing approaches can include use of For an introduction to multigene panels click When the diagnosis of APDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Activated PI3K Delta Syndrome Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with APDS. • Recurrent sinopulmonary infections from early childhood • Evidence of lymphoproliferation, such as lymphadenopathy and hepatosplenomegaly, or nodular lymphoid hyperplasia in the absence of an alternative explanation • Autoimmune manifestations, particularly autoimmune cytopenias and inflammatory bowel disease-like symptoms • Laboratory findings indicative of immune dysregulation, including elevated IgM levels with decreased IgG and IgA, and poor vaccine responses following T-cell-dependent immunizations (e.g. tetanus toxoid) and T-cell-independent immunizations (e.g., • A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving • A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving ## Clinical Diagnosis The clinical diagnosis of APDS primarily relies on a constellation of suggestive findings, including clinical manifestations, laboratory findings, and imaging results. While no consensus clinical diagnostic criteria have been universally accepted at this time, the following features are strongly indicative of APDS when combined: Recurrent sinopulmonary infections from early childhood Evidence of lymphoproliferation, such as lymphadenopathy and hepatosplenomegaly, or nodular lymphoid hyperplasia in the absence of an alternative explanation Autoimmune manifestations, particularly autoimmune cytopenias and inflammatory bowel disease-like symptoms Laboratory findings indicative of immune dysregulation, including elevated IgM levels with decreased IgG and IgA, and poor vaccine responses following T-cell-dependent immunizations (e.g. tetanus toxoid) and T-cell-independent immunizations (e.g., • Recurrent sinopulmonary infections from early childhood • Evidence of lymphoproliferation, such as lymphadenopathy and hepatosplenomegaly, or nodular lymphoid hyperplasia in the absence of an alternative explanation • Autoimmune manifestations, particularly autoimmune cytopenias and inflammatory bowel disease-like symptoms • Laboratory findings indicative of immune dysregulation, including elevated IgM levels with decreased IgG and IgA, and poor vaccine responses following T-cell-dependent immunizations (e.g. tetanus toxoid) and T-cell-independent immunizations (e.g., ## Molecular Diagnosis The molecular diagnosis of APDS A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic and laboratory findings suggest the diagnosis of APDS, molecular genetic testing approaches can include use of For an introduction to multigene panels click When the diagnosis of APDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Activated PI3K Delta Syndrome Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with APDS. • A heterozygous pathogenic (or likely pathogenic) gain-of-function variant involving • A heterozygous pathogenic (or likely pathogenic) loss-of-function variant involving ## When the phenotypic and laboratory findings suggest the diagnosis of APDS, molecular genetic testing approaches can include use of For an introduction to multigene panels click ## When the diagnosis of APDS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Activated PI3K Delta Syndrome Genes are listed in alphabetic order. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Exome and genome sequencing may be able to detect deletions/duplications using breakpoint detection or read depth; however, sensitivity can be lower than gene-targeted deletion/duplication analysis. To date, no large intragenic deletions/duplications have been reported in individuals with APDS. ## Clinical Characteristics Activated PI3K delta syndrome (APDS) is a rare inborn error of immunity characterized primarily by frequent infections, lymphoproliferation, and autoimmune manifestations. To date, at least 250 individuals have been identified with a pathogenic variant in It is important to note that the severity and presence of these clinical findings can vary widely among affected individuals. Some may present with mild symptoms, while others experience severe manifestations that significantly impact quality of life. The variability within the spectrum of APDS highlights the importance of individualized care and management strategies. Activated PI3K Delta Syndrome: Frequency of Select Features Based on A hallmark of bronchiectasis in APDS is a chronic productive cough associated with increased frequency of respiratory infections, including pneumonia and bronchitis. These recurrent infections contribute to the progressive destruction and dilation of bronchial walls, perpetuating the cycle of infection and inflammation. Individuals often develop symptoms of obstructive lung disease, including dyspnea, wheezing, and hemoptysis. High-resolution computed tomography (HRCT) is the imaging modality of choice for diagnosing and evaluating the extent of bronchiectasis. Typical findings on HRCT include bronchial dilatation, lack of tapering of the bronchi, and bronchial wall thickening. Chronic bronchiectasis can lead to several severe complications, including respiratory failure, group 3 pulmonary hypertension leading to cor pulmonale (right-sided heart failure secondary to lung disease). Following molecular genetic testing, the pAKT/pS6 functional assay (see APDS1 is caused by a heterozygous pathogenic gain-of-function variant in Growth delay and short stature are notable features of APDS2 and are more common in APDS2 than in APDS1. Gastrointestinal complications, such as chronic diarrhea and enteropathy, are more frequently reported in APDS2 compared to APDS1. APDS2 is associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1. APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels. No clinically relevant genotype-phenotype correlations have been identified to date. Penetrance in APDS is believed to approach 100%. However, there is considerable clinical variability, with presentations ranging from nearly asymptomatic with mild laboratory findings to severe manifestations of the disease [ The estimated prevalence of APDS is around one in one million [ • Growth delay and short stature are notable features of APDS2 and are more common in APDS2 than in APDS1. • Gastrointestinal complications, such as chronic diarrhea and enteropathy, are more frequently reported in APDS2 compared to APDS1. • APDS2 is associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1. • APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels. ## Clinical Description Activated PI3K delta syndrome (APDS) is a rare inborn error of immunity characterized primarily by frequent infections, lymphoproliferation, and autoimmune manifestations. To date, at least 250 individuals have been identified with a pathogenic variant in It is important to note that the severity and presence of these clinical findings can vary widely among affected individuals. Some may present with mild symptoms, while others experience severe manifestations that significantly impact quality of life. The variability within the spectrum of APDS highlights the importance of individualized care and management strategies. Activated PI3K Delta Syndrome: Frequency of Select Features Based on A hallmark of bronchiectasis in APDS is a chronic productive cough associated with increased frequency of respiratory infections, including pneumonia and bronchitis. These recurrent infections contribute to the progressive destruction and dilation of bronchial walls, perpetuating the cycle of infection and inflammation. Individuals often develop symptoms of obstructive lung disease, including dyspnea, wheezing, and hemoptysis. High-resolution computed tomography (HRCT) is the imaging modality of choice for diagnosing and evaluating the extent of bronchiectasis. Typical findings on HRCT include bronchial dilatation, lack of tapering of the bronchi, and bronchial wall thickening. Chronic bronchiectasis can lead to several severe complications, including respiratory failure, group 3 pulmonary hypertension leading to cor pulmonale (right-sided heart failure secondary to lung disease). Following molecular genetic testing, the pAKT/pS6 functional assay (see ## Phenotype Correlations by Gene APDS1 is caused by a heterozygous pathogenic gain-of-function variant in Growth delay and short stature are notable features of APDS2 and are more common in APDS2 than in APDS1. Gastrointestinal complications, such as chronic diarrhea and enteropathy, are more frequently reported in APDS2 compared to APDS1. APDS2 is associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1. APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels. • Growth delay and short stature are notable features of APDS2 and are more common in APDS2 than in APDS1. • Gastrointestinal complications, such as chronic diarrhea and enteropathy, are more frequently reported in APDS2 compared to APDS1. • APDS2 is associated with delayed tooth eruption due to its overlap with SHORT syndrome, a feature not typically seen in APDS1. • APDS2 is characterized by a higher incidence of B-cell lymphopenia, increased transitional B cells, and decreased serum IgA and IgG levels. ## Genotype-Phenotype Correlations No clinically relevant genotype-phenotype correlations have been identified to date. ## Penetrance Penetrance in APDS is believed to approach 100%. However, there is considerable clinical variability, with presentations ranging from nearly asymptomatic with mild laboratory findings to severe manifestations of the disease [ ## Prevalence The estimated prevalence of APDS is around one in one million [ ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders Associated with Germline A heterozygous pathogenic variant resulting in an amino acid substitution in the N-terminal SH2 domain of Mosaic postzygotic pathogenic variants in • A heterozygous pathogenic variant resulting in an amino acid substitution in the N-terminal SH2 domain of ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Activated PI3K Delta Syndrome AD = autosomal dominant; APDS = activated PI3K delta syndrome; AR = autosomal recessive; CTLA-4 = cytotoxic T-lymphocyte protein 4; EBV = Epstein-Barr virus; MOI = mode of inheritance; STAT3 = signal transducer and activator of transcription 3; XL = X-linked Caused by ## Management No clinical practice guidelines for activated PI3K delta syndrome (APDS) 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 APDS, the evaluations summarized in Activated PI3K Delta Syndrome: Recommended Evaluations Following Initial Diagnosis Detailed review of infection history EBV, CMV, HSV PCR in blood & relevant serologic testing JCV PCR if patient received rituximab CBC w/differential Immunoglobulin levels (IgG, IgA, IgM, & IgE) Lymphocyte subset analysis incl naïve/memory T cells & B-cell subsets Vaccine-specific antibody titers B-cell clonality studies by V-beta spectratyping LDH, EBV/CMV PCR Spirometry Consider chest CT Endoscopy or imaging studies Liver function tests Liver ultrasound with Doppler Fibroscan Thyroid function tests TPO antibodies ESR, CRP, ANA testing Cognitive & developmental evals Consider formal psychiatric eval. Community or Social work involvement for parental support Home nursing referral ANA = antinuclear antibody; APDS = activated PI3K delta syndrome; CBC = complete blood count; CMV = cytomegalovirus; CRP = C-reactive protein; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; HSV = herpes simplex virus; JCV = human polyomavirus 2; LDH = lactate dehydrogenase; MOI = mode of inheritance; PCR = polymerase chain reaction; TPO = thyroid peroxidase Rituximab, a monoclonal antibody, has been reported to be effective as an immunosuppressive therapy in individuals with APDS; however, it can cause persistent, often permanent, B-cell depletion [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Activated PI3K Delta Syndrome: Targeted Treatment 70 mg every 12 hrs, w/ or w/o food For women of reproductive age, pregnancy status should be verified prior to treatment. Recommended as first-line treatment of significant lymphoproliferative disease, incl lymphadenopathy & splenomegaly FDA approved in persons w/APDS age ≥12 yrs weighing ≥45 kg Dosed to a target trough blood level of 10-15 ng/mL Dose may need to be titrated depending on kidney function or ↓ in persons w/cytopenias. Recommended for persons w/lymphoproliferative disease or organomegaly when leniolisib is unavailable Is also used off-label due to its immunosuppressive & antiproliferative properties Conditioning regimens should be individualized; often incl fludarabine & treosulfan Pre- & post-HSCT optimization w/mTOR or PI3Kδ inhibitors is recommended. APDS = activated PI3K delta syndrome; mTOR = mammalian target of rapamycin; PI3Kδ = PI3K delta In a randomized, placebo-controlled Phase III clinical trial evaluating leniolisib for APDS, results included a significant reduction in the size of the index lymph node, an increase in the percentage of naïve B cells in peripheral blood, decreased spleen volume, and improved immune cell subsets. The treatment was well tolerated [ While leniolisib and sirolimus are used as immunomodulators in APDS, their absorption may be impaired by gastrointestinal inflammation, warranting the need to bridge with glucocorticoids as discussed below. Further, while some PI3Kδ inhibitors have shown efficacy in treating APDS, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematologic malignancies [ Sirolimus has demonstrated effectiveness in treating APDS by inhibiting the hyperactivated PI3K/AKT/mTOR signaling pathway [ Studies on HSCT outcomes in APDS provide helpful insights on the role of this treatment modality. In a cohort of 23 individuals, nine underwent HSCT with varying conditioning regimens, achieving an overall survival rate of 86.1% over 30 years despite challenges such as graft failure, viral reactivation, and treatment-related mortality [ Successful HSCT requires careful pre-transplant optimization, including stabilizing individuals with mTOR inhibitors or PI3Kδ inhibitors as bridging therapies. Conditioning regimens such as fludarabine and treosulfan are critical to balance effective engraftment with minimizing toxicity. HLA-matched donors are ideal, but haploidentical or mismatched donors have also been used with heightened risks. Post-transplant complications, including viral reactivation, graft failure, and transplant-related mortality, remain significant challenges, necessitating early identification and prompt intervention. 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 Activated PI3K Delta Syndrome: Treatment of Manifestations PET/CT scan Consider lymph node biopsy. Address enteropathy & hepatosplenomegaly; consider liver function monitoring & appropriate imaging. Close monitoring of gastrointestinal symptoms, nutritional status, & inflammatory markers is essential. Endoscopic & imaging evals are recommended to assess disease progression & treatment response. The need for assisted enteral/parenteral nutrition should be reassessed w/dietician. Extra doses of IV or SC immunoglobulins may be required in acute gastrointestinal disease due to enteric immunoglobulin losses. This must be weighed judiciously by treating clinician. CT = computed tomography; IV = intravenous; PET = positron emission tomography; OT = occupational therapy; PT = physical therapy; SC = subcutaneous Rituximab, a monoclonal antibody, has been reported to be effective in treating lymphoma and autoimmune disease in individuals with APDS; however, it can cause persistent, often permanent, B-cell depletion [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Activated PI3K Delta Syndrome: Recommended Surveillance IgG, IgA, IgM CD4+, CD8+, B cell subsets ANA = antinuclear antibody; CMV = cytomegalovirus; EVB = Epstein-Barr virus; HSV= herpes simplex virus; LDH = lactate dehydrogenase; PCR = polymerase chain reaction; TSH = thyroid-stimulating hormone; TPO = thyroid peroxidase Molecular genetic testing for the APDS pathogenic variant identified in the proband is recommended for all at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Detailed clinical and laboratory evaluation to assess for possible clinical features related to APDS is recommended for family members who have an APDS pathogenic variant. See The use of sirolimus in pregnancy is not recommended due to limited safety data and potential risks to the developing fetus. Animal studies have shown sirolimus to be harmful to the developing fetus. Therefore, contraception is recommended for females of reproductive age. The same applies for leniolisib, given that animal studies have shown that it interferes with organogenesis. Both leniolisib and sirolimus should therefore be discontinued in individuals planning for pregnancy. See There are currently two clinical trials evaluating the safety and efficacy of leniolisib in individuals age one to six years ( Search • Detailed review of infection history • EBV, CMV, HSV PCR in blood & relevant serologic testing • JCV PCR if patient received rituximab • CBC w/differential • Immunoglobulin levels (IgG, IgA, IgM, & IgE) • Lymphocyte subset analysis incl naïve/memory T cells & B-cell subsets • Vaccine-specific antibody titers • B-cell clonality studies by V-beta spectratyping • LDH, EBV/CMV PCR • Spirometry • Consider chest CT • Endoscopy or imaging studies • Liver function tests • Liver ultrasound with Doppler • Fibroscan • Thyroid function tests • TPO antibodies • ESR, CRP, ANA testing • Cognitive & developmental evals • Consider formal psychiatric eval. • Community or • Social work involvement for parental support • Home nursing referral • 70 mg every 12 hrs, w/ or w/o food • For women of reproductive age, pregnancy status should be verified prior to treatment. • Recommended as first-line treatment of significant lymphoproliferative disease, incl lymphadenopathy & splenomegaly • FDA approved in persons w/APDS age ≥12 yrs weighing ≥45 kg • Dosed to a target trough blood level of 10-15 ng/mL • Dose may need to be titrated depending on kidney function or ↓ in persons w/cytopenias. • Recommended for persons w/lymphoproliferative disease or organomegaly when leniolisib is unavailable • Is also used off-label due to its immunosuppressive & antiproliferative properties • Conditioning regimens should be individualized; often incl fludarabine & treosulfan • Pre- & post-HSCT optimization w/mTOR or PI3Kδ inhibitors is recommended. • PET/CT scan • Consider lymph node biopsy. • Address enteropathy & hepatosplenomegaly; consider liver function monitoring & appropriate imaging. • Close monitoring of gastrointestinal symptoms, nutritional status, & inflammatory markers is essential. Endoscopic & imaging evals are recommended to assess disease progression & treatment response. The need for assisted enteral/parenteral nutrition should be reassessed w/dietician. • Extra doses of IV or SC immunoglobulins may be required in acute gastrointestinal disease due to enteric immunoglobulin losses. This must be weighed judiciously by treating clinician. • IgG, IgA, IgM • CD4+, CD8+, B cell subsets ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with APDS, the evaluations summarized in Activated PI3K Delta Syndrome: Recommended Evaluations Following Initial Diagnosis Detailed review of infection history EBV, CMV, HSV PCR in blood & relevant serologic testing JCV PCR if patient received rituximab CBC w/differential Immunoglobulin levels (IgG, IgA, IgM, & IgE) Lymphocyte subset analysis incl naïve/memory T cells & B-cell subsets Vaccine-specific antibody titers B-cell clonality studies by V-beta spectratyping LDH, EBV/CMV PCR Spirometry Consider chest CT Endoscopy or imaging studies Liver function tests Liver ultrasound with Doppler Fibroscan Thyroid function tests TPO antibodies ESR, CRP, ANA testing Cognitive & developmental evals Consider formal psychiatric eval. Community or Social work involvement for parental support Home nursing referral ANA = antinuclear antibody; APDS = activated PI3K delta syndrome; CBC = complete blood count; CMV = cytomegalovirus; CRP = C-reactive protein; EBV = Epstein-Barr virus; ESR = erythrocyte sedimentation rate; HSV = herpes simplex virus; JCV = human polyomavirus 2; LDH = lactate dehydrogenase; MOI = mode of inheritance; PCR = polymerase chain reaction; TPO = thyroid peroxidase Rituximab, a monoclonal antibody, has been reported to be effective as an immunosuppressive therapy in individuals with APDS; however, it can cause persistent, often permanent, B-cell depletion [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Detailed review of infection history • EBV, CMV, HSV PCR in blood & relevant serologic testing • JCV PCR if patient received rituximab • CBC w/differential • Immunoglobulin levels (IgG, IgA, IgM, & IgE) • Lymphocyte subset analysis incl naïve/memory T cells & B-cell subsets • Vaccine-specific antibody titers • B-cell clonality studies by V-beta spectratyping • LDH, EBV/CMV PCR • Spirometry • Consider chest CT • Endoscopy or imaging studies • Liver function tests • Liver ultrasound with Doppler • Fibroscan • Thyroid function tests • TPO antibodies • ESR, CRP, ANA testing • Cognitive & developmental evals • Consider formal psychiatric eval. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Activated PI3K Delta Syndrome: Targeted Treatment 70 mg every 12 hrs, w/ or w/o food For women of reproductive age, pregnancy status should be verified prior to treatment. Recommended as first-line treatment of significant lymphoproliferative disease, incl lymphadenopathy & splenomegaly FDA approved in persons w/APDS age ≥12 yrs weighing ≥45 kg Dosed to a target trough blood level of 10-15 ng/mL Dose may need to be titrated depending on kidney function or ↓ in persons w/cytopenias. Recommended for persons w/lymphoproliferative disease or organomegaly when leniolisib is unavailable Is also used off-label due to its immunosuppressive & antiproliferative properties Conditioning regimens should be individualized; often incl fludarabine & treosulfan Pre- & post-HSCT optimization w/mTOR or PI3Kδ inhibitors is recommended. APDS = activated PI3K delta syndrome; mTOR = mammalian target of rapamycin; PI3Kδ = PI3K delta In a randomized, placebo-controlled Phase III clinical trial evaluating leniolisib for APDS, results included a significant reduction in the size of the index lymph node, an increase in the percentage of naïve B cells in peripheral blood, decreased spleen volume, and improved immune cell subsets. The treatment was well tolerated [ While leniolisib and sirolimus are used as immunomodulators in APDS, their absorption may be impaired by gastrointestinal inflammation, warranting the need to bridge with glucocorticoids as discussed below. Further, while some PI3Kδ inhibitors have shown efficacy in treating APDS, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematologic malignancies [ Sirolimus has demonstrated effectiveness in treating APDS by inhibiting the hyperactivated PI3K/AKT/mTOR signaling pathway [ Studies on HSCT outcomes in APDS provide helpful insights on the role of this treatment modality. In a cohort of 23 individuals, nine underwent HSCT with varying conditioning regimens, achieving an overall survival rate of 86.1% over 30 years despite challenges such as graft failure, viral reactivation, and treatment-related mortality [ Successful HSCT requires careful pre-transplant optimization, including stabilizing individuals with mTOR inhibitors or PI3Kδ inhibitors as bridging therapies. Conditioning regimens such as fludarabine and treosulfan are critical to balance effective engraftment with minimizing toxicity. HLA-matched donors are ideal, but haploidentical or mismatched donors have also been used with heightened risks. Post-transplant complications, including viral reactivation, graft failure, and transplant-related mortality, remain significant challenges, necessitating early identification and prompt intervention. 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 Activated PI3K Delta Syndrome: Treatment of Manifestations PET/CT scan Consider lymph node biopsy. Address enteropathy & hepatosplenomegaly; consider liver function monitoring & appropriate imaging. Close monitoring of gastrointestinal symptoms, nutritional status, & inflammatory markers is essential. Endoscopic & imaging evals are recommended to assess disease progression & treatment response. The need for assisted enteral/parenteral nutrition should be reassessed w/dietician. Extra doses of IV or SC immunoglobulins may be required in acute gastrointestinal disease due to enteric immunoglobulin losses. This must be weighed judiciously by treating clinician. CT = computed tomography; IV = intravenous; PET = positron emission tomography; OT = occupational therapy; PT = physical therapy; SC = subcutaneous Rituximab, a monoclonal antibody, has been reported to be effective in treating lymphoma and autoimmune disease in individuals with APDS; however, it can cause persistent, often permanent, B-cell depletion [ • 70 mg every 12 hrs, w/ or w/o food • For women of reproductive age, pregnancy status should be verified prior to treatment. • Recommended as first-line treatment of significant lymphoproliferative disease, incl lymphadenopathy & splenomegaly • FDA approved in persons w/APDS age ≥12 yrs weighing ≥45 kg • Dosed to a target trough blood level of 10-15 ng/mL • Dose may need to be titrated depending on kidney function or ↓ in persons w/cytopenias. • Recommended for persons w/lymphoproliferative disease or organomegaly when leniolisib is unavailable • Is also used off-label due to its immunosuppressive & antiproliferative properties • Conditioning regimens should be individualized; often incl fludarabine & treosulfan • Pre- & post-HSCT optimization w/mTOR or PI3Kδ inhibitors is recommended. • PET/CT scan • Consider lymph node biopsy. • Address enteropathy & hepatosplenomegaly; consider liver function monitoring & appropriate imaging. • Close monitoring of gastrointestinal symptoms, nutritional status, & inflammatory markers is essential. Endoscopic & imaging evals are recommended to assess disease progression & treatment response. The need for assisted enteral/parenteral nutrition should be reassessed w/dietician. • Extra doses of IV or SC immunoglobulins may be required in acute gastrointestinal disease due to enteric immunoglobulin losses. This must be weighed judiciously by treating clinician. ## Targeted Therapies Activated PI3K Delta Syndrome: Targeted Treatment 70 mg every 12 hrs, w/ or w/o food For women of reproductive age, pregnancy status should be verified prior to treatment. Recommended as first-line treatment of significant lymphoproliferative disease, incl lymphadenopathy & splenomegaly FDA approved in persons w/APDS age ≥12 yrs weighing ≥45 kg Dosed to a target trough blood level of 10-15 ng/mL Dose may need to be titrated depending on kidney function or ↓ in persons w/cytopenias. Recommended for persons w/lymphoproliferative disease or organomegaly when leniolisib is unavailable Is also used off-label due to its immunosuppressive & antiproliferative properties Conditioning regimens should be individualized; often incl fludarabine & treosulfan Pre- & post-HSCT optimization w/mTOR or PI3Kδ inhibitors is recommended. APDS = activated PI3K delta syndrome; mTOR = mammalian target of rapamycin; PI3Kδ = PI3K delta In a randomized, placebo-controlled Phase III clinical trial evaluating leniolisib for APDS, results included a significant reduction in the size of the index lymph node, an increase in the percentage of naïve B cells in peripheral blood, decreased spleen volume, and improved immune cell subsets. The treatment was well tolerated [ While leniolisib and sirolimus are used as immunomodulators in APDS, their absorption may be impaired by gastrointestinal inflammation, warranting the need to bridge with glucocorticoids as discussed below. Further, while some PI3Kδ inhibitors have shown efficacy in treating APDS, severe immune-mediated adverse events such as colitis, neutropenia, and hepatotoxicity have been observed with other PI3Kδ inhibitors, particularly those indicated for hematologic malignancies [ Sirolimus has demonstrated effectiveness in treating APDS by inhibiting the hyperactivated PI3K/AKT/mTOR signaling pathway [ Studies on HSCT outcomes in APDS provide helpful insights on the role of this treatment modality. In a cohort of 23 individuals, nine underwent HSCT with varying conditioning regimens, achieving an overall survival rate of 86.1% over 30 years despite challenges such as graft failure, viral reactivation, and treatment-related mortality [ Successful HSCT requires careful pre-transplant optimization, including stabilizing individuals with mTOR inhibitors or PI3Kδ inhibitors as bridging therapies. Conditioning regimens such as fludarabine and treosulfan are critical to balance effective engraftment with minimizing toxicity. HLA-matched donors are ideal, but haploidentical or mismatched donors have also been used with heightened risks. Post-transplant complications, including viral reactivation, graft failure, and transplant-related mortality, remain significant challenges, necessitating early identification and prompt intervention. • 70 mg every 12 hrs, w/ or w/o food • For women of reproductive age, pregnancy status should be verified prior to treatment. • Recommended as first-line treatment of significant lymphoproliferative disease, incl lymphadenopathy & splenomegaly • FDA approved in persons w/APDS age ≥12 yrs weighing ≥45 kg • Dosed to a target trough blood level of 10-15 ng/mL • Dose may need to be titrated depending on kidney function or ↓ in persons w/cytopenias. • Recommended for persons w/lymphoproliferative disease or organomegaly when leniolisib is unavailable • Is also used off-label due to its immunosuppressive & antiproliferative properties • Conditioning regimens should be individualized; often incl fludarabine & treosulfan • Pre- & post-HSCT optimization w/mTOR or PI3Kδ inhibitors is recommended. ## 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 Activated PI3K Delta Syndrome: Treatment of Manifestations PET/CT scan Consider lymph node biopsy. Address enteropathy & hepatosplenomegaly; consider liver function monitoring & appropriate imaging. Close monitoring of gastrointestinal symptoms, nutritional status, & inflammatory markers is essential. Endoscopic & imaging evals are recommended to assess disease progression & treatment response. The need for assisted enteral/parenteral nutrition should be reassessed w/dietician. Extra doses of IV or SC immunoglobulins may be required in acute gastrointestinal disease due to enteric immunoglobulin losses. This must be weighed judiciously by treating clinician. CT = computed tomography; IV = intravenous; PET = positron emission tomography; OT = occupational therapy; PT = physical therapy; SC = subcutaneous Rituximab, a monoclonal antibody, has been reported to be effective in treating lymphoma and autoimmune disease in individuals with APDS; however, it can cause persistent, often permanent, B-cell depletion [ • PET/CT scan • Consider lymph node biopsy. • Address enteropathy & hepatosplenomegaly; consider liver function monitoring & appropriate imaging. • Close monitoring of gastrointestinal symptoms, nutritional status, & inflammatory markers is essential. Endoscopic & imaging evals are recommended to assess disease progression & treatment response. The need for assisted enteral/parenteral nutrition should be reassessed w/dietician. • Extra doses of IV or SC immunoglobulins may be required in acute gastrointestinal disease due to enteric immunoglobulin losses. This must be weighed judiciously by treating clinician. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Activated PI3K Delta Syndrome: Recommended Surveillance IgG, IgA, IgM CD4+, CD8+, B cell subsets ANA = antinuclear antibody; CMV = cytomegalovirus; EVB = Epstein-Barr virus; HSV= herpes simplex virus; LDH = lactate dehydrogenase; PCR = polymerase chain reaction; TSH = thyroid-stimulating hormone; TPO = thyroid peroxidase • IgG, IgA, IgM • CD4+, CD8+, B cell subsets ## Evaluation of Relatives at Risk Molecular genetic testing for the APDS pathogenic variant identified in the proband is recommended for all at-risk relatives in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Detailed clinical and laboratory evaluation to assess for possible clinical features related to APDS is recommended for family members who have an APDS pathogenic variant. See ## Pregnancy Management The use of sirolimus in pregnancy is not recommended due to limited safety data and potential risks to the developing fetus. Animal studies have shown sirolimus to be harmful to the developing fetus. Therefore, contraception is recommended for females of reproductive age. The same applies for leniolisib, given that animal studies have shown that it interferes with organogenesis. Both leniolisib and sirolimus should therefore be discontinued in individuals planning for pregnancy. See ## Therapies Under Investigation There are currently two clinical trials evaluating the safety and efficacy of leniolisib in individuals age one to six years ( Search ## Genetic Counseling Activated PI3K delta syndrome (APDS) is inherited in an autosomal dominant manner. APDS1 is caused by a heterozygous Approximately 80% of individuals diagnosed with APDS have an affected parent [ Approximately 20% of individuals diagnosed with APDS have the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical evaluation for features of APDS. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the Although penetrance of APDS is high among sibs who inherit a If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the APDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and 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 80% of individuals diagnosed with APDS have an affected parent [ • Approximately 20% of individuals diagnosed with APDS have the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical evaluation for features of APDS. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • Although penetrance of APDS is high among sibs who inherit a • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Activated PI3K delta syndrome (APDS) is inherited in an autosomal dominant manner. APDS1 is caused by a heterozygous ## Risk to Family Members Approximately 80% of individuals diagnosed with APDS have an affected parent [ Approximately 20% of individuals diagnosed with APDS have the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical evaluation for features of APDS. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. If a parent of the proband is affected and/or is known to have the Although penetrance of APDS is high among sibs who inherit a If the proband has a known If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. • Approximately 80% of individuals diagnosed with APDS have an affected parent [ • Approximately 20% of individuals diagnosed with APDS have the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and determine their need for clinical evaluation for features of APDS. Note: A proband may appear to be the only affected family member because of failure to recognize the disorder in affected family members, reduced penetrance, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore, • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • If a parent of the proband is affected and/or is known to have the • Although penetrance of APDS is high among sibs who inherit a • If the proband has a known • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental gonadal mosaicism. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected 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 APDS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible. Differences in perspective may exist among medical professionals and 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 Activated PI3K Delta Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Activated PI3K Delta Syndrome ( ## Molecular Pathogenesis ## Chapter Notes Contact Dr Uzel to inquire about review of 30 January 2025 (gm) Review posted live 15 July 2024 (ks) Original submission • 30 January 2025 (gm) Review posted live • 15 July 2024 (ks) Original submission ## Author Notes Contact Dr Uzel to inquire about review of ## Revision History 30 January 2025 (gm) Review posted live 15 July 2024 (ks) Original submission • 30 January 2025 (gm) Review posted live • 15 July 2024 (ks) Original submission ## Key Sections in This ## References ## Literature Cited	[]	30/1/2025			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
apert	apert	[ "Acrocephalosyndactyly Type I", "Fibroblast growth factor receptor 2", "FGFR2", "Apert Syndrome" ]	Apert Syndrome	Tara L Wenger, Anne V Hing, Kelly N Evans	Summary Apert syndrome is characterized by the presence of multisuture craniosynostosis, midface retrusion, and syndactyly of the hands with fusion of the second through fourth nails. Almost all affected individuals have coronal craniosynostosis, and a majority also have involvement of the sagittal and lambdoid sutures. The midface in Apert syndrome is underdeveloped as well as retruded; a subset of affected individuals have cleft palate. The hand in Apert syndrome always includes fusion of the middle three digits; the thumb and fifth finger are sometimes also involved. Feeding issues, dental abnormalities, hearing loss, hyperhidrosis, and progressive synostosis of multiple bones (skull, hands, feet, carpus, tarsus, and cervical vertebrae) are also common. Multilevel airway obstruction may be present and can be due to narrowing of the nasal passages, tongue-based airway obstruction, and/or tracheal anomalies. Nonprogressive ventriculomegaly is present in a majority of individuals, with a small subset having true hydrocephalus. Most individuals with Apert syndrome have normal intelligence or mild intellectual disability; moderate-to-severe intellectual disability has been reported in some individuals. A minority of affected individuals have structural cardiac abnormalities, true gastrointestinal malformations, and anomalies of the genitourinary tract. The diagnosis of Apert syndrome is established in a proband with classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly) and/or by the identification of a heterozygous pathogenic variant in Apert syndrome is inherited in an autosomal dominant manner. However, most individuals with Apert syndrome have the disorder as the result of a	## Diagnosis Consensus clinical diagnostic criteria for Apert syndrome have not been published. Apert syndrome Multisuture craniosynostosis, most commonly involving bilateral coronal sutures with variable involvement of the remaining cranial sutures Midface retrusion with a greater degree of vertical impaction than Crouzon syndrome (See Prominent eyes with downslanting palpebral fissures Relative prognathism with malocclusion Syndactyly of the hands, including soft tissue and bone The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." Syndactyly of the feet, which may or may not include the great toe Tendency toward progressive bony fusion at multiple sites (e.g., progressive craniosynostosis, cervical vertebral fusions, bones of the hands and feet, carpus, and tarsus). Bony fusions (especially of the skull) may also occur after birth. The diagnosis of Apert syndrome Classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly); OR Suggestive clinical features AND a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ When the phenotypic findings suggest the diagnosis of Apert syndrome, molecular genetic testing approaches can include Note: All individuals with Apert syndrome have a heterozygous pathogenic variant in Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For an introduction to multigene panels click Molecular Genetic Testing Used in Apert 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 Several pathogenic variants are recurrent and commonly seen: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Multisuture craniosynostosis, most commonly involving bilateral coronal sutures with variable involvement of the remaining cranial sutures • Midface retrusion with a greater degree of vertical impaction than Crouzon syndrome (See • Prominent eyes with downslanting palpebral fissures • Relative prognathism with malocclusion • Syndactyly of the hands, including soft tissue and bone • The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. • Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." • The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. • Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." • Syndactyly of the feet, which may or may not include the great toe • Tendency toward progressive bony fusion at multiple sites (e.g., progressive craniosynostosis, cervical vertebral fusions, bones of the hands and feet, carpus, and tarsus). Bony fusions (especially of the skull) may also occur after birth. • The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. • Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." • Classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly); OR • Suggestive clinical features AND a heterozygous pathogenic (or likely pathogenic) variant in • Perform sequence analysis first. • If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. ## Suggestive Findings Apert syndrome Multisuture craniosynostosis, most commonly involving bilateral coronal sutures with variable involvement of the remaining cranial sutures Midface retrusion with a greater degree of vertical impaction than Crouzon syndrome (See Prominent eyes with downslanting palpebral fissures Relative prognathism with malocclusion Syndactyly of the hands, including soft tissue and bone The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." Syndactyly of the feet, which may or may not include the great toe Tendency toward progressive bony fusion at multiple sites (e.g., progressive craniosynostosis, cervical vertebral fusions, bones of the hands and feet, carpus, and tarsus). Bony fusions (especially of the skull) may also occur after birth. • Multisuture craniosynostosis, most commonly involving bilateral coronal sutures with variable involvement of the remaining cranial sutures • Midface retrusion with a greater degree of vertical impaction than Crouzon syndrome (See • Prominent eyes with downslanting palpebral fissures • Relative prognathism with malocclusion • Syndactyly of the hands, including soft tissue and bone • The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. • Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." • The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. • Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." • Syndactyly of the feet, which may or may not include the great toe • Tendency toward progressive bony fusion at multiple sites (e.g., progressive craniosynostosis, cervical vertebral fusions, bones of the hands and feet, carpus, and tarsus). Bony fusions (especially of the skull) may also occur after birth. • The second, third, and fourth fingers are always included in the fusion, while the thumb and fifth digit may or may not be included. • Synonychia (fusion of ≥2 nails) of the second through fourth fingers is common. The appearance is sometimes referred to as a "mitten hand." ## Establishing the Diagnosis The diagnosis of Apert syndrome Classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly); OR Suggestive clinical features AND a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ When the phenotypic findings suggest the diagnosis of Apert syndrome, molecular genetic testing approaches can include Note: All individuals with Apert syndrome have a heterozygous pathogenic variant in Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. For an introduction to multigene panels click Molecular Genetic Testing Used in Apert 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 Several pathogenic variants are recurrent and commonly seen: Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly); OR • Suggestive clinical features AND a heterozygous pathogenic (or likely pathogenic) variant in • Perform sequence analysis first. • If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. ## Clinical Characteristics Apert syndrome shows substantial overlap with the clinical characteristics seen in other Depending on the involved sutures, most children with Apert syndrome have a large anterior fontanelle, which is displaced anteriorly onto the forehead [ Coronal (near 100%), though many will have multisuture craniosynostosis or pan synostosis resulting in cloverleaf skull Sagittal (~85%) Lambdoid (81%) Narrowing of the choanae or nasal turbinates can cause respiratory distress, which can be mistaken for a primary feeding issue. In this case, the infant will often suck a few times and then unlatch to breathe through an open mouth. Infants who have a primary respiratory cause for their feeding issues generally have difficulty breathing through the nose and have other signs of upper-respiratory obstruction. Children with Apert syndrome are at risk for gastrointestinal issues (see Clinical feeding evaluation and/or video fluoroscopic swallow study should be performed for all infants to identify aspiration (see Strabismus (60%) Refractive error (34%) Anisometropia (19%) Secondary ophthalmologic findings that may develop over time include exposure keratopathy and corneal scarring (8%) and optic atrophy (8%). These secondary findings may be preventable with aggressive surveillance and treatment of incomplete lid closure and increased intracranial pressure [ Abnormalities of the semicircular canals are found in 70% of affected individuals. Narrowing of the nasal passages or choanae can lead to upper-airway obstruction, and may contribute to respiratory distress as well as feeding difficulties. Tongue-based airway obstruction may also occur. In children with cleft palate, repair of the cleft palate may unmask obstruction at the level of the pharynx and result in worsening of obstructive sleep apnea. Tracheal anomalies, including fused rings and tracheal cartilaginous sleeves, have been reported in a number of individuals. Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. Synostosis of the radius and humerus Preaxial and/or postaxial polydactyly of the hands and/or feet Broad distal phalanx of the thumb or broad distal hallux Restriction of movement involving the shoulder due to glenohumeral dysplasia can lead to functional impairment. This restriction tends to be progressive with decrease in forward flexion and abduction of the upper arm limiting the ability of the individual with Apert syndrome to perform "overhead" tasks [ Children with Apert syndrome may experience progressive deformities of the foot leading to pain and difficulty with gait. Over time the first metatarsal bone becomes relatively short with resultant shift in the weight-bearing function of the first metatarsal to the second metatarsal bone, and the great toes become increasingly short and angulated. Callus formation develops as weight is redistributed laterally leading to pain and limitation of daily activities. Affected individuals experience difficulty finding footwear that fits properly [ Approximately 60% of individuals with Apert syndrome have nonprogressive ventriculomegaly and 6%-13% have hydrocephalus. Stable ventriculomegaly does not necessarily require surgical intervention. Progressive ventriculomegaly can indicate hydrocephalus, which may require evaluation for endoscopic third ventriculostomy and/or ventriculoperitoneal shunt. Structural brain malformations in Apert syndrome include the following [ Abnormalities of the corpus callosum (23%) Absent septum pellucidum (17%) Chiari I malformation and/or low-lying cerebellar tonsils (17%) Note: Only 2% of individuals with Apert syndrome were found to have chronic tonsillar herniation, which is present in 73% of those with Crouzon syndrome. Posterior fossa arachnoid cyst (7%) Limbic malformations Factors associated with a higher risk for intellectual disability include the following: Delay of first craniectomy until after one year of age Presence of structural brain malformations Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. One of 15 individuals with Apert syndrome had intestinal malrotation in one study, though it was unclear whether the remaining affected individuals had undergone formal radiologic evaluation for malrotation (upper GI); therefore, the true prevalence may be higher than reported [ Distal esophageal stenosis has also been reported [ Other gastrointestinal malformations reported in Apert syndrome include the following: Pyloric stenosis Esophageal atresia Ectopic anus Reports regarding genotype-phenotype correlations in Apert syndrome are variable. Some studies suggest no clear correlations [ Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ No other features of Apert syndrome have been found to vary based on genotype [ Apert syndrome may also be referred to as acrocephalysyndactyly type I. The estimated birth prevalence of Apert syndrome ranges from 1: 80,000 to 1:160,000 live births [ • Coronal (near 100%), though many will have multisuture craniosynostosis or pan synostosis resulting in cloverleaf skull • Sagittal (~85%) • Lambdoid (81%) • Strabismus (60%) • Refractive error (34%) • Anisometropia (19%) • Narrowing of the nasal passages or choanae can lead to upper-airway obstruction, and may contribute to respiratory distress as well as feeding difficulties. • Tongue-based airway obstruction may also occur. • In children with cleft palate, repair of the cleft palate may unmask obstruction at the level of the pharynx and result in worsening of obstructive sleep apnea. • Tracheal anomalies, including fused rings and tracheal cartilaginous sleeves, have been reported in a number of individuals. • Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. • Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. • Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. • Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. • Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. • Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. • Synostosis of the radius and humerus • Preaxial and/or postaxial polydactyly of the hands and/or feet • Broad distal phalanx of the thumb or broad distal hallux • Stable ventriculomegaly does not necessarily require surgical intervention. • Progressive ventriculomegaly can indicate hydrocephalus, which may require evaluation for endoscopic third ventriculostomy and/or ventriculoperitoneal shunt. • Abnormalities of the corpus callosum (23%) • Absent septum pellucidum (17%) • Chiari I malformation and/or low-lying cerebellar tonsils (17%) • Note: Only 2% of individuals with Apert syndrome were found to have chronic tonsillar herniation, which is present in 73% of those with Crouzon syndrome. • Posterior fossa arachnoid cyst (7%) • Limbic malformations • Delay of first craniectomy until after one year of age • Presence of structural brain malformations • Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. • Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. • Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. • Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. • Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. • Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. • Pyloric stenosis • Esophageal atresia • Ectopic anus • Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. • One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ • Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. • One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ • Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. • One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ ## Clinical Description Apert syndrome shows substantial overlap with the clinical characteristics seen in other Depending on the involved sutures, most children with Apert syndrome have a large anterior fontanelle, which is displaced anteriorly onto the forehead [ Coronal (near 100%), though many will have multisuture craniosynostosis or pan synostosis resulting in cloverleaf skull Sagittal (~85%) Lambdoid (81%) Narrowing of the choanae or nasal turbinates can cause respiratory distress, which can be mistaken for a primary feeding issue. In this case, the infant will often suck a few times and then unlatch to breathe through an open mouth. Infants who have a primary respiratory cause for their feeding issues generally have difficulty breathing through the nose and have other signs of upper-respiratory obstruction. Children with Apert syndrome are at risk for gastrointestinal issues (see Clinical feeding evaluation and/or video fluoroscopic swallow study should be performed for all infants to identify aspiration (see Strabismus (60%) Refractive error (34%) Anisometropia (19%) Secondary ophthalmologic findings that may develop over time include exposure keratopathy and corneal scarring (8%) and optic atrophy (8%). These secondary findings may be preventable with aggressive surveillance and treatment of incomplete lid closure and increased intracranial pressure [ Abnormalities of the semicircular canals are found in 70% of affected individuals. Narrowing of the nasal passages or choanae can lead to upper-airway obstruction, and may contribute to respiratory distress as well as feeding difficulties. Tongue-based airway obstruction may also occur. In children with cleft palate, repair of the cleft palate may unmask obstruction at the level of the pharynx and result in worsening of obstructive sleep apnea. Tracheal anomalies, including fused rings and tracheal cartilaginous sleeves, have been reported in a number of individuals. Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. Synostosis of the radius and humerus Preaxial and/or postaxial polydactyly of the hands and/or feet Broad distal phalanx of the thumb or broad distal hallux Restriction of movement involving the shoulder due to glenohumeral dysplasia can lead to functional impairment. This restriction tends to be progressive with decrease in forward flexion and abduction of the upper arm limiting the ability of the individual with Apert syndrome to perform "overhead" tasks [ Children with Apert syndrome may experience progressive deformities of the foot leading to pain and difficulty with gait. Over time the first metatarsal bone becomes relatively short with resultant shift in the weight-bearing function of the first metatarsal to the second metatarsal bone, and the great toes become increasingly short and angulated. Callus formation develops as weight is redistributed laterally leading to pain and limitation of daily activities. Affected individuals experience difficulty finding footwear that fits properly [ Approximately 60% of individuals with Apert syndrome have nonprogressive ventriculomegaly and 6%-13% have hydrocephalus. Stable ventriculomegaly does not necessarily require surgical intervention. Progressive ventriculomegaly can indicate hydrocephalus, which may require evaluation for endoscopic third ventriculostomy and/or ventriculoperitoneal shunt. Structural brain malformations in Apert syndrome include the following [ Abnormalities of the corpus callosum (23%) Absent septum pellucidum (17%) Chiari I malformation and/or low-lying cerebellar tonsils (17%) Note: Only 2% of individuals with Apert syndrome were found to have chronic tonsillar herniation, which is present in 73% of those with Crouzon syndrome. Posterior fossa arachnoid cyst (7%) Limbic malformations Factors associated with a higher risk for intellectual disability include the following: Delay of first craniectomy until after one year of age Presence of structural brain malformations Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. One of 15 individuals with Apert syndrome had intestinal malrotation in one study, though it was unclear whether the remaining affected individuals had undergone formal radiologic evaluation for malrotation (upper GI); therefore, the true prevalence may be higher than reported [ Distal esophageal stenosis has also been reported [ Other gastrointestinal malformations reported in Apert syndrome include the following: Pyloric stenosis Esophageal atresia Ectopic anus • Coronal (near 100%), though many will have multisuture craniosynostosis or pan synostosis resulting in cloverleaf skull • Sagittal (~85%) • Lambdoid (81%) • Strabismus (60%) • Refractive error (34%) • Anisometropia (19%) • Narrowing of the nasal passages or choanae can lead to upper-airway obstruction, and may contribute to respiratory distress as well as feeding difficulties. • Tongue-based airway obstruction may also occur. • In children with cleft palate, repair of the cleft palate may unmask obstruction at the level of the pharynx and result in worsening of obstructive sleep apnea. • Tracheal anomalies, including fused rings and tracheal cartilaginous sleeves, have been reported in a number of individuals. • Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. • Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. • Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. • Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. • Significant variability in severity is seen, ranging from mild respiratory symptoms requiring little intervention to severe obstruction requiring placement of tracheostomy. • Some children who require tracheostomy need a ventilator for delivery of positive airway pressure during sleep. • Synostosis of the radius and humerus • Preaxial and/or postaxial polydactyly of the hands and/or feet • Broad distal phalanx of the thumb or broad distal hallux • Stable ventriculomegaly does not necessarily require surgical intervention. • Progressive ventriculomegaly can indicate hydrocephalus, which may require evaluation for endoscopic third ventriculostomy and/or ventriculoperitoneal shunt. • Abnormalities of the corpus callosum (23%) • Absent septum pellucidum (17%) • Chiari I malformation and/or low-lying cerebellar tonsils (17%) • Note: Only 2% of individuals with Apert syndrome were found to have chronic tonsillar herniation, which is present in 73% of those with Crouzon syndrome. • Posterior fossa arachnoid cyst (7%) • Limbic malformations • Delay of first craniectomy until after one year of age • Presence of structural brain malformations • Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. • Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. • Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. • Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. • Abnormalities of the septum pellicudum have been shown to be associated with lower IQ. • Data regarding the possible impact on IQ of an abnormal callosum and/or corpus callosum are conflicting. • Pyloric stenosis • Esophageal atresia • Ectopic anus ## Genotype-Phenotype Correlations Reports regarding genotype-phenotype correlations in Apert syndrome are variable. Some studies suggest no clear correlations [ Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ No other features of Apert syndrome have been found to vary based on genotype [ • Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. • One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ • Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. • One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ • Some studies have suggested more significant hand and foot involvement in individuals with this pathogenic variant. • One study suggested better postsurgical craniofacial appearance in affected individuals with this variant, but the generalizability of this study is limited due to significant evolution of surgical techniques since the study was published [ ## Nomenclature Apert syndrome may also be referred to as acrocephalysyndactyly type I. ## Prevalence The estimated birth prevalence of Apert syndrome ranges from 1: 80,000 to 1:160,000 live births [ ## Genetically Related (Allelic) Disorders Other phenotypes associated with germline pathogenic variants in Allelic Disorders to Consider in the Differential Diagnosis of Apert Syndrome Craniosynostosis (coronal & lambdoidal) Brachyturricephaly w/frontal bossing Ocular proptosis Downslanting palpebral fissures Radiohumeral synostosis Depression of nasal bridge Low-set, protruding ears Medial bowing of ulnae Bowing of femurs Slender hands & feet Contractures at proximal IP joints Fractures Advanced bone age Congenital heart disease Renal anomalies Abnormalities of female genitalia Signs of congenital adrenal hyperplasia Craniosynostosis (coronal most common) Midface hypoplasia Natal teeth Pyloric stenosis Furrowed palms & soles Widespread cutis gyrata Acanthosis nigricans Skin tags Prominent umbilicus Accessory nipples Bifid scrotum Prominent labial raphe Rugated labia majora Craniosynostosis (multisuture, coronal most common) Brachyturricephaly Maxillary hypoplasia Obstructive sleep apnea Tracheal cartilaginous sleeve Hypertelorism Ocular proptosis Papilledema Strabismus Atresia of auditory canals Conductive hearing loss Hydrocephalus Cervical spine fusions Chiari 1 malformation more common Midface retrusion w/less vertical impaction Craniosynostosis (coronal most common) Maxillary hypoplasia Obstructive sleep apnea Hypertelorism Ocular proptosis Strabismus Fusion of tarsal & metatarsal bones 2-3 syndactyly Broad & medially deviated great toes Short 1st metatarsals Broad proximal phalanges Craniosynostosis (multisuture, coronal most common) Brachyturricephaly Maxillary hypoplasia Obstructive sleep apnea Tracheal cartilaginous sleeve Hypertelorism Ocular proptosis Papilledema Strabismus Downslanting palpebral fissures Atresia of auditory canals Conductive hearing loss Hydrocephalus Cervical spine fusions Radiohumeral fusions Chiari 1 malformation more common Broad & deviated thumbs & great toes Brachydactyly Craniosynostosis (unilateral or bilateral coronal) Brachyturricephaly Maxillary hypoplasia Obstructive sleep apnea High-arched palate Hypertelorism Downslanting palpebral fissures Hearing loss Ptosis Facial asymmetry Low anterior hairline Parietal foramina Characteristic ear (small pinna w/a prominent crus) Partial 2-3 syndactyly of fingers Duplicated distal phalanx of hallux AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Antley-Bixler syndrome is caused by mutation of See See Other Allelic Disorders (not in the Differential Diagnosis of Apert Syndrome) Sporadic tumors (including gastric cancer) occurring as single tumors in the absence of any other findings of Apert syndrome frequently harbor somatic variants in • Craniosynostosis (coronal & lambdoidal) • Brachyturricephaly w/frontal bossing • Ocular proptosis • Downslanting palpebral fissures • Radiohumeral synostosis • Depression of nasal bridge • Low-set, protruding ears • Medial bowing of ulnae • Bowing of femurs • Slender hands & feet • Contractures at proximal IP joints • Fractures • Advanced bone age • Congenital heart disease • Renal anomalies • Abnormalities of female genitalia • Signs of congenital adrenal hyperplasia • Craniosynostosis (coronal most common) • Midface hypoplasia • Natal teeth • Pyloric stenosis • Furrowed palms & soles • Widespread cutis gyrata • Acanthosis nigricans • Skin tags • Prominent umbilicus • Accessory nipples • Bifid scrotum • Prominent labial raphe • Rugated labia majora • Craniosynostosis (multisuture, coronal most common) • Brachyturricephaly • Maxillary hypoplasia • Obstructive sleep apnea • Tracheal cartilaginous sleeve • Hypertelorism • Ocular proptosis • Papilledema • Strabismus • Atresia of auditory canals • Conductive hearing loss • Hydrocephalus • Cervical spine fusions • Chiari 1 malformation more common • Midface retrusion w/less vertical impaction • Craniosynostosis (coronal most common) • Maxillary hypoplasia • Obstructive sleep apnea • Hypertelorism • Ocular proptosis • Strabismus • Fusion of tarsal & metatarsal bones • 2-3 syndactyly • Broad & medially deviated great toes • Short 1st metatarsals • Broad proximal phalanges • Craniosynostosis (multisuture, coronal most common) • Brachyturricephaly • Maxillary hypoplasia • Obstructive sleep apnea • Tracheal cartilaginous sleeve • Hypertelorism • Ocular proptosis • Papilledema • Strabismus • Downslanting palpebral fissures • Atresia of auditory canals • Conductive hearing loss • Hydrocephalus • Cervical spine fusions • Radiohumeral fusions • Chiari 1 malformation more common • Broad & deviated thumbs & great toes • Brachydactyly • Craniosynostosis (unilateral or bilateral coronal) • Brachyturricephaly • Maxillary hypoplasia • Obstructive sleep apnea • High-arched palate • Hypertelorism • Downslanting palpebral fissures • Hearing loss • Ptosis • Facial asymmetry • Low anterior hairline • Parietal foramina • Characteristic ear (small pinna w/a prominent crus) • Partial 2-3 syndactyly of fingers • Duplicated distal phalanx of hallux ## Differential Diagnosis Most children with multisuture synostosis will have a syndromic form of craniosynostosis. The presence of specific craniofacial characteristics and hand and foot anomalies allow for the clinical diagnosis of Apert syndrome in most cases. Establishing an accurate diagnosis has important implications for screening, surveillance, management, and counseling (see Select syndromes to consider in the differential diagnosis of Apert syndrome include the allelic disorders listed in Nonallelic Craniosynostosis Syndromes to Consider in the Differential Diagnosis of Apert Syndrome Craniosynostosis (multisuture, coronal most common) Brachyturricephaly Maxillary hypoplasia Obstructive sleep apnea Hypertelorism Ocular proptosis Craniosynostosis (unilateral or bilateral coronal) Mild maxillary hypoplasia Downslanting palpebral fissures Cervical spine fusions Sensorineural hearing loss Brachydactyly Carpal-tarsal fusion Carpal bone malsegregation Coned epiphyses AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked Antley-Bixler syndrome is caused by mutation of Pfeiffer syndrome is caused by mutation of Saethre-Chotzen syndrome is typically caused by mutation of • Craniosynostosis (multisuture, coronal most common) • Brachyturricephaly • Maxillary hypoplasia • Obstructive sleep apnea • Hypertelorism • Ocular proptosis • Craniosynostosis (unilateral or bilateral coronal) • Mild maxillary hypoplasia • Downslanting palpebral fissures • Cervical spine fusions • Sensorineural hearing loss • Brachydactyly • Carpal-tarsal fusion • Carpal bone malsegregation • Coned epiphyses ## Management To establish the extent of disease and needs in an individual diagnosed with Apert syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Apert Syndrome CNS = central nervous system; CT = computed tomography; GI = gastrointestinal; MRI = magnetic resonance imaging Early detection and management of amblyopia, encouraging timely decompressive surgery before the presence of optic nerve atrophy, and protection of the cornea are the management goals for ophthalmologists [ Treatment of Manifestations in Individuals with Apert Syndrome Placement of nasal stents Endotracheal intubation Tracheotomy Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased ICP and reduce progressive abnormal craniofacial development. Several techniques including endoscopic strip craniectomy, advancement through posterior distraction, and traditional cranioplasty are in current use. Early surgery may be performed to reduce intracranial pressure; however, young infants with Apert syndrome may have minimal reserve. Later surgeries tend to lead to a more stable bony correction [ A staged approach to increase intracranial volume and protect the globes is often pursued, and most children with Apert and bicoronal craniosynostosis will benefit from a front-orbital advancement. The goals of craniofacial surgery are to provide adequate intracranial volume to allow brain development and to improve skull shape. The timing and sequence of surgical interventions are dependent on the patient's functional, aesthetic, and psychological needs [ Timing of jaw surgery is guided by the affected individual's occlusion and degree of airway obstruction. Compared with Le Fort III distraction, Le Fort II distraction with simultaneous repositioning of the zygomas improves the facial and orbital relationships for older children with Apert syndrome [ Articulation, resonance, language development, voice, feeding, and swallowing may be affected in individuals with Apert syndrome. Serious caution must be taken in the placement and care of tracheostomies in patients with tracheal cartilaginous sleeve malformation because of abnormal tissue healing and granulation tissue formation [ Recent studies describe novel techniques to improve aesthetic outcomes in children with complex syndactylies [ Evidence suggests that oral isotretinoin may be more effective than standard therapies, and biologic models support a role for isotretinoin in regulating androgens and Suggested areas of focus include the parents' and family's emotional, social, and financial needs; the child's neurocognitive development and educational needs; and potential barriers to care [ 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. Comprehensive care provided by a specialized craniofacial center that includes psychosocial support and holistic transition (to adult care) planning may improve quality of life for adults with Apert syndrome. Prevention of Secondary Manifestations in Individuals with Apert Syndrome Vigilance regarding spine precautions Consultation w/spine surgeon will guide precautions & positioning prior to surgery & anesthesia. Most commonly upper-airway obstruction (6.1%) [ While upper-airway obstruction is the most common, lower respiratory-tract complications during anesthesia have also been reported [ A craniofacial team made up of the appropriate specialties allows for proper planning and coordination so that the affected individual may receive the best possible care [ Ideally, the composition of the multidisciplinary team caring for a child with Apert syndrome should include the following specialists: Audiologist Dentist Dermatologist Feeding specialist Geneticist Neurodevelopmental and behavioral pediatrician Neurosurgeon Nurse Nutritionist Ophthalmologist Oral surgeon Orthodontist Orthopedist (hand and foot surgery) Otolaryngologist Pediatrician Plastic surgeon Psychologist Pulmonologist / sleep medicine Social worker Speech pathologist Spine surgeon Recommended Surveillance for Individuals with Apert Syndrome For those with cleft palate Orthognathic and airway procedures may also alter velopharyngeal function. Surveillance by an orthodontist with craniofacial expertise beginning in mixed dentition will help guide orthodontic and orthognathic interventions. Papilledema in individuals with multisuture craniosynostosis can occur before and after cranial decompression [ The type of surveillance needed depends on the types of surgery that the child has had and will be determined by the neurosurgeon and craniofacial team. The craniofacial team should be contacted urgently if there are symptoms that suggest increased pressure such as unexplained persistent vomiting, headaches, or changes in head circumference. Contact sports and activities that involve neck hyperflexion or extension should be avoided, unless the individual has had the cervical spine assessed and cleared. Avoid factors that potentiate hearing loss (ototoxic medications, overly loud stimuli). Use of CPAP/BiPAP for long-term treatment of sleep apnea should be avoided when possible because pressure on the midface will exacerbate midfacial retrusion. See No published studies address management of pregnancy in women with Apert syndrome. Affected pregnant women should be monitored carefully for signs and symptoms of worsening obstructive sleep apnea. A pregnant woman with Apert syndrome should have a careful anesthesia evaluation prior to initiation of labor to determine whether multilevel airway anomalies or vertebral anomalies would result in additional risk with certain types of anesthesia. If an obstetric emergency necessitates use of general anesthesia, fiberoptic intubation could be required. If this need were identified prior to delivery, the delivery location and timing could be chosen to ensure that adequate personnel were present to perform fiberoptic intubation, if needed. Search • Placement of nasal stents • Endotracheal intubation • Tracheotomy • 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. • Vigilance regarding spine precautions • Consultation w/spine surgeon will guide precautions & positioning prior to surgery & anesthesia. • Audiologist • Dentist • Dermatologist • Feeding specialist • Geneticist • Neurodevelopmental and behavioral pediatrician • Neurosurgeon • Nurse • Nutritionist • Ophthalmologist • Oral surgeon • Orthodontist • Orthopedist (hand and foot surgery) • Otolaryngologist • Pediatrician • Plastic surgeon • Psychologist • Pulmonologist / sleep medicine • Social worker • Speech pathologist • Spine surgeon • If an obstetric emergency necessitates use of general anesthesia, fiberoptic intubation could be required. • If this need were identified prior to delivery, the delivery location and timing could be chosen to ensure that adequate personnel were present to perform fiberoptic intubation, if needed. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Apert syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Apert Syndrome CNS = central nervous system; CT = computed tomography; GI = gastrointestinal; MRI = magnetic resonance imaging Early detection and management of amblyopia, encouraging timely decompressive surgery before the presence of optic nerve atrophy, and protection of the cornea are the management goals for ophthalmologists [ ## Treatment of Manifestations Treatment of Manifestations in Individuals with Apert Syndrome Placement of nasal stents Endotracheal intubation Tracheotomy Cranioplasty involves release of fused sutures and repositioning and reconstruction of the calvaria, in order to prevent increased ICP and reduce progressive abnormal craniofacial development. Several techniques including endoscopic strip craniectomy, advancement through posterior distraction, and traditional cranioplasty are in current use. Early surgery may be performed to reduce intracranial pressure; however, young infants with Apert syndrome may have minimal reserve. Later surgeries tend to lead to a more stable bony correction [ A staged approach to increase intracranial volume and protect the globes is often pursued, and most children with Apert and bicoronal craniosynostosis will benefit from a front-orbital advancement. The goals of craniofacial surgery are to provide adequate intracranial volume to allow brain development and to improve skull shape. The timing and sequence of surgical interventions are dependent on the patient's functional, aesthetic, and psychological needs [ Timing of jaw surgery is guided by the affected individual's occlusion and degree of airway obstruction. Compared with Le Fort III distraction, Le Fort II distraction with simultaneous repositioning of the zygomas improves the facial and orbital relationships for older children with Apert syndrome [ Articulation, resonance, language development, voice, feeding, and swallowing may be affected in individuals with Apert syndrome. Serious caution must be taken in the placement and care of tracheostomies in patients with tracheal cartilaginous sleeve malformation because of abnormal tissue healing and granulation tissue formation [ Recent studies describe novel techniques to improve aesthetic outcomes in children with complex syndactylies [ Evidence suggests that oral isotretinoin may be more effective than standard therapies, and biologic models support a role for isotretinoin in regulating androgens and Suggested areas of focus include the parents' and family's emotional, social, and financial needs; the child's neurocognitive development and educational needs; and potential barriers to care [ 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. Comprehensive care provided by a specialized craniofacial center that includes psychosocial support and holistic transition (to adult care) planning may improve quality of life for adults with Apert syndrome. • Placement of nasal stents • Endotracheal intubation • Tracheotomy • 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 ## Adults Comprehensive care provided by a specialized craniofacial center that includes psychosocial support and holistic transition (to adult care) planning may improve quality of life for adults with Apert syndrome. ## Prevention of Secondary Complications Prevention of Secondary Manifestations in Individuals with Apert Syndrome Vigilance regarding spine precautions Consultation w/spine surgeon will guide precautions & positioning prior to surgery & anesthesia. Most commonly upper-airway obstruction (6.1%) [ While upper-airway obstruction is the most common, lower respiratory-tract complications during anesthesia have also been reported [ • Vigilance regarding spine precautions • Consultation w/spine surgeon will guide precautions & positioning prior to surgery & anesthesia. ## Surveillance A craniofacial team made up of the appropriate specialties allows for proper planning and coordination so that the affected individual may receive the best possible care [ Ideally, the composition of the multidisciplinary team caring for a child with Apert syndrome should include the following specialists: Audiologist Dentist Dermatologist Feeding specialist Geneticist Neurodevelopmental and behavioral pediatrician Neurosurgeon Nurse Nutritionist Ophthalmologist Oral surgeon Orthodontist Orthopedist (hand and foot surgery) Otolaryngologist Pediatrician Plastic surgeon Psychologist Pulmonologist / sleep medicine Social worker Speech pathologist Spine surgeon Recommended Surveillance for Individuals with Apert Syndrome For those with cleft palate Orthognathic and airway procedures may also alter velopharyngeal function. Surveillance by an orthodontist with craniofacial expertise beginning in mixed dentition will help guide orthodontic and orthognathic interventions. Papilledema in individuals with multisuture craniosynostosis can occur before and after cranial decompression [ The type of surveillance needed depends on the types of surgery that the child has had and will be determined by the neurosurgeon and craniofacial team. The craniofacial team should be contacted urgently if there are symptoms that suggest increased pressure such as unexplained persistent vomiting, headaches, or changes in head circumference. • Audiologist • Dentist • Dermatologist • Feeding specialist • Geneticist • Neurodevelopmental and behavioral pediatrician • Neurosurgeon • Nurse • Nutritionist • Ophthalmologist • Oral surgeon • Orthodontist • Orthopedist (hand and foot surgery) • Otolaryngologist • Pediatrician • Plastic surgeon • Psychologist • Pulmonologist / sleep medicine • Social worker • Speech pathologist • Spine surgeon ## Agents/Circumstances to Avoid Contact sports and activities that involve neck hyperflexion or extension should be avoided, unless the individual has had the cervical spine assessed and cleared. Avoid factors that potentiate hearing loss (ototoxic medications, overly loud stimuli). Use of CPAP/BiPAP for long-term treatment of sleep apnea should be avoided when possible because pressure on the midface will exacerbate midfacial retrusion. ## Evaluation of Relatives at Risk See ## Pregnancy Management No published studies address management of pregnancy in women with Apert syndrome. Affected pregnant women should be monitored carefully for signs and symptoms of worsening obstructive sleep apnea. A pregnant woman with Apert syndrome should have a careful anesthesia evaluation prior to initiation of labor to determine whether multilevel airway anomalies or vertebral anomalies would result in additional risk with certain types of anesthesia. If an obstetric emergency necessitates use of general anesthesia, fiberoptic intubation could be required. If this need were identified prior to delivery, the delivery location and timing could be chosen to ensure that adequate personnel were present to perform fiberoptic intubation, if needed. • If an obstetric emergency necessitates use of general anesthesia, fiberoptic intubation could be required. • If this need were identified prior to delivery, the delivery location and timing could be chosen to ensure that adequate personnel were present to perform fiberoptic intubation, if needed. ## Therapies Under Investigation Search ## Genetic Counseling Apert syndrome is inherited in an autosomal dominant manner. Some individuals diagnosed with Apert syndrome have an affected parent. Most individuals diagnosed with Apert syndrome have the disorder as the result of a Molecular genetic testing can be performed on the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred If a parent of the proband is affected, the risk to sibs is 50%. If the parents are unaffected and/or the proband has a known The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. 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 Apert syndrome have an affected parent. • Most individuals diagnosed with Apert syndrome have the disorder as the result of a • Molecular genetic testing can be performed on the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred • If a parent of the proband is affected, the risk to sibs is 50%. • If the parents are unaffected and/or the proband has a known • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. ## Mode of Inheritance Apert syndrome is inherited in an autosomal dominant manner. ## Risk to Family Members Some individuals diagnosed with Apert syndrome have an affected parent. Most individuals diagnosed with Apert syndrome have the disorder as the result of a Molecular genetic testing can be performed on the parents of a proband with an apparent If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred If a parent of the proband is affected, the risk to sibs is 50%. If the parents are unaffected and/or the proband has a known • Some individuals diagnosed with Apert syndrome have an affected parent. • Most individuals diagnosed with Apert syndrome have the disorder as the result of a • Molecular genetic testing can be performed on the parents of a proband with an apparent • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the pathogenic variant most likely occurred • If a parent of the proband is affected, the risk to sibs is 50%. • If the parents are unaffected and/or the proband has a known ## 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 13140 Coit Road Suite 517 Dallas TX 75240 • • • • 13140 Coit Road • Suite 517 • Dallas TX 75240 • • • ## Molecular Genetics Apert Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Apert Syndrome ( FGFR2 belongs to a complex system of intracellular signaling consisting of multiple fibroblast growth factors (FGFs) and their receptors FGFRs. This signaling network functions in the control of cell proliferation, differentiation, migration, and death in many different contexts such as embryonic development, angiogenesis, immunity, and cancer. Diseases result from loss-of-function, gain-of-function, postzygotic mosaic, and/or somatic alterations in components of this network. For an excellent overview of this signaling network, along with effects of germline and somatic alterations in FGFs and FGFRs that result in human disease, see Note that some literature describing pathogenic variants confuses the terminology of exon and domain. Alterations in exons 8 and 9, which encode IG-like domain IIIb and IIIc, respectively, may be referred to as alterations in exon IIIb and exon IIIc. Variants listed in the table have been provided by the authors. See Originally published as C934G [ See Originally published as C937G [ A signal peptide, residues 1-21, is cleaved in post-translational processing to give the mature peptide, residues 22-821, which consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. Residues Ser252 and Pro253, the sites of recurrent pathogenic variants, are located in the linker between the second and third immunoglobulin-like domains. Sporadic tumors occurring as single tumors in the absence of any other clinical findings of Apert syndrome frequently harbor somatic variants in Somatic loss-of-function, gain-of-function, and gene fusions involving ## Molecular Pathogenesis FGFR2 belongs to a complex system of intracellular signaling consisting of multiple fibroblast growth factors (FGFs) and their receptors FGFRs. This signaling network functions in the control of cell proliferation, differentiation, migration, and death in many different contexts such as embryonic development, angiogenesis, immunity, and cancer. Diseases result from loss-of-function, gain-of-function, postzygotic mosaic, and/or somatic alterations in components of this network. For an excellent overview of this signaling network, along with effects of germline and somatic alterations in FGFs and FGFRs that result in human disease, see Note that some literature describing pathogenic variants confuses the terminology of exon and domain. Alterations in exons 8 and 9, which encode IG-like domain IIIb and IIIc, respectively, may be referred to as alterations in exon IIIb and exon IIIc. Variants listed in the table have been provided by the authors. See Originally published as C934G [ See Originally published as C937G [ A signal peptide, residues 1-21, is cleaved in post-translational processing to give the mature peptide, residues 22-821, which consists of an extracellular region composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment, and a cytoplasmic tyrosine kinase domain. Residues Ser252 and Pro253, the sites of recurrent pathogenic variants, are located in the linker between the second and third immunoglobulin-like domains. ## Cancer and Benign Tumors Sporadic tumors occurring as single tumors in the absence of any other clinical findings of Apert syndrome frequently harbor somatic variants in Somatic loss-of-function, gain-of-function, and gene fusions involving ## Chapter Notes The authors would like to acknowledge Dr Carrie Heike for her critical review of this 30 May 2019 (ma) Review posted live 31 December 2017 (tw) Original submission • 30 May 2019 (ma) Review posted live • 31 December 2017 (tw) Original submission ## Acknowledgments The authors would like to acknowledge Dr Carrie Heike for her critical review of this ## Revision History 30 May 2019 (ma) Review posted live 31 December 2017 (tw) Original submission • 30 May 2019 (ma) Review posted live • 31 December 2017 (tw) Original submission ## References ## Literature Cited	[ "NB Agochukwu, BD Solomon, M Muenke. 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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", "EW Schauerte, PM St-Aubin. Progressive synosteosis in Apert's syndrome (acrocephalosyndactyly): with a description of roentgenographic changes in the feet.. Am J Roentgenol Radium Ther Nucl Med. 1966;97:67-73", "SS Sidhu, R Deshmukh. Recessive inheritance of apparent Apert syndrome with polysyndactyly?. Am J Med Genet. 1988;31:179-80", "SF Slaney, M Oldridge, JA Hurst, GM Morriss-Kay, CM Hall, MD Poole, AOM Wilkie. Differential effects of FGFR2 mutations on syndactyly and cleft palate in Apert syndrome.. Am J Hum Genet. 1996;58:923-32", "AP Tan, K Mankad. Apert syndrome: magnetic resonance imaging (MRI) of associated intracranial anomalies.. Childs Nerv Syst. 2018;34:205-16", "JA Taylor, SP Bartlett. Discussion: first vault expansion in Apert and Crouzon-Pfeiffer syndromes: front or back?. Plast Reconstr Surg. 2016;137:122e-4e", "MM Tolarova, JA Harris, DE Ordway, K Vargervik. Birth prevalence, mutation rate, sex ratio, parents' age, and ethnicity in Apert syndrome.. Am J Med Genet. 1997;72:394-8", "L Torres, G Hernández, A Barrera, S Ospina, R Prada. Molecular analysis of exons 8, 9 and 10 of the fibroblast growth factor receptor 2 (FGFR2) gene in two families with index cases of Apert syndrome.. Colomb Med (Cali) 2015;46:150-3", "R Tovetjärn, P Tarnow, G Maltese, S Fischer, PE Sahlin, L Kölby. Children with Apert syndrome as adults: a follow-up study of 28 Scandinavian patients.. Plast Reconstr Surg. 2012;130:572e-6e", "J. Upton. Classification and pathologic anatomy of limb anomalies.. Clin Plast Surg. 1991;18:321-55", "S von Gernet, A Golla, Y Ehrenfels, S Schuffenhauer, JD Fairley. Genotype-phenotype analysis in Apert syndrome suggests opposite effects of the two recurrent mutations on syndactyly and outcome of craniofacial surgery.. Clin Genet. 2000;57:137-9", "TL Wenger, J Dahl, EJ Bhoj, A Rosen, D McDonald-McGinn, E Zackai, I Jacobs, CL Heike, A Hing, A Santani, AF Inglis, KC Sie, M Cunningham, J. Perkins. Tracheal cartilaginous sleeves in children with syndromic craniosynostosis.. Genet Med. 2017;19:62-8", "AO Wilkie, SF Slaney, M Oldridge, MD Poole, GJ Ashworth, AD Hockley, RD Hayward, DJ David, LJ Pulleyn, P Rutland, S Malcolm, RM Winter, W Reardon. Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.. Nature Genet. 1995;9:165-72", "SR Yoon, J Qin, RL Glaser, EW Jabs, NS Wexler, R Sokol, N Arnheim, P Calabrese. The ups and downs of mutation frequencies during aging can account for the Apert syndrome paternal age effect.. PLoS Genet. 2009;5" ]	30/5/2019			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
apob-hbl	apob-hbl	[ "Biallelic APOB-Related Familial Hypobetalipoproteinemia (FHBL)", "Heterozygous APOB-Related Hypobetalipoproteinemia (FHBL)", "Apolipoprotein B-100", "APOB", "APOB-Related Familial Hypobetalipoproteinemia" ]		John R Burnett, Amanda J Hooper, Robert A Hegele	Summary Individuals with biallelic Individuals with a heterozygous, typically truncating pathogenic variant in The diagnosis of biallelic Individuals with biallelic Individuals with heterozygous Individuals with biallelic Individuals with heterozygous	Biallelic Heterozygous For synonyms and outdated names see For other genetic causes of these phenotypes, see • Biallelic • Heterozygous ## Diagnosis In this Biallelic Heterozygous Note: Both heterozygous and biallelic pathogenic variants in Biallelic Failure to thrive, with diarrhea Fat malabsorption with steatorrhea Acquired atypical pigmentation of the retina Ataxia with or without absent reflexes Hepatomegaly Hepatic steatosis Marked hypocholesterolemia (total cholesterol ~1.0 mmol/L [40 mg/dL]) Plasma LDL cholesterol (measured or calculated) absent or extremely low Plasma apo B absent or very low Plasma triglyceride very low Plasma HDL cholesterol at a low to average level Acanthocytosis Abnormal liver transaminases (ALT and AST 1-1.5x the upper reference limit) Prolonged international normalized ratio (INR) Low serum concentrations of fat-soluble vitamins (A, D, E, and K) Heterozygous Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual Note: Absence of a known family history of first degree relatives with asymptomatic hepatic steatosis and/or hypocholesterolemia does not preclude the diagnosis. The diagnosis of biallelic Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ When the phenotype and laboratory findings suggest the diagnosis of Perform sequence analysis first. If no pathogenic variant or only one pathogenic variant is identified in a symptomatic individual, consider gene-targeted deletion/duplication testing. If no pathogenic variant is identified in an asymptomatic individual who has suggestive laboratory, imaging, and/or family history findings, consider gene-targeted deletion/duplication testing. For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions/duplications are very rare [ • Biallelic • Heterozygous • Note: Both heterozygous and biallelic pathogenic variants in • Failure to thrive, with diarrhea • Fat malabsorption with steatorrhea • Acquired atypical pigmentation of the retina • Ataxia with or without absent reflexes • Hepatomegaly • Hepatic steatosis • Marked hypocholesterolemia (total cholesterol ~1.0 mmol/L [40 mg/dL]) • Plasma LDL cholesterol (measured or calculated) absent or extremely low • Plasma apo B absent or very low • Plasma triglyceride very low • Plasma HDL cholesterol at a low to average level • Acanthocytosis • Abnormal liver transaminases (ALT and AST 1-1.5x the upper reference limit) • Prolonged international normalized ratio (INR) • Low serum concentrations of fat-soluble vitamins (A, D, E, and K) • • Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) • Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) • Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) • Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) • Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual • Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) • Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) • Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) • Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) • Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual • Note: Absence of a known family history of first degree relatives with asymptomatic hepatic steatosis and/or hypocholesterolemia does not preclude the diagnosis. • Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) • Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) • Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) • Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) • Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual • Perform sequence analysis first. • If no pathogenic variant or only one pathogenic variant is identified in a symptomatic individual, consider gene-targeted deletion/duplication testing. • If no pathogenic variant is identified in an asymptomatic individual who has suggestive laboratory, imaging, and/or family history findings, consider gene-targeted deletion/duplication testing. ## Suggestive Findings Biallelic Failure to thrive, with diarrhea Fat malabsorption with steatorrhea Acquired atypical pigmentation of the retina Ataxia with or without absent reflexes Hepatomegaly Hepatic steatosis Marked hypocholesterolemia (total cholesterol ~1.0 mmol/L [40 mg/dL]) Plasma LDL cholesterol (measured or calculated) absent or extremely low Plasma apo B absent or very low Plasma triglyceride very low Plasma HDL cholesterol at a low to average level Acanthocytosis Abnormal liver transaminases (ALT and AST 1-1.5x the upper reference limit) Prolonged international normalized ratio (INR) Low serum concentrations of fat-soluble vitamins (A, D, E, and K) Heterozygous Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual Note: Absence of a known family history of first degree relatives with asymptomatic hepatic steatosis and/or hypocholesterolemia does not preclude the diagnosis. • Failure to thrive, with diarrhea • Fat malabsorption with steatorrhea • Acquired atypical pigmentation of the retina • Ataxia with or without absent reflexes • Hepatomegaly • Hepatic steatosis • Marked hypocholesterolemia (total cholesterol ~1.0 mmol/L [40 mg/dL]) • Plasma LDL cholesterol (measured or calculated) absent or extremely low • Plasma apo B absent or very low • Plasma triglyceride very low • Plasma HDL cholesterol at a low to average level • Acanthocytosis • Abnormal liver transaminases (ALT and AST 1-1.5x the upper reference limit) • Prolonged international normalized ratio (INR) • Low serum concentrations of fat-soluble vitamins (A, D, E, and K) • • Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) • Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) • Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) • Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) • Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual • Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) • Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) • Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) • Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) • Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual • Note: Absence of a known family history of first degree relatives with asymptomatic hepatic steatosis and/or hypocholesterolemia does not preclude the diagnosis. • Plasma total cholesterol level below the 5th percentile for age and sex (~3.0 mmol/L [115 mg/dL]) • Plasma LDL cholesterol level below the 5th percentile for age and sex (~1.3 mmol/L [50 mg/dL]) • Plasma apo B level below the 5th percentile for age and sex (~0.5 g/L) • Plasma triglyceride level less than 0.5 mmol/L (45 mg/dL) • Elevated liver enzymes (AST and ALT) in an otherwise asymptomatic individual ## Establishing the Diagnosis The diagnosis of biallelic Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ When the phenotype and laboratory findings suggest the diagnosis of Perform sequence analysis first. If no pathogenic variant or only one pathogenic variant is identified in a symptomatic individual, consider gene-targeted deletion/duplication testing. If no pathogenic variant is identified in an asymptomatic individual who has suggestive laboratory, imaging, and/or family history findings, consider gene-targeted deletion/duplication testing. For an introduction to multigene panels click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Large deletions/duplications are very rare [ • Perform sequence analysis first. • If no pathogenic variant or only one pathogenic variant is identified in a symptomatic individual, consider gene-targeted deletion/duplication testing. • If no pathogenic variant is identified in an asymptomatic individual who has suggestive laboratory, imaging, and/or family history findings, consider gene-targeted deletion/duplication testing. ## Clinical Characteristics The clinical features of individuals with biallelic Individuals with biallelic Biallelic NASH = nonalcoholic steatohepatitis This table refers only to clinical features in those individuals with biallelic As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention. Fat-soluble vitamin malabsorption is severe, and if untreated can lead to irreversible systemic features that affect the eyes (see Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant. Hepatomegaly and hepatic steatosis can be observed in adulthood, and may subsequently progress to steatohepatitis, fibrosis, and (rarely) cirrhosis or (in extremely rare instances) hepatocellular carcinoma. Acanthocytosis, defined as irregularly spiculated erythrocytes (present from birth) Low erythrocyte sedimentation rate Low-grade anemia Reticulocytosis Hyperbilirubinemia Hemolysis Prolonged INR due to vitamin K deficiency, with easy bruising and prolonged bleeding (present in childhood) Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. As the disease progresses, affected individuals may experience progressively expanding scotomas. Without treatment, progression to complete visual loss may occur. Note: It is hypothesized that the possible cause of the ophthalmoplegia is vitamin E deficiency leading to cranial nerve demyelination. Progressive loss of deep tendon reflexes, vibratory sense, and proprioception Muscle pain or weakness Dysarthria Ataxia, broad-based gait Tremors Similar to the ophthalmologic manifestations, the neuromuscular manifestations can also be arrested but not reversed with vitamin supplementation. However, they can be averted altogether with early diagnosis and treatment Individuals with a heterozygous, typically truncating pathogenic variant in Heterozygous While sibs inheriting a pathogenic variant demonstrate low cholesterol from birth, hepatic steatosis takes years to develop, with 54% of individuals with heterozygous FHBL developing this finding in one study [ The majority of In general, pathogenic variants that lead to truncated proteins that are 30% in length or shorter have more severe signs and symptoms than those whose truncated protein length is predicted to be 32% or longer; the latter tend to have moderate disease. It has been hypothesized that longer apoB truncated proteins may be able to maintain some residual capacity to bind lipid and form lipoproteins [ Biallelic Heterozygous In a blood donor cohort with plasma cholesterol below the fifth centile (128 mg/dL), apoB truncations were identified in 0.55% [ • As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. • Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention. • Fat-soluble vitamin malabsorption is severe, and if untreated can lead to irreversible systemic features that affect the eyes (see • Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant. • Hepatomegaly and hepatic steatosis can be observed in adulthood, and may subsequently progress to steatohepatitis, fibrosis, and (rarely) cirrhosis or (in extremely rare instances) hepatocellular carcinoma. • Acanthocytosis, defined as irregularly spiculated erythrocytes (present from birth) • Low erythrocyte sedimentation rate • Low-grade anemia • Reticulocytosis • Hyperbilirubinemia • Hemolysis • Prolonged INR due to vitamin K deficiency, with easy bruising and prolonged bleeding (present in childhood) • Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. • As the disease progresses, affected individuals may experience progressively expanding scotomas. • Without treatment, progression to complete visual loss may occur. • Progressive loss of deep tendon reflexes, vibratory sense, and proprioception • Muscle pain or weakness • Dysarthria • Ataxia, broad-based gait • Tremors • In general, pathogenic variants that lead to truncated proteins that are 30% in length or shorter have more severe signs and symptoms than those whose truncated protein length is predicted to be 32% or longer; the latter tend to have moderate disease. • It has been hypothesized that longer apoB truncated proteins may be able to maintain some residual capacity to bind lipid and form lipoproteins [ ## Clinical Description The clinical features of individuals with biallelic Individuals with biallelic Biallelic NASH = nonalcoholic steatohepatitis This table refers only to clinical features in those individuals with biallelic As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention. Fat-soluble vitamin malabsorption is severe, and if untreated can lead to irreversible systemic features that affect the eyes (see Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant. Hepatomegaly and hepatic steatosis can be observed in adulthood, and may subsequently progress to steatohepatitis, fibrosis, and (rarely) cirrhosis or (in extremely rare instances) hepatocellular carcinoma. Acanthocytosis, defined as irregularly spiculated erythrocytes (present from birth) Low erythrocyte sedimentation rate Low-grade anemia Reticulocytosis Hyperbilirubinemia Hemolysis Prolonged INR due to vitamin K deficiency, with easy bruising and prolonged bleeding (present in childhood) Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. As the disease progresses, affected individuals may experience progressively expanding scotomas. Without treatment, progression to complete visual loss may occur. Note: It is hypothesized that the possible cause of the ophthalmoplegia is vitamin E deficiency leading to cranial nerve demyelination. Progressive loss of deep tendon reflexes, vibratory sense, and proprioception Muscle pain or weakness Dysarthria Ataxia, broad-based gait Tremors Similar to the ophthalmologic manifestations, the neuromuscular manifestations can also be arrested but not reversed with vitamin supplementation. However, they can be averted altogether with early diagnosis and treatment Individuals with a heterozygous, typically truncating pathogenic variant in Heterozygous While sibs inheriting a pathogenic variant demonstrate low cholesterol from birth, hepatic steatosis takes years to develop, with 54% of individuals with heterozygous FHBL developing this finding in one study [ • As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. • Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention. • Fat-soluble vitamin malabsorption is severe, and if untreated can lead to irreversible systemic features that affect the eyes (see • Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant. • Hepatomegaly and hepatic steatosis can be observed in adulthood, and may subsequently progress to steatohepatitis, fibrosis, and (rarely) cirrhosis or (in extremely rare instances) hepatocellular carcinoma. • Acanthocytosis, defined as irregularly spiculated erythrocytes (present from birth) • Low erythrocyte sedimentation rate • Low-grade anemia • Reticulocytosis • Hyperbilirubinemia • Hemolysis • Prolonged INR due to vitamin K deficiency, with easy bruising and prolonged bleeding (present in childhood) • Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. • As the disease progresses, affected individuals may experience progressively expanding scotomas. • Without treatment, progression to complete visual loss may occur. • Progressive loss of deep tendon reflexes, vibratory sense, and proprioception • Muscle pain or weakness • Dysarthria • Ataxia, broad-based gait • Tremors ## Biallelic Individuals with biallelic Biallelic NASH = nonalcoholic steatohepatitis This table refers only to clinical features in those individuals with biallelic As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention. Fat-soluble vitamin malabsorption is severe, and if untreated can lead to irreversible systemic features that affect the eyes (see Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant. Hepatomegaly and hepatic steatosis can be observed in adulthood, and may subsequently progress to steatohepatitis, fibrosis, and (rarely) cirrhosis or (in extremely rare instances) hepatocellular carcinoma. Acanthocytosis, defined as irregularly spiculated erythrocytes (present from birth) Low erythrocyte sedimentation rate Low-grade anemia Reticulocytosis Hyperbilirubinemia Hemolysis Prolonged INR due to vitamin K deficiency, with easy bruising and prolonged bleeding (present in childhood) Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. As the disease progresses, affected individuals may experience progressively expanding scotomas. Without treatment, progression to complete visual loss may occur. Note: It is hypothesized that the possible cause of the ophthalmoplegia is vitamin E deficiency leading to cranial nerve demyelination. Progressive loss of deep tendon reflexes, vibratory sense, and proprioception Muscle pain or weakness Dysarthria Ataxia, broad-based gait Tremors Similar to the ophthalmologic manifestations, the neuromuscular manifestations can also be arrested but not reversed with vitamin supplementation. However, they can be averted altogether with early diagnosis and treatment • As affected individuals age, they learn to avoid dietary fat, which improves steatorrhea. • Global caloric deficiency is associated with delayed growth trajectory, with both height and weight typically below the tenth centile without intervention. • Fat-soluble vitamin malabsorption is severe, and if untreated can lead to irreversible systemic features that affect the eyes (see • Hepatic involvement as identified on laboratory studies is frequently stable over many years and may not evolve to be clinically significant. • Hepatomegaly and hepatic steatosis can be observed in adulthood, and may subsequently progress to steatohepatitis, fibrosis, and (rarely) cirrhosis or (in extremely rare instances) hepatocellular carcinoma. • Acanthocytosis, defined as irregularly spiculated erythrocytes (present from birth) • Low erythrocyte sedimentation rate • Low-grade anemia • Reticulocytosis • Hyperbilirubinemia • Hemolysis • Prolonged INR due to vitamin K deficiency, with easy bruising and prolonged bleeding (present in childhood) • Many affected individuals are asymptomatic until adulthood, when they experience loss of night vision and/or color vision. • As the disease progresses, affected individuals may experience progressively expanding scotomas. • Without treatment, progression to complete visual loss may occur. • Progressive loss of deep tendon reflexes, vibratory sense, and proprioception • Muscle pain or weakness • Dysarthria • Ataxia, broad-based gait • Tremors ## Heterozygous Individuals with a heterozygous, typically truncating pathogenic variant in Heterozygous While sibs inheriting a pathogenic variant demonstrate low cholesterol from birth, hepatic steatosis takes years to develop, with 54% of individuals with heterozygous FHBL developing this finding in one study [ ## Genotype-Phenotype Correlations The majority of In general, pathogenic variants that lead to truncated proteins that are 30% in length or shorter have more severe signs and symptoms than those whose truncated protein length is predicted to be 32% or longer; the latter tend to have moderate disease. It has been hypothesized that longer apoB truncated proteins may be able to maintain some residual capacity to bind lipid and form lipoproteins [ • In general, pathogenic variants that lead to truncated proteins that are 30% in length or shorter have more severe signs and symptoms than those whose truncated protein length is predicted to be 32% or longer; the latter tend to have moderate disease. • It has been hypothesized that longer apoB truncated proteins may be able to maintain some residual capacity to bind lipid and form lipoproteins [ ## Nomenclature Biallelic ## Prevalence Heterozygous In a blood donor cohort with plasma cholesterol below the fifth centile (128 mg/dL), apoB truncations were identified in 0.55% [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Biallelic Mean age of diagnosis 3.8 yrs (vs persons w/biallelic AD = autosomal dominant; ## 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 Biallelic Total cholesterol LDL cholesterol HDL cholesterol Triglyceride Apo B For eval of visual acuity & pigmentary retinopathy Consider electroretinography. HDL = high-density lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; MOI = mode of inheritance This is a sensitive method to detect early neuropathy [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse Recommended Evaluations Following Initial Diagnosis in Individuals with Heterozygous Total cholesterol LDL cholesterol HDL cholesterol Triglyceride Apo B The following treatment is recommended for individuals with biallelic Treatment of Manifestations in Individuals with Biallelic Low-fat diet (<30% of total calories) Oral essential fatty acid supplements may be considered. Vitamin E (100-300 IU/kg/d) Vitamin A (100-400 IU/kg/d) Vitamin D (800-1200 IU/d) Vitamin K (5-35 mg/wk) Anemia is usually mild. Iron therapy does not improve anemia in this condition. INR = international normalized ratio; OT = occupational therapy; PT = physical therapy As outlined in Recommended Surveillance for Individuals with Biallelic Measurement of growth parameters For any new or progressive signs/symptoms of gastrointestinal issues Lipid profile Liver function tests Vitamin A, vitamin E, 25-OH vitamin D INR Calcium, phosphate, uric acid CBC & measurement of vitamin B TSH Ophthalmology eval Neurologic exam Hepatic ultrasound Bone mineral densitometry CBC = complete blood count; INR = international normalized ratio; TSH = thyroid-stimulating hormone Including for hepatomegaly and diarrhea To include total, LDL and HDL cholesterol, triglyceride, and apo B concentrations To include AST and ALT Abnormal vitamin B Abnormal thyroid function is not a primary feature of biallelic An affected individual found to have a bone mineral density >1 SD below the lower limit of normal often prompts an increase in vitamin D dosage. Recommended Surveillance for Individuals with Heterozygous Lipid profile Liver function tests To include total, LDL and HDL cholesterol, triglyceride, and apo B concentrations To include AST and ALT Individuals with biallelic It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with biallelic A full lipid profile, including apo B concentration; Molecular genetic testing for the See Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended [ Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity. See Search • Total cholesterol • LDL cholesterol • HDL cholesterol • Triglyceride • Apo B • For eval of visual acuity & pigmentary retinopathy • Consider electroretinography. • Total cholesterol • LDL cholesterol • HDL cholesterol • Triglyceride • Apo B • Low-fat diet (<30% of total calories) • Oral essential fatty acid supplements may be considered. • Vitamin E (100-300 IU/kg/d) • Vitamin A (100-400 IU/kg/d) • Vitamin D (800-1200 IU/d) • Vitamin K (5-35 mg/wk) • Anemia is usually mild. • Iron therapy does not improve anemia in this condition. • Measurement of growth parameters • For any new or progressive signs/symptoms of gastrointestinal issues • Lipid profile • Liver function tests • Vitamin A, vitamin E, 25-OH vitamin D • INR • Calcium, phosphate, uric acid • CBC & measurement of vitamin B • TSH • Ophthalmology eval • Neurologic exam • Hepatic ultrasound • Bone mineral densitometry • Lipid profile • Liver function tests • A full lipid profile, including apo B concentration; • Molecular genetic testing for the ## 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 Biallelic Total cholesterol LDL cholesterol HDL cholesterol Triglyceride Apo B For eval of visual acuity & pigmentary retinopathy Consider electroretinography. HDL = high-density lipoprotein; INR = international normalized ratio; LDL = low-density lipoprotein; MOI = mode of inheritance This is a sensitive method to detect early neuropathy [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse Recommended Evaluations Following Initial Diagnosis in Individuals with Heterozygous Total cholesterol LDL cholesterol HDL cholesterol Triglyceride Apo B • Total cholesterol • LDL cholesterol • HDL cholesterol • Triglyceride • Apo B • For eval of visual acuity & pigmentary retinopathy • Consider electroretinography. • Total cholesterol • LDL cholesterol • HDL cholesterol • Triglyceride • Apo B ## Treatment of Manifestations The following treatment is recommended for individuals with biallelic Treatment of Manifestations in Individuals with Biallelic Low-fat diet (<30% of total calories) Oral essential fatty acid supplements may be considered. Vitamin E (100-300 IU/kg/d) Vitamin A (100-400 IU/kg/d) Vitamin D (800-1200 IU/d) Vitamin K (5-35 mg/wk) Anemia is usually mild. Iron therapy does not improve anemia in this condition. INR = international normalized ratio; OT = occupational therapy; PT = physical therapy • Low-fat diet (<30% of total calories) • Oral essential fatty acid supplements may be considered. • Vitamin E (100-300 IU/kg/d) • Vitamin A (100-400 IU/kg/d) • Vitamin D (800-1200 IU/d) • Vitamin K (5-35 mg/wk) • Anemia is usually mild. • Iron therapy does not improve anemia in this condition. ## Prevention of Primary Manifestations As outlined in ## Surveillance Recommended Surveillance for Individuals with Biallelic Measurement of growth parameters For any new or progressive signs/symptoms of gastrointestinal issues Lipid profile Liver function tests Vitamin A, vitamin E, 25-OH vitamin D INR Calcium, phosphate, uric acid CBC & measurement of vitamin B TSH Ophthalmology eval Neurologic exam Hepatic ultrasound Bone mineral densitometry CBC = complete blood count; INR = international normalized ratio; TSH = thyroid-stimulating hormone Including for hepatomegaly and diarrhea To include total, LDL and HDL cholesterol, triglyceride, and apo B concentrations To include AST and ALT Abnormal vitamin B Abnormal thyroid function is not a primary feature of biallelic An affected individual found to have a bone mineral density >1 SD below the lower limit of normal often prompts an increase in vitamin D dosage. Recommended Surveillance for Individuals with Heterozygous Lipid profile Liver function tests To include total, LDL and HDL cholesterol, triglyceride, and apo B concentrations To include AST and ALT • Measurement of growth parameters • For any new or progressive signs/symptoms of gastrointestinal issues • Lipid profile • Liver function tests • Vitamin A, vitamin E, 25-OH vitamin D • INR • Calcium, phosphate, uric acid • CBC & measurement of vitamin B • TSH • Ophthalmology eval • Neurologic exam • Hepatic ultrasound • Bone mineral densitometry • Lipid profile • Liver function tests ## Agents/Circumstances to Avoid Individuals with biallelic ## 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 biallelic A full lipid profile, including apo B concentration; Molecular genetic testing for the See • A full lipid profile, including apo B concentration; • Molecular genetic testing for the ## Pregnancy Management Vitamin A excess can be harmful to the developing fetus. Therefore, women who are pregnant or who are planning to become pregnant should reduce their vitamin A supplement dose by 50%. Additionally, close monitoring of serum vitamin A levels throughout pregnancy is recommended [ Because vitamin A is an essential vitamin, however, vitamin A supplementation for affected women should not be discontinued during pregnancy. Vitamin A deficiency can lead to maternal morbidity. See ## Therapies Under Investigation Search ## Genetic Counseling Note: The inheritance of The parents of an individual with biallelic 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. Individuals with a heterozygous FHBL If both parents are known to be heterozygous for an Individuals with a heterozygous FHBL Molecular genetic testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have biallelic 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 individual with biallelic • 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. • Individuals with a heterozygous FHBL • 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 • Individuals with a heterozygous FHBL • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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 biallelic ## Mode of Inheritance Note: The inheritance of ## Risk to Family Members (Autosomal Recessive Inheritance) The parents of an individual with biallelic 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. Individuals with a heterozygous FHBL If both parents are known to be heterozygous for an Individuals with a heterozygous FHBL • The parents of an individual with biallelic • 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. • Individuals with a heterozygous FHBL • 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 • Individuals with a heterozygous FHBL ## Heterozygote Detection Molecular genetic testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who have biallelic • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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 biallelic ## 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 APOB-Related Familial Hypobetalipoproteinemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for APOB-Related Familial Hypobetalipoproteinemia ( ApoB is essential for the formation of intestinally derived chylomicrons and hepatically derived very low-density lipoprotein (VLDL) and their metabolites, including low-density lipoprotein (LDL). In Truncated proteins are named as a proportion of full-length wild type protein (apoB-100). Apo B proteins shorter than 30% of full-length apoB are not detectable in plasma by Western blot, while those larger than apoB-32 are detectable in plasma. Those individuals with longer truncated proteins that are detectable in plasma are more likely to have moderate disease compared to those with undetectable plasma levels, who typically have severe disease [ ## Molecular Pathogenesis ApoB is essential for the formation of intestinally derived chylomicrons and hepatically derived very low-density lipoprotein (VLDL) and their metabolites, including low-density lipoprotein (LDL). In Truncated proteins are named as a proportion of full-length wild type protein (apoB-100). Apo B proteins shorter than 30% of full-length apoB are not detectable in plasma by Western blot, while those larger than apoB-32 are detectable in plasma. Those individuals with longer truncated proteins that are detectable in plasma are more likely to have moderate disease compared to those with undetectable plasma levels, who typically have severe disease [ ## Chapter Notes Hooper AJ, Burnett JR. Genetic hypobetalipoproteinaemia and abetalipoproteinaemia. In: Garg A, ed. Hooper AJ, Burnett JR. Abetalipoproteinemia and hypobetalipoproteinemia. In: Hollak CEM, Lachman R, Sedel F, eds. 9 September 2021 (jrb) Revision: clarification of 13 May 2021 (ma) Review posted live 3 March 2021 (jrb) Original submission • Hooper AJ, Burnett JR. Genetic hypobetalipoproteinaemia and abetalipoproteinaemia. In: Garg A, ed. • Hooper AJ, Burnett JR. Abetalipoproteinemia and hypobetalipoproteinemia. In: Hollak CEM, Lachman R, Sedel F, eds. • 9 September 2021 (jrb) Revision: clarification of • 13 May 2021 (ma) Review posted live • 3 March 2021 (jrb) Original submission ## Author Notes Hooper AJ, Burnett JR. Genetic hypobetalipoproteinaemia and abetalipoproteinaemia. In: Garg A, ed. Hooper AJ, Burnett JR. Abetalipoproteinemia and hypobetalipoproteinemia. In: Hollak CEM, Lachman R, Sedel F, eds. • Hooper AJ, Burnett JR. Genetic hypobetalipoproteinaemia and abetalipoproteinaemia. In: Garg A, ed. • Hooper AJ, Burnett JR. Abetalipoproteinemia and hypobetalipoproteinemia. In: Hollak CEM, Lachman R, Sedel F, eds. ## Revision History 9 September 2021 (jrb) Revision: clarification of 13 May 2021 (ma) Review posted live 3 March 2021 (jrb) Original submission • 9 September 2021 (jrb) Revision: clarification of • 13 May 2021 (ma) Review posted live • 3 March 2021 (jrb) Original submission ## References ## Literature Cited	[]	13/5/2021		9/9/2021	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
apoe-leu167del	apoe-leu167del	[ "Inherited Lipemic Splenomegaly", "Autosomal Dominant Hypercholesterolemia", "Familial Combined Hyperlipidemia", "Apolipoprotein E", "APOE", "APOE p.Leu167del-Related Lipid Disorders" ]		Nicole Greyshock, John R Guyton, Siby Sebastian, Daniel Okorodudu	Summary Inherited lipemic splenomegaly (also known as sea-blue histiocytosis) characterized by hypertriglyceridemia and splenomegaly. Variable manifestations include thrombocytopenia, liver function abnormalities, and cardiovascular disease Autosomal dominant hypercholesterolemia (ADH) characterized by markedly elevated LDL cholesterol levels that leads to premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD) Familial combined hyperlipidemia (FCHL) characterized by variable elevations of total cholesterol, triglycerides, or LDL cholesterol and a high risk of premature ASCVD It has been suggested that the phenotype associated with the Diagnosis relies on detection of a heterozygous Lipoprotein profile one year after diagnosis and every 2-5 years thereafter (if normal). If abnormal, follow at regular intervals for treatment of hyperlipidemia. Liver function panel, albumin, INR (prothrombin time) one year after diagnosis and every 2-5 years thereafter (if normal) Platelet count one year after diagnosis and every 2-5 years thereafter (if normal) The	Inherited lipemic splenomegaly Autosomal dominant hypercholesterolemia Familial combined hyperlipidemia For synonyms and outdated names see For other genetic causes of these phenotypes see • Inherited lipemic splenomegaly • Autosomal dominant hypercholesterolemia • Familial combined hyperlipidemia ## Diagnosis Establishing the diagnosis of an Use of molecular genetic testing to confirm the molecular diagnosis in an individual with clinical findings that suggest one of the three associated phenotypes Use of clinical evaluation to establish the clinical findings in an individual with the The Determining whether the second Note: While genetic testing to determine whether the second Inherited lipemic splenomegaly (also known as sea-blue histiocytosis) Autosomal dominant hypercholesterolemia (ADH) Familial combined hyperlipidemia (FCHL) Mean Lipoprotein Values by Adapted from N = number reported TC = total cholesterol HDL-C = high-density lipoprotein cholesterol TG = triglyceride SD = standard deviation To date, the (<200 mg/dL) (≥40 mg/dL or ≥50 mg/dL in a woman) (<150 mg/dL) All individuals with this genotype had splenomegaly. Three of four lipid panels were measured pre-splenectomy. One individual also had a pathogenic variant in One individual (the son of the person described in footnote 3) also had a pathogenic variant in Splenomegaly is seen in some individuals with The four individuals who underwent splenectomy had markedly enlarged spleens that weighed between 727 g and 1200 g (normal 70 - 250 g) [ Clinical findings include the following: Very high LDL cholesterol levels from birth (>95 Premature atherosclerosis Tendon xanthomas. Development of tendon xanthomas requires prolonged exposure to high LDL and may not occur in mildly affected or treated individuals. Tendon xanthomas have been described in one of the two sibs reported by Note: Triglycerides are typically normal; however, hypertriglyceridemia can sometimes be observed in ADH due to common genetic and environmental factors contributing to triglyceride elevation. Clinical findings include the following: Familial aggregation of total plasma cholesterol and/or triglyceride concentrations >90 Three different lipid phenotypes: Increased total cholesterol (Frederickson type IIa hyperlipidemia) Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). Note: The lipid phenotype can also vary in a given individual over time, making the diagnosis of FCHL challenging [ • Use of molecular genetic testing to confirm the molecular diagnosis in an individual with clinical findings that suggest one of the three associated phenotypes • Use of clinical evaluation to establish the clinical findings in an individual with the • The • Determining whether the second • Note: While genetic testing to determine whether the second • Inherited lipemic splenomegaly (also known as sea-blue histiocytosis) • Autosomal dominant hypercholesterolemia (ADH) • Familial combined hyperlipidemia (FCHL) • Splenomegaly is seen in some individuals with • The four individuals who underwent splenectomy had markedly enlarged spleens that weighed between 727 g and 1200 g (normal 70 - 250 g) [ • Very high LDL cholesterol levels from birth (>95 • Premature atherosclerosis • Tendon xanthomas. Development of tendon xanthomas requires prolonged exposure to high LDL and may not occur in mildly affected or treated individuals. Tendon xanthomas have been described in one of the two sibs reported by • Familial aggregation of total plasma cholesterol and/or triglyceride concentrations >90 • Three different lipid phenotypes: • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). • Note: The lipid phenotype can also vary in a given individual over time, making the diagnosis of FCHL challenging [ • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). ## Clinical Findings Mean Lipoprotein Values by Adapted from N = number reported TC = total cholesterol HDL-C = high-density lipoprotein cholesterol TG = triglyceride SD = standard deviation To date, the (<200 mg/dL) (≥40 mg/dL or ≥50 mg/dL in a woman) (<150 mg/dL) All individuals with this genotype had splenomegaly. Three of four lipid panels were measured pre-splenectomy. One individual also had a pathogenic variant in One individual (the son of the person described in footnote 3) also had a pathogenic variant in Splenomegaly is seen in some individuals with The four individuals who underwent splenectomy had markedly enlarged spleens that weighed between 727 g and 1200 g (normal 70 - 250 g) [ Clinical findings include the following: Very high LDL cholesterol levels from birth (>95 Premature atherosclerosis Tendon xanthomas. Development of tendon xanthomas requires prolonged exposure to high LDL and may not occur in mildly affected or treated individuals. Tendon xanthomas have been described in one of the two sibs reported by Note: Triglycerides are typically normal; however, hypertriglyceridemia can sometimes be observed in ADH due to common genetic and environmental factors contributing to triglyceride elevation. Clinical findings include the following: Familial aggregation of total plasma cholesterol and/or triglyceride concentrations >90 Three different lipid phenotypes: Increased total cholesterol (Frederickson type IIa hyperlipidemia) Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). Note: The lipid phenotype can also vary in a given individual over time, making the diagnosis of FCHL challenging [ • Splenomegaly is seen in some individuals with • The four individuals who underwent splenectomy had markedly enlarged spleens that weighed between 727 g and 1200 g (normal 70 - 250 g) [ • Very high LDL cholesterol levels from birth (>95 • Premature atherosclerosis • Tendon xanthomas. Development of tendon xanthomas requires prolonged exposure to high LDL and may not occur in mildly affected or treated individuals. Tendon xanthomas have been described in one of the two sibs reported by • Familial aggregation of total plasma cholesterol and/or triglyceride concentrations >90 • Three different lipid phenotypes: • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). • Note: The lipid phenotype can also vary in a given individual over time, making the diagnosis of FCHL challenging [ • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). ## Inherited Lipemic Splenomegaly Phenotype Mean Lipoprotein Values by Adapted from N = number reported TC = total cholesterol HDL-C = high-density lipoprotein cholesterol TG = triglyceride SD = standard deviation To date, the (<200 mg/dL) (≥40 mg/dL or ≥50 mg/dL in a woman) (<150 mg/dL) All individuals with this genotype had splenomegaly. Three of four lipid panels were measured pre-splenectomy. One individual also had a pathogenic variant in One individual (the son of the person described in footnote 3) also had a pathogenic variant in Splenomegaly is seen in some individuals with The four individuals who underwent splenectomy had markedly enlarged spleens that weighed between 727 g and 1200 g (normal 70 - 250 g) [ • Splenomegaly is seen in some individuals with • The four individuals who underwent splenectomy had markedly enlarged spleens that weighed between 727 g and 1200 g (normal 70 - 250 g) [ Clinical findings include the following: Very high LDL cholesterol levels from birth (>95 Premature atherosclerosis Tendon xanthomas. Development of tendon xanthomas requires prolonged exposure to high LDL and may not occur in mildly affected or treated individuals. Tendon xanthomas have been described in one of the two sibs reported by Note: Triglycerides are typically normal; however, hypertriglyceridemia can sometimes be observed in ADH due to common genetic and environmental factors contributing to triglyceride elevation. • Very high LDL cholesterol levels from birth (>95 • Premature atherosclerosis • Tendon xanthomas. Development of tendon xanthomas requires prolonged exposure to high LDL and may not occur in mildly affected or treated individuals. Tendon xanthomas have been described in one of the two sibs reported by ## Familial Combined Hyperlipidemia (FCHL) Phenotype Clinical findings include the following: Familial aggregation of total plasma cholesterol and/or triglyceride concentrations >90 Three different lipid phenotypes: Increased total cholesterol (Frederickson type IIa hyperlipidemia) Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). Note: The lipid phenotype can also vary in a given individual over time, making the diagnosis of FCHL challenging [ • Familial aggregation of total plasma cholesterol and/or triglyceride concentrations >90 • Three different lipid phenotypes: • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). • Note: The lipid phenotype can also vary in a given individual over time, making the diagnosis of FCHL challenging [ • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). • Increased total cholesterol (Frederickson type IIa hyperlipidemia) • Increased total cholesterol and increased triglycerides (Frederickson type IIb hyperlipidemia) • Isolated hypertriglyceridemia (Frederickson type IV hyperlipidemia). ## Clinical Characteristics To date, only 38 individuals with the Of these 38 individuals, only seven have had splenomegaly and are thus characterized as having the inherited lipemic splenomegaly phenotype [ Given the limited number of reports in the literature to date, little is known about the natural history of the phenotypes associated with the Inherited lipemic splenomegaly is characterized by hypertriglyceridemia and splenomegaly in individuals with the The association of the pathogenic variant The age of onset is unknown. All individuals with splenomegaly have been in their late 20s to 50s. It is thought that hyperlipidemia directly causes splenomegaly as it has been shown in vitro that The proband in Given the resolution of splenomegaly in the proband reported by Findings in Families in Which ≥1 Individuals with the CAD = coronary artery disease; LFT = liver function test; NA = not available; PLT = platelets; TG = triglycerides Age (in years) at which the Triglyceride level >150 mg/dL prior to splenectomy. The majority of patients were on lipid-modifying agents. All who underwent splenectomy subsequently developed hypertriglyceridemia or worsening of triglyceride levels. The relationship of liver enzyme elevations to the In individuals with ADH, elevated LDL cholesterol levels lead to tendon xanthomas and premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD). Early treatment of hypercholesterolemia in other causes of ADH (e.g., mutation of one of three genes – Early treatment of hypercholesterolemia in individuals with the The phenotype of FCHL is highly variable. Depending on genetic and environmental factors, affected individuals may have variable degrees of elevated total cholesterol, triglycerides, or LDL cholesterol. Affected individuals are at high risk for premature atherosclerotic cardiovascular disease (ASCVD). In general, early recognition and treatment of hyperlipidemia can prevent the morbidity and mortality of ASCVD. Whether the clinical course of At this time genotype-phenotype correlations are incompletely understood. It has been suggested that the phenotypic expression of the Six of the seven individuals with splenomegaly have been male ( A more severe phenotype is generally seen in individuals with the It has been hypothesized that medical control of hypertriglyceridemia can prevent or induce resolution of splenomegaly [ To date the The designation sea-blue histiocytosis was coined by Silverstein [ In the literature the pathogenic variant has been referred to as both Familial combined hyperlipidemia (FCHL) is a common and diverse phenotype, generally not mendelian, which may simply represent the intersection of familial genetic and environmental influences on blood cholesterol and triglycerides. In a French database of nine families with ADH of unknown cause, one family (including 14 affected individuals) and one unrelated individual (whose father died of myocardial infarction at age 51 years) were found to have the In the family with 14 cases, hypercholesterolemia clearly segregated with the • Six of the seven individuals with splenomegaly have been male ( • A more severe phenotype is generally seen in individuals with the • It has been hypothesized that medical control of hypertriglyceridemia can prevent or induce resolution of splenomegaly [ • In a French database of nine families with ADH of unknown cause, one family (including 14 affected individuals) and one unrelated individual (whose father died of myocardial infarction at age 51 years) were found to have the • In the family with 14 cases, hypercholesterolemia clearly segregated with the ## Clinical Description To date, only 38 individuals with the Of these 38 individuals, only seven have had splenomegaly and are thus characterized as having the inherited lipemic splenomegaly phenotype [ Given the limited number of reports in the literature to date, little is known about the natural history of the phenotypes associated with the Inherited lipemic splenomegaly is characterized by hypertriglyceridemia and splenomegaly in individuals with the The association of the pathogenic variant The age of onset is unknown. All individuals with splenomegaly have been in their late 20s to 50s. It is thought that hyperlipidemia directly causes splenomegaly as it has been shown in vitro that The proband in Given the resolution of splenomegaly in the proband reported by Findings in Families in Which ≥1 Individuals with the CAD = coronary artery disease; LFT = liver function test; NA = not available; PLT = platelets; TG = triglycerides Age (in years) at which the Triglyceride level >150 mg/dL prior to splenectomy. The majority of patients were on lipid-modifying agents. All who underwent splenectomy subsequently developed hypertriglyceridemia or worsening of triglyceride levels. The relationship of liver enzyme elevations to the In individuals with ADH, elevated LDL cholesterol levels lead to tendon xanthomas and premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD). Early treatment of hypercholesterolemia in other causes of ADH (e.g., mutation of one of three genes – Early treatment of hypercholesterolemia in individuals with the The phenotype of FCHL is highly variable. Depending on genetic and environmental factors, affected individuals may have variable degrees of elevated total cholesterol, triglycerides, or LDL cholesterol. Affected individuals are at high risk for premature atherosclerotic cardiovascular disease (ASCVD). In general, early recognition and treatment of hyperlipidemia can prevent the morbidity and mortality of ASCVD. Whether the clinical course of ## Inherited Lipemic Splenomegaly Inherited lipemic splenomegaly is characterized by hypertriglyceridemia and splenomegaly in individuals with the The association of the pathogenic variant The age of onset is unknown. All individuals with splenomegaly have been in their late 20s to 50s. It is thought that hyperlipidemia directly causes splenomegaly as it has been shown in vitro that The proband in Given the resolution of splenomegaly in the proband reported by Findings in Families in Which ≥1 Individuals with the CAD = coronary artery disease; LFT = liver function test; NA = not available; PLT = platelets; TG = triglycerides Age (in years) at which the Triglyceride level >150 mg/dL prior to splenectomy. The majority of patients were on lipid-modifying agents. All who underwent splenectomy subsequently developed hypertriglyceridemia or worsening of triglyceride levels. The relationship of liver enzyme elevations to the ## Autosomal Dominant Hypercholesterolemia (ADH) In individuals with ADH, elevated LDL cholesterol levels lead to tendon xanthomas and premature morbidity and mortality from atherosclerotic cardiovascular disease (ASCVD). Early treatment of hypercholesterolemia in other causes of ADH (e.g., mutation of one of three genes – Early treatment of hypercholesterolemia in individuals with the ## Familial Combined Hyperlipidemia (FCHL) The phenotype of FCHL is highly variable. Depending on genetic and environmental factors, affected individuals may have variable degrees of elevated total cholesterol, triglycerides, or LDL cholesterol. Affected individuals are at high risk for premature atherosclerotic cardiovascular disease (ASCVD). In general, early recognition and treatment of hyperlipidemia can prevent the morbidity and mortality of ASCVD. Whether the clinical course of ## Genotype-Phenotype Correlations At this time genotype-phenotype correlations are incompletely understood. It has been suggested that the phenotypic expression of the Six of the seven individuals with splenomegaly have been male ( A more severe phenotype is generally seen in individuals with the It has been hypothesized that medical control of hypertriglyceridemia can prevent or induce resolution of splenomegaly [ • Six of the seven individuals with splenomegaly have been male ( • A more severe phenotype is generally seen in individuals with the • It has been hypothesized that medical control of hypertriglyceridemia can prevent or induce resolution of splenomegaly [ ## Penetrance To date the ## Nomenclature The designation sea-blue histiocytosis was coined by Silverstein [ In the literature the pathogenic variant has been referred to as both Familial combined hyperlipidemia (FCHL) is a common and diverse phenotype, generally not mendelian, which may simply represent the intersection of familial genetic and environmental influences on blood cholesterol and triglycerides. ## Prevalence In a French database of nine families with ADH of unknown cause, one family (including 14 affected individuals) and one unrelated individual (whose father died of myocardial infarction at age 51 years) were found to have the In the family with 14 cases, hypercholesterolemia clearly segregated with the • In a French database of nine families with ADH of unknown cause, one family (including 14 affected individuals) and one unrelated individual (whose father died of myocardial infarction at age 51 years) were found to have the • In the family with 14 cases, hypercholesterolemia clearly segregated with the ## Differential Diagnosis It is important to note that the pathogenic variant Diseases with Splenomegaly and Dyslipidemia Splenomegaly Hyperlipidemia Thrombocytopenia Adrenal gland calcification & insufficiency Hepatic fibrosis Cirrhosis Skin angiokeratomas & telangiectasias Acroparesthesias Left ventricular hypertrophy Stroke Renal failure Type 1: bone erosion & anemia Type 2: severe neurologic involvement & death age <1 yr Type 3a/b/c: infantile onset w/neurologic deficits Prolonged fever Lymphadenopathy Icterus Rash Edema Seizures Very low HDL Anemia Renal insufficiency Striking corneal opacities Fish eye disease = corneal opacities only Xanthomatous rash Anemia Fever Cherry-red macular spot Pulmonary infiltrates Neurologic deterioration Very low HDL & ApoA-1 Low LDL & high TG Enlarged orange tonsils, very mild corneal opacifications, peripheral neuropathy, variable premature CHD ApoA-I = apolipoprotein A-I; CHD = coronary heart disease; HDL = high density lipoprotein; LDL = low density lipoprotein; MOI = mode of inheritance; TG = triglyceride ADH is genetically heterogeneous. Mutation of FCHL, a common and diverse disorder of lipid metabolism that occurs in up to 6% of the general population [ FCHL is a genetically complex disorder with reduced penetrance. Most cases of FCHL are considered polygenic with the interaction of multiple susceptibility genes and the environment. Many of the genes contributing to FCHL are unknown; however, the The lipid phenotype can vary among family members. Environmental factors thought to affect disease expression are visceral adiposity, insulin resistance, and diabetes mellitus. • Splenomegaly • Hyperlipidemia • Thrombocytopenia • Adrenal gland calcification & insufficiency • Hepatic fibrosis • Cirrhosis • Skin angiokeratomas & telangiectasias • Acroparesthesias • Left ventricular hypertrophy • Stroke • Renal failure • Type 1: bone erosion & anemia • Type 2: severe neurologic involvement & death age <1 yr • Type 3a/b/c: infantile onset w/neurologic deficits • Prolonged fever • Lymphadenopathy • Icterus • Rash • Edema • Seizures • Very low HDL • Anemia • Renal insufficiency • Striking corneal opacities • Fish eye disease = corneal opacities only • Xanthomatous rash • Anemia • Fever • Cherry-red macular spot • Pulmonary infiltrates • Neurologic deterioration • Very low HDL & ApoA-1 • Low LDL & high TG • Enlarged orange tonsils, very mild corneal opacifications, peripheral neuropathy, variable premature CHD ## Inherited Lipemic Splenomegaly It is important to note that the pathogenic variant Diseases with Splenomegaly and Dyslipidemia Splenomegaly Hyperlipidemia Thrombocytopenia Adrenal gland calcification & insufficiency Hepatic fibrosis Cirrhosis Skin angiokeratomas & telangiectasias Acroparesthesias Left ventricular hypertrophy Stroke Renal failure Type 1: bone erosion & anemia Type 2: severe neurologic involvement & death age <1 yr Type 3a/b/c: infantile onset w/neurologic deficits Prolonged fever Lymphadenopathy Icterus Rash Edema Seizures Very low HDL Anemia Renal insufficiency Striking corneal opacities Fish eye disease = corneal opacities only Xanthomatous rash Anemia Fever Cherry-red macular spot Pulmonary infiltrates Neurologic deterioration Very low HDL & ApoA-1 Low LDL & high TG Enlarged orange tonsils, very mild corneal opacifications, peripheral neuropathy, variable premature CHD ApoA-I = apolipoprotein A-I; CHD = coronary heart disease; HDL = high density lipoprotein; LDL = low density lipoprotein; MOI = mode of inheritance; TG = triglyceride • Splenomegaly • Hyperlipidemia • Thrombocytopenia • Adrenal gland calcification & insufficiency • Hepatic fibrosis • Cirrhosis • Skin angiokeratomas & telangiectasias • Acroparesthesias • Left ventricular hypertrophy • Stroke • Renal failure • Type 1: bone erosion & anemia • Type 2: severe neurologic involvement & death age <1 yr • Type 3a/b/c: infantile onset w/neurologic deficits • Prolonged fever • Lymphadenopathy • Icterus • Rash • Edema • Seizures • Very low HDL • Anemia • Renal insufficiency • Striking corneal opacities • Fish eye disease = corneal opacities only • Xanthomatous rash • Anemia • Fever • Cherry-red macular spot • Pulmonary infiltrates • Neurologic deterioration • Very low HDL & ApoA-1 • Low LDL & high TG • Enlarged orange tonsils, very mild corneal opacifications, peripheral neuropathy, variable premature CHD ADH is genetically heterogeneous. Mutation of ## Familial Combined Hyperlipidemia (FCHL) FCHL, a common and diverse disorder of lipid metabolism that occurs in up to 6% of the general population [ FCHL is a genetically complex disorder with reduced penetrance. Most cases of FCHL are considered polygenic with the interaction of multiple susceptibility genes and the environment. Many of the genes contributing to FCHL are unknown; however, the The lipid phenotype can vary among family members. Environmental factors thought to affect disease expression are visceral adiposity, insulin resistance, and diabetes mellitus. ## Management To establish the extent of disease and needs in an individual diagnosed with an Baseline lipoprotein profile, including total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides Liver function panel, albumin, INR (prothrombin time) Platelet count Physical examination to screen for splenomegaly. If splenomegaly is suspected, an abdominal ultrasound examination could be performed to further characterize the extent of splenomegaly. Consultation with a clinical geneticist and/or genetic counselor There are no formal management guidelines for Given the limited number of reports of individuals with an Treatment for individuals with documented ASCVD or at high risk of developing ASCVD begins with lifestyle changes (adherence to a heart-healthy diet, exercise, tobacco avoidance, maintenance of a healthy weight). Medical therapy may include a statin (generally the mainstay of therapy to reduce ASCVD risk), a fibrate, high-dose fish oil, and/or niacin. If present, diabetes mellitus should be well controlled, as uncontrolled diabetes can worsen hypertriglyceridemia. In patients with fasting triglyceride levels: >500 mg/dL, the first goal of treatment should be to lower triglyceride levels to prevent pancreatitis. >1000 mg/dL, elimination of fat from the diet is essential. <500-1000 mg/dL, the focus may shift to the avoidance of high glycemic carbohydrates. Additionally, if identified, excessive intake of sucrose- or fructose-containing food and beverages should be limited. Although caloric restriction with the goal of weight loss can also be helpful in lowering triglyceride levels, it should not be the primary focus in patients with severe hypertriglyceridemia. Splenectomy should be avoided as it may worsen hyperlipidemia. Patients who underwent splenectomy were reported to have markedly worsened hypertriglyceridemia after splenectomy [ Persistent nausea Vomiting Abdominal pain Yellow discoloration of the skin Bruising Bleeding Any new petechial rash Patients with splenomegaly should avoid contact sports given the increased risk for splenic rupture. There are no formal guidelines regarding surveillance. The authors suggest obtaining the following: Lipoprotein profile one year after diagnosis and every two to five years thereafter (if normal). If abnormal, follow at regular intervals for treatment of hyperlipidemia. Liver function panel, albumin, INR (prothrombin time) one year after diagnosis and every two to five years thereafter (if normal). Counsel patients regarding the signs of liver dysfunction. Platelet count one year after diagnosis and every two to five years thereafter (if normal). Counsel patients to notify their provider immediately in the event of bleeding or petechial rash. Avoid the following: Splenectomy as it worsens the hypertriglyceridemia For those with splenomegaly: contact sports given the increased risk for splenic rupture It is appropriate to evaluate relatives at risk of inheriting the Molecular genetic testing can be used to determine if a family member has inherited the If the See A woman with the Treatment of hypertriglyceridemia in pregnant women is similar to that for nonpregnant individuals. The goal of therapy is to achieve fasting triglyceride levels below 500 mg/dL (see If acceptable triglyceride levels are not achieved in a pregnant woman with dietary changes alone, medical therapy may be required. Medical management in pregnancy usually consists of fibrates (pregnancy category C). Prior to taking a medication during pregnancy, a pregnant woman should discuss with her physician the risks and benefits of the specific medication being prescribed. Due to theoretic concerns regarding the role of cholesterol in embryonic development and the fact that hypercholesterolemia alone does not present a risk in pregnancy, statin therapy is contraindicated during pregnancy. Women who are taking a statin should discontinue the use of this medication prior to conception, if possible, or as soon as the pregnancy is recognized. However, inadvertent exposure early in gestation is unlikely to lead to a significantly increased risk for adverse fetal outcomes [ Fish oil could be considered, but could alter prostaglandin metabolism in the fetus. Severe hypertriglyceridemia-induced pancreatitis can require apheresis and use of intravenous insulin and glucose. In these circumstances, consultation with a lipid specialist is recommended. Search • Baseline lipoprotein profile, including total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides • Liver function panel, albumin, INR (prothrombin time) • Platelet count • Physical examination to screen for splenomegaly. If splenomegaly is suspected, an abdominal ultrasound examination could be performed to further characterize the extent of splenomegaly. • Consultation with a clinical geneticist and/or genetic counselor • >500 mg/dL, the first goal of treatment should be to lower triglyceride levels to prevent pancreatitis. • >1000 mg/dL, elimination of fat from the diet is essential. • <500-1000 mg/dL, the focus may shift to the avoidance of high glycemic carbohydrates. Additionally, if identified, excessive intake of sucrose- or fructose-containing food and beverages should be limited. • Persistent nausea • Vomiting • Abdominal pain • Yellow discoloration of the skin • Persistent nausea • Vomiting • Abdominal pain • Yellow discoloration of the skin • Bruising • Bleeding • Any new petechial rash • Bruising • Bleeding • Any new petechial rash • Persistent nausea • Vomiting • Abdominal pain • Yellow discoloration of the skin • Bruising • Bleeding • Any new petechial rash • Lipoprotein profile one year after diagnosis and every two to five years thereafter (if normal). If abnormal, follow at regular intervals for treatment of hyperlipidemia. • Liver function panel, albumin, INR (prothrombin time) one year after diagnosis and every two to five years thereafter (if normal). Counsel patients regarding the signs of liver dysfunction. • Platelet count one year after diagnosis and every two to five years thereafter (if normal). Counsel patients to notify their provider immediately in the event of bleeding or petechial rash. • Splenectomy as it worsens the hypertriglyceridemia • For those with splenomegaly: contact sports given the increased risk for splenic rupture • Molecular genetic testing can be used to determine if a family member has inherited the • If the • Medical management in pregnancy usually consists of fibrates (pregnancy category C). Prior to taking a medication during pregnancy, a pregnant woman should discuss with her physician the risks and benefits of the specific medication being prescribed. • Due to theoretic concerns regarding the role of cholesterol in embryonic development and the fact that hypercholesterolemia alone does not present a risk in pregnancy, statin therapy is contraindicated during pregnancy. Women who are taking a statin should discontinue the use of this medication prior to conception, if possible, or as soon as the pregnancy is recognized. However, inadvertent exposure early in gestation is unlikely to lead to a significantly increased risk for adverse fetal outcomes [ • Fish oil could be considered, but could alter prostaglandin metabolism in the fetus. • Severe hypertriglyceridemia-induced pancreatitis can require apheresis and use of intravenous insulin and glucose. In these circumstances, consultation with a lipid specialist is recommended. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an Baseline lipoprotein profile, including total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides Liver function panel, albumin, INR (prothrombin time) Platelet count Physical examination to screen for splenomegaly. If splenomegaly is suspected, an abdominal ultrasound examination could be performed to further characterize the extent of splenomegaly. Consultation with a clinical geneticist and/or genetic counselor • Baseline lipoprotein profile, including total cholesterol, HDL cholesterol, LDL cholesterol, and triglycerides • Liver function panel, albumin, INR (prothrombin time) • Platelet count • Physical examination to screen for splenomegaly. If splenomegaly is suspected, an abdominal ultrasound examination could be performed to further characterize the extent of splenomegaly. • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations There are no formal management guidelines for Given the limited number of reports of individuals with an Treatment for individuals with documented ASCVD or at high risk of developing ASCVD begins with lifestyle changes (adherence to a heart-healthy diet, exercise, tobacco avoidance, maintenance of a healthy weight). Medical therapy may include a statin (generally the mainstay of therapy to reduce ASCVD risk), a fibrate, high-dose fish oil, and/or niacin. If present, diabetes mellitus should be well controlled, as uncontrolled diabetes can worsen hypertriglyceridemia. In patients with fasting triglyceride levels: >500 mg/dL, the first goal of treatment should be to lower triglyceride levels to prevent pancreatitis. >1000 mg/dL, elimination of fat from the diet is essential. <500-1000 mg/dL, the focus may shift to the avoidance of high glycemic carbohydrates. Additionally, if identified, excessive intake of sucrose- or fructose-containing food and beverages should be limited. Although caloric restriction with the goal of weight loss can also be helpful in lowering triglyceride levels, it should not be the primary focus in patients with severe hypertriglyceridemia. Splenectomy should be avoided as it may worsen hyperlipidemia. Patients who underwent splenectomy were reported to have markedly worsened hypertriglyceridemia after splenectomy [ Persistent nausea Vomiting Abdominal pain Yellow discoloration of the skin Bruising Bleeding Any new petechial rash • >500 mg/dL, the first goal of treatment should be to lower triglyceride levels to prevent pancreatitis. • >1000 mg/dL, elimination of fat from the diet is essential. • <500-1000 mg/dL, the focus may shift to the avoidance of high glycemic carbohydrates. Additionally, if identified, excessive intake of sucrose- or fructose-containing food and beverages should be limited. • Persistent nausea • Vomiting • Abdominal pain • Yellow discoloration of the skin • Persistent nausea • Vomiting • Abdominal pain • Yellow discoloration of the skin • Bruising • Bleeding • Any new petechial rash • Bruising • Bleeding • Any new petechial rash • Persistent nausea • Vomiting • Abdominal pain • Yellow discoloration of the skin • Bruising • Bleeding • Any new petechial rash ## Prevention of Secondary Complications Patients with splenomegaly should avoid contact sports given the increased risk for splenic rupture. ## Surveillance There are no formal guidelines regarding surveillance. The authors suggest obtaining the following: Lipoprotein profile one year after diagnosis and every two to five years thereafter (if normal). If abnormal, follow at regular intervals for treatment of hyperlipidemia. Liver function panel, albumin, INR (prothrombin time) one year after diagnosis and every two to five years thereafter (if normal). Counsel patients regarding the signs of liver dysfunction. Platelet count one year after diagnosis and every two to five years thereafter (if normal). Counsel patients to notify their provider immediately in the event of bleeding or petechial rash. • Lipoprotein profile one year after diagnosis and every two to five years thereafter (if normal). If abnormal, follow at regular intervals for treatment of hyperlipidemia. • Liver function panel, albumin, INR (prothrombin time) one year after diagnosis and every two to five years thereafter (if normal). Counsel patients regarding the signs of liver dysfunction. • Platelet count one year after diagnosis and every two to five years thereafter (if normal). Counsel patients to notify their provider immediately in the event of bleeding or petechial rash. ## Agents/Circumstances to Avoid Avoid the following: Splenectomy as it worsens the hypertriglyceridemia For those with splenomegaly: contact sports given the increased risk for splenic rupture • Splenectomy as it worsens the hypertriglyceridemia • For those with splenomegaly: contact sports given the increased risk for splenic rupture ## Evaluation of Relatives at Risk It is appropriate to evaluate relatives at risk of inheriting the Molecular genetic testing can be used to determine if a family member has inherited the If the See • Molecular genetic testing can be used to determine if a family member has inherited the • If the ## Pregnancy Management A woman with the Treatment of hypertriglyceridemia in pregnant women is similar to that for nonpregnant individuals. The goal of therapy is to achieve fasting triglyceride levels below 500 mg/dL (see If acceptable triglyceride levels are not achieved in a pregnant woman with dietary changes alone, medical therapy may be required. Medical management in pregnancy usually consists of fibrates (pregnancy category C). Prior to taking a medication during pregnancy, a pregnant woman should discuss with her physician the risks and benefits of the specific medication being prescribed. Due to theoretic concerns regarding the role of cholesterol in embryonic development and the fact that hypercholesterolemia alone does not present a risk in pregnancy, statin therapy is contraindicated during pregnancy. Women who are taking a statin should discontinue the use of this medication prior to conception, if possible, or as soon as the pregnancy is recognized. However, inadvertent exposure early in gestation is unlikely to lead to a significantly increased risk for adverse fetal outcomes [ Fish oil could be considered, but could alter prostaglandin metabolism in the fetus. Severe hypertriglyceridemia-induced pancreatitis can require apheresis and use of intravenous insulin and glucose. In these circumstances, consultation with a lipid specialist is recommended. • Medical management in pregnancy usually consists of fibrates (pregnancy category C). Prior to taking a medication during pregnancy, a pregnant woman should discuss with her physician the risks and benefits of the specific medication being prescribed. • Due to theoretic concerns regarding the role of cholesterol in embryonic development and the fact that hypercholesterolemia alone does not present a risk in pregnancy, statin therapy is contraindicated during pregnancy. Women who are taking a statin should discontinue the use of this medication prior to conception, if possible, or as soon as the pregnancy is recognized. However, inadvertent exposure early in gestation is unlikely to lead to a significantly increased risk for adverse fetal outcomes [ • Fish oil could be considered, but could alter prostaglandin metabolism in the fetus. • Severe hypertriglyceridemia-induced pancreatitis can require apheresis and use of intravenous insulin and glucose. In these circumstances, consultation with a lipid specialist is recommended. ## Therapies Under Investigation Search ## Genetic Counseling Some individuals diagnosed with an The proportion of If the Recommendations for the evaluation of parents of a proband in whom the The family history of some individuals with an 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 When the parents are clinically unaffected, the risk to the sibs of a proband of inheriting the The sibs of a proband with clinically unaffected parents are still at increased risk of inheriting the If the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Once the 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 decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate. • Some individuals diagnosed with an • The proportion of • If the • Recommendations for the evaluation of parents of a proband in whom the • The family history of some individuals with an • 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 • When the parents are clinically unaffected, the risk to the sibs of a proband of inheriting the • The sibs of a proband with clinically unaffected parents are still at increased risk of inheriting the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance ## Risk to Family Members Some individuals diagnosed with an The proportion of If the Recommendations for the evaluation of parents of a proband in whom the The family history of some individuals with an 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 When the parents are clinically unaffected, the risk to the sibs of a proband of inheriting the The sibs of a proband with clinically unaffected parents are still at increased risk of inheriting the If the • Some individuals diagnosed with an • The proportion of • If the • Recommendations for the evaluation of parents of a proband in whom the • The family history of some individuals with an • 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 • When the parents are clinically unaffected, the risk to the sibs of a proband of inheriting the • The sibs of a proband with clinically unaffected parents are still at increased risk of inheriting the • If the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Prenatal Testing and Preimplantation Genetic 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 decisions regarding prenatal testing are the choice of the parents, discussion of these issues is appropriate. ## Resources United Kingdom • • United Kingdom • • • ## Molecular Genetics APOE p.Leu167del-Related Lipid Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for APOE p.Leu167del-Related Lipid Disorders ( Apolipoprotein E (APOE), a 34,000 molecular mass protein, is a major apolipoprotein that controls lipoprotein metabolism. APOE is a component of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (LDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). As a ligand for the LDL receptor, APOE is required for receptor-mediated clearance of chylomicron and VLDL remnants from circulation. APOE is a ligand for the LDL receptor. The APOE is synthesized primarily in the liver. However, other organs and tissues synthesize APOE, including the spleen, macrophages, brain, kidneys, gonads, and adrenals. The widespread production of APOE indicates its importance in lipid transport and possibly in additional unrelated roles. APOE2 has cysteine at both positions. APOE3 has cysteine at 130 and arginine at 176. APOE4 has arginine at both sites. Note: The polymorphic amino acid residues are referred to as: 130 and 176 when numbering begins at the initiating AUG codon and includes the signal peptide; 112 and 158 when numbering begins at the mature peptide after cleavage of the signal peptide The allelic variants e2, e3, and e4 are designated by their common names in the literature and not by conventions of the Human Genome Variation Society. Many studies have sought an association between the The homozygous The Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Nomenclature in the preprocessed peptide (including the signal peptide) Nomenclature in the processed peptide (after cleavage of the signal peptide) APOE accounts for a significant fraction of the normal variation in plasma cholesterol levels. Studies have estimated the total variance for LDL cholesterol accounted for by APOE at between 1% and 8.3%. APOE contributes more to normal cholesterol variability than any other protein identified in cholesterol metabolism thus far [ Although other rare protein variants exist, the variant (isoform) proteins APOE2, APOE3, and APOE4 (encoded by the three common benign variants e2, e3, and e4, respectively) have been studied the most. APOE3, the most common protein isoform, is seen in more than 60% of all populations studied [ The different isoforms have different affinity for binding to the LDL receptor. APOE3 and APOE4 bind with nearly equal affinity whereas APOE2 binds with less than 2% of this affinity [ APOE2 is associated with lower LDL cholesterol except for 2% of APOE4 is associated with higher total and LDL cholesterol levels. This may relate to a higher affinity of APOE4 for VLDL and LDL, whereas APOE2 and APOE3 binding preference is for HDL. The relative enrichment of APOE4 in VLDL is thought to cause accelerated hepatic uptake and consequent downregulation of LDL receptor expression, thus leading to increased levels of LDL in persons heterozygous for On average, APOE2 lowers total cholesterol levels by approximately 14 mg/dL and APOE4 raises them by approximately 8 mg/dL [ • APOE2 has cysteine at both positions. • APOE3 has cysteine at 130 and arginine at 176. • APOE4 has arginine at both sites. • 130 and 176 when numbering begins at the initiating AUG codon and includes the signal peptide; • 112 and 158 when numbering begins at the mature peptide after cleavage of the signal peptide • The homozygous • The • APOE2 is associated with lower LDL cholesterol except for 2% of • APOE4 is associated with higher total and LDL cholesterol levels. This may relate to a higher affinity of APOE4 for VLDL and LDL, whereas APOE2 and APOE3 binding preference is for HDL. The relative enrichment of APOE4 in VLDL is thought to cause accelerated hepatic uptake and consequent downregulation of LDL receptor expression, thus leading to increased levels of LDL in persons heterozygous for ## Molecular Pathogenesis Apolipoprotein E (APOE), a 34,000 molecular mass protein, is a major apolipoprotein that controls lipoprotein metabolism. APOE is a component of chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density lipoproteins (LDL), low-density lipoproteins (LDL), and high-density lipoproteins (HDL). As a ligand for the LDL receptor, APOE is required for receptor-mediated clearance of chylomicron and VLDL remnants from circulation. APOE is a ligand for the LDL receptor. The APOE is synthesized primarily in the liver. However, other organs and tissues synthesize APOE, including the spleen, macrophages, brain, kidneys, gonads, and adrenals. The widespread production of APOE indicates its importance in lipid transport and possibly in additional unrelated roles. APOE2 has cysteine at both positions. APOE3 has cysteine at 130 and arginine at 176. APOE4 has arginine at both sites. Note: The polymorphic amino acid residues are referred to as: 130 and 176 when numbering begins at the initiating AUG codon and includes the signal peptide; 112 and 158 when numbering begins at the mature peptide after cleavage of the signal peptide The allelic variants e2, e3, and e4 are designated by their common names in the literature and not by conventions of the Human Genome Variation Society. Many studies have sought an association between the The homozygous The Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Nomenclature in the preprocessed peptide (including the signal peptide) Nomenclature in the processed peptide (after cleavage of the signal peptide) APOE accounts for a significant fraction of the normal variation in plasma cholesterol levels. Studies have estimated the total variance for LDL cholesterol accounted for by APOE at between 1% and 8.3%. APOE contributes more to normal cholesterol variability than any other protein identified in cholesterol metabolism thus far [ Although other rare protein variants exist, the variant (isoform) proteins APOE2, APOE3, and APOE4 (encoded by the three common benign variants e2, e3, and e4, respectively) have been studied the most. APOE3, the most common protein isoform, is seen in more than 60% of all populations studied [ The different isoforms have different affinity for binding to the LDL receptor. APOE3 and APOE4 bind with nearly equal affinity whereas APOE2 binds with less than 2% of this affinity [ APOE2 is associated with lower LDL cholesterol except for 2% of APOE4 is associated with higher total and LDL cholesterol levels. This may relate to a higher affinity of APOE4 for VLDL and LDL, whereas APOE2 and APOE3 binding preference is for HDL. The relative enrichment of APOE4 in VLDL is thought to cause accelerated hepatic uptake and consequent downregulation of LDL receptor expression, thus leading to increased levels of LDL in persons heterozygous for On average, APOE2 lowers total cholesterol levels by approximately 14 mg/dL and APOE4 raises them by approximately 8 mg/dL [ • APOE2 has cysteine at both positions. • APOE3 has cysteine at 130 and arginine at 176. • APOE4 has arginine at both sites. • 130 and 176 when numbering begins at the initiating AUG codon and includes the signal peptide; • 112 and 158 when numbering begins at the mature peptide after cleavage of the signal peptide • The homozygous • The • APOE2 is associated with lower LDL cholesterol except for 2% of • APOE4 is associated with higher total and LDL cholesterol levels. This may relate to a higher affinity of APOE4 for VLDL and LDL, whereas APOE2 and APOE3 binding preference is for HDL. The relative enrichment of APOE4 in VLDL is thought to cause accelerated hepatic uptake and consequent downregulation of LDL receptor expression, thus leading to increased levels of LDL in persons heterozygous for ## References ## Published Guidelines / Consensus Statements ## Literature Cited ## Chapter Notes Nicole Greyshock, MD completed a fellowship in Endocrinology at Duke University Medical Center in 2014. She currently practices endocrinology in Fayetteville, NC. 7 November 2019 (ma) Chapter retired: extremely rare 12 June 2014 (me) Review posted live 31 October 2013 (ng) Original submission • 7 November 2019 (ma) Chapter retired: extremely rare • 12 June 2014 (me) Review posted live • 31 October 2013 (ng) Original submission ## Author Notes Nicole Greyshock, MD completed a fellowship in Endocrinology at Duke University Medical Center in 2014. She currently practices endocrinology in Fayetteville, NC. ## Revision History 7 November 2019 (ma) Chapter retired: extremely rare 12 June 2014 (me) Review posted live 31 October 2013 (ng) Original submission • 7 November 2019 (ma) Chapter retired: extremely rare • 12 June 2014 (me) Review posted live • 31 October 2013 (ng) Original submission	[]	12/6/2014			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aprt-def	aprt-def	[ "2,8-Dihydroxyadeninuria", "APRT Deficiency", "2,8-Dihydroxyadeninuria", "APRT Deficiency", "Adenine phosphoribosyltransferase", "APRT", "Adenine Phosphoribosyltransferase Deficiency" ]	Adenine Phosphoribosyltransferase Deficiency	Vidar Orn Edvardsson, Amrik Sahota, Runolfur Palsson	Summary Adenine phosphoribosyltransferase (APRT) deficiency is characterized by excessive production and renal excretion of 2,8-dihydroxyadenine (DHA), which leads to kidney stone formation and crystal-induced kidney damage (i.e., DHA crystal nephropathy) causing acute kidney injury episodes and progressive chronic kidney disease (CKD). Kidney stones, the most common clinical manifestation of APRT deficiency, can occur at any age; in at least 50% of affected persons symptoms do not occur until adulthood. If adequate treatment is not provided, approximately 20%-25% of affected individuals develop end-stage renal disease (ESRD), usually in adult life. The diagnosis of APRT deficiency is established in a proband by absence of APRT enzyme activity in red cell lysates or identification of biallelic pathogenic variants in APRT 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 normal. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible if the pathogenic variants in the family have been identified.	## Diagnosis Adenine phosphoribosyltransferase (APRT) deficiency (also known as 2,8-dihydroxyadeninuria) Kidney stone disease and renal colic Chronic kidney disease (CKD) Crystal nephropathy (confirmed by kidney biopsy; see Reddish-brown diaper stain in infants and young children Allograft dysfunction following kidney transplantation Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray. Ultrasound examination frequently demonstrates increased echogenicity of the kidneys. Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced DHA clearance by the kidney [ Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. Note: It is important not to confuse the histopathologic manifestations of DHA crystal nephropathy with those of other crystal nephropathies, particularly those caused by oxalate (particularly primary hyperoxaluria) and uric acid deposits [ The diagnosis of APRT deficiency Note: Kidney stone analysis suggesting APRT deficiency is not reliable enough to establish the diagnosis. APRT activity measured in red cell lysates ranges from 16 to 32 nmol/hr per mg hemoglobin in healthy individuals. In almost all individuals with APRT deficiency, APRT enzyme activity measured in red cell lysates (or other cell extracts) is absent; however, exceptions do occur. For example, two enzyme isoforms resulting from the following Thus, in individuals with these two pathogenic variants, in vivo assays (e.g., uptake of adenine by intact erythrocytes or leukocytes) are required to verify APRT deficiency. Note: (1) If enzyme activity is within normal limits or in the heterozygote range in an individual who has recently received a red cell transfusion, enzyme activity measurement should be repeated after three months. (2) Heterozygotes for an Approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Adenine Phosphoribosyltransferase 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 Approximately 50 pathogenic variants have been identified in the coding region of DNA sequence analysis 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. Rare deletions of both Note that enzyme activity measurements in cell extracts alone may not be sufficient to determine the functional significance of novel variants (see • Kidney stone disease and renal colic • Chronic kidney disease (CKD) • Crystal nephropathy (confirmed by kidney biopsy; see • Reddish-brown diaper stain in infants and young children • Allograft dysfunction following kidney transplantation • Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray. • Ultrasound examination frequently demonstrates increased echogenicity of the kidneys. • Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced DHA clearance by the kidney [ • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. • For an introduction to multigene panels click ## Suggestive Findings Adenine phosphoribosyltransferase (APRT) deficiency (also known as 2,8-dihydroxyadeninuria) Kidney stone disease and renal colic Chronic kidney disease (CKD) Crystal nephropathy (confirmed by kidney biopsy; see Reddish-brown diaper stain in infants and young children Allograft dysfunction following kidney transplantation Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray. Ultrasound examination frequently demonstrates increased echogenicity of the kidneys. Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced DHA clearance by the kidney [ Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. Note: It is important not to confuse the histopathologic manifestations of DHA crystal nephropathy with those of other crystal nephropathies, particularly those caused by oxalate (particularly primary hyperoxaluria) and uric acid deposits [ • Kidney stone disease and renal colic • Chronic kidney disease (CKD) • Crystal nephropathy (confirmed by kidney biopsy; see • Reddish-brown diaper stain in infants and young children • Allograft dysfunction following kidney transplantation • Radiolucent kidney stones, detected by ultrasound or computed tomography (CT). Stones are not seen on a plain abdominal x-ray. • Ultrasound examination frequently demonstrates increased echogenicity of the kidneys. • Note: (1) DHA crystals may be difficult to identify in individuals with advanced CKD, possibly due to reduced DHA clearance by the kidney [ • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. • Kidney stone analysis using the above techniques is dependent on skilled personnel and, thus, cannot be used to establish a diagnosis of APRT deficiency (see • Stone analysis employing standard chemical and thermogravimetric methods does not distinguish DHA from other purines (e.g., uric acid) and is not recommended. ## Establishing the Diagnosis The diagnosis of APRT deficiency Note: Kidney stone analysis suggesting APRT deficiency is not reliable enough to establish the diagnosis. APRT activity measured in red cell lysates ranges from 16 to 32 nmol/hr per mg hemoglobin in healthy individuals. In almost all individuals with APRT deficiency, APRT enzyme activity measured in red cell lysates (or other cell extracts) is absent; however, exceptions do occur. For example, two enzyme isoforms resulting from the following Thus, in individuals with these two pathogenic variants, in vivo assays (e.g., uptake of adenine by intact erythrocytes or leukocytes) are required to verify APRT deficiency. Note: (1) If enzyme activity is within normal limits or in the heterozygote range in an individual who has recently received a red cell transfusion, enzyme activity measurement should be repeated after three months. (2) Heterozygotes for an Approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Adenine Phosphoribosyltransferase 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 Approximately 50 pathogenic variants have been identified in the coding region of DNA sequence analysis 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. Rare deletions of both Note that enzyme activity measurements in cell extracts alone may not be sufficient to determine the functional significance of novel variants (see • For an introduction to multigene panels click ## APRT Enzyme Activity APRT activity measured in red cell lysates ranges from 16 to 32 nmol/hr per mg hemoglobin in healthy individuals. In almost all individuals with APRT deficiency, APRT enzyme activity measured in red cell lysates (or other cell extracts) is absent; however, exceptions do occur. For example, two enzyme isoforms resulting from the following Thus, in individuals with these two pathogenic variants, in vivo assays (e.g., uptake of adenine by intact erythrocytes or leukocytes) are required to verify APRT deficiency. Note: (1) If enzyme activity is within normal limits or in the heterozygote range in an individual who has recently received a red cell transfusion, enzyme activity measurement should be repeated after three months. (2) Heterozygotes for an ## Molecular Genetic Testing Approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Adenine Phosphoribosyltransferase 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 Approximately 50 pathogenic variants have been identified in the coding region of DNA sequence analysis 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. Rare deletions of both Note that enzyme activity measurements in cell extracts alone may not be sufficient to determine the functional significance of novel variants (see • For an introduction to multigene panels click ## Clinical Characteristics More than 400 individuals with adenine phosphoribosyltransferase (APRT) deficiency have been reported in the medical literature [ Presenting Renal Manifestations in APRT Deficiency In both children and adults In adult life Due to DHA crystal nephropathy Due to urinary tract obstruction The age at diagnosis among individuals in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC) ranged from six months to 72 years (median age: 37 years) [ Approximately 35% of persons with APRT deficiency are diagnosed before age 18 years. In a significant number of asymptomatic individuals, a diagnosis of APRT deficiency has been suggested by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals and subsequently confirmed by enzyme activity or genetic testing. Of note, abdominal ultrasound and CT examinations performed for other reasons may identify kidney stones in individuals with APRT deficiency who may be otherwise asymptomatic [ In some of these individuals, the diagnosis was not made until after kidney transplantation had been performed. The relatively frequent occurrence of advanced CKD and even ESRD at the time of diagnosis is concerning and suggests a lack of familiarity with this easily treatable condition [ Importantly, individuals with APRT deficiency who are diagnosed and treated early with allopurinol or febuxostat have a much more favorable renal outcome [ Timely diagnosis and institution of pharmacologic therapy appears to reduce stone burden and retard or possibly prevent CKD progression to ESRD, even in severely affected individuals. APRT deficiency is not known to affect organs other than the kidney; however, the authors and other investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort [ No genotype-phenotype correlations have been established; clinical features are known to vary greatly among individuals with the same pathogenic variants [ Originally, two types of APRT deficiency with identical clinical manifestations were described, based on the level of residual APRT activity in cell extracts (erythrocyte lysates) [ The estimated heterozygote frequency in different populations ranges from 0.4% to 1.2% [ If this holds true, at least 70,000-80,000 individuals should be affected worldwide, of whom 40,000 would be expected to be in Asia, 9,000 in Europe, and 8,000 in the Americas, including at least 3,000 affected individuals in the US alone. Most of these individuals are currently unrecognized, and thus not benefitting from medical therapy. Evidence suggests that APRT deficiency may be a seriously underrecognized cause of kidney stones and crystal nephropathy, progressing over time to ESRD in a significant proportion of untreated individuals [ • The age at diagnosis among individuals in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC) ranged from six months to 72 years (median age: 37 years) [ • Approximately 35% of persons with APRT deficiency are diagnosed before age 18 years. • In a significant number of asymptomatic individuals, a diagnosis of APRT deficiency has been suggested by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals and subsequently confirmed by enzyme activity or genetic testing. • In some of these individuals, the diagnosis was not made until after kidney transplantation had been performed. • The relatively frequent occurrence of advanced CKD and even ESRD at the time of diagnosis is concerning and suggests a lack of familiarity with this easily treatable condition [ • Importantly, individuals with APRT deficiency who are diagnosed and treated early with allopurinol or febuxostat have a much more favorable renal outcome [ • Timely diagnosis and institution of pharmacologic therapy appears to reduce stone burden and retard or possibly prevent CKD progression to ESRD, even in severely affected individuals. ## Clinical Description More than 400 individuals with adenine phosphoribosyltransferase (APRT) deficiency have been reported in the medical literature [ Presenting Renal Manifestations in APRT Deficiency In both children and adults In adult life Due to DHA crystal nephropathy Due to urinary tract obstruction The age at diagnosis among individuals in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC) ranged from six months to 72 years (median age: 37 years) [ Approximately 35% of persons with APRT deficiency are diagnosed before age 18 years. In a significant number of asymptomatic individuals, a diagnosis of APRT deficiency has been suggested by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals and subsequently confirmed by enzyme activity or genetic testing. Of note, abdominal ultrasound and CT examinations performed for other reasons may identify kidney stones in individuals with APRT deficiency who may be otherwise asymptomatic [ In some of these individuals, the diagnosis was not made until after kidney transplantation had been performed. The relatively frequent occurrence of advanced CKD and even ESRD at the time of diagnosis is concerning and suggests a lack of familiarity with this easily treatable condition [ Importantly, individuals with APRT deficiency who are diagnosed and treated early with allopurinol or febuxostat have a much more favorable renal outcome [ Timely diagnosis and institution of pharmacologic therapy appears to reduce stone burden and retard or possibly prevent CKD progression to ESRD, even in severely affected individuals. APRT deficiency is not known to affect organs other than the kidney; however, the authors and other investigators have encountered occasional individuals with APRT deficiency complaining of eye discomfort [ • The age at diagnosis among individuals in the APRT Deficiency Registry of the Rare Kidney Stone Consortium (RKSC) ranged from six months to 72 years (median age: 37 years) [ • Approximately 35% of persons with APRT deficiency are diagnosed before age 18 years. • In a significant number of asymptomatic individuals, a diagnosis of APRT deficiency has been suggested by the detection of DHA crystals on routine urine microscopy or through the screening of sibs of affected individuals and subsequently confirmed by enzyme activity or genetic testing. • In some of these individuals, the diagnosis was not made until after kidney transplantation had been performed. • The relatively frequent occurrence of advanced CKD and even ESRD at the time of diagnosis is concerning and suggests a lack of familiarity with this easily treatable condition [ • Importantly, individuals with APRT deficiency who are diagnosed and treated early with allopurinol or febuxostat have a much more favorable renal outcome [ • Timely diagnosis and institution of pharmacologic therapy appears to reduce stone burden and retard or possibly prevent CKD progression to ESRD, even in severely affected individuals. ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been established; clinical features are known to vary greatly among individuals with the same pathogenic variants [ ## Nomenclature Originally, two types of APRT deficiency with identical clinical manifestations were described, based on the level of residual APRT activity in cell extracts (erythrocyte lysates) [ ## Prevalence The estimated heterozygote frequency in different populations ranges from 0.4% to 1.2% [ If this holds true, at least 70,000-80,000 individuals should be affected worldwide, of whom 40,000 would be expected to be in Asia, 9,000 in Europe, and 8,000 in the Americas, including at least 3,000 affected individuals in the US alone. Most of these individuals are currently unrecognized, and thus not benefitting from medical therapy. Evidence suggests that APRT deficiency may be a seriously underrecognized cause of kidney stones and crystal nephropathy, progressing over time to ESRD in a significant proportion of untreated individuals [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Differential diagnosis of APRT deficiency includes other known causes of radiolucent kidney stones such as uric acid nephrolithiasis (OMIM The diagnosis of APRT deficiency should be considered in all individuals with chronic kidney disease or kidney failure, particularly in those with renal histopathologic features of crystal nephropathy, even in the absence of a history of nephrolithiasis. Pathologists and physicians must be aware that kidney biopsy findings in persons with APRT deficiency may have a similar appearance to and be confused with those of ## Management To establish the extent of disease and needs of an individual diagnosed with adenine phosphoribosyltransferase (APRT) deficiency, the evaluations in Recommended Evaluations Following Initial Diagnosis in Individuals with APRT Deficiency DHA = 2,8-dihydroxyadenine Targeted Treatment for Prevention/Reduction of Kidney Stones in Individuals with APRT Deficiency CKD = chronic kidney disease; DHA = 2,8-dihydroxyadenine; NA = not applicable There are no data to support dietary purine restriction as a treatment of this condition, particularly when treatment with allopurinol or febuxostat is used and urine DHA excretion is already very low. Both allopurinol and febuxostat are oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase). Generally effective and well tolerated Minimizes urinary DHA excretion and crystalluria, stone formation, crystal deposition in the kidney, and development of kidney failure [ No data are available on appropriate dosing for pediatric age groups. A comparison between allopurinol (400 mg/day) and febuxostat (80 mg/day) on urinary DHA excretion found that febuxostat was significantly more efficacious [ Treatment of Manifestations in Individuals with APRT Deficiency ACE = angiotensin-converting enzyme; CKD = chronic kidney disease; DHA = 2,8-dihydroxyadenine; ESRD = end-stage renal disease For prevention of new kidney stone formation, see Including measures to relieve symptoms, control complications, and slow the progression of the disease (See the KDIGO CKD Management of APRT deficiency in those with ESRD Author, unpublished observation Adequate treatment of APRT deficiency with allopurinol or febuxostat prevents kidney stone formation and the development of CKD in most, if not all, individuals with the disorder [ No consensus surveillance guidelines have been established. Recommended Surveillance for Individuals with APRT Deficiency eGFR = estimated glomerular filtration rate Using first morning void urine specimen, if possible In those receiving pharmacotherapy Although not optimal, the absence of DHA crystals on urine microscopy can be considered indicative of adequate treatment. A highly significant correlation between 24-hour urinary DHA excretion and DHA crystalluria has been observed [ See To evaluate for new, asymptomatic kidney stones Azathioprine and mercaptopurine should be avoided by individuals taking XOR inhibitors (allopurinol or febuxostat). Inhibition of xanthine oxidase may cause increased plasma concentrations of azathioprine or mercaptopurine, leading to toxicity. It is appropriate to evaluate apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Approximately 15% of individuals with APRT deficiency may be asymptomatic [ Evaluations can include the following: Molecular genetic testing if the pathogenic variants in the family are known. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants. APRT enzyme activity measurements, particularly if the pathogenic variants in the family are not known See The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied. Animal studies using high doses of allopurinol have revealed evidence of adverse fetal effects in mice but not in rabbits or rats; it is not clear if these effects are a result of direct fetal toxicity or maternal toxicity. Thus, allopurinol should only be prescribed during pregnancy when the benefit of treatment is believed to outweigh the risk. Treatment with allopurinol during pregnancy should be considered in women with APRT deficiency who have CKD with reduced glomerular filtration rate (GFR) or who have undergone kidney transplantation. Animal studies using high doses of febuxostat in rats and rabbits have not supported a teratogenic effect. However, very high doses in pregnant rats have been associated with neonatal loss and low pup birthweight. Some post-transplantation immunosuppressive therapies can also have adverse effects on the developing fetus. A thorough discussion of the risks and benefits of maternal medication use during pregnancy should ideally take place with an appropriate health care provider prior to conception. See Search • Molecular genetic testing if the pathogenic variants in the family are known. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants. • APRT enzyme activity measurements, particularly if the pathogenic variants in the family are not known ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with adenine phosphoribosyltransferase (APRT) deficiency, the evaluations in Recommended Evaluations Following Initial Diagnosis in Individuals with APRT Deficiency DHA = 2,8-dihydroxyadenine ## Treatment of Manifestations Targeted Treatment for Prevention/Reduction of Kidney Stones in Individuals with APRT Deficiency CKD = chronic kidney disease; DHA = 2,8-dihydroxyadenine; NA = not applicable There are no data to support dietary purine restriction as a treatment of this condition, particularly when treatment with allopurinol or febuxostat is used and urine DHA excretion is already very low. Both allopurinol and febuxostat are oxidoreductase inhibitors (XOR; xanthine dehydrogenase/oxidase). Generally effective and well tolerated Minimizes urinary DHA excretion and crystalluria, stone formation, crystal deposition in the kidney, and development of kidney failure [ No data are available on appropriate dosing for pediatric age groups. A comparison between allopurinol (400 mg/day) and febuxostat (80 mg/day) on urinary DHA excretion found that febuxostat was significantly more efficacious [ Treatment of Manifestations in Individuals with APRT Deficiency ACE = angiotensin-converting enzyme; CKD = chronic kidney disease; DHA = 2,8-dihydroxyadenine; ESRD = end-stage renal disease For prevention of new kidney stone formation, see Including measures to relieve symptoms, control complications, and slow the progression of the disease (See the KDIGO CKD Management of APRT deficiency in those with ESRD Author, unpublished observation ## Prevention of Primary Manifestations Adequate treatment of APRT deficiency with allopurinol or febuxostat prevents kidney stone formation and the development of CKD in most, if not all, individuals with the disorder [ ## Surveillance No consensus surveillance guidelines have been established. Recommended Surveillance for Individuals with APRT Deficiency eGFR = estimated glomerular filtration rate Using first morning void urine specimen, if possible In those receiving pharmacotherapy Although not optimal, the absence of DHA crystals on urine microscopy can be considered indicative of adequate treatment. A highly significant correlation between 24-hour urinary DHA excretion and DHA crystalluria has been observed [ See To evaluate for new, asymptomatic kidney stones ## Agents/Circumstances to Avoid Azathioprine and mercaptopurine should be avoided by individuals taking XOR inhibitors (allopurinol or febuxostat). Inhibition of xanthine oxidase may cause increased plasma concentrations of azathioprine or mercaptopurine, leading to toxicity. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Approximately 15% of individuals with APRT deficiency may be asymptomatic [ Evaluations can include the following: Molecular genetic testing if the pathogenic variants in the family are known. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants. APRT enzyme activity measurements, particularly if the pathogenic variants in the family are not known See • Molecular genetic testing if the pathogenic variants in the family are known. Further investigations, including assessment of renal function and urinalysis, are warranted in individuals with biallelic pathogenic variants. • APRT enzyme activity measurements, particularly if the pathogenic variants in the family are not known ## Pregnancy Management The safety of allopurinol and febuxostat in human pregnancy has not been systematically studied. Animal studies using high doses of allopurinol have revealed evidence of adverse fetal effects in mice but not in rabbits or rats; it is not clear if these effects are a result of direct fetal toxicity or maternal toxicity. Thus, allopurinol should only be prescribed during pregnancy when the benefit of treatment is believed to outweigh the risk. Treatment with allopurinol during pregnancy should be considered in women with APRT deficiency who have CKD with reduced glomerular filtration rate (GFR) or who have undergone kidney transplantation. Animal studies using high doses of febuxostat in rats and rabbits have not supported a teratogenic effect. However, very high doses in pregnant rats have been associated with neonatal loss and low pup birthweight. Some post-transplantation immunosuppressive therapies can also have adverse effects on the developing fetus. A thorough discussion of the risks and benefits of maternal medication use during pregnancy should ideally take place with an appropriate health care provider prior to conception. See ## Therapies and Assays Under Investigation Search ## Genetic Counseling Adenine phosphoribosyltransferase (APRT) deficiency is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of inheriting two As many as 15%-20% of individuals who have inherited two Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they 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, the availability of effective, preventive drug treatment (see Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of inheriting two • As many as 15%-20% of individuals who have inherited two • Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they 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, the availability of effective, preventive drug treatment (see ## Mode of Inheritance Adenine phosphoribosyltransferase (APRT) deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of inheriting two As many as 15%-20% of individuals who have inherited two Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they are not at risk of developing the disorder. • The parents of an affected individual are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of inheriting two • As many as 15%-20% of individuals who have inherited two • Heterozygotes (carriers) are asymptomatic. Urine microscopy does not reveal DHA crystals and they 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, the availability of effective, preventive drug treatment (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, the availability of effective, preventive drug treatment (see ## 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 Landspitali - The National University Hospital of Iceland Iceland • • • • Landspitali - The National University Hospital of Iceland • Iceland • ## Molecular Genetics Adenine Phosphoribosyltransferase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Adenine Phosphoribosyltransferase Deficiency ( The crystal structure of recombinant human APRT in complex with adenosine monophosphate (AMP) has been determined [ A core that includes the PRPP-binding motif A flexible loop besides the core region which may be involved in the catalytic function A variable region primarily involved in base recognition More than 50 pathogenic variants have been identified in the coding region of Rarely, large deletions of both APRT Deficiency: Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions • A core that includes the PRPP-binding motif • A flexible loop besides the core region which may be involved in the catalytic function • A variable region primarily involved in base recognition ## Molecular Pathogenesis The crystal structure of recombinant human APRT in complex with adenosine monophosphate (AMP) has been determined [ A core that includes the PRPP-binding motif A flexible loop besides the core region which may be involved in the catalytic function A variable region primarily involved in base recognition More than 50 pathogenic variants have been identified in the coding region of Rarely, large deletions of both APRT Deficiency: Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions • A core that includes the PRPP-binding motif • A flexible loop besides the core region which may be involved in the catalytic function • A variable region primarily involved in base recognition ## References ## Consensus Statements / Published Guidelines ## Literature Cited ## Chapter Notes The official website of the Rare Kidney Stone Consortium: The APRT Deficiency Research Program at Landspítali – The National University Hospital of Iceland, headed by Drs Vidar Orn Edvardsson and Runolfur Palsson, is part of the international Rare Kidney Stone Consortium (RKSC) ( Authors V Edvardsson and R Palsson gratefully acknowledge the support of the Rare Kidney Stone Consortium (U54DK083908), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research. The Rare Kidney Stone Consortium is funded through a collaboration between NCATS and National Institute of Diabetes and Digestive and Kidney Diseases. We thank Hrafnhildur Linnet Runolfsdottir, MD, Faculty of Medicine, School of Health Sciences, University of Iceland, and Landspítali – The National University Hospital of Iceland, Reykjavik, Iceland, for generating the images of the urinary DHA crystals, and Sverrir Hardarson, MD, Department of Pathology, Landspítali – The National University Hospital of Iceland, for providing the photomicrographs of the kidney biopsy specimens. 26 September 2019 (ma) Comprehensive update posted live 18 June 2015 (me) Comprehensive update posted live 30 August 2012 (me) Review posted live 2 May 2012 (ve) Original submission • 26 September 2019 (ma) Comprehensive update posted live • 18 June 2015 (me) Comprehensive update posted live • 30 August 2012 (me) Review posted live • 2 May 2012 (ve) Original submission ## Author Notes The official website of the Rare Kidney Stone Consortium: The APRT Deficiency Research Program at Landspítali – The National University Hospital of Iceland, headed by Drs Vidar Orn Edvardsson and Runolfur Palsson, is part of the international Rare Kidney Stone Consortium (RKSC) ( ## Acknowledgments Authors V Edvardsson and R Palsson gratefully acknowledge the support of the Rare Kidney Stone Consortium (U54DK083908), a part of the National Center for Advancing Translational Sciences (NCATS) Rare Diseases Clinical Research Network (RDCRN). RDCRN is an initiative of the Office of Rare Diseases Research. The Rare Kidney Stone Consortium is funded through a collaboration between NCATS and National Institute of Diabetes and Digestive and Kidney Diseases. We thank Hrafnhildur Linnet Runolfsdottir, MD, Faculty of Medicine, School of Health Sciences, University of Iceland, and Landspítali – The National University Hospital of Iceland, Reykjavik, Iceland, for generating the images of the urinary DHA crystals, and Sverrir Hardarson, MD, Department of Pathology, Landspítali – The National University Hospital of Iceland, for providing the photomicrographs of the kidney biopsy specimens. ## Revision History 26 September 2019 (ma) Comprehensive update posted live 18 June 2015 (me) Comprehensive update posted live 30 August 2012 (me) Review posted live 2 May 2012 (ve) Original submission • 26 September 2019 (ma) Comprehensive update posted live • 18 June 2015 (me) Comprehensive update posted live • 30 August 2012 (me) Review posted live • 2 May 2012 (ve) Original submission Urinary 2,8-dihydroxyadenine (DHA) crystals from an individual with adenine phosphoribosyltransferase deficiency. These crystals have a characteristic appearance and polarization pattern. A. Conventional light microscopy shows the typical brown DHA crystals. Note the dark outline and central spicules (original magnification x 400). B. The same field viewed with polarized light microscopy. The smaller crystals appear yellow and have a central Maltese cross pattern (original magnification x 400). Kidney biopsy findings from an individual with adenine phosphoribosyltransferase deficiency and kidney failure due to 2,8- dihydroxyadenine crystal nephropathy A. 2,8-dihydroxyadenine crystals are seen within tubular lumens (arrows). Significant tubular atrophy, interstitial inflammation, and fibrosis are present (hematoxylin and eosin stain; original magnification x 100). B. Higher magnification of the biopsy specimen shown in A. 2,8-dihydroxyadenine crystals are seen within tubular lumens (long arrow), inside tubular epithelial cells (short arrow), and in the interstitium (arrowhead) (hematoxylin and eosin stain; original magnification x 400). C. The same microscopic field of the kidney biopsy specimen as shown in B viewed with polarized light microscopy. Crystals are seen within a tubular lumen (long arrow), inside tubular epithelial cells (short arrows), and in the interstitium (arrowheads) (hematoxylin and eosin stain; original magnification x 400). Algorithm for diagnostic evaluation of adenine phosphoribosyltransferase (APRT) deficiency and 2,8-dihydroxyadeninuria From	[ "Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease.. Kidney Int 2013:1-150" ]	30/8/2012	26/9/2019		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
arg1	arg1	[ "ARG1 Deficiency", "Arginase-1 Deficiency", "Hyperargininemia", "ARG1 Deficiency", "Arginase-1 Deficiency", "Hyperargininemia", "Arginase-1", "ARG1", "Arginase Deficiency" ]	Arginase Deficiency	Angela Sun, Eric A Crombez, Derek Wong	Summary Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms. The diagnosis of arginase deficiency is established in a proband with suggestive clinical and/or biochemical findings and confirmed by identification of biallelic pathogenic variants in Arginase 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. Heterozygotes (carriers) are asymptomatic. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk are possible if the	## Diagnosis NBS for arginase deficiency is primarily based on quantification of the analyte arginine on dried blood spots. Arginine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see If these studies support the diagnosis of arginase deficiency, additional testing is required to establish the diagnosis (see Note: (1) Some infants with arginase deficiency may have follow-up arginine levels in the normal range, and thus infants who continue to have elevated arginine-to-ornithine ratios and arginine toward the upper limit of normal should undergo additional diagnostic testing (see NBS not performed False negative NBS result Caregivers not adherent to recommended treatment following a positive NBS result Supportive but nonspecific clinical findings and preliminary laboratory findings can include the following. Slowing of linear growth at age one to three years Development of spasticity in the lower extremities Plateauing of cognitive development Loss of developmental milestones Seizures Note: Up to twofold the upper limit of normal may be seen in infants who do not have arginase deficiency and who are otherwise normal. Note: Because elevations of these metabolites individually are not entirely specific to arginase deficiency, follow-up testing is required to establish or rule out the diagnosis of arginase deficiency (see The diagnosis of arginase deficiency Note: (1) Enzyme assay can be helpful if two pathogenic variants are not found on molecular genetic testing. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: In individuals of French Canadian ancestry, the For an introduction to multigene panels click If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see When the diagnosis of arginase deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Arginase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Three single or multiexon deletions have been reported [ Most affected individuals have no detectable arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Note: (1) Although arginase is stable, a control sample should be obtained and treated identically if the cells are to be shipped to a distant site. (2) Liver and red blood cell arginase activity correlate well; therefore, it is not necessary to perform a liver biopsy when enzyme activity can be measured from a blood sample. • NBS for arginase deficiency is primarily based on quantification of the analyte arginine on dried blood spots. • Arginine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see • If these studies support the diagnosis of arginase deficiency, additional testing is required to establish the diagnosis (see • NBS not performed • False negative NBS result • Caregivers not adherent to recommended treatment following a positive NBS result • Slowing of linear growth at age one to three years • Development of spasticity in the lower extremities • Plateauing of cognitive development • Loss of developmental milestones • Seizures • Note: Up to twofold the upper limit of normal may be seen in infants who do not have arginase deficiency and who are otherwise normal. • Note: In individuals of French Canadian ancestry, the • For an introduction to multigene panels click • If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see • When the diagnosis of arginase deficiency has not been considered, • For an introduction to comprehensive genomic testing click ## Suggestive Findings NBS for arginase deficiency is primarily based on quantification of the analyte arginine on dried blood spots. Arginine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see If these studies support the diagnosis of arginase deficiency, additional testing is required to establish the diagnosis (see Note: (1) Some infants with arginase deficiency may have follow-up arginine levels in the normal range, and thus infants who continue to have elevated arginine-to-ornithine ratios and arginine toward the upper limit of normal should undergo additional diagnostic testing (see NBS not performed False negative NBS result Caregivers not adherent to recommended treatment following a positive NBS result Supportive but nonspecific clinical findings and preliminary laboratory findings can include the following. Slowing of linear growth at age one to three years Development of spasticity in the lower extremities Plateauing of cognitive development Loss of developmental milestones Seizures Note: Up to twofold the upper limit of normal may be seen in infants who do not have arginase deficiency and who are otherwise normal. Note: Because elevations of these metabolites individually are not entirely specific to arginase deficiency, follow-up testing is required to establish or rule out the diagnosis of arginase deficiency (see • NBS for arginase deficiency is primarily based on quantification of the analyte arginine on dried blood spots. • Arginine values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see • If these studies support the diagnosis of arginase deficiency, additional testing is required to establish the diagnosis (see • NBS not performed • False negative NBS result • Caregivers not adherent to recommended treatment following a positive NBS result • Slowing of linear growth at age one to three years • Development of spasticity in the lower extremities • Plateauing of cognitive development • Loss of developmental milestones • Seizures • Note: Up to twofold the upper limit of normal may be seen in infants who do not have arginase deficiency and who are otherwise normal. ## Establishing the Diagnosis The diagnosis of arginase deficiency Note: (1) Enzyme assay can be helpful if two pathogenic variants are not found on molecular genetic testing. (2) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Note: In individuals of French Canadian ancestry, the For an introduction to multigene panels click If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see When the diagnosis of arginase deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Arginase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Three single or multiexon deletions have been reported [ Most affected individuals have no detectable arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Note: (1) Although arginase is stable, a control sample should be obtained and treated identically if the cells are to be shipped to a distant site. (2) Liver and red blood cell arginase activity correlate well; therefore, it is not necessary to perform a liver biopsy when enzyme activity can be measured from a blood sample. • Note: In individuals of French Canadian ancestry, the • For an introduction to multigene panels click • If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see • When the diagnosis of arginase deficiency has not been considered, • For an introduction to comprehensive genomic testing click ## Molecular Genetic Testing Approaches Note: In individuals of French Canadian ancestry, the For an introduction to multigene panels click If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see When the diagnosis of arginase deficiency has not been considered, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Arginase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Three single or multiexon deletions have been reported [ • Note: In individuals of French Canadian ancestry, the • For an introduction to multigene panels click • If arginase deficiency is suspected, single-gene testing or a multigene panel may be performed (see • When the diagnosis of arginase deficiency has not been considered, • For an introduction to comprehensive genomic testing click ## Measurement of Red Blood Cell Arginase Enzyme Activity Most affected individuals have no detectable arginase enzyme activity (usually <1% of normal) in red blood cell extracts. Note: (1) Although arginase is stable, a control sample should be obtained and treated identically if the cells are to be shipped to a distant site. (2) Liver and red blood cell arginase activity correlate well; therefore, it is not necessary to perform a liver biopsy when enzyme activity can be measured from a blood sample. ## Clinical Characteristics To date, more than 260 individuals with arginase deficiency have been identified [ At age one to three years, linear growth slows and eventually the majority of affected children demonstrate growth deficiency, which persists if arginase deficiency goes untreated. Microcephaly is common and is congenital in some cases. Feeding issues may develop, leading to inadequate nutrition. Some require a supplemental feeding tube. Starting at age one to three years, previously normal cognitive development slows or stops and the child begins to lose developmental milestones. If untreated, arginase deficiency usually progresses to severe intellectual disability with accompanying neurologic findings (see Full scale IQ in adults is in the 70s, and about half are able to live independently, though they experience significant memory and fine motor deficits [ Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures. Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. Severe spasticity can lead to joint contractures and lordosis. Episodic hyperammonemia of variable degree may occur during illness but is rarely severe enough to be life threatening, although death has been reported. Hyperammonemia presents with vomiting, lethargy, and altered mental status but in some cases is asymptomatic and only recognized if blood ammonia is obtained during an acute illness. Older individuals may present with postoperative encephalopathy. Genotype-phenotype correlations indicate that the amount of residual enzyme activity modulates the phenotype [ Homozygosity or compound heterozygosity for predicted loss-of-function variants such as Missense changes such as Arginase deficiency is one of the rarest urea cycle defects. Its incidence has been estimated at between 1:350,000 and 1:1,000,000; the true incidence in nonrelated populations is unknown. Arginase deficiency is pan ethnic but may be more common among French Canadians due to a pathogenic founder variant [ • At age one to three years, linear growth slows and eventually the majority of affected children demonstrate growth deficiency, which persists if arginase deficiency goes untreated. • Microcephaly is common and is congenital in some cases. • Feeding issues may develop, leading to inadequate nutrition. Some require a supplemental feeding tube. • Starting at age one to three years, previously normal cognitive development slows or stops and the child begins to lose developmental milestones. • If untreated, arginase deficiency usually progresses to severe intellectual disability with accompanying neurologic findings (see • Full scale IQ in adults is in the 70s, and about half are able to live independently, though they experience significant memory and fine motor deficits [ • Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures. • Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. • Severe spasticity can lead to joint contractures and lordosis. • Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. • Severe spasticity can lead to joint contractures and lordosis. • Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. • Severe spasticity can lead to joint contractures and lordosis. • Episodic hyperammonemia of variable degree may occur during illness but is rarely severe enough to be life threatening, although death has been reported. • Hyperammonemia presents with vomiting, lethargy, and altered mental status but in some cases is asymptomatic and only recognized if blood ammonia is obtained during an acute illness. • Older individuals may present with postoperative encephalopathy. • Homozygosity or compound heterozygosity for predicted loss-of-function variants such as • Missense changes such as ## Clinical Description To date, more than 260 individuals with arginase deficiency have been identified [ At age one to three years, linear growth slows and eventually the majority of affected children demonstrate growth deficiency, which persists if arginase deficiency goes untreated. Microcephaly is common and is congenital in some cases. Feeding issues may develop, leading to inadequate nutrition. Some require a supplemental feeding tube. Starting at age one to three years, previously normal cognitive development slows or stops and the child begins to lose developmental milestones. If untreated, arginase deficiency usually progresses to severe intellectual disability with accompanying neurologic findings (see Full scale IQ in adults is in the 70s, and about half are able to live independently, though they experience significant memory and fine motor deficits [ Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures. Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. Severe spasticity can lead to joint contractures and lordosis. Episodic hyperammonemia of variable degree may occur during illness but is rarely severe enough to be life threatening, although death has been reported. Hyperammonemia presents with vomiting, lethargy, and altered mental status but in some cases is asymptomatic and only recognized if blood ammonia is obtained during an acute illness. Older individuals may present with postoperative encephalopathy. • At age one to three years, linear growth slows and eventually the majority of affected children demonstrate growth deficiency, which persists if arginase deficiency goes untreated. • Microcephaly is common and is congenital in some cases. • Feeding issues may develop, leading to inadequate nutrition. Some require a supplemental feeding tube. • Starting at age one to three years, previously normal cognitive development slows or stops and the child begins to lose developmental milestones. • If untreated, arginase deficiency usually progresses to severe intellectual disability with accompanying neurologic findings (see • Full scale IQ in adults is in the 70s, and about half are able to live independently, though they experience significant memory and fine motor deficits [ • Some children are more severely affected cognitively, whereas others have more severe spasticity and secondary joint contractures. • Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. • Severe spasticity can lead to joint contractures and lordosis. • Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. • Severe spasticity can lead to joint contractures and lordosis. • Spastic diplegia typically appears between ages two and four years and is often misdiagnosed as cerebral palsy. • Severe spasticity can lead to joint contractures and lordosis. • Episodic hyperammonemia of variable degree may occur during illness but is rarely severe enough to be life threatening, although death has been reported. • Hyperammonemia presents with vomiting, lethargy, and altered mental status but in some cases is asymptomatic and only recognized if blood ammonia is obtained during an acute illness. • Older individuals may present with postoperative encephalopathy. ## Genotype-Phenotype Correlations Genotype-phenotype correlations indicate that the amount of residual enzyme activity modulates the phenotype [ Homozygosity or compound heterozygosity for predicted loss-of-function variants such as Missense changes such as • Homozygosity or compound heterozygosity for predicted loss-of-function variants such as • Missense changes such as ## Prevalence Arginase deficiency is one of the rarest urea cycle defects. Its incidence has been estimated at between 1:350,000 and 1:1,000,000; the true incidence in nonrelated populations is unknown. Arginase deficiency is pan ethnic but may be more common among French Canadians due to a pathogenic founder variant [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Other causes of hyperammonemia from a urea cycle disorder; and The differences between the urea cycle disorders themselves. • Other causes of hyperammonemia from a urea cycle disorder; and • The differences between the urea cycle disorders themselves. ## Management No consensus clinical management guidelines for arginase deficiency have been published. However, general guidelines for the management of urea cycle disorders are available [ To establish the extent of disease and needs in an individual diagnosed with arginase deficiency, the following evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Arginase Deficiency To incl eval of aspiration risk & nutritional status Consultation w/metabolic dietitian Consider eval for gastrostomy tube placement in those unable to meet nutritional needs orally. Albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, prothrombin time (PT), and partial thromboplastin time (PTT). The management of individuals with arginase deficiency should closely mirror that described in the Routine Outpatient Management in Individuals with Arginase Deficiency At least half of dietary protein from natural (complete) sources Supplementation w/arginine-free essential amino acid formula Protein requirement varies by age. Ideally, affected person should be on the minimum protein intake needed to maintain protein biosynthetic function, growth, & normal plasma amino acid concentrations. Dietary modification does not lead to normalization of plasma arginine concentration but does cause improvement of some clinical symptoms. 250 mg/kg/day ≤250 mg/kg/day if <20 kg 5 g/m Medications to be taken in = amts w/each meal or feeding (i.e., 3-4x/day) Not all affected individuals require nitrogen scavengers. Use only for chronic or recurrent hyperammonemia. The goal should be maintenance of plasma arginine concentration as near normal as possible. Acute Outpatient Management in Individuals with Arginase Deficiency Carbohydrate supplementation orally or by feeding tube ↓ natural protein intake Fever; vomiting, diarrhea, dehydration Some centers advocate reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (24-48 hours) in the outpatient setting during intercurrent illness. Alterations in mentation/alertness, fever, and enteral feeding tolerance with any new or evolving clinical features should be discussed with the designated center of expertise for inherited metabolic diseases. Acute Inpatient Management in Individuals with Arginase Deficiency IV fluids w/≥10% dextrose at 1-1.5x maintenance rate Protein-free oral formula, e.g., Mead Johnson PFD or Ross Formula ProPhree Enteral: Sodium benzoate, sodium phenylbutyrate, or glycerol phenylbutyrate IV: Sodium phenylacetate & sodium benzoate (Ammonul TPN = total parenteral nutrition High parenteral glucose plus insulin can be used acutely to diminish catabolism. The duration of cerebral edema correlates with poor neurologic outcome. Treatment of choice to most rapidly decrease serum ammonia concentration. The method employed depends on the affected person's circumstances. Management of Other Complications in Individuals with Arginase Deficiency In most cases, only clinical monitoring is necessary. W/more severe coagulopathy, FFP is administered prior to surgical procedures. Physical therapy Tendon release procedures ASM = anti-seizure medication; FFP = fresh-frozen plasma Valproic acid should be avoided (see Particularly elevated prothrombin time 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. 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. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. The treatment goal is maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein intake, supplementation with arginine-free essential amino acid formula, and use of nitrogen-scavenging drugs as needed to treat hyperammonemia. Liver transplantation eliminates hyperargininemia and presumably the risk for hyperammonemia but (in contrast to other urea cycle disorders) is rarely necessary in arginase deficiency; see also Prevention of Secondary Manifestations in Individuals with Arginase Deficiency Essential information including written treatment protocols should be provided Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature is >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur. Regular follow up at intervals determined by age and degree of metabolic stability is recommended (see Recommended Surveillance for Individuals with Arginase Deficiency Developmental stagnation and/or regression; seizures; spasticity; development of joint contractures Referral to neurologist, orthopedist, and/or physical therapist as indicated Albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, prothrombin time (PT), and partial thromboplastin time (PTT). Valproic acid should be avoided as it exacerbates hyperammonemia in urea cycle defects and other inborn errors of metabolism [ Because the age of onset of arginase deficiency is delayed beyond the newborn period and the manifestations can vary, the genetic status of all sibs of a proband (especially the younger ones) should be clarified so that morbidity can be reduced by early diagnosis and treatment in those who are affected. Testing methods can include any one of the following: Plasma quantitative amino acid analysis Molecular genetic testing (if the family-specific Analysis of enzymatic activity in red blood cells See The authors are not aware of any instance in which pregnancy has been reported in a woman with arginase deficiency. To achieve metabolic control that will enable normal fetal growth and development, affected pregnant women should generally continue dietary protein restriction and ammonia-scavenging medications (after an appropriate benefit/risk calculation) based on their clinical course before pregnancy. Protein restriction during pregnancy is challenging given the complications that commonly arise during pregnancy (i.e., nausea, vomiting, anorexia). Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with adherence, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery. Plasma amino acid levels can help guide quick adjustments to diet in order to achieve normal plasma amino acid profiles that prevent catabolism and hyperammonemia while allowing for normal fetal growth and development. There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate, or phenylbutyrate during human pregnancy, although there are several case reports. In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years. In the second pregnancy, emergency treatment with Ammonul Although the mother responded well to emergency treatment, the baby experienced intrauterine growth restriction and remained in the NICU due to prematurity and low birth weight. At age two years, the child exhibited speech delay and autism. How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known. Sodium benzoate has been reported to lead to malformations and neurotoxicity/nephrotoxicity in zebrafish larvae [ See A clinical trial for enzyme replacement therapy using pegylated synthetic human arginase I is currently under way (Clinical Trials Identifier A variety of genomic therapies are under investigation including mRNA therapy [ Search Immunizations can be provided on the usual schedule. Appropriate use of antipyretics is indicated. Ibuprofen is preferred over acetaminophen. • To incl eval of aspiration risk & nutritional status • Consultation w/metabolic dietitian • Consider eval for gastrostomy tube placement in those unable to meet nutritional needs orally. • At least half of dietary protein from natural (complete) sources • Supplementation w/arginine-free essential amino acid formula • Protein requirement varies by age. Ideally, affected person should be on the minimum protein intake needed to maintain protein biosynthetic function, growth, & normal plasma amino acid concentrations. • Dietary modification does not lead to normalization of plasma arginine concentration but does cause improvement of some clinical symptoms. • 250 mg/kg/day • ≤250 mg/kg/day if <20 kg • 5 g/m • Medications to be taken in = amts w/each meal or feeding (i.e., 3-4x/day) • Not all affected individuals require nitrogen scavengers. Use only for chronic or recurrent hyperammonemia. • Carbohydrate supplementation orally or by feeding tube • ↓ natural protein intake • IV fluids w/≥10% dextrose at 1-1.5x maintenance rate • Protein-free oral formula, e.g., Mead Johnson PFD or Ross Formula ProPhree • Enteral: Sodium benzoate, sodium phenylbutyrate, or glycerol phenylbutyrate • IV: Sodium phenylacetate & sodium benzoate (Ammonul • In most cases, only clinical monitoring is necessary. • W/more severe coagulopathy, FFP is administered prior to surgical procedures. • Physical therapy • Tendon release procedures • 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. • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. • Plasma quantitative amino acid analysis • Molecular genetic testing (if the family-specific • Analysis of enzymatic activity in red blood cells • Protein restriction during pregnancy is challenging given the complications that commonly arise during pregnancy (i.e., nausea, vomiting, anorexia). • Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with adherence, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery. • Plasma amino acid levels can help guide quick adjustments to diet in order to achieve normal plasma amino acid profiles that prevent catabolism and hyperammonemia while allowing for normal fetal growth and development. • In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years. • In the second pregnancy, emergency treatment with Ammonul • Although the mother responded well to emergency treatment, the baby experienced intrauterine growth restriction and remained in the NICU due to prematurity and low birth weight. At age two years, the child exhibited speech delay and autism. • How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with arginase deficiency, the following evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Arginase Deficiency To incl eval of aspiration risk & nutritional status Consultation w/metabolic dietitian Consider eval for gastrostomy tube placement in those unable to meet nutritional needs orally. Albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, prothrombin time (PT), and partial thromboplastin time (PTT). • To incl eval of aspiration risk & nutritional status • Consultation w/metabolic dietitian • Consider eval for gastrostomy tube placement in those unable to meet nutritional needs orally. ## Treatment of Manifestations The management of individuals with arginase deficiency should closely mirror that described in the Routine Outpatient Management in Individuals with Arginase Deficiency At least half of dietary protein from natural (complete) sources Supplementation w/arginine-free essential amino acid formula Protein requirement varies by age. Ideally, affected person should be on the minimum protein intake needed to maintain protein biosynthetic function, growth, & normal plasma amino acid concentrations. Dietary modification does not lead to normalization of plasma arginine concentration but does cause improvement of some clinical symptoms. 250 mg/kg/day ≤250 mg/kg/day if <20 kg 5 g/m Medications to be taken in = amts w/each meal or feeding (i.e., 3-4x/day) Not all affected individuals require nitrogen scavengers. Use only for chronic or recurrent hyperammonemia. The goal should be maintenance of plasma arginine concentration as near normal as possible. Acute Outpatient Management in Individuals with Arginase Deficiency Carbohydrate supplementation orally or by feeding tube ↓ natural protein intake Fever; vomiting, diarrhea, dehydration Some centers advocate reducing natural protein intake to zero or to 50% of the normal prescribed regimen for short periods (24-48 hours) in the outpatient setting during intercurrent illness. Alterations in mentation/alertness, fever, and enteral feeding tolerance with any new or evolving clinical features should be discussed with the designated center of expertise for inherited metabolic diseases. Acute Inpatient Management in Individuals with Arginase Deficiency IV fluids w/≥10% dextrose at 1-1.5x maintenance rate Protein-free oral formula, e.g., Mead Johnson PFD or Ross Formula ProPhree Enteral: Sodium benzoate, sodium phenylbutyrate, or glycerol phenylbutyrate IV: Sodium phenylacetate & sodium benzoate (Ammonul TPN = total parenteral nutrition High parenteral glucose plus insulin can be used acutely to diminish catabolism. The duration of cerebral edema correlates with poor neurologic outcome. Treatment of choice to most rapidly decrease serum ammonia concentration. The method employed depends on the affected person's circumstances. Management of Other Complications in Individuals with Arginase Deficiency In most cases, only clinical monitoring is necessary. W/more severe coagulopathy, FFP is administered prior to surgical procedures. Physical therapy Tendon release procedures ASM = anti-seizure medication; FFP = fresh-frozen plasma Valproic acid should be avoided (see Particularly elevated prothrombin time 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. 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. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • At least half of dietary protein from natural (complete) sources • Supplementation w/arginine-free essential amino acid formula • Protein requirement varies by age. Ideally, affected person should be on the minimum protein intake needed to maintain protein biosynthetic function, growth, & normal plasma amino acid concentrations. • Dietary modification does not lead to normalization of plasma arginine concentration but does cause improvement of some clinical symptoms. • 250 mg/kg/day • ≤250 mg/kg/day if <20 kg • 5 g/m • Medications to be taken in = amts w/each meal or feeding (i.e., 3-4x/day) • Not all affected individuals require nitrogen scavengers. Use only for chronic or recurrent hyperammonemia. • Carbohydrate supplementation orally or by feeding tube • ↓ natural protein intake • IV fluids w/≥10% dextrose at 1-1.5x maintenance rate • Protein-free oral formula, e.g., Mead Johnson PFD or Ross Formula ProPhree • Enteral: Sodium benzoate, sodium phenylbutyrate, or glycerol phenylbutyrate • IV: Sodium phenylacetate & sodium benzoate (Ammonul • In most cases, only clinical monitoring is necessary. • W/more severe coagulopathy, FFP is administered prior to surgical procedures. • Physical therapy • Tendon release procedures • 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. • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Developmental Delay / Intellectual Disability Management Issues 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. 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. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. ## Prevention of Primary Manifestations The treatment goal is maintenance of plasma arginine concentration as near normal as possible through restriction of dietary protein intake, supplementation with arginine-free essential amino acid formula, and use of nitrogen-scavenging drugs as needed to treat hyperammonemia. Liver transplantation eliminates hyperargininemia and presumably the risk for hyperammonemia but (in contrast to other urea cycle disorders) is rarely necessary in arginase deficiency; see also ## Prevention of Secondary Complications Prevention of Secondary Manifestations in Individuals with Arginase Deficiency Essential information including written treatment protocols should be provided Parents or local hospitals should immediately inform the designated metabolic center if: (1) temperature is >38.5°C; (2) vomiting/diarrhea or other symptoms of intercurrent illness develop; or (3) new neurologic symptoms occur. ## Surveillance Regular follow up at intervals determined by age and degree of metabolic stability is recommended (see Recommended Surveillance for Individuals with Arginase Deficiency Developmental stagnation and/or regression; seizures; spasticity; development of joint contractures Referral to neurologist, orthopedist, and/or physical therapist as indicated Albumin, bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, prothrombin time (PT), and partial thromboplastin time (PTT). ## Agents/Circumstances to Avoid Valproic acid should be avoided as it exacerbates hyperammonemia in urea cycle defects and other inborn errors of metabolism [ ## Evaluation of Relatives at Risk Because the age of onset of arginase deficiency is delayed beyond the newborn period and the manifestations can vary, the genetic status of all sibs of a proband (especially the younger ones) should be clarified so that morbidity can be reduced by early diagnosis and treatment in those who are affected. Testing methods can include any one of the following: Plasma quantitative amino acid analysis Molecular genetic testing (if the family-specific Analysis of enzymatic activity in red blood cells See • Plasma quantitative amino acid analysis • Molecular genetic testing (if the family-specific • Analysis of enzymatic activity in red blood cells ## Pregnancy Management The authors are not aware of any instance in which pregnancy has been reported in a woman with arginase deficiency. To achieve metabolic control that will enable normal fetal growth and development, affected pregnant women should generally continue dietary protein restriction and ammonia-scavenging medications (after an appropriate benefit/risk calculation) based on their clinical course before pregnancy. Protein restriction during pregnancy is challenging given the complications that commonly arise during pregnancy (i.e., nausea, vomiting, anorexia). Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with adherence, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery. Plasma amino acid levels can help guide quick adjustments to diet in order to achieve normal plasma amino acid profiles that prevent catabolism and hyperammonemia while allowing for normal fetal growth and development. There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate, or phenylbutyrate during human pregnancy, although there are several case reports. In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years. In the second pregnancy, emergency treatment with Ammonul Although the mother responded well to emergency treatment, the baby experienced intrauterine growth restriction and remained in the NICU due to prematurity and low birth weight. At age two years, the child exhibited speech delay and autism. How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known. Sodium benzoate has been reported to lead to malformations and neurotoxicity/nephrotoxicity in zebrafish larvae [ See • Protein restriction during pregnancy is challenging given the complications that commonly arise during pregnancy (i.e., nausea, vomiting, anorexia). • Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with adherence, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery. • Plasma amino acid levels can help guide quick adjustments to diet in order to achieve normal plasma amino acid profiles that prevent catabolism and hyperammonemia while allowing for normal fetal growth and development. • In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years. • In the second pregnancy, emergency treatment with Ammonul • Although the mother responded well to emergency treatment, the baby experienced intrauterine growth restriction and remained in the NICU due to prematurity and low birth weight. At age two years, the child exhibited speech delay and autism. • How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known. ## Prior to and During Pregancy To achieve metabolic control that will enable normal fetal growth and development, affected pregnant women should generally continue dietary protein restriction and ammonia-scavenging medications (after an appropriate benefit/risk calculation) based on their clinical course before pregnancy. Protein restriction during pregnancy is challenging given the complications that commonly arise during pregnancy (i.e., nausea, vomiting, anorexia). Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with adherence, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery. Plasma amino acid levels can help guide quick adjustments to diet in order to achieve normal plasma amino acid profiles that prevent catabolism and hyperammonemia while allowing for normal fetal growth and development. • Protein restriction during pregnancy is challenging given the complications that commonly arise during pregnancy (i.e., nausea, vomiting, anorexia). • Due to increased protein and energy requirements in pregnancy and, oftentimes, difficulty with adherence, weekly to every two-week monitoring of plasma amino acids and ammonia is recommended, especially in the first and third trimester, and close monitoring immediately after delivery. • Plasma amino acid levels can help guide quick adjustments to diet in order to achieve normal plasma amino acid profiles that prevent catabolism and hyperammonemia while allowing for normal fetal growth and development. ## Fetal Outcomes There are no well-controlled epidemiologic studies of the fetal effects of sodium benzoate, phenylacetate, or phenylbutyrate during human pregnancy, although there are several case reports. In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years. In the second pregnancy, emergency treatment with Ammonul Although the mother responded well to emergency treatment, the baby experienced intrauterine growth restriction and remained in the NICU due to prematurity and low birth weight. At age two years, the child exhibited speech delay and autism. How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known. • In the first pregnancy sodium phenylbutyrate (5.5 g/4x/day) was used as maintenance therapy. This resulted in the delivery of a healthy female who was noted to have typical growth and development at age five years. • In the second pregnancy, emergency treatment with Ammonul • Although the mother responded well to emergency treatment, the baby experienced intrauterine growth restriction and remained in the NICU due to prematurity and low birth weight. At age two years, the child exhibited speech delay and autism. • How severe metabolic decompensation, elevated plasma ornithine, and/or side effects of sodium phenylbutyrate, phenylacetate, and/or benzoate may have contributed to the speech delay and/or autism is not known. ## Theoretic Concerns Sodium benzoate has been reported to lead to malformations and neurotoxicity/nephrotoxicity in zebrafish larvae [ See ## Therapies Under Investigation A clinical trial for enzyme replacement therapy using pegylated synthetic human arginase I is currently under way (Clinical Trials Identifier A variety of genomic therapies are under investigation including mRNA therapy [ Search ## Other Immunizations can be provided on the usual schedule. Appropriate use of antipyretics is indicated. Ibuprofen is preferred over acetaminophen. ## Genetic Counseling Arginase 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. Although most severely affected individuals have not reproduced, those who are successfully treated are likely to be fertile. Unless an affected individual's reproductive partner also has arginase deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in 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 under treatment for arginase deficiency, are carriers, or are at risk of being carriers. Neither amniocytes nor chorionic villous cells have arginase enzyme activity and thus are unsuitable for prenatal diagnosis using biochemical testing. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While 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. • Although most severely affected individuals have not reproduced, those who are successfully treated are likely to be fertile. • Unless an affected individual's reproductive partner also has arginase deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic 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 under treatment for arginase deficiency, are carriers, or are at risk of being carriers. ## Mode of Inheritance Arginase 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. Although most severely affected individuals have not reproduced, those who are successfully treated are likely to be fertile. Unless an affected individual's reproductive partner also has arginase deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Although most severely affected individuals have not reproduced, those who are successfully treated are likely to be fertile. • Unless an affected individual's reproductive partner also has arginase deficiency or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in ## Carrier Detection ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are under treatment for arginase deficiency, 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 under treatment for arginase deficiency, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Neither amniocytes nor chorionic villous cells have arginase enzyme activity and thus are unsuitable for prenatal diagnosis using biochemical testing. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom United Kingdom Health Resources & Services Administration Children's National Medical Center • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • • • • • • • United Kingdom • • • Health Resources & Services Administration • • • • • • • • • Children's National Medical Center • ## Molecular Genetics Arginase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Arginase Deficiency ( Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Notable Variants listed in the table have been provided by the authors. ## Chapter Notes Angela Sun is a specialist in biochemical genetics and an Associate Professor of Pediatrics at the University of Washington and Seattle Children's Hospital. Eric Crombez is a specialist in biochemical genetics. He was formerly co-director, with Dr Stephen Cederbaum, of the Urea Cycle Disorders Consortium site at UCLA and is now at Shire HGT in Cambridge, MA. Derek Wong is Associate Clinical Professor of Pediatrics at UCLA. He is the Director of the Urea Cycle Disorders Consortium site at UCLA, and is the Head of Biochemical Genetics. Stephen Cederbaum, MD; University of California Los Angeles (2004-2020)Eric Crombez, MD (2004-present)Angela Sun, MD (2020-present)Derek Wong, MD (2004-present) 28 May 2020 (ma) Comprehensive update posted live 28 August 2014 (me) Comprehensive update posted live 9 February 2012(me) Comprehensive update posted live 1 September 2009 (me) Comprehensive update posted live 13 February 2007 (me) Comprehensive update posted live 21 October 2004 (me) Review posted live 2 March 2004 (sc) Original submission • 28 May 2020 (ma) Comprehensive update posted live • 28 August 2014 (me) Comprehensive update posted live • 9 February 2012(me) Comprehensive update posted live • 1 September 2009 (me) Comprehensive update posted live • 13 February 2007 (me) Comprehensive update posted live • 21 October 2004 (me) Review posted live • 2 March 2004 (sc) Original submission ## Author Notes Angela Sun is a specialist in biochemical genetics and an Associate Professor of Pediatrics at the University of Washington and Seattle Children's Hospital. Eric Crombez is a specialist in biochemical genetics. He was formerly co-director, with Dr Stephen Cederbaum, of the Urea Cycle Disorders Consortium site at UCLA and is now at Shire HGT in Cambridge, MA. Derek Wong is Associate Clinical Professor of Pediatrics at UCLA. He is the Director of the Urea Cycle Disorders Consortium site at UCLA, and is the Head of Biochemical Genetics. ## Author History Stephen Cederbaum, MD; University of California Los Angeles (2004-2020)Eric Crombez, MD (2004-present)Angela Sun, MD (2020-present)Derek Wong, MD (2004-present) ## Revision History 28 May 2020 (ma) Comprehensive update posted live 28 August 2014 (me) Comprehensive update posted live 9 February 2012(me) Comprehensive update posted live 1 September 2009 (me) Comprehensive update posted live 13 February 2007 (me) Comprehensive update posted live 21 October 2004 (me) Review posted live 2 March 2004 (sc) Original submission • 28 May 2020 (ma) Comprehensive update posted live • 28 August 2014 (me) Comprehensive update posted live • 9 February 2012(me) Comprehensive update posted live • 1 September 2009 (me) Comprehensive update posted live • 13 February 2007 (me) Comprehensive update posted live • 21 October 2004 (me) Review posted live • 2 March 2004 (sc) Original submission ## References ## Literature Cited	[]	21/10/2004	28/5/2020	5/10/2010	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
args-aciduria	args-aciduria	[ "Argininosuccinic Acid Lyase Deficiency (ASLD)", "Argininosuccinic Aciduria (ASA)", "Argininosuccinic Aciduria (ASA)", "Argininosuccinic Acid Lyase Deficiency (ASLD)", "Argininosuccinate lyase", "ASL", "Argininosuccinate Lyase Deficiency" ]	Argininosuccinate Lyase Deficiency	Sandesh CS Nagamani, Lindsay C Burrage, Brendan Lee	Summary Argininosuccinate lyase deficiency (ASLD), an inborn error of urea synthesis, may present as a neonatal- or late-onset disease. The diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine; or identification of biallelic pathogenic variants in ASLD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis Suggested guidelines for the diagnosis of argininosuccinate lyase deficiency (ASLD) have been published [ ASLD should be suspected in: An infant with An infant with An individual at any age with NBS for ASLD is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify citrulline concentrations by tandem mass spectrometry (MS/MS). In the United States 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 citrulline), further evaluation to Inform the family of the out-of-range NBS result. Ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea). Consult with a metabolic specialist immediately. If poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures, or signs of liver disease are present or if the newborn is ill, transport them to the hospital for further treatment and consultation with a metabolic specialist. Measure plasma ammonia (the sample for ammonia testing should be drawn as a stat order, transported to the laboratory on ice, with results being available within 30 minutes of the lab draw). Initiate confirmatory/diagnostic testing and management, as recommended by the metabolic specialist. Provide family with basic information about the possible diagnosis and its management. Note: Citrulline values above the cutoff reported by the NBS laboratory are considered positive, but elevation of citrulline can also be seen in other disorders (see If follow-up biochemical testing supports a diagnosis of ASLD, additional testing is not typically required prior to initiation of treatment. However, molecular genetic testing is recommended for molecular confirmation of the diagnosis (see An infant with severe neonatal-onset manifestations (age <28 days) can have (1) onset of clinical findings prior to availability of NBS results or (2) untreated neonatal-onset ASLD due to NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Suggestive clinical and laboratory findings in a symptomatic infant include: Lethargy, somnolence, refusal to feed Vomiting Tachypnea Hyperammonemia The initial plasma ammonia concentration may be >1,000 µmol/L, although typically plasma ammonia is in the range of a few hundred µmol/L. Respiratory alkalosis Elevated plasma citrulline The initial citrulline concentration is typically 100-300 µmol/L. Initial plasma level of argininosuccinate is typically in the range of 5-110 µmol/L. Normal plasma argininosuccinate is generally <5 µmol/L (dependent on normative data of each laboratory). Elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD. Note: Many laboratories provide only a qualitative estimation and not actual concentration of argininosuccinate. A proband of any age (including late onset) may have the following suggestive clinical, laboratory, and imaging findings and family history. History of protein aversion, self-protein restriction Attention-deficit/hyperactivity disorder, developmental delay, learning disabilities, intellectual disabilities, seizures, and abnormalities of motor functioning and coordination Liver disease including hepatomegaly, steatosis, fibrosis, or cirrhosis Trichorrhexis nodosa (coarse, brittle hair that breaks easily) Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes Episodic hyperammonemia triggered by metabolic stressors (e.g., acute infection, stress, or nonadherence to dietary restrictions or medications) Elevated liver transaminases Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium Plasma amino acid analysis typically shows elevated citrulline (usually 100-300 µmol/L) and argininosucciate and low arginine. Plasma glutamine concentration may be elevated, as in other urea cycle disorders (UCDs). Urine orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed. The biochemical diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine. The molecular diagnosis of ASLD is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in 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 When NBS results, clinical findings, or other laboratory findings suggest the diagnosis of ASLD, 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 Argininosuccinate Lyase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large intragenic deletions/duplications have been reported in individuals with ASLD. • An infant with • An infant with • An individual at any age with • Inform the family of the out-of-range NBS result. • Ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea). • Consult with a metabolic specialist immediately. • If poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures, or signs of liver disease are present or if the newborn is ill, transport them to the hospital for further treatment and consultation with a metabolic specialist. • Measure plasma ammonia (the sample for ammonia testing should be drawn as a stat order, transported to the laboratory on ice, with results being available within 30 minutes of the lab draw). • Initiate confirmatory/diagnostic testing and management, as recommended by the metabolic specialist. • Provide family with basic information about the possible diagnosis and its management. • Lethargy, somnolence, refusal to feed • Vomiting • Tachypnea • Hyperammonemia • The initial plasma ammonia concentration may be >1,000 µmol/L, although typically plasma ammonia is in the range of a few hundred µmol/L. • Respiratory alkalosis • Elevated plasma citrulline • The initial citrulline concentration is typically 100-300 µmol/L. • Initial plasma level of argininosuccinate is typically in the range of 5-110 µmol/L. • Normal plasma argininosuccinate is generally <5 µmol/L (dependent on normative data of each laboratory). Elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD. Note: Many laboratories provide only a qualitative estimation and not actual concentration of argininosuccinate. • History of protein aversion, self-protein restriction • Attention-deficit/hyperactivity disorder, developmental delay, learning disabilities, intellectual disabilities, seizures, and abnormalities of motor functioning and coordination • Liver disease including hepatomegaly, steatosis, fibrosis, or cirrhosis • Trichorrhexis nodosa (coarse, brittle hair that breaks easily) • Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes • Episodic hyperammonemia triggered by metabolic stressors (e.g., acute infection, stress, or nonadherence to dietary restrictions or medications) • Elevated liver transaminases • Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium • Plasma amino acid analysis typically shows elevated citrulline (usually 100-300 µmol/L) and argininosucciate and low arginine. Plasma glutamine concentration may be elevated, as in other urea cycle disorders (UCDs). • Urine orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed. • For an introduction to multigene panels click ## Suggestive Findings ASLD should be suspected in: An infant with An infant with An individual at any age with NBS for ASLD is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify citrulline concentrations by tandem mass spectrometry (MS/MS). In the United States 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 citrulline), further evaluation to Inform the family of the out-of-range NBS result. Ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea). Consult with a metabolic specialist immediately. If poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures, or signs of liver disease are present or if the newborn is ill, transport them to the hospital for further treatment and consultation with a metabolic specialist. Measure plasma ammonia (the sample for ammonia testing should be drawn as a stat order, transported to the laboratory on ice, with results being available within 30 minutes of the lab draw). Initiate confirmatory/diagnostic testing and management, as recommended by the metabolic specialist. Provide family with basic information about the possible diagnosis and its management. Note: Citrulline values above the cutoff reported by the NBS laboratory are considered positive, but elevation of citrulline can also be seen in other disorders (see If follow-up biochemical testing supports a diagnosis of ASLD, additional testing is not typically required prior to initiation of treatment. However, molecular genetic testing is recommended for molecular confirmation of the diagnosis (see An infant with severe neonatal-onset manifestations (age <28 days) can have (1) onset of clinical findings prior to availability of NBS results or (2) untreated neonatal-onset ASLD due to NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Suggestive clinical and laboratory findings in a symptomatic infant include: Lethargy, somnolence, refusal to feed Vomiting Tachypnea Hyperammonemia The initial plasma ammonia concentration may be >1,000 µmol/L, although typically plasma ammonia is in the range of a few hundred µmol/L. Respiratory alkalosis Elevated plasma citrulline The initial citrulline concentration is typically 100-300 µmol/L. Initial plasma level of argininosuccinate is typically in the range of 5-110 µmol/L. Normal plasma argininosuccinate is generally <5 µmol/L (dependent on normative data of each laboratory). Elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD. Note: Many laboratories provide only a qualitative estimation and not actual concentration of argininosuccinate. A proband of any age (including late onset) may have the following suggestive clinical, laboratory, and imaging findings and family history. History of protein aversion, self-protein restriction Attention-deficit/hyperactivity disorder, developmental delay, learning disabilities, intellectual disabilities, seizures, and abnormalities of motor functioning and coordination Liver disease including hepatomegaly, steatosis, fibrosis, or cirrhosis Trichorrhexis nodosa (coarse, brittle hair that breaks easily) Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes Episodic hyperammonemia triggered by metabolic stressors (e.g., acute infection, stress, or nonadherence to dietary restrictions or medications) Elevated liver transaminases Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium Plasma amino acid analysis typically shows elevated citrulline (usually 100-300 µmol/L) and argininosucciate and low arginine. Plasma glutamine concentration may be elevated, as in other urea cycle disorders (UCDs). Urine orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed. • An infant with • An infant with • An individual at any age with • Inform the family of the out-of-range NBS result. • Ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea). • Consult with a metabolic specialist immediately. • If poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures, or signs of liver disease are present or if the newborn is ill, transport them to the hospital for further treatment and consultation with a metabolic specialist. • Measure plasma ammonia (the sample for ammonia testing should be drawn as a stat order, transported to the laboratory on ice, with results being available within 30 minutes of the lab draw). • Initiate confirmatory/diagnostic testing and management, as recommended by the metabolic specialist. • Provide family with basic information about the possible diagnosis and its management. • Lethargy, somnolence, refusal to feed • Vomiting • Tachypnea • Hyperammonemia • The initial plasma ammonia concentration may be >1,000 µmol/L, although typically plasma ammonia is in the range of a few hundred µmol/L. • Respiratory alkalosis • Elevated plasma citrulline • The initial citrulline concentration is typically 100-300 µmol/L. • Initial plasma level of argininosuccinate is typically in the range of 5-110 µmol/L. • Normal plasma argininosuccinate is generally <5 µmol/L (dependent on normative data of each laboratory). Elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD. Note: Many laboratories provide only a qualitative estimation and not actual concentration of argininosuccinate. • History of protein aversion, self-protein restriction • Attention-deficit/hyperactivity disorder, developmental delay, learning disabilities, intellectual disabilities, seizures, and abnormalities of motor functioning and coordination • Liver disease including hepatomegaly, steatosis, fibrosis, or cirrhosis • Trichorrhexis nodosa (coarse, brittle hair that breaks easily) • Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes • Episodic hyperammonemia triggered by metabolic stressors (e.g., acute infection, stress, or nonadherence to dietary restrictions or medications) • Elevated liver transaminases • Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium • Plasma amino acid analysis typically shows elevated citrulline (usually 100-300 µmol/L) and argininosucciate and low arginine. Plasma glutamine concentration may be elevated, as in other urea cycle disorders (UCDs). • Urine orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed. ## Infant with Out-of-Range NBS Result NBS for ASLD is primarily based on use of dried blood spots collected between 24 and 72 hours after birth to quantify citrulline concentrations by tandem mass spectrometry (MS/MS). In the United States 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 citrulline), further evaluation to Inform the family of the out-of-range NBS result. Ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea). Consult with a metabolic specialist immediately. If poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures, or signs of liver disease are present or if the newborn is ill, transport them to the hospital for further treatment and consultation with a metabolic specialist. Measure plasma ammonia (the sample for ammonia testing should be drawn as a stat order, transported to the laboratory on ice, with results being available within 30 minutes of the lab draw). Initiate confirmatory/diagnostic testing and management, as recommended by the metabolic specialist. Provide family with basic information about the possible diagnosis and its management. Note: Citrulline values above the cutoff reported by the NBS laboratory are considered positive, but elevation of citrulline can also be seen in other disorders (see If follow-up biochemical testing supports a diagnosis of ASLD, additional testing is not typically required prior to initiation of treatment. However, molecular genetic testing is recommended for molecular confirmation of the diagnosis (see • Inform the family of the out-of-range NBS result. • Ascertain clinical status (poor feeding, vomiting, lethargy, tachypnea). • Consult with a metabolic specialist immediately. • If poor feeding, vomiting, lethargy, hypotonia, tachypnea, seizures, or signs of liver disease are present or if the newborn is ill, transport them to the hospital for further treatment and consultation with a metabolic specialist. • Measure plasma ammonia (the sample for ammonia testing should be drawn as a stat order, transported to the laboratory on ice, with results being available within 30 minutes of the lab draw). • Initiate confirmatory/diagnostic testing and management, as recommended by the metabolic specialist. • Provide family with basic information about the possible diagnosis and its management. ## Severe Neonatal-Onset Manifestations An infant with severe neonatal-onset manifestations (age <28 days) can have (1) onset of clinical findings prior to availability of NBS results or (2) untreated neonatal-onset ASLD due to NBS not performed, false negative NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Suggestive clinical and laboratory findings in a symptomatic infant include: Lethargy, somnolence, refusal to feed Vomiting Tachypnea Hyperammonemia The initial plasma ammonia concentration may be >1,000 µmol/L, although typically plasma ammonia is in the range of a few hundred µmol/L. Respiratory alkalosis Elevated plasma citrulline The initial citrulline concentration is typically 100-300 µmol/L. Initial plasma level of argininosuccinate is typically in the range of 5-110 µmol/L. Normal plasma argininosuccinate is generally <5 µmol/L (dependent on normative data of each laboratory). Elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD. Note: Many laboratories provide only a qualitative estimation and not actual concentration of argininosuccinate. • Lethargy, somnolence, refusal to feed • Vomiting • Tachypnea • Hyperammonemia • The initial plasma ammonia concentration may be >1,000 µmol/L, although typically plasma ammonia is in the range of a few hundred µmol/L. • Respiratory alkalosis • Elevated plasma citrulline • The initial citrulline concentration is typically 100-300 µmol/L. • Initial plasma level of argininosuccinate is typically in the range of 5-110 µmol/L. • Normal plasma argininosuccinate is generally <5 µmol/L (dependent on normative data of each laboratory). Elevated argininosuccinate on plasma and/or urine amino acids is pathognomonic of ASLD. Note: Many laboratories provide only a qualitative estimation and not actual concentration of argininosuccinate. ## Proband with Suggestive Findings A proband of any age (including late onset) may have the following suggestive clinical, laboratory, and imaging findings and family history. History of protein aversion, self-protein restriction Attention-deficit/hyperactivity disorder, developmental delay, learning disabilities, intellectual disabilities, seizures, and abnormalities of motor functioning and coordination Liver disease including hepatomegaly, steatosis, fibrosis, or cirrhosis Trichorrhexis nodosa (coarse, brittle hair that breaks easily) Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes Episodic hyperammonemia triggered by metabolic stressors (e.g., acute infection, stress, or nonadherence to dietary restrictions or medications) Elevated liver transaminases Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium Plasma amino acid analysis typically shows elevated citrulline (usually 100-300 µmol/L) and argininosucciate and low arginine. Plasma glutamine concentration may be elevated, as in other urea cycle disorders (UCDs). Urine orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed. • History of protein aversion, self-protein restriction • Attention-deficit/hyperactivity disorder, developmental delay, learning disabilities, intellectual disabilities, seizures, and abnormalities of motor functioning and coordination • Liver disease including hepatomegaly, steatosis, fibrosis, or cirrhosis • Trichorrhexis nodosa (coarse, brittle hair that breaks easily) • Hypertension that may occur in late childhood and adolescence, in the absence of secondary causes • Episodic hyperammonemia triggered by metabolic stressors (e.g., acute infection, stress, or nonadherence to dietary restrictions or medications) • Elevated liver transaminases • Hypokalemia of unknown etiology that may be chronic and secondary to excess urinary loss of potassium • Plasma amino acid analysis typically shows elevated citrulline (usually 100-300 µmol/L) and argininosucciate and low arginine. Plasma glutamine concentration may be elevated, as in other urea cycle disorders (UCDs). • Urine orotic acid excretion is typically normal (0.3-2.8 mmol/mol of creatinine); however, orotic aciduria may be observed. ## Establishing the Diagnosis The biochemical diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine. The molecular diagnosis of ASLD is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in 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 When NBS results, clinical findings, or other laboratory findings suggest the diagnosis of ASLD, 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 Argininosuccinate Lyase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large intragenic deletions/duplications have been reported in individuals with ASLD. • For an introduction to multigene panels click ## Biochemical Diagnosis The biochemical diagnosis of ASLD can be established by identification of increased argininosuccinate in plasma or urine. ## Molecular Diagnosis The molecular diagnosis of ASLD is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in 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 When NBS results, clinical findings, or other laboratory findings suggest the diagnosis of ASLD, 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 Argininosuccinate Lyase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large intragenic deletions/duplications have been reported in individuals with ASLD. • For an introduction to multigene panels click ## When NBS results, clinical findings, or other laboratory findings suggest the diagnosis of ASLD, 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 Argininosuccinate Lyase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. To date, no large intragenic deletions/duplications have been reported in individuals with ASLD. ## Clinical Characteristics The clinical presentation of arginosuccinate lyase deficiency (ASLD) is variable. The clinical presentation of neonatal-onset ASLD is indistinguishable from that of other urea cycle disorders (UCDs). Newborns typically appear healthy for the first 24 hours after birth. Hyperammonemia occurs within the first few days after birth. Within days, vomiting, lethargy, refusal to accept feeds, tachypnea, and respiratory alkalosis develops [ The findings of hepatomegaly and trichorrhexis nodosa at this early stage may be the only clinical findings that suggest a diagnosis of ASLD [ In contrast to the neonatal-onset form, the manifestations of late-onset ASLD range from episodic hyperammonemia (triggered by acute infection, stress, or nonadherence to dietary and/or medication recommendations) to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia [ Whereas manifestations secondary to hyperammonemia are common to all UCDs, many individuals with ASLD can present with a complex clinical phenotype. The incidence of (1) neurocognitive deficiencies; (2) hepatitis, hepatomegaly, fibrosis, and cirrhosis; and (3) systemic hypertension is overrepresented in individuals with ASLD [ Intellectual and developmental disabilities, learning disabilities, seizures, attention-deficit/hyperactivity disorder (ADHD), and abnormalities of motor functioning and coordination have been reported in individuals with ASLD. The increasing availability of newborn screening (NBS) for ASLD has provided the opportunity to study the effects of early diagnosis and treatment on neurologic and neurocognitive outcomes. In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ Although these data suggest more favorable neurologic and neurocognitive outcomes in individuals identified by NBS, they must be interpreted within the limitations of each dataset and analyses. Whereas the benefits observed may be due to early initiation of dietary and therapeutic interventions and a decrease in severity of hyperammonemic episodes, it is possible that the results may be confounded by the fact that NBS may have detected individuals with very mild disease, in whom it would be reasonable to expect a milder neurologic phenotype [ Liver disease has been documented in individuals with neonatal- and late-onset ASLD. Liver disease can develop even in individuals treated with known In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ There have been anecdotal reports of hypertension in individuals with ASLD. Preclinical data and systematic analysis of blood pressures from one controlled clinical trial have shown that ASLD can directly result in endothelial dysfunction and hypertension [ Homozygosity for a few pathogenic variants (e.g., p.Arg12Gln, p.Asp31Asn, p.Arg95Cys, p.Ile100Thr, p.Val178Met, p.Glu189Gly, p.Arg191Trp, p.Val335Leu, p.Arg379Cys, p.Arg385Cys, and p.Arg445Pro) has been observed in individuals with a milder phenotype [ The estimated prevalence is 1:70,000-218,000 live births [ Three pathogenic variants with a founder effect have been identified: c.346C>T (p.Gln116Ter) and • In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ • In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ • In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ • From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ • c.346C>T (p.Gln116Ter) and ## Clinical Description The clinical presentation of arginosuccinate lyase deficiency (ASLD) is variable. The clinical presentation of neonatal-onset ASLD is indistinguishable from that of other urea cycle disorders (UCDs). Newborns typically appear healthy for the first 24 hours after birth. Hyperammonemia occurs within the first few days after birth. Within days, vomiting, lethargy, refusal to accept feeds, tachypnea, and respiratory alkalosis develops [ The findings of hepatomegaly and trichorrhexis nodosa at this early stage may be the only clinical findings that suggest a diagnosis of ASLD [ In contrast to the neonatal-onset form, the manifestations of late-onset ASLD range from episodic hyperammonemia (triggered by acute infection, stress, or nonadherence to dietary and/or medication recommendations) to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia [ Whereas manifestations secondary to hyperammonemia are common to all UCDs, many individuals with ASLD can present with a complex clinical phenotype. The incidence of (1) neurocognitive deficiencies; (2) hepatitis, hepatomegaly, fibrosis, and cirrhosis; and (3) systemic hypertension is overrepresented in individuals with ASLD [ Intellectual and developmental disabilities, learning disabilities, seizures, attention-deficit/hyperactivity disorder (ADHD), and abnormalities of motor functioning and coordination have been reported in individuals with ASLD. The increasing availability of newborn screening (NBS) for ASLD has provided the opportunity to study the effects of early diagnosis and treatment on neurologic and neurocognitive outcomes. In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ Although these data suggest more favorable neurologic and neurocognitive outcomes in individuals identified by NBS, they must be interpreted within the limitations of each dataset and analyses. Whereas the benefits observed may be due to early initiation of dietary and therapeutic interventions and a decrease in severity of hyperammonemic episodes, it is possible that the results may be confounded by the fact that NBS may have detected individuals with very mild disease, in whom it would be reasonable to expect a milder neurologic phenotype [ Liver disease has been documented in individuals with neonatal- and late-onset ASLD. Liver disease can develop even in individuals treated with known In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ There have been anecdotal reports of hypertension in individuals with ASLD. Preclinical data and systematic analysis of blood pressures from one controlled clinical trial have shown that ASLD can directly result in endothelial dysfunction and hypertension [ • In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ • In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ • In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ • From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ ## Neonatal-Onset ASLD The clinical presentation of neonatal-onset ASLD is indistinguishable from that of other urea cycle disorders (UCDs). Newborns typically appear healthy for the first 24 hours after birth. Hyperammonemia occurs within the first few days after birth. Within days, vomiting, lethargy, refusal to accept feeds, tachypnea, and respiratory alkalosis develops [ The findings of hepatomegaly and trichorrhexis nodosa at this early stage may be the only clinical findings that suggest a diagnosis of ASLD [ ## Late-Onset ASLD In contrast to the neonatal-onset form, the manifestations of late-onset ASLD range from episodic hyperammonemia (triggered by acute infection, stress, or nonadherence to dietary and/or medication recommendations) to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia [ ## Long-Term Manifestations of ASLD Whereas manifestations secondary to hyperammonemia are common to all UCDs, many individuals with ASLD can present with a complex clinical phenotype. The incidence of (1) neurocognitive deficiencies; (2) hepatitis, hepatomegaly, fibrosis, and cirrhosis; and (3) systemic hypertension is overrepresented in individuals with ASLD [ Intellectual and developmental disabilities, learning disabilities, seizures, attention-deficit/hyperactivity disorder (ADHD), and abnormalities of motor functioning and coordination have been reported in individuals with ASLD. The increasing availability of newborn screening (NBS) for ASLD has provided the opportunity to study the effects of early diagnosis and treatment on neurologic and neurocognitive outcomes. In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ Although these data suggest more favorable neurologic and neurocognitive outcomes in individuals identified by NBS, they must be interpreted within the limitations of each dataset and analyses. Whereas the benefits observed may be due to early initiation of dietary and therapeutic interventions and a decrease in severity of hyperammonemic episodes, it is possible that the results may be confounded by the fact that NBS may have detected individuals with very mild disease, in whom it would be reasonable to expect a milder neurologic phenotype [ Liver disease has been documented in individuals with neonatal- and late-onset ASLD. Liver disease can develop even in individuals treated with known In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ There have been anecdotal reports of hypertension in individuals with ASLD. Preclinical data and systematic analysis of blood pressures from one controlled clinical trial have shown that ASLD can directly result in endothelial dysfunction and hypertension [ • In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ • In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ • In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ • From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ ## Intellectual and developmental disabilities, learning disabilities, seizures, attention-deficit/hyperactivity disorder (ADHD), and abnormalities of motor functioning and coordination have been reported in individuals with ASLD. The increasing availability of newborn screening (NBS) for ASLD has provided the opportunity to study the effects of early diagnosis and treatment on neurologic and neurocognitive outcomes. In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ Although these data suggest more favorable neurologic and neurocognitive outcomes in individuals identified by NBS, they must be interpreted within the limitations of each dataset and analyses. Whereas the benefits observed may be due to early initiation of dietary and therapeutic interventions and a decrease in severity of hyperammonemic episodes, it is possible that the results may be confounded by the fact that NBS may have detected individuals with very mild disease, in whom it would be reasonable to expect a milder neurologic phenotype [ • In a cohort of 17 individuals with ASLD diagnosed by NBS in Austria, IQ was average or above average in 11 (65%), low average in five (29%), and in the mild intellectual disability range in one (6%). Four had an abnormal EEG without evidence of clinical seizures [ • In analyses from large, prospective, observational, multicenter studies conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from 503 individuals with UCDs who had comprehensive neurocognitive testing with a cumulative follow up of 702 patient-years were analyzed. In this cohort, 56 individuals with ASLD were included and the overall mean z scores for cognitive outcome as measured by neuropsychological testing was −0.69 for individuals with ASLD identified by NBS as compared to −2.24 for individuals diagnosed after onset of manifestations [ ## Liver disease has been documented in individuals with neonatal- and late-onset ASLD. Liver disease can develop even in individuals treated with known In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ • In a cohort of 102 individuals with UCDs in which 28 individuals had ASLD (median age at evaluation was 15 years, with 64% having neonatal-onset disease), the mean plasma aminotransferase levels were significantly higher in individuals with ASLD compared to other UCDs. Similarly, individuals with ASLD had the highest rate of abnormal findings on liver ultrasound. Imaging abnormalities included hepatomegaly, hyperechoic liver, dyshomogenous hepatic parenchyma, and irregular liver edge [ • From a large, prospective, observational, multicenter study conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium, data from 640 participants with UCDs that collectively represented nearly 3,000 measurements of plasma aminotransferases were analyzed. A high prevalence of liver injury (37%) was observed in individuals with ASLD. ALT was higher among participants with ASLD as compared to other UCDs (e.g., OTC deficiency and citrullinemia type 1) [ ## There have been anecdotal reports of hypertension in individuals with ASLD. Preclinical data and systematic analysis of blood pressures from one controlled clinical trial have shown that ASLD can directly result in endothelial dysfunction and hypertension [ ## ## Genotype-Phenotype Correlations Homozygosity for a few pathogenic variants (e.g., p.Arg12Gln, p.Asp31Asn, p.Arg95Cys, p.Ile100Thr, p.Val178Met, p.Glu189Gly, p.Arg191Trp, p.Val335Leu, p.Arg379Cys, p.Arg385Cys, and p.Arg445Pro) has been observed in individuals with a milder phenotype [ ## Prevalence The estimated prevalence is 1:70,000-218,000 live births [ Three pathogenic variants with a founder effect have been identified: c.346C>T (p.Gln116Ter) and • c.346C>T (p.Gln116Ter) and ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis ## Management When arginosuccinate lyase deficiency (ASLD) is suspected during the diagnostic evaluation due to Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of adverse effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach including multiple subspecialists, with oversight and expertise from a specialized metabolic center. Arginosuccinate Lyase Deficiency: Recommended Evaluations Following an Out-of-Range Newborn Screening Result Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended). Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). Plasma ammonia Plasma (or urine) amino acids Urine organic acids Urine orotic acid Comprehensive metabolic panel ASLD = argininosuccinate lyase deficiency; MOI = mode of inheritance After a new diagnosis of ASLD 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). To establish the extent of disease and needs of an individual with ASLD following diagnosis, the evaluations summarized in Argininosuccinate Lyase Deficiency: Recommended Evaluations After Confirming a Diagnosis Transfer to a specialist center w/experience in management of inherited metabolic diseases (strongly recommended). Consider a visit or short hospitalization as required at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute crises) for caregivers. Plasma ammonia concentration Plasma amino acid analysis Laboratory values that reflect nutritional status (e.g., prealbumin, 25-hydroxyvitamin D, vitamin B Kidney function tests (BUN, creatinine) Electrolytes (sodium, potassium, chloride, bicarbonate) Consider referral to developmental pediatrician, psychologist, &/or neurologist at appropriate age(s). Consider referral to physical, occupational, & speech therapist as needed. Plasma AST, ALT, bilirubin, albumin, PT, & INR Liver ultrasound to identify hepatomegaly, fibrosis, & additional complications Referral to hepatologist as required ALT = alanine transaminase; ASLD = argininosuccinate lyase deficiency; AST = aspartate transaminase; BUN = blood urea nitrogen; INR = international normalized ratio; MOI = mode of inheritance; PT = prothrombin time After a new diagnosis of ASLD 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) Treatment involves rapid control of hyperammonemia during metabolic compensation, prevention of episodes of hyperammonemia, and management of long-term complications [ Argininosuccinate Lyase Deficiency: Targeted Therapies Protein intake is typically limited to minimal daily requirement for age. Typically, half the protein is provided as essential amino acids supplement. Supplementation w/non-protein-containing formula (only fats & carbohydrates) may be required to provide age-appropriate calories. Dietary therapy should be monitored using plasma ammonia, BCAAs, arginine, total protein, & prealbumin levels. Maintain plasma glutamine concentrations at ˂1,000 µmol/L if possible. 100-300 mg/kg/day in persons weighing ˂20 kg 2.2-5.5 g/m Arginine is deficient in persons w/ASLD & arginine promotes excretion of nitrogen through urea cycle as argininosuccinate. Arginine base is preferred for long-term treatment, as chronic use of arginine hydrochloride may lead to hyperchloremic acidosis. In 1 controlled clinical trial, higher doses of arginine were assoc w/↑ plasma AST & ALT. 450-600 mg/kg/day for persons weighing ≤20 kg 9.9-13 g/m These medications should be considered when persons have recurrent hyperammonemia or there is suboptimal metabolic control in spite of dietary therapy & arginine base supplementation. Phenylbutyrate metabolite levels can be used for monitoring therapy. ALT = alanine transaminase; ASLD = argininosuccinate lyase deficiency; AST = aspartate transaminase; BCAA = branched-chain amino acids; BSA = body surface area; DRI = dietary reference intakes Some of the correlations between adherence to the prescribed diet and outcome are contradictory. Although in some individuals dietary therapy along with arginine supplementation have been shown to reverse the hair abnormalities, improve cognitive outcome, and reverse abnormalities on EEG [ Argininosuccinate Lyase Deficiency: Outpatient Routine Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Valproic acid may induce hyperammonemia & should be avoided. Education of parents/caregivers Salt restriction Antihypertensive medications Nitrites & nitrate-containing supplements There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. Dietary foods rich in nitrates might be considered as a supplemental treatment. Encourage medical alert bracelet. Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. Provide families w/letter to optimize social & school services. ASL = argininosuccinate lyase; ASLD = argininosuccinate lyase deficiency; NO = nitric oxide; OT = occupational therapist; PT = physical therapist 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 In one systematic analysis of outcomes with liver transplantation versus medical management conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from the severe phenotype group included nine individuals with ASLD who had undergone liver transplantation and 12 individuals whose liver disease was managed medically. The median z scores for cognitive outcomes as assessed by neuropsychological testing were not different between liver transplantation and medical management. However, in a case series of nine children with neonatal-onset disease who underwent liver transplantation, prevention of further hyperammonemic episodes and improvements in cognitive and developmental functioning, behavior, and quality of life were reported [ 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 types of therapy can be made by a developmental pediatrician. As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 the 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 Argininosuccinate Lyase Deficiency: Emergency Management Argininosuccinate Lyase Deficiency: Acute Inpatient Treatment Temporary withholding of oral protein intake (~24 hrs) Supplementation w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism Mgmt of airway, circulation, seizures, & intracranial pressure Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, & urine pH/ketone screening may be useful in guiding treatment. Assessment of hemodynamic status Continuous assessment of neurologic status is critical. Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg When available, monitor plasma concentrations of phenylacetic acid & phenylacetylglutamine to avoid toxicity. Plasma phenylacetic acid levels <200 μg/L & phenylacetic acid-to-phenylacetylglutamine ratio of 2.5 are generally considered to be safe. In the absence of drug levels, a serum anion gap of >15 mEq/L & an anion gap that has risen >6 mEq/L could indicate drug accumulation & ↑ risk for toxicity of phenylacetic acid. KRT should be initial therapy for treatment of severe hyperammonemia. Failure to control ammonia w/scavenger therapy requires emergency KRT. Hemodialysis or continuous venovenous hemofiltration under supervision of metabolic geneticist & nephrologist Some centers use extracorporeal membrane oxygenation w/hemodialysis IV = intravenous; PO = oral Inpatient emergency treatment should: (1) take place at the closest medical facility equipped to treat individuals with metabolic disorders; (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. Due to fever, perioperative/peri-interventional fasting periods, repeated vomiting/diarrhea S Nagamani, personal observation Argininosuccinate Lyase Deficiency: Anticipatory Perioperative Management Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt). Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary. Perioperative/perianesthetic management precautions may include visits at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications. In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Argininosuccinate Lyase Deficiency: Recommended Surveillance Height, weight, body mass index Laboratory indices of nutritional status (e.g., prealbumin, BCAAs [leucine, isoleucine, & valine], plasma amino acids, & plasma ammonia to identify deficiency of essential amino acids & assess for impending hyperammonemia Phenylbutyrate metabolite levels may be used for monitoring persons on phenylbutyrate medications. Neonates: every 2 wks Infants (age 2 mos-1 yr): every 1-3 mos Children (age ≥2 yrs): every 3-4 mos Assess developmental progress & educational needs. Behavioral assessment incl ADHD assessment Assess for new manifestations such as seizures, abnormal motor function, & problems w/coordination. PT &/or OT assessment as needed ADHD = attention-deficit/hyperactivity disorder; ALT = alanine transaminase; AST = aspartate transaminase; BCAA = branched-chain amino acids; INR = international normalized ratio; OT = occupational therapy; PT= physical therapy Early signs of impending hyperammonemic episodes in older individuals include mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus, and elevated plasma concentrations of glutamine, alanine, and glycine. Plasma glutamine concentration may rise 48 hours in advance of increases in plasma ammonia concentration in such individuals. S Nagamani, LC Burrage, and B Lee, unpublished data Avoid the following: Excess protein intake; large boluses of protein or amino acids Less than recommended intake of protein; prolonged fasting or starvation Exposure to communicable diseases Valproic acid Oral or parenteral administration of corticosteroids, if possible. If steroids are medically required for treatment of a coexisting medical condition, contact the metabolic specialist for recommendations to prevent hyperammonemia with steroid therapy. Hepatotoxic drugs in individuals with liver disease See There are no guidelines for management of pregnancy in affected females. However, as pregnancy can pose significant stress in females with all UCDs, close monitoring and management is recommended for prevention of hyperammonemia in females with ASLD. Search • Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended). • Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). • Plasma ammonia • Plasma (or urine) amino acids • Urine organic acids • Urine orotic acid • Comprehensive metabolic panel • Transfer to a specialist center w/experience in management of inherited metabolic diseases (strongly recommended). • Consider a visit or short hospitalization as required at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute crises) for caregivers. • Plasma ammonia concentration • Plasma amino acid analysis • Laboratory values that reflect nutritional status (e.g., prealbumin, 25-hydroxyvitamin D, vitamin B • Kidney function tests (BUN, creatinine) • Electrolytes (sodium, potassium, chloride, bicarbonate) • Consider referral to developmental pediatrician, psychologist, &/or neurologist at appropriate age(s). • Consider referral to physical, occupational, & speech therapist as needed. • Plasma AST, ALT, bilirubin, albumin, PT, & INR • Liver ultrasound to identify hepatomegaly, fibrosis, & additional complications • Referral to hepatologist as required • Protein intake is typically limited to minimal daily requirement for age. • Typically, half the protein is provided as essential amino acids supplement. • Supplementation w/non-protein-containing formula (only fats & carbohydrates) may be required to provide age-appropriate calories. • Dietary therapy should be monitored using plasma ammonia, BCAAs, arginine, total protein, & prealbumin levels. • Maintain plasma glutamine concentrations at ˂1,000 µmol/L if possible. • 100-300 mg/kg/day in persons weighing ˂20 kg • 2.2-5.5 g/m • Arginine is deficient in persons w/ASLD & arginine promotes excretion of nitrogen through urea cycle as argininosuccinate. • Arginine base is preferred for long-term treatment, as chronic use of arginine hydrochloride may lead to hyperchloremic acidosis. • In 1 controlled clinical trial, higher doses of arginine were assoc w/↑ plasma AST & ALT. • 450-600 mg/kg/day for persons weighing ≤20 kg • 9.9-13 g/m • These medications should be considered when persons have recurrent hyperammonemia or there is suboptimal metabolic control in spite of dietary therapy & arginine base supplementation. • Phenylbutyrate metabolite levels can be used for monitoring therapy. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Valproic acid may induce hyperammonemia & should be avoided. • Education of parents/caregivers • Salt restriction • Antihypertensive medications • Nitrites & nitrate-containing supplements • There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. • Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. • NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. • Dietary foods rich in nitrates might be considered as a supplemental treatment. • Encourage medical alert bracelet. • Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. • Provide families w/letter to optimize social & school services. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 the 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 • Temporary withholding of oral protein intake (~24 hrs) • Supplementation w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism • Mgmt of airway, circulation, seizures, & intracranial pressure • Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, & urine pH/ketone screening may be useful in guiding treatment. • Assessment of hemodynamic status • Continuous assessment of neurologic status is critical. • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • When available, monitor plasma concentrations of phenylacetic acid & phenylacetylglutamine to avoid toxicity. • Plasma phenylacetic acid levels <200 μg/L & phenylacetic acid-to-phenylacetylglutamine ratio of 2.5 are generally considered to be safe. • In the absence of drug levels, a serum anion gap of >15 mEq/L & an anion gap that has risen >6 mEq/L could indicate drug accumulation & ↑ risk for toxicity of phenylacetic acid. • KRT should be initial therapy for treatment of severe hyperammonemia. • Failure to control ammonia w/scavenger therapy requires emergency KRT. • Hemodialysis or continuous venovenous hemofiltration under supervision of metabolic geneticist & nephrologist • Some centers use extracorporeal membrane oxygenation w/hemodialysis • Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. • Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt). • Height, weight, body mass index • Laboratory indices of nutritional status (e.g., prealbumin, BCAAs [leucine, isoleucine, & valine], plasma amino acids, & plasma ammonia to identify deficiency of essential amino acids & assess for impending hyperammonemia • Phenylbutyrate metabolite levels may be used for monitoring persons on phenylbutyrate medications. • Neonates: every 2 wks • Infants (age 2 mos-1 yr): every 1-3 mos • Children (age ≥2 yrs): every 3-4 mos • Assess developmental progress & educational needs. • Behavioral assessment incl ADHD assessment • Assess for new manifestations such as seizures, abnormal motor function, & problems w/coordination. • PT &/or OT assessment as needed • Excess protein intake; large boluses of protein or amino acids • Less than recommended intake of protein; prolonged fasting or starvation • Exposure to communicable diseases • Valproic acid • Oral or parenteral administration of corticosteroids, if possible. If steroids are medically required for treatment of a coexisting medical condition, contact the metabolic specialist for recommendations to prevent hyperammonemia with steroid therapy. • Hepatotoxic drugs in individuals with liver disease ## Evaluation of a Newborn with an Out-of-Range NBS Result Arginosuccinate Lyase Deficiency: Recommended Evaluations Following an Out-of-Range Newborn Screening Result Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended). Consider short hospitalization at a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). Plasma ammonia Plasma (or urine) amino acids Urine organic acids Urine orotic acid Comprehensive metabolic panel ASLD = argininosuccinate lyase deficiency; MOI = mode of inheritance After a new diagnosis of ASLD 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 a center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises). • Plasma ammonia • Plasma (or urine) amino acids • Urine organic acids • Urine orotic acid • Comprehensive metabolic panel ## Evaluations Following Initial Confirmatory Diagnosis To establish the extent of disease and needs of an individual with ASLD following diagnosis, the evaluations summarized in Argininosuccinate Lyase Deficiency: Recommended Evaluations After Confirming a Diagnosis Transfer to a specialist center w/experience in management of inherited metabolic diseases (strongly recommended). Consider a visit or short hospitalization as required at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute crises) for caregivers. Plasma ammonia concentration Plasma amino acid analysis Laboratory values that reflect nutritional status (e.g., prealbumin, 25-hydroxyvitamin D, vitamin B Kidney function tests (BUN, creatinine) Electrolytes (sodium, potassium, chloride, bicarbonate) Consider referral to developmental pediatrician, psychologist, &/or neurologist at appropriate age(s). Consider referral to physical, occupational, & speech therapist as needed. Plasma AST, ALT, bilirubin, albumin, PT, & INR Liver ultrasound to identify hepatomegaly, fibrosis, & additional complications Referral to hepatologist as required ALT = alanine transaminase; ASLD = argininosuccinate lyase deficiency; AST = aspartate transaminase; BUN = blood urea nitrogen; INR = international normalized ratio; MOI = mode of inheritance; PT = prothrombin time After a new diagnosis of ASLD 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 a specialist center w/experience in management of inherited metabolic diseases (strongly recommended). • Consider a visit or short hospitalization as required at a center of expertise for inherited metabolic conditions to provide detailed education (natural history, maintenance & emergency treatment, prognosis & risks for acute crises) for caregivers. • Plasma ammonia concentration • Plasma amino acid analysis • Laboratory values that reflect nutritional status (e.g., prealbumin, 25-hydroxyvitamin D, vitamin B • Kidney function tests (BUN, creatinine) • Electrolytes (sodium, potassium, chloride, bicarbonate) • Consider referral to developmental pediatrician, psychologist, &/or neurologist at appropriate age(s). • Consider referral to physical, occupational, & speech therapist as needed. • Plasma AST, ALT, bilirubin, albumin, PT, & INR • Liver ultrasound to identify hepatomegaly, fibrosis, & additional complications • Referral to hepatologist as required ## Treatment of Manifestations Treatment involves rapid control of hyperammonemia during metabolic compensation, prevention of episodes of hyperammonemia, and management of long-term complications [ Argininosuccinate Lyase Deficiency: Targeted Therapies Protein intake is typically limited to minimal daily requirement for age. Typically, half the protein is provided as essential amino acids supplement. Supplementation w/non-protein-containing formula (only fats & carbohydrates) may be required to provide age-appropriate calories. Dietary therapy should be monitored using plasma ammonia, BCAAs, arginine, total protein, & prealbumin levels. Maintain plasma glutamine concentrations at ˂1,000 µmol/L if possible. 100-300 mg/kg/day in persons weighing ˂20 kg 2.2-5.5 g/m Arginine is deficient in persons w/ASLD & arginine promotes excretion of nitrogen through urea cycle as argininosuccinate. Arginine base is preferred for long-term treatment, as chronic use of arginine hydrochloride may lead to hyperchloremic acidosis. In 1 controlled clinical trial, higher doses of arginine were assoc w/↑ plasma AST & ALT. 450-600 mg/kg/day for persons weighing ≤20 kg 9.9-13 g/m These medications should be considered when persons have recurrent hyperammonemia or there is suboptimal metabolic control in spite of dietary therapy & arginine base supplementation. Phenylbutyrate metabolite levels can be used for monitoring therapy. ALT = alanine transaminase; ASLD = argininosuccinate lyase deficiency; AST = aspartate transaminase; BCAA = branched-chain amino acids; BSA = body surface area; DRI = dietary reference intakes Some of the correlations between adherence to the prescribed diet and outcome are contradictory. Although in some individuals dietary therapy along with arginine supplementation have been shown to reverse the hair abnormalities, improve cognitive outcome, and reverse abnormalities on EEG [ Argininosuccinate Lyase Deficiency: Outpatient Routine Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Valproic acid may induce hyperammonemia & should be avoided. Education of parents/caregivers Salt restriction Antihypertensive medications Nitrites & nitrate-containing supplements There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. Dietary foods rich in nitrates might be considered as a supplemental treatment. Encourage medical alert bracelet. Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. Provide families w/letter to optimize social & school services. ASL = argininosuccinate lyase; ASLD = argininosuccinate lyase deficiency; NO = nitric oxide; OT = occupational therapist; PT = physical therapist 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 In one systematic analysis of outcomes with liver transplantation versus medical management conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from the severe phenotype group included nine individuals with ASLD who had undergone liver transplantation and 12 individuals whose liver disease was managed medically. The median z scores for cognitive outcomes as assessed by neuropsychological testing were not different between liver transplantation and medical management. However, in a case series of nine children with neonatal-onset disease who underwent liver transplantation, prevention of further hyperammonemic episodes and improvements in cognitive and developmental functioning, behavior, and quality of life were reported [ 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 types of therapy can be made by a developmental pediatrician. As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 the 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 Argininosuccinate Lyase Deficiency: Emergency Management Argininosuccinate Lyase Deficiency: Acute Inpatient Treatment Temporary withholding of oral protein intake (~24 hrs) Supplementation w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism Mgmt of airway, circulation, seizures, & intracranial pressure Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, & urine pH/ketone screening may be useful in guiding treatment. Assessment of hemodynamic status Continuous assessment of neurologic status is critical. Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg When available, monitor plasma concentrations of phenylacetic acid & phenylacetylglutamine to avoid toxicity. Plasma phenylacetic acid levels <200 μg/L & phenylacetic acid-to-phenylacetylglutamine ratio of 2.5 are generally considered to be safe. In the absence of drug levels, a serum anion gap of >15 mEq/L & an anion gap that has risen >6 mEq/L could indicate drug accumulation & ↑ risk for toxicity of phenylacetic acid. KRT should be initial therapy for treatment of severe hyperammonemia. Failure to control ammonia w/scavenger therapy requires emergency KRT. Hemodialysis or continuous venovenous hemofiltration under supervision of metabolic geneticist & nephrologist Some centers use extracorporeal membrane oxygenation w/hemodialysis IV = intravenous; PO = oral Inpatient emergency treatment should: (1) take place at the closest medical facility equipped to treat individuals with metabolic disorders; (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. Due to fever, perioperative/peri-interventional fasting periods, repeated vomiting/diarrhea S Nagamani, personal observation Argininosuccinate Lyase Deficiency: Anticipatory Perioperative Management Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt). Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary. Perioperative/perianesthetic management precautions may include visits at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications. • Protein intake is typically limited to minimal daily requirement for age. • Typically, half the protein is provided as essential amino acids supplement. • Supplementation w/non-protein-containing formula (only fats & carbohydrates) may be required to provide age-appropriate calories. • Dietary therapy should be monitored using plasma ammonia, BCAAs, arginine, total protein, & prealbumin levels. • Maintain plasma glutamine concentrations at ˂1,000 µmol/L if possible. • 100-300 mg/kg/day in persons weighing ˂20 kg • 2.2-5.5 g/m • Arginine is deficient in persons w/ASLD & arginine promotes excretion of nitrogen through urea cycle as argininosuccinate. • Arginine base is preferred for long-term treatment, as chronic use of arginine hydrochloride may lead to hyperchloremic acidosis. • In 1 controlled clinical trial, higher doses of arginine were assoc w/↑ plasma AST & ALT. • 450-600 mg/kg/day for persons weighing ≤20 kg • 9.9-13 g/m • These medications should be considered when persons have recurrent hyperammonemia or there is suboptimal metabolic control in spite of dietary therapy & arginine base supplementation. • Phenylbutyrate metabolite levels can be used for monitoring therapy. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Valproic acid may induce hyperammonemia & should be avoided. • Education of parents/caregivers • Salt restriction • Antihypertensive medications • Nitrites & nitrate-containing supplements • There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. • Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. • NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. • Dietary foods rich in nitrates might be considered as a supplemental treatment. • Encourage medical alert bracelet. • Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. • Provide families w/letter to optimize social & school services. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 the 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 • Temporary withholding of oral protein intake (~24 hrs) • Supplementation w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism • Mgmt of airway, circulation, seizures, & intracranial pressure • Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, & urine pH/ketone screening may be useful in guiding treatment. • Assessment of hemodynamic status • Continuous assessment of neurologic status is critical. • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • When available, monitor plasma concentrations of phenylacetic acid & phenylacetylglutamine to avoid toxicity. • Plasma phenylacetic acid levels <200 μg/L & phenylacetic acid-to-phenylacetylglutamine ratio of 2.5 are generally considered to be safe. • In the absence of drug levels, a serum anion gap of >15 mEq/L & an anion gap that has risen >6 mEq/L could indicate drug accumulation & ↑ risk for toxicity of phenylacetic acid. • KRT should be initial therapy for treatment of severe hyperammonemia. • Failure to control ammonia w/scavenger therapy requires emergency KRT. • Hemodialysis or continuous venovenous hemofiltration under supervision of metabolic geneticist & nephrologist • Some centers use extracorporeal membrane oxygenation w/hemodialysis • Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. • Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt). ## Targeted Therapies Argininosuccinate Lyase Deficiency: Targeted Therapies Protein intake is typically limited to minimal daily requirement for age. Typically, half the protein is provided as essential amino acids supplement. Supplementation w/non-protein-containing formula (only fats & carbohydrates) may be required to provide age-appropriate calories. Dietary therapy should be monitored using plasma ammonia, BCAAs, arginine, total protein, & prealbumin levels. Maintain plasma glutamine concentrations at ˂1,000 µmol/L if possible. 100-300 mg/kg/day in persons weighing ˂20 kg 2.2-5.5 g/m Arginine is deficient in persons w/ASLD & arginine promotes excretion of nitrogen through urea cycle as argininosuccinate. Arginine base is preferred for long-term treatment, as chronic use of arginine hydrochloride may lead to hyperchloremic acidosis. In 1 controlled clinical trial, higher doses of arginine were assoc w/↑ plasma AST & ALT. 450-600 mg/kg/day for persons weighing ≤20 kg 9.9-13 g/m These medications should be considered when persons have recurrent hyperammonemia or there is suboptimal metabolic control in spite of dietary therapy & arginine base supplementation. Phenylbutyrate metabolite levels can be used for monitoring therapy. ALT = alanine transaminase; ASLD = argininosuccinate lyase deficiency; AST = aspartate transaminase; BCAA = branched-chain amino acids; BSA = body surface area; DRI = dietary reference intakes Some of the correlations between adherence to the prescribed diet and outcome are contradictory. Although in some individuals dietary therapy along with arginine supplementation have been shown to reverse the hair abnormalities, improve cognitive outcome, and reverse abnormalities on EEG [ • Protein intake is typically limited to minimal daily requirement for age. • Typically, half the protein is provided as essential amino acids supplement. • Supplementation w/non-protein-containing formula (only fats & carbohydrates) may be required to provide age-appropriate calories. • Dietary therapy should be monitored using plasma ammonia, BCAAs, arginine, total protein, & prealbumin levels. • Maintain plasma glutamine concentrations at ˂1,000 µmol/L if possible. • 100-300 mg/kg/day in persons weighing ˂20 kg • 2.2-5.5 g/m • Arginine is deficient in persons w/ASLD & arginine promotes excretion of nitrogen through urea cycle as argininosuccinate. • Arginine base is preferred for long-term treatment, as chronic use of arginine hydrochloride may lead to hyperchloremic acidosis. • In 1 controlled clinical trial, higher doses of arginine were assoc w/↑ plasma AST & ALT. • 450-600 mg/kg/day for persons weighing ≤20 kg • 9.9-13 g/m • These medications should be considered when persons have recurrent hyperammonemia or there is suboptimal metabolic control in spite of dietary therapy & arginine base supplementation. • Phenylbutyrate metabolite levels can be used for monitoring therapy. ## Supportive Care Argininosuccinate Lyase Deficiency: Outpatient Routine Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Valproic acid may induce hyperammonemia & should be avoided. Education of parents/caregivers Salt restriction Antihypertensive medications Nitrites & nitrate-containing supplements There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. Dietary foods rich in nitrates might be considered as a supplemental treatment. Encourage medical alert bracelet. Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. Provide families w/letter to optimize social & school services. ASL = argininosuccinate lyase; ASLD = argininosuccinate lyase deficiency; NO = nitric oxide; OT = occupational therapist; PT = physical therapist 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 In one systematic analysis of outcomes with liver transplantation versus medical management conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from the severe phenotype group included nine individuals with ASLD who had undergone liver transplantation and 12 individuals whose liver disease was managed medically. The median z scores for cognitive outcomes as assessed by neuropsychological testing were not different between liver transplantation and medical management. However, in a case series of nine children with neonatal-onset disease who underwent liver transplantation, prevention of further hyperammonemic episodes and improvements in cognitive and developmental functioning, behavior, and quality of life were reported [ 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 types of therapy can be made by a developmental pediatrician. As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 the 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 • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Valproic acid may induce hyperammonemia & should be avoided. • Education of parents/caregivers • Salt restriction • Antihypertensive medications • Nitrites & nitrate-containing supplements • There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. • Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. • NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. • Dietary foods rich in nitrates might be considered as a supplemental treatment. • Encourage medical alert bracelet. • Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. • Provide families w/letter to optimize social & school services. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 the 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 ## Argininosuccinate Lyase Deficiency: Outpatient Routine Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Valproic acid may induce hyperammonemia & should be avoided. Education of parents/caregivers Salt restriction Antihypertensive medications Nitrites & nitrate-containing supplements There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. Dietary foods rich in nitrates might be considered as a supplemental treatment. Encourage medical alert bracelet. Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. Provide families w/letter to optimize social & school services. ASL = argininosuccinate lyase; ASLD = argininosuccinate lyase deficiency; NO = nitric oxide; OT = occupational therapist; PT = physical therapist 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 • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Valproic acid may induce hyperammonemia & should be avoided. • Education of parents/caregivers • Salt restriction • Antihypertensive medications • Nitrites & nitrate-containing supplements • There are no data on comparative efficacy of different classes of antihypertensive medications in ASLD. • Preclinical models demonstrate that hypertension is due to vascular tissue-specific loss of ASL & resulting deficiency of NO. • NO synthase-independent NO supplements (e.g., isosorbinde mono- & dinitrates) have been used anecdotally for hypertension. • Dietary foods rich in nitrates might be considered as a supplemental treatment. • Encourage medical alert bracelet. • Provide letter & written protocols for mgmt of intercurrent illnesses or other catabolic stressors. • Provide families w/letter to optimize social & school services. ## In one systematic analysis of outcomes with liver transplantation versus medical management conducted by the NIH Rare Diseases Clinical Research Network's Urea Cycle Disorders Consortium and the European Registry and Network for Intoxication Type Metabolic Diseases, data from the severe phenotype group included nine individuals with ASLD who had undergone liver transplantation and 12 individuals whose liver disease was managed medically. The median z scores for cognitive outcomes as assessed by neuropsychological testing were not different between liver transplantation and medical management. However, in a case series of nine children with neonatal-onset disease who underwent liver transplantation, prevention of further hyperammonemic episodes and improvements in cognitive and developmental functioning, behavior, and quality of life were reported [ ## 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 types of therapy can be made by a developmental pediatrician. As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or 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 types of therapy can be made by a developmental pediatrician. • As a child enters their teens, a transition plan should 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 the 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 the 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 ## Emergency Management Argininosuccinate Lyase Deficiency: Emergency Management ## Acute Inpatient Treatment Argininosuccinate Lyase Deficiency: Acute Inpatient Treatment Temporary withholding of oral protein intake (~24 hrs) Supplementation w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism Mgmt of airway, circulation, seizures, & intracranial pressure Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, & urine pH/ketone screening may be useful in guiding treatment. Assessment of hemodynamic status Continuous assessment of neurologic status is critical. Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg Sodium benzoate: 20 kg: 5.5 g/m Sodium phenylacetate: 20 kg: 5.5 g/m 10% arginine HCl: 20 kg: 600 mg/kg When available, monitor plasma concentrations of phenylacetic acid & phenylacetylglutamine to avoid toxicity. Plasma phenylacetic acid levels <200 μg/L & phenylacetic acid-to-phenylacetylglutamine ratio of 2.5 are generally considered to be safe. In the absence of drug levels, a serum anion gap of >15 mEq/L & an anion gap that has risen >6 mEq/L could indicate drug accumulation & ↑ risk for toxicity of phenylacetic acid. KRT should be initial therapy for treatment of severe hyperammonemia. Failure to control ammonia w/scavenger therapy requires emergency KRT. Hemodialysis or continuous venovenous hemofiltration under supervision of metabolic geneticist & nephrologist Some centers use extracorporeal membrane oxygenation w/hemodialysis IV = intravenous; PO = oral Inpatient emergency treatment should: (1) take place at the closest medical facility equipped to treat individuals with metabolic disorders; (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. Due to fever, perioperative/peri-interventional fasting periods, repeated vomiting/diarrhea S Nagamani, personal observation • Temporary withholding of oral protein intake (~24 hrs) • Supplementation w/IV lipids, glucose, & insulin if needed (w/close monitoring of blood glucose) to promote anabolism • Mgmt of airway, circulation, seizures, & intracranial pressure • Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, & urine pH/ketone screening may be useful in guiding treatment. • Assessment of hemodynamic status • Continuous assessment of neurologic status is critical. • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • Sodium benzoate: 20 kg: 5.5 g/m • Sodium phenylacetate: 20 kg: 5.5 g/m • 10% arginine HCl: 20 kg: 600 mg/kg • When available, monitor plasma concentrations of phenylacetic acid & phenylacetylglutamine to avoid toxicity. • Plasma phenylacetic acid levels <200 μg/L & phenylacetic acid-to-phenylacetylglutamine ratio of 2.5 are generally considered to be safe. • In the absence of drug levels, a serum anion gap of >15 mEq/L & an anion gap that has risen >6 mEq/L could indicate drug accumulation & ↑ risk for toxicity of phenylacetic acid. • KRT should be initial therapy for treatment of severe hyperammonemia. • Failure to control ammonia w/scavenger therapy requires emergency KRT. • Hemodialysis or continuous venovenous hemofiltration under supervision of metabolic geneticist & nephrologist • Some centers use extracorporeal membrane oxygenation w/hemodialysis ## Anticipatory Perioperative Management Argininosuccinate Lyase Deficiency: Anticipatory Perioperative Management Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt). Essential information including written treatment protocols should be provided before inpatient emergency treatment might be necessary. Perioperative/perianesthetic management precautions may include visits at specialist anesthetic clinics for affected individuals deemed to be high risk for perioperative complications. • Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists. • Emergency surgeries/procedures require planning input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt). ## Surveillance In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in Argininosuccinate Lyase Deficiency: Recommended Surveillance Height, weight, body mass index Laboratory indices of nutritional status (e.g., prealbumin, BCAAs [leucine, isoleucine, & valine], plasma amino acids, & plasma ammonia to identify deficiency of essential amino acids & assess for impending hyperammonemia Phenylbutyrate metabolite levels may be used for monitoring persons on phenylbutyrate medications. Neonates: every 2 wks Infants (age 2 mos-1 yr): every 1-3 mos Children (age ≥2 yrs): every 3-4 mos Assess developmental progress & educational needs. Behavioral assessment incl ADHD assessment Assess for new manifestations such as seizures, abnormal motor function, & problems w/coordination. PT &/or OT assessment as needed ADHD = attention-deficit/hyperactivity disorder; ALT = alanine transaminase; AST = aspartate transaminase; BCAA = branched-chain amino acids; INR = international normalized ratio; OT = occupational therapy; PT= physical therapy Early signs of impending hyperammonemic episodes in older individuals include mood changes, headache, lethargy, nausea, vomiting, refusal to feed, ankle clonus, and elevated plasma concentrations of glutamine, alanine, and glycine. Plasma glutamine concentration may rise 48 hours in advance of increases in plasma ammonia concentration in such individuals. S Nagamani, LC Burrage, and B Lee, unpublished data • Height, weight, body mass index • Laboratory indices of nutritional status (e.g., prealbumin, BCAAs [leucine, isoleucine, & valine], plasma amino acids, & plasma ammonia to identify deficiency of essential amino acids & assess for impending hyperammonemia • Phenylbutyrate metabolite levels may be used for monitoring persons on phenylbutyrate medications. • Neonates: every 2 wks • Infants (age 2 mos-1 yr): every 1-3 mos • Children (age ≥2 yrs): every 3-4 mos • Assess developmental progress & educational needs. • Behavioral assessment incl ADHD assessment • Assess for new manifestations such as seizures, abnormal motor function, & problems w/coordination. • PT &/or OT assessment as needed ## Agents/Circumstances to Avoid Avoid the following: Excess protein intake; large boluses of protein or amino acids Less than recommended intake of protein; prolonged fasting or starvation Exposure to communicable diseases Valproic acid Oral or parenteral administration of corticosteroids, if possible. If steroids are medically required for treatment of a coexisting medical condition, contact the metabolic specialist for recommendations to prevent hyperammonemia with steroid therapy. Hepatotoxic drugs in individuals with liver disease • Excess protein intake; large boluses of protein or amino acids • Less than recommended intake of protein; prolonged fasting or starvation • Exposure to communicable diseases • Valproic acid • Oral or parenteral administration of corticosteroids, if possible. If steroids are medically required for treatment of a coexisting medical condition, contact the metabolic specialist for recommendations to prevent hyperammonemia with steroid therapy. • Hepatotoxic drugs in individuals with liver disease ## Evaluation of Relatives at Risk See ## Pregnancy Management There are no guidelines for management of pregnancy in affected females. However, as pregnancy can pose significant stress in females with all UCDs, close monitoring and management is recommended for prevention of hyperammonemia in females with ASLD. ## Therapies Under Investigation Search ## Genetic Counseling Arginosuccinate lyase deficiency (ASLD) is inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents 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. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Though the phenotypic manifestations may vary, affected sibs of a proband with severe neonatal-onset ASLD are likely to have neonatal-onset disease. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with ASL deficiency, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an • 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 • 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 • Though the phenotypic manifestations may vary, affected sibs of a proband with severe neonatal-onset ASLD are likely to have neonatal-onset disease. • 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 ASL deficiency, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see ## Mode of Inheritance Arginosuccinate lyase deficiency (ASLD) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to confirm that both parents 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. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for an Though the phenotypic manifestations may vary, affected sibs of a proband with severe neonatal-onset ASLD are likely to have neonatal-onset disease. 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 an • 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 • 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 • Though the phenotypic manifestations may vary, affected sibs of a proband with severe neonatal-onset ASLD are likely to have neonatal-onset disease. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with ASL deficiency, 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 ASL deficiency, 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 Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources TEMPLE (Tools Enabling Metabolic Parents LEarning) United Kingdom United Kingdom Health Resources & Services Administration Children's National Medical Center • • TEMPLE (Tools Enabling Metabolic Parents LEarning) • United Kingdom • • • • • • • United Kingdom • • • Health Resources & Services Administration • • • • • Children's National Medical Center • ## Molecular Genetics Argininosuccinate Lyase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Argininosuccinate Lyase Deficiency ( In the liver, the site of ureagenesis, argininosuccinate lyase (ASL) cleaves argininosuccinate to produce arginine and fumarate. Arginine is hydrolyzed by arginase 1 to urea, which is excreted by the kidney, and ornithine, which reenters the urea cycle (see ASLD is characterized by accumulation of argininosuccinate and depletion of arginine [ Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis In the liver, the site of ureagenesis, argininosuccinate lyase (ASL) cleaves argininosuccinate to produce arginine and fumarate. Arginine is hydrolyzed by arginase 1 to urea, which is excreted by the kidney, and ornithine, which reenters the urea cycle (see ASLD is characterized by accumulation of argininosuccinate and depletion of arginine [ Notable Variants listed in the table have been provided by the authors. ## Chapter Notes The authors would like to acknowledge The Urea Cycle Disorders Consortium (UCDC; U54HD061221) which is part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the National Center for Advancing Translational Science (NCATS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute for Diabetes and Digestive and Kidney Diseases. The UCDC has also been supported by the O'Malley Foundation, the Rotenberg Family Fund, the Dietmar Hopp Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. Sandesh Nagamani is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under Award Number P50HD103555 for use of the BCM IDDRC. Lindsay C Burrage is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK126786 and by a Burroughs Wellcome Career Award for Medical Scientists. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Lindsay C Burrage, MD, PhD (2025-present)Ayelet Erez, MD, PhD; Weizmann Institute of Science (2011-2025)Brendan Lee, MD, PhD (2011-present)Sandesh CS Nagamani, MBBS, MD (2011-present) 14 August 2025 (sw) Comprehensive update posted live 28 March 2019 (ha) Comprehensive update posted live 3 February 2011 (me) Review posted live 31 August 2010 (ae) Original submission • 14 August 2025 (sw) Comprehensive update posted live • 28 March 2019 (ha) Comprehensive update posted live • 3 February 2011 (me) Review posted live • 31 August 2010 (ae) Original submission ## Acknowledgments The authors would like to acknowledge The Urea Cycle Disorders Consortium (UCDC; U54HD061221) which is part of the National Institutes of Health (NIH) Rare Disease Clinical Research Network (RDCRN), supported through a collaboration between the National Center for Advancing Translational Science (NCATS), the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), and the National Institute for Diabetes and Digestive and Kidney Diseases. The UCDC has also been supported by the O'Malley Foundation, the Rotenberg Family Fund, the Dietmar Hopp Foundation, the Kettering Fund, and the National Urea Cycle Disorders Foundation. Sandesh Nagamani is supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under Award Number P50HD103555 for use of the BCM IDDRC. Lindsay C Burrage is supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health under Award Number R01DK126786 and by a Burroughs Wellcome Career Award for Medical Scientists. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. ## Author History Lindsay C Burrage, MD, PhD (2025-present)Ayelet Erez, MD, PhD; Weizmann Institute of Science (2011-2025)Brendan Lee, MD, PhD (2011-present)Sandesh CS Nagamani, MBBS, MD (2011-present) ## Revision History 14 August 2025 (sw) Comprehensive update posted live 28 March 2019 (ha) Comprehensive update posted live 3 February 2011 (me) Review posted live 31 August 2010 (ae) Original submission • 14 August 2025 (sw) Comprehensive update posted live • 28 March 2019 (ha) Comprehensive update posted live • 3 February 2011 (me) Review posted live • 31 August 2010 (ae) Original submission ## Key Sections in This ## References ## Literature Cited	[]	3/2/2011	14/8/2025	2/2/2012	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
arid1b-dis	arid1b-dis	[ "ARID1B Intellectual Disability with Nonspecific Dysmorphic Features", "AT-rich interactive domain-containing protein 1B", "ARID1B", "ARID1B-Related Disorder" ]		Samantha A Vergano, Pleuntje J van der Sluijs, Gijs Santen	Summary The diagnosis of	For other genetic causes of these phenotypes see See also ## Diagnosis Heterozygous pathogenic variants in Note: The information presented in the Coffin-Siris syndrome Fifth-digit nail and/or distal phalanx hypoplasia (although other digits may be affected) OR aplasia of the hands or feet Developmental or cognitive delay of variable degree Typical facial features including a wide mouth with thick, everted vermilion of the upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows, and long eyelashes Central hypotonia Hypertrichosis in atypical areas (e.g., the back) or excessive hair growth on the arms or face Sparse scalp hair, especially in infancy, particularly in the temporal regions Though admittedly a large group, Mild-to-profound developmental delay (DD) and/or intellectual disability (ID) AND Any of the following features presenting in infancy or childhood: Generalized hypotonia of infancy Infant feeding difficulties Spasticity Epilepsy (predominately tonic-clonic) Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features Cryptorchidism Laryngomalacia Myopia Delayed speech development Suggestive dysmorphic features (see The diagnosis of an Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. Molecular genetic testing approaches can include a combination of When the phenotypic findings suggest the diagnosis of 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 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. Microdeletions of chromosome 6q25.3 that include Although the Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • Fifth-digit nail and/or distal phalanx hypoplasia (although other digits may be affected) OR aplasia of the hands or feet • Developmental or cognitive delay of variable degree • Typical facial features including a wide mouth with thick, everted vermilion of the upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows, and long eyelashes • Central hypotonia • Hypertrichosis in atypical areas (e.g., the back) or excessive hair growth on the arms or face • Sparse scalp hair, especially in infancy, particularly in the temporal regions • Mild-to-profound developmental delay (DD) and/or intellectual disability (ID) • AND • Any of the following features presenting in infancy or childhood: • Generalized hypotonia of infancy • Infant feeding difficulties • Spasticity • Epilepsy (predominately tonic-clonic) • Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features • Cryptorchidism • Laryngomalacia • Myopia • Delayed speech development • Suggestive dysmorphic features (see • Generalized hypotonia of infancy • Infant feeding difficulties • Spasticity • Epilepsy (predominately tonic-clonic) • Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features • Cryptorchidism • Laryngomalacia • Myopia • Delayed speech development • Suggestive dysmorphic features (see • Generalized hypotonia of infancy • Infant feeding difficulties • Spasticity • Epilepsy (predominately tonic-clonic) • Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features • Cryptorchidism • Laryngomalacia • Myopia • Delayed speech development • Suggestive dysmorphic features (see • For an introduction to multigene panels click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Fifth-digit nail and/or distal phalanx hypoplasia (although other digits may be affected) OR aplasia of the hands or feet Developmental or cognitive delay of variable degree Typical facial features including a wide mouth with thick, everted vermilion of the upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows, and long eyelashes Central hypotonia Hypertrichosis in atypical areas (e.g., the back) or excessive hair growth on the arms or face Sparse scalp hair, especially in infancy, particularly in the temporal regions Though admittedly a large group, Mild-to-profound developmental delay (DD) and/or intellectual disability (ID) AND Any of the following features presenting in infancy or childhood: Generalized hypotonia of infancy Infant feeding difficulties Spasticity Epilepsy (predominately tonic-clonic) Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features Cryptorchidism Laryngomalacia Myopia Delayed speech development Suggestive dysmorphic features (see • Fifth-digit nail and/or distal phalanx hypoplasia (although other digits may be affected) OR aplasia of the hands or feet • Developmental or cognitive delay of variable degree • Typical facial features including a wide mouth with thick, everted vermilion of the upper and lower lips, broad nasal bridge with broad nasal tip, thick eyebrows, and long eyelashes • Central hypotonia • Hypertrichosis in atypical areas (e.g., the back) or excessive hair growth on the arms or face • Sparse scalp hair, especially in infancy, particularly in the temporal regions • Mild-to-profound developmental delay (DD) and/or intellectual disability (ID) • AND • Any of the following features presenting in infancy or childhood: • Generalized hypotonia of infancy • Infant feeding difficulties • Spasticity • Epilepsy (predominately tonic-clonic) • Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features • Cryptorchidism • Laryngomalacia • Myopia • Delayed speech development • Suggestive dysmorphic features (see • Generalized hypotonia of infancy • Infant feeding difficulties • Spasticity • Epilepsy (predominately tonic-clonic) • Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features • Cryptorchidism • Laryngomalacia • Myopia • Delayed speech development • Suggestive dysmorphic features (see • Generalized hypotonia of infancy • Infant feeding difficulties • Spasticity • Epilepsy (predominately tonic-clonic) • Behavior problems, such as attention-deficit/hyperactivity disorder (ADHD) and autistic features • Cryptorchidism • Laryngomalacia • Myopia • Delayed speech development • Suggestive dysmorphic features (see ## Establishing the Diagnosis The diagnosis of an Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. Molecular genetic testing approaches can include a combination of When the phenotypic findings suggest the diagnosis of 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 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. Microdeletions of chromosome 6q25.3 that include Although the Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • For an introduction to multigene panels click • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Classic When the phenotypic findings suggest the diagnosis of For an introduction to multigene panels click • 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 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. Microdeletions of chromosome 6q25.3 that include Although the Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Most individuals with a heterozygous pathogenic variant in Note: (1) The Coffin-Siris syndrome To date, approximately 100 individuals who do not have the classic Coffin-Siris syndrome phenotype have been identified with a heterozygous pathogenic variant in A comparison between individuals with a heterozygous pathogenic variant in The majority of affected individuals appear to have a Bone age appears to be delayed in approximately 50% of individuals who have been evaluated. Individuals with feeding difficulties commencing around the time of birth appear to have more severe issues and tend to require a feeding tube of some type (nasogastric or gastrostomy tube). In older children, milder feeding difficulties may occur, including oral aversion, particularly in those who required tube feeding as an infant or younger child. Constipation and gastroesophageal reflux disease are also common and may approximate that seen in individuals with CSS or other genetic syndromes with varying degrees of neurologic impairment [ Approximately 25%-30% of affected individuals have some Similarly, 25%-40% of affected individuals have some degree of To date, only loss-of-function variants (e.g., nonsense, splice site, frameshift, whole-gene deletions) cause There do not appear to be specific genotype-phenotype correlations among individuals with This condition is estimated to occur in approximately 1:10,000 to 1:100,000 individuals [ • The majority of affected individuals appear to have a • Bone age appears to be delayed in approximately 50% of individuals who have been evaluated. • Individuals with feeding difficulties commencing around the time of birth appear to have more severe issues and tend to require a feeding tube of some type (nasogastric or gastrostomy tube). • In older children, milder feeding difficulties may occur, including oral aversion, particularly in those who required tube feeding as an infant or younger child. • Constipation and gastroesophageal reflux disease are also common and may approximate that seen in individuals with CSS or other genetic syndromes with varying degrees of neurologic impairment [ • Approximately 25%-30% of affected individuals have some • Similarly, 25%-40% of affected individuals have some degree of ## Clinical Description Most individuals with a heterozygous pathogenic variant in Note: (1) The Coffin-Siris syndrome To date, approximately 100 individuals who do not have the classic Coffin-Siris syndrome phenotype have been identified with a heterozygous pathogenic variant in A comparison between individuals with a heterozygous pathogenic variant in The majority of affected individuals appear to have a Bone age appears to be delayed in approximately 50% of individuals who have been evaluated. Individuals with feeding difficulties commencing around the time of birth appear to have more severe issues and tend to require a feeding tube of some type (nasogastric or gastrostomy tube). In older children, milder feeding difficulties may occur, including oral aversion, particularly in those who required tube feeding as an infant or younger child. Constipation and gastroesophageal reflux disease are also common and may approximate that seen in individuals with CSS or other genetic syndromes with varying degrees of neurologic impairment [ Approximately 25%-30% of affected individuals have some Similarly, 25%-40% of affected individuals have some degree of • The majority of affected individuals appear to have a • Bone age appears to be delayed in approximately 50% of individuals who have been evaluated. • Individuals with feeding difficulties commencing around the time of birth appear to have more severe issues and tend to require a feeding tube of some type (nasogastric or gastrostomy tube). • In older children, milder feeding difficulties may occur, including oral aversion, particularly in those who required tube feeding as an infant or younger child. • Constipation and gastroesophageal reflux disease are also common and may approximate that seen in individuals with CSS or other genetic syndromes with varying degrees of neurologic impairment [ • Approximately 25%-30% of affected individuals have some • Similarly, 25%-40% of affected individuals have some degree of ## Genotype-Phenotype Correlations To date, only loss-of-function variants (e.g., nonsense, splice site, frameshift, whole-gene deletions) cause There do not appear to be specific genotype-phenotype correlations among individuals with ## Prevalence This condition is estimated to occur in approximately 1:10,000 to 1:100,000 individuals [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic tumors (including predisposition to childhood neuroblastoma) occurring as single tumors in the absence of any other findings of ## Differential Diagnosis Other Disorders to Consider in the Differential Diagnosis of Characteristic coarse facial features Sparse scalp hair ID Prominence of interphalangeal joints & distal phalanges due to ↓ subcutaneous fat Absence of 5th-digit nail / distal phalanx hypo/aplasia Other digital anomalies incl tapering of digits, hammer toes, syndactyly of toes Distinct facial gestalt incl prominent supraorbital ridges, deeply set eyes, prominent nasal bridge, short nose w/bulbous nasal tip Hypotonia Behavior anomalies Very mild hypoplasia of 5th fingernails & hypoplasia of 5th toenails in some individuals Facies: coarse features, flat nasal bridge, slightly broad nose, prominent philtrum, & large mouth w/thick lower vermilion ID Hypoplastic terminal phalanges &/or nail anomalies Deafness Neurologic abnormalities ID Osteodystrophy Profound hearing loss (can occasionally occur in Delayed development & ID Seizures Coarse facial features Hypoplastic 5th digits Limb anomalies may incl 5th-finger hypoplasia. ID Other findings may incl cardiac defects, gastrointestinal anomalies, & genitourinary malformations. Curved, volar, 5th-digit nail that may resemble a hypoplastic distal phalanx ID Facial gestalt may incl broad forehead, widely spaced eyes, & frontal bossing. Postnatal growth restriction may be severe. AD = autosomal dominant; AR = autosomal recessive; CSS = Coffin-Siris syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked To date, all reported probands have had the disorder as the result of a While some of these features demonstrate overlap with CSS, an assessment of a larger cohort of individuals with The following genetic and teratogenic disorders may also be considered in the differential diagnosis of Because the phenotypic features associated with • Characteristic coarse facial features • Sparse scalp hair • ID • Prominence of interphalangeal joints & distal phalanges due to ↓ subcutaneous fat • Absence of 5th-digit nail / distal phalanx hypo/aplasia • Other digital anomalies incl tapering of digits, hammer toes, syndactyly of toes • Distinct facial gestalt incl prominent supraorbital ridges, deeply set eyes, prominent nasal bridge, short nose w/bulbous nasal tip • Hypotonia • Behavior anomalies • Very mild hypoplasia of 5th fingernails & hypoplasia of 5th toenails in some individuals • Facies: coarse features, flat nasal bridge, slightly broad nose, prominent philtrum, & large mouth w/thick lower vermilion • ID • Hypoplastic terminal phalanges &/or nail anomalies • Deafness • Neurologic abnormalities • ID • Osteodystrophy • Profound hearing loss (can occasionally occur in • Delayed development & ID • Seizures • Coarse facial features • Hypoplastic 5th digits • Limb anomalies may incl 5th-finger hypoplasia. • ID • Other findings may incl cardiac defects, gastrointestinal anomalies, & genitourinary malformations. • Curved, volar, 5th-digit nail that may resemble a hypoplastic distal phalanx • ID • Facial gestalt may incl broad forehead, widely spaced eyes, & frontal bossing. • Postnatal growth restriction may be severe. Other Disorders to Consider in the Differential Diagnosis of Characteristic coarse facial features Sparse scalp hair ID Prominence of interphalangeal joints & distal phalanges due to ↓ subcutaneous fat Absence of 5th-digit nail / distal phalanx hypo/aplasia Other digital anomalies incl tapering of digits, hammer toes, syndactyly of toes Distinct facial gestalt incl prominent supraorbital ridges, deeply set eyes, prominent nasal bridge, short nose w/bulbous nasal tip Hypotonia Behavior anomalies Very mild hypoplasia of 5th fingernails & hypoplasia of 5th toenails in some individuals Facies: coarse features, flat nasal bridge, slightly broad nose, prominent philtrum, & large mouth w/thick lower vermilion ID Hypoplastic terminal phalanges &/or nail anomalies Deafness Neurologic abnormalities ID Osteodystrophy Profound hearing loss (can occasionally occur in Delayed development & ID Seizures Coarse facial features Hypoplastic 5th digits Limb anomalies may incl 5th-finger hypoplasia. ID Other findings may incl cardiac defects, gastrointestinal anomalies, & genitourinary malformations. Curved, volar, 5th-digit nail that may resemble a hypoplastic distal phalanx ID Facial gestalt may incl broad forehead, widely spaced eyes, & frontal bossing. Postnatal growth restriction may be severe. AD = autosomal dominant; AR = autosomal recessive; CSS = Coffin-Siris syndrome; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked To date, all reported probands have had the disorder as the result of a While some of these features demonstrate overlap with CSS, an assessment of a larger cohort of individuals with The following genetic and teratogenic disorders may also be considered in the differential diagnosis of • Characteristic coarse facial features • Sparse scalp hair • ID • Prominence of interphalangeal joints & distal phalanges due to ↓ subcutaneous fat • Absence of 5th-digit nail / distal phalanx hypo/aplasia • Other digital anomalies incl tapering of digits, hammer toes, syndactyly of toes • Distinct facial gestalt incl prominent supraorbital ridges, deeply set eyes, prominent nasal bridge, short nose w/bulbous nasal tip • Hypotonia • Behavior anomalies • Very mild hypoplasia of 5th fingernails & hypoplasia of 5th toenails in some individuals • Facies: coarse features, flat nasal bridge, slightly broad nose, prominent philtrum, & large mouth w/thick lower vermilion • ID • Hypoplastic terminal phalanges &/or nail anomalies • Deafness • Neurologic abnormalities • ID • Osteodystrophy • Profound hearing loss (can occasionally occur in • Delayed development & ID • Seizures • Coarse facial features • Hypoplastic 5th digits • Limb anomalies may incl 5th-finger hypoplasia. • ID • Other findings may incl cardiac defects, gastrointestinal anomalies, & genitourinary malformations. • Curved, volar, 5th-digit nail that may resemble a hypoplastic distal phalanx • ID • Facial gestalt may incl broad forehead, widely spaced eyes, & frontal bossing. • Postnatal growth restriction may be severe. Because the phenotypic features associated with ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder An echocardiogram is recommended for those individuals with Echocardiogram may not be warranted in older children without obvious cardiovascular signs or symptoms based on exam. Treatment of Manifestations in Individuals with ASM = anti-seizure medication; GERD = gastroesophageal reflux disease Education of parents regarding common seizure presentations is appropriate. For additional information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers/standers or gait trainers, 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 ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with To assess for poor growth velocity and/or short stature; specific hormonal evaluations depend on the clinical scenario but could include thyroid function tests and evaluation of growth-specific factors (e.g., IGF1 and IGFBP3 levels). 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 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/standers or gait trainers, bath chairs, orthotics, adaptive strollers). ## Evaluations Following Initial Diagnosis of 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 An echocardiogram is recommended for those individuals with Echocardiogram may not be warranted in older children without obvious cardiovascular signs or symptoms based on exam. ## Treatment of Manifestations Treatment of Manifestations in Individuals with ASM = anti-seizure medication; GERD = gastroesophageal reflux disease Education of parents regarding common seizure presentations is appropriate. For additional information on non-medical interventions and coping strategies for parents or caregivers of children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers/standers or gait trainers, 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 ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers/standers or gait trainers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management 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. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. • Discussion about transition plans including financial, vocation/employment, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers/standers or gait trainers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers/standers or gait trainers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Difficulties 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 ADHD, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with To assess for poor growth velocity and/or short stature; specific hormonal evaluations depend on the clinical scenario but could include thyroid function tests and evaluation of growth-specific factors (e.g., IGF1 and IGFBP3 levels). ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Most probands reported to date with Parental transmission of Molecular genetic testing is recommended for the parents of a proband with an apparent If the The family history of some individuals diagnosed with Theoretically, if the parent is the individual in whom the If a parent of the proband has the If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most probands reported to date with • Parental transmission of • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • The family history of some individuals diagnosed with • Theoretically, if the parent is the individual in whom the • If a parent of the proband has the • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members Most probands reported to date with Parental transmission of Molecular genetic testing is recommended for the parents of a proband with an apparent If the The family history of some individuals diagnosed with Theoretically, if the parent is the individual in whom the If a parent of the proband has the If the • Most probands reported to date with • Parental transmission of • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • The family history of some individuals diagnosed with • Theoretically, if the parent is the individual in whom the • If a parent of the proband has the • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, 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 • ## Molecular Genetics ARID1B-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ARID1B-Related Disorder ( The ARID1B protein serves the largest alternating subunit of the SWI/SNF complex, along with ARID1A. It functions as a primary chromatin remodeler, regulating gene transcription and protein-protein interactions, and acts as a tumor suppressor [ See A Loss-of-function variants associated with CSS are rarely seen at the 5' end of In addition, microdeletions and nonsense variants have been reported in several individuals with nonspecific intellectual disability. However, evaluation of several of these subjects revealed some mild overlap with CSS features suggesting a range of clinical features for individuals with haploinsufficiency of ARID1B [ Pathogenic Variants listed in the table have been provided by the authors. Both somatic deletions and mutations of ## Molecular Pathogenesis The ARID1B protein serves the largest alternating subunit of the SWI/SNF complex, along with ARID1A. It functions as a primary chromatin remodeler, regulating gene transcription and protein-protein interactions, and acts as a tumor suppressor [ See A Loss-of-function variants associated with CSS are rarely seen at the 5' end of In addition, microdeletions and nonsense variants have been reported in several individuals with nonspecific intellectual disability. However, evaluation of several of these subjects revealed some mild overlap with CSS features suggesting a range of clinical features for individuals with haploinsufficiency of ARID1B [ Pathogenic Variants listed in the table have been provided by the authors. ## Cancer and Benign Tumors Both somatic deletions and mutations of ## Chapter Notes Dr Samantha Schrier Vergano is a clinical geneticist at the Children's Hospital of The King's Daughters in Norfolk, Virginia. Her primary research interest is Coffin-Siris syndrome. She runs an international IRB-approved registry for the condition. For more information, please visit Dr Gijs Santen is a clinical geneticist at the Leiden University Medical Center striving to improve clinical delineation of Cofﬁn-Siris syndrome. He has a registry for individuals with pathogenic variants in 23 May 2019 (ma) Review posted live 26 July 2018 (sv, gs) Original submission • 23 May 2019 (ma) Review posted live • 26 July 2018 (sv, gs) Original submission ## Author Notes Dr Samantha Schrier Vergano is a clinical geneticist at the Children's Hospital of The King's Daughters in Norfolk, Virginia. Her primary research interest is Coffin-Siris syndrome. She runs an international IRB-approved registry for the condition. For more information, please visit Dr Gijs Santen is a clinical geneticist at the Leiden University Medical Center striving to improve clinical delineation of Cofﬁn-Siris syndrome. He has a registry for individuals with pathogenic variants in ## Revision History 23 May 2019 (ma) Review posted live 26 July 2018 (sv, gs) Original submission • 23 May 2019 (ma) Review posted live • 26 July 2018 (sv, gs) Original submission ## References ## Literature Cited	[ "S Ben-Salem, N Sobreira, NA Akawi, AM Al-Shamsi, A John, T Pramathan, D Valle, BR Ali, L Al-Gazali. Gonadal mosaicism in ARID1B gene causes intellectual disability and dysmorphic features in three siblings.. Am J Med Genet Part A 2016;170A:156-61", "N Bögershausen, B Wollnik. Mutational landscapes and phenotypic spectrum of SWI/SNF-related intellectual disability disorders.. Front Mol Neurosci. 2018;11:252", "C Celen, JC Chuang, X Luo, N Nijem, AK Walker, F Chen, S Zhang, AS Chung, L Nguyen, I Nassour, A Budhipramono, X Sun, LA Bok, M McEntagart, EF Gevers, SG Birnbaum, AJ Eisch, CM Powell, WP Ge, GWE Santen, M Chahrour, H Zhu. Arid1b haploinsufficieent mice reveal neuropsychiatric phenotypes and reversible causes of growth impairment.. Elife. 2017;6", "AM Elliott, AS Teebi. New autosomal dominant syndrome reminiscent of Coffin-Siris syndrome and brachymorphism-onychodysplasia-dysphalangism syndrome.. Clin Dysmorphol. 2000;9:15-9", "BJ Fleck, A Pandya, L Vanner, K Kerkering, J Bodurtha. Coffin-Siris syndrome: review and presentation of new cases from a questionnaire study.. Am J Med Genet. 2001;99:1-7", "C Halgren, S Kjaergaard, M Bak, C Hansen, Z El-Schich, CM Anderson, KF Henriksen, H Hjalgrim, M Kirchhoff, EK Bijlsma, M Nielsen, NS den Hollander, CA Ruivenkamp, B Isidor, C Le Caignec, R Zannolli, M Mucciolo, A Renieri, F Mari, BM Anderlid, J Andrieux, A Dieux, N Tommerup, I Bache. Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1B.. Clin Genet. 2012;82:248-55", "J Hoyer, AB Ekici, S Endele, B Popp, C Zweier, A Wiesener, E Wohlleber, A Durfke, E Rossier, C Petsch, M Zweier, I Gohring, AM Zink, G Rappold, E Schrock, D Wieczorek, O Riess, H Engels, A Rauch, A Reis. Haploinsufficiency of ARID1B, a member of the SWI/SNF-a chromatin-remodeling complex, is a frequent cause of intellectual disability.. Am J Hum Genet. 2012;90:565-72", "T Kosho, N Okamoto. Genotype-phenotype correlation of Coffin-Siris syndrome caused by mutations in SMARCB1, SMARCA4, SMARCE1, and ARID1A.. Am J Med Genet C Semin Med Genet. 2014;166C:262-75", "T Kushnick, GM Adessa. Partial trisomy 9 with resemblance to Coffin-Siris syndrome.. J Med Genet. 1976;13:237-9", "L Määttänen, M Hietala, J Ignatius, M. A Arvio. 69-year-old woman with Coffin-Siris syndrome.. Am J Med Genet A. 2018;176:1764-7", "EA Mannino, H Miyawaki, G Santen, SA Schrier Vergano. First data from a parent-reported registry of 81 individuals with Coffin-Siris syndrome: natural history and management recommendations.. Am J Med Genet A. 2018;176:2250-8", "M Michelson, A Ben-Sasson, C Vinkler, E Leshinsky-Silver, I Netzer, A Frumkin, S Kivity, T Lerman-Sagie, D Lev. Delineation of the interstitial 6q25 microdeletion syndrome: refinement of the critical causative region.. Am J Med Genet A. 2012;158A:1395-9", "C Mignot, ML Moutard, A Rastetter, L Boutaud, S Heide, T Billette, D Doummar, C Garel, A Afenjar, A Jacquette, D Lacombe, A Verloes, C Bole-Feysot, P Nitschke, C Masson, A Faudet, F Lesne, T Bienvenu, C Alby, T Attie-Bitach, C Depienne, C Nava, D Heron. ARID1B mutations are the major genetic cause of corpus callosum anomalies in patients with intellectual disability.. Brain. 2016;139", "SC Nagamani, A Erez, C Eng, Z Ou, C Chinault, L Workman, J Coldwell, P Stankiewicz, A Patel, JR Lupski, SW Cheung. Interstitial deletion of 6q25.2-q25.3: a novel microdeletion syndrome associated with microcephaly, developmental delay, dysmorphic features and hearing loss.. Eur J Hum Genet. 2009;17:573-81", "GW Santen, E Aten, AT Vulto-van Silfhout, C Pottinger, BW van Bon, IJ van Minderhout, R Snowdown. van der LAns CA, Boogaard M, Linssen MM, Vijfhuizen L, van der Wielen MJ, Vollebregt MJ, Coffin-Siris consortium, Breuning MH, Kriek M, van Haeringen A, den Dunnen JT, Hoischen A, Clayton-Smith J, de Vries BB, Hennekam RC, van Belzen MJ. Coffin-Siris syndrome and the BAF complex: genotype-phenotype study in 63 patients.. Hum Mutat. 2013;34:1519-28", "GWE Santen, J Clayton-Smith. The. Am J Med Genet C Semin Med Genet. 2014;166C:276-89", "GWE Santen, M Kriek, H van Atticum. SWI/SNF complex in disorder: SWItching from malignancies to intellectual disability.. Epigenetics. 2012;7:1219-24", "M Sausen, RJ Lear, S Jones, J Wu, CP Reynolds, X Liu, A Blackford, G Parmigiani, LA Diaz, N Papadopoulos, B Voeglstein, KW Kinzler, VE Velculescu, MD Hogarty. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma.. Nat Genet. 2013;45:12-7", "SA Schrier, JN Bodurtha, B Burton, AE Chudley, MA Chiong, MG D'avanzo, SA Lynch, A Musio, DM Nyazov, PA Sanchez-Lara, SA Shalev, MA Deardorff. The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases.. Am J Med Genet A. 2012;158A:1865-76", "JA Smith, KR Holden, MJ Friez, JR Jones, MJ Lyons. A novel familial autosomal dominant mutation in ARID1B causing neurodevelopmental delays, short stature, and dysmorphic features.. Am J Med Genet A. 2016;170:3313-8", "Y Tsurusaki, N Okamoto, H Ohashi, T Kosho, Y Imai, Y Hibi-Ko, T Kaname, K Naritomi, H Kawame, K Wakui, Y Fukushima, T Homma, M Kato, Y Hiraki, T Yamagata, S Yano, S Mizuno, S Sakazume, T Ishii, T Nagai, M Shiina, K Ogata, T Ohta, N Niikawa, S Miyatake, I Okada, T Mizuguchi, H Doi, H Saitsu, N Miyake, N. Matsumoto. Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome.. Nat Genet. 2012;44:376-8", "PJ van der Sluijs, S Jansen, SA Vergano, M Adachi-Fukuda, Y Alanay, A AlKindy, A Baban, A Bayat, S Beck-Wödl, K Berry, EK Bijlsma, LA Bok, AFJ Brouwer, I van der Burgt, PM Campeau, N Canham, K Chrzanowska, YWY Chu, BHY Chung, K Dahan, M De Rademaeker, A Destree, T Dudding-Byth, R Earl, N Elcioglu, ER Elias, C Fagerberg, A Gardham, B Gener. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome.. Genet Med. 2019;21:1295-307", "A Verloes, D Bonneau, O Guidi, M Berthier, D Oriot, L Van Maldergem, L. Koulischer. Brachymorphism-onychodysplasia-dysphalangism syndrome.. J Med Genet. 1993;30:158-61", "C Zweier, O Rittinger, I Bader, S Berland, T Cole, F Degenhardt, N Di Donato, L Graul-Neumann, J Hoyer, SA Lynch, I Vlasak, D Wieczorek. Females with de novo aberrations in PHF6: clinical overlap of Borjeson-Forssman-Lehmann with Coffin-Siris syndrome.. Am J Med Genet C Semin Med Genet 2014;166C:290-301" ]	23/5/2019			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
arsacs	arsacs	[ "Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay", "Autosomal Recessive Spastic Ataxia Type 6", "ATX/HSP-SACS", "Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay", "Autosomal Recessive Spastic Ataxia Type 6", "ATX/HSP-SACS", "Sacsin", "SACS", "ARSACS" ]	ARSACS	Sascha Vermeer, Bart P van de Warrenburg, Erik-Jan Kamsteeg, Bernard Brais, Matthis Synofzik	Summary The diagnosis of ARSACS is established in a proband with suggestive clinical findings and biallelic pathogenic variants in ARSACS is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a	## Diagnosis ARSACS Slowly progressive cerebellar ataxia with difficulty walking and gait unsteadiness noted as early as age 12 to 18 months, or appearing later Spasticity of the lower limbs Peripheral neuropathy with distal wasting and weakness Brain MRI findings of vermis atrophy with upper predominance and/or atrophy of the cerebellar hemispheres and hypointense bilateral stripes in the paramedian pons Thickened retinal hypermyelinated fibers identified as: Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. The diagnosis of ARSACS 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 ARSACS is broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of ARSACS, molecular genetic testing approaches can include Note: The majority of deletions reported in For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by ataxia and/or spasticity, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ARSACS 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 Note: Targeted analysis for pathogenic variants in 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. 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 • Slowly progressive cerebellar ataxia with difficulty walking and gait unsteadiness noted as early as age 12 to 18 months, or appearing later • Spasticity of the lower limbs • Peripheral neuropathy with distal wasting and weakness • Brain MRI findings of vermis atrophy with upper predominance and/or atrophy of the cerebellar hemispheres and hypointense bilateral stripes in the paramedian pons • Thickened retinal hypermyelinated fibers identified as: • Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; • A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. • Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; • A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. • Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; • A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. • Note: The majority of deletions reported in • For an introduction to multigene panels click ## Suggestive Findings ARSACS Slowly progressive cerebellar ataxia with difficulty walking and gait unsteadiness noted as early as age 12 to 18 months, or appearing later Spasticity of the lower limbs Peripheral neuropathy with distal wasting and weakness Brain MRI findings of vermis atrophy with upper predominance and/or atrophy of the cerebellar hemispheres and hypointense bilateral stripes in the paramedian pons Thickened retinal hypermyelinated fibers identified as: Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. • Slowly progressive cerebellar ataxia with difficulty walking and gait unsteadiness noted as early as age 12 to 18 months, or appearing later • Spasticity of the lower limbs • Peripheral neuropathy with distal wasting and weakness • Brain MRI findings of vermis atrophy with upper predominance and/or atrophy of the cerebellar hemispheres and hypointense bilateral stripes in the paramedian pons • Thickened retinal hypermyelinated fibers identified as: • Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; • A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. • Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; • A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. • Yellow streaks radiating from the edges of the optic disc on ophthalmic exam; • A thicker-than-119-µm average peripapillary retinal nerve fiber layer on optical coherence tomography. ## Establishing the Diagnosis The diagnosis of ARSACS 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 ARSACS is broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of ARSACS, molecular genetic testing approaches can include Note: The majority of deletions reported in For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by ataxia and/or spasticity, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ARSACS 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 Note: Targeted analysis for pathogenic variants in 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. 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: The majority of deletions reported in • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of ARSACS, molecular genetic testing approaches can include Note: The majority of deletions reported in For an introduction to multigene panels click • Note: The majority of deletions reported in • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by ataxia and/or spasticity, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in ARSACS 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 Note: Targeted analysis for pathogenic variants in 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. 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 ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) defines a spastic ataxia first described in 1978 among a cohort of about 325 French-Canadian individuals from 200 families born in the Saguenay-Lac-St-Jean area of northeastern Quebec [ In addition to the classic triad of symptoms of progressive cerebellar ataxia, peripheral neuropathy, and lower-limb spasticity, some individuals with ARSACS have features such as hearing loss, intellectual disability, and myoclonic epilepsy [ Both intra- and interfamilial phenotypic variability has been observed in ARSACS. To date, more than 190 individuals have been identified with biallelic pathogenic variants in Features of ARSACS Most individuals show the highly characteristic triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs [ Electrophysiology often confirms a mixed demyelinating and axonal neuropathy [ Distal amyotrophy, which leads to loss of ankle reflexes and sometimes bilateral foot drop, is found in most individuals after age 21 years. Other deep tendon reflexes may remain brisk or disappear with time. Oculomotor disturbances (nystagmus), dysarthria, and upper-limb ataxia usually progress much slower than gait ataxia, spasticity, and neuropathy. Detailed neuropsychiatric and neurophysiologic assessments were reported in two individuals with ARSACS. Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunction were present [ Cognitive abilities tend to be preserved into late adult life, although in the oldest affected individuals cognitive decline has been documented. The extent to which cognitive impairment is a feature of ARSACS is still unclear and is being studied. Retinal nerve fiber hypertrophy as demonstrated on ocular coherence tomography has been reported in several individuals with ARSACS [ A thicker-than-119-µm average peripapillary retinal nerve fibre layer provides a sensitivity of 100% and specificity of 99.4% in individuals with ARSACS [ These ocular findings do not have an impact on vision in most affected individuals, though the oldest individuals with ARSACS may have visual impairment. No clear genotype-phenotype correlations for Guided by the classification system developed by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders, The exact prevalence of ARSACS is unknown in most countries. More than 300 individuals with ARSACS live in Quebec: The estimated carrier frequency of The birth incidence of ARSACS was 1:1,932, but is now declining because of voluntary carrier screening. A founder effect for Although thought to be largely confined to Quebec, genetically confirmed ARSACS has now been reported in individuals all over Europe, Tunisia, Japan, and Turkey ( • Electrophysiology often confirms a mixed demyelinating and axonal neuropathy [ • Distal amyotrophy, which leads to loss of ankle reflexes and sometimes bilateral foot drop, is found in most individuals after age 21 years. Other deep tendon reflexes may remain brisk or disappear with time. • Oculomotor disturbances (nystagmus), dysarthria, and upper-limb ataxia usually progress much slower than gait ataxia, spasticity, and neuropathy. • Detailed neuropsychiatric and neurophysiologic assessments were reported in two individuals with ARSACS. Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunction were present [ • Cognitive abilities tend to be preserved into late adult life, although in the oldest affected individuals cognitive decline has been documented. • The estimated carrier frequency of • The birth incidence of ARSACS was 1:1,932, but is now declining because of voluntary carrier screening. A founder effect for ## Clinical Description ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) defines a spastic ataxia first described in 1978 among a cohort of about 325 French-Canadian individuals from 200 families born in the Saguenay-Lac-St-Jean area of northeastern Quebec [ In addition to the classic triad of symptoms of progressive cerebellar ataxia, peripheral neuropathy, and lower-limb spasticity, some individuals with ARSACS have features such as hearing loss, intellectual disability, and myoclonic epilepsy [ Both intra- and interfamilial phenotypic variability has been observed in ARSACS. To date, more than 190 individuals have been identified with biallelic pathogenic variants in Features of ARSACS Most individuals show the highly characteristic triad of cerebellar ataxia, peripheral neuropathy, and pyramidal tract signs [ Electrophysiology often confirms a mixed demyelinating and axonal neuropathy [ Distal amyotrophy, which leads to loss of ankle reflexes and sometimes bilateral foot drop, is found in most individuals after age 21 years. Other deep tendon reflexes may remain brisk or disappear with time. Oculomotor disturbances (nystagmus), dysarthria, and upper-limb ataxia usually progress much slower than gait ataxia, spasticity, and neuropathy. Detailed neuropsychiatric and neurophysiologic assessments were reported in two individuals with ARSACS. Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunction were present [ Cognitive abilities tend to be preserved into late adult life, although in the oldest affected individuals cognitive decline has been documented. The extent to which cognitive impairment is a feature of ARSACS is still unclear and is being studied. Retinal nerve fiber hypertrophy as demonstrated on ocular coherence tomography has been reported in several individuals with ARSACS [ A thicker-than-119-µm average peripapillary retinal nerve fibre layer provides a sensitivity of 100% and specificity of 99.4% in individuals with ARSACS [ These ocular findings do not have an impact on vision in most affected individuals, though the oldest individuals with ARSACS may have visual impairment. • Electrophysiology often confirms a mixed demyelinating and axonal neuropathy [ • Distal amyotrophy, which leads to loss of ankle reflexes and sometimes bilateral foot drop, is found in most individuals after age 21 years. Other deep tendon reflexes may remain brisk or disappear with time. • Oculomotor disturbances (nystagmus), dysarthria, and upper-limb ataxia usually progress much slower than gait ataxia, spasticity, and neuropathy. • Detailed neuropsychiatric and neurophysiologic assessments were reported in two individuals with ARSACS. Apart from motor symptoms, motivational deficits along with cognitive and behavioral dysfunction were present [ • Cognitive abilities tend to be preserved into late adult life, although in the oldest affected individuals cognitive decline has been documented. ## Genotype-Phenotype Correlations No clear genotype-phenotype correlations for ## Nomenclature Guided by the classification system developed by the International Parkinson and Movement Disorder Society Task Force on Classification and Nomenclature of Genetic Movement Disorders, ## Prevalence The exact prevalence of ARSACS is unknown in most countries. More than 300 individuals with ARSACS live in Quebec: The estimated carrier frequency of The birth incidence of ARSACS was 1:1,932, but is now declining because of voluntary carrier screening. A founder effect for Although thought to be largely confined to Quebec, genetically confirmed ARSACS has now been reported in individuals all over Europe, Tunisia, Japan, and Turkey ( • The estimated carrier frequency of • The birth incidence of ARSACS was 1:1,932, but is now declining because of voluntary carrier screening. A founder effect for ## Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with pathogenic variants in ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of ARSACS Slowly progressive ataxia Depressed tendon reflexes, dysarthria, Babinski responses, & loss of position & vibration sense Later onset Cardiomyopathy Absence of hypermyelinated retinal fibers Absence of white matter lesions on MRI Early-onset unsteady spastic gait & hyperreflexia of lower limbs Mildly impaired sensation & cerebellar involvement Sensory neuropathy Hypoacusis Mild ataxia Anemia Acanthocytosis Retinitis pigmentosa Gastrointestinal disease Spastic paraplegia w/distal arm & leg amyotrophy Dysarthria & mild cerebellar signs ↑ prevalence of Troyer syndrome in the Amish population Short stature Distal wasting White matter lesions on MRI Cerebellar ataxia Lower-limb spasticity Optic atrophy Scoliosis Absence of neuropathy Vitamin E deficiency Retinitis pigmentosa Cardiomyopathy AR = autosomal recessive; ARSACS = autosomal recessive spastic ataxia of Charlevoix-Saguenay; DiffDx = differential diagnosis; MOI = mode of inheritance; SPG = spastic paraplegia The classification of autosomal recessive ataxias has been greatly expanded (for review, see Friedreich ataxia has the highest worldwide prevalence of the autosomal recessive ataxic disorders. • Slowly progressive ataxia • Depressed tendon reflexes, dysarthria, Babinski responses, & loss of position & vibration sense • Later onset • Cardiomyopathy • Absence of hypermyelinated retinal fibers • Absence of white matter lesions on MRI • Early-onset unsteady spastic gait & hyperreflexia of lower limbs • Mildly impaired sensation & cerebellar involvement • Sensory neuropathy • Hypoacusis • Mild ataxia • Anemia • Acanthocytosis • Retinitis pigmentosa • Gastrointestinal disease • Spastic paraplegia w/distal arm & leg amyotrophy • Dysarthria & mild cerebellar signs • ↑ prevalence of Troyer syndrome in the Amish population • Short stature • Distal wasting • White matter lesions on MRI • Cerebellar ataxia • Lower-limb spasticity • Optic atrophy • Scoliosis • Absence of neuropathy • Vitamin E deficiency • Retinitis pigmentosa • Cardiomyopathy ## Management To establish the extent of disease and needs in an individual diagnosed with ARSACS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ARSACS OT = occupational therapy; PT = physical therapy Curative therapy is not available; all treatments are symptomatic and tailored to the needs of the individual patient. Treatment of Manifestations in Individuals with ARSACS PT & oral medication such as baclofen Botulinum toxin injections Orthotic devices Use early in disease course may prevent tendon shortening & joint contractures. May help to postpone major functional disabilities until severe muscle weakness or cerebellar ataxia occur PT = physical therapy Recommended Surveillance for Individuals with ARSACS There is no absolute contraindication to specific drugs in ARSACS. As in all conditions with neuropathic components, known neurotoxic drugs (e.g., some chemotherapies) should be given with caution. See Search Women with ARSACS have experienced normal pregnancy and delivery. Some will have a functional decline during pregnancy that is reversible when they recover their prepregnancy weight and level of activity. See • PT & oral medication such as baclofen • Botulinum toxin injections • Orthotic devices • Use early in disease course may prevent tendon shortening & joint contractures. • May help to postpone major functional disabilities until severe muscle weakness or cerebellar ataxia occur ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ARSACS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with ARSACS OT = occupational therapy; PT = physical therapy ## Treatment of Manifestations Curative therapy is not available; all treatments are symptomatic and tailored to the needs of the individual patient. Treatment of Manifestations in Individuals with ARSACS PT & oral medication such as baclofen Botulinum toxin injections Orthotic devices Use early in disease course may prevent tendon shortening & joint contractures. May help to postpone major functional disabilities until severe muscle weakness or cerebellar ataxia occur PT = physical therapy • PT & oral medication such as baclofen • Botulinum toxin injections • Orthotic devices • Use early in disease course may prevent tendon shortening & joint contractures. • May help to postpone major functional disabilities until severe muscle weakness or cerebellar ataxia occur ## Surveillance Recommended Surveillance for Individuals with ARSACS ## Agents/Circumstances to Avoid There is no absolute contraindication to specific drugs in ARSACS. As in all conditions with neuropathic components, known neurotoxic drugs (e.g., some chemotherapies) should be given with caution. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Pregnancy Management Women with ARSACS have experienced normal pregnancy and delivery. Some will have a functional decline during pregnancy that is reversible when they recover their prepregnancy weight and level of activity. See ## Genetic Counseling ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one A report of uniparental isodisomy of the paternal chromosome 13 resulting in a homozygous p.Arg4378Ter pathogenic variant in an affected individual suggests that not all parents are heterozygous [ Note: The finding of a single Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a Heterozygotes are asymptomatic and are not at risk of developing the disorder. If each parent is known to be heterozygous for a Heterozygotes are asymptomatic and are not at risk of developing the disorder. Carrier detection for at-risk relatives requires 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 parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • A report of uniparental isodisomy of the paternal chromosome 13 resulting in a homozygous p.Arg4378Ter pathogenic variant in an affected individual suggests that not all parents are heterozygous [ • Note: The finding of a single • Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • If each parent is known to be heterozygous for a • Heterozygotes 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 ARSACS (autosomal recessive spastic ataxia of Charlevoix-Saguenay) 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 A report of uniparental isodisomy of the paternal chromosome 13 resulting in a homozygous p.Arg4378Ter pathogenic variant in an affected individual suggests that not all parents are heterozygous [ Note: The finding of a single Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a Heterozygotes are asymptomatic and are not at risk of developing the disorder. If each parent is known to be heterozygous for a Heterozygotes 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 • A report of uniparental isodisomy of the paternal chromosome 13 resulting in a homozygous p.Arg4378Ter pathogenic variant in an affected individual suggests that not all parents are heterozygous [ • Note: The finding of a single • Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for a • Heterozygotes are asymptomatic and are not at risk of developing the disorder. • If each parent is known to be heterozygous for a • Heterozygotes are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier detection for at-risk relatives requires prior identification of the See ## 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 Canada United Kingdom • • Canada • • • United Kingdom • • • • • ## Molecular Genetics ARSACS: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ARSACS ( An N-terminal ubiquitin-like domain shown to bind to the proteasome; A C-terminal DnaJ domain followed by a higher eukaryote and prokaryote nucleotide-binding (HEPN) domain. Sacsin localizes in close proximity to mitochondria in non-neuronal cells and primary neurons. In addition, it interacts with dynamin-related protein 1, which participates in mitochondrial fission [ Consistent with these observations, an altered mitochondrial network (displaying fused mitochondria and altered mitochondrial morphology with reduced mitochondrial oxygen consumption in primary culture fibroblasts) and vimentin intermediate filament bundling appear to be hallmarks of ARSACS [ Quantifying sacsin levels by western blot in human circulating blood lymphoblasts and fibroblasts has been used to evaluate disease-associated variants [ Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions • An N-terminal ubiquitin-like domain shown to bind to the proteasome; • A C-terminal DnaJ domain followed by a higher eukaryote and prokaryote nucleotide-binding (HEPN) domain. ## Molecular Pathogenesis An N-terminal ubiquitin-like domain shown to bind to the proteasome; A C-terminal DnaJ domain followed by a higher eukaryote and prokaryote nucleotide-binding (HEPN) domain. Sacsin localizes in close proximity to mitochondria in non-neuronal cells and primary neurons. In addition, it interacts with dynamin-related protein 1, which participates in mitochondrial fission [ Consistent with these observations, an altered mitochondrial network (displaying fused mitochondria and altered mitochondrial morphology with reduced mitochondrial oxygen consumption in primary culture fibroblasts) and vimentin intermediate filament bundling appear to be hallmarks of ARSACS [ Quantifying sacsin levels by western blot in human circulating blood lymphoblasts and fibroblasts has been used to evaluate disease-associated variants [ Notable Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions • An N-terminal ubiquitin-like domain shown to bind to the proteasome; • A C-terminal DnaJ domain followed by a higher eukaryote and prokaryote nucleotide-binding (HEPN) domain. ## Chapter Notes Jean-Pierre Bouchard, MD; Laval University (2003-2012)Bernard Brais, MD, PhD (2020-present)Erik-Jan Kamsteeg, PhD (2012-present)Jean Mathieu, MD, FRCPC; Complexe Hospitalier de la Sagamie (2003-2012)Andrea Richter, PhD; University of Montreal (2003-2012)Yves Robitaille, MD, FCAP; University of Montreal (2003-2012)Matthis Synofzik, MD (2020-present)Bart P van de Warrenburg, MD, PhD (2012-present)Sascha Vermeer, MD, PhD (2012-present) This project was supported, in part, via the European Union's Horizon 2020 research and innovation program by the BMBF under the frame of the E-Rare-3 network PREPARE (01GM1607 to MS, BvW, and BB) and grant 779257 "Solve-RD" (to MS and BvW). 2 January 2020 (ha) Comprehensive update posted live 11 October 2012 (me) Comprehensive update posted live 11 April 2007 (me) Comprehensive update posted live 3 January 2005 (me) Comprehensive update posted live 9 December 2003 (me) Review posted live 2 July 2003 (yr) Original submission • 2 January 2020 (ha) Comprehensive update posted live • 11 October 2012 (me) Comprehensive update posted live • 11 April 2007 (me) Comprehensive update posted live • 3 January 2005 (me) Comprehensive update posted live • 9 December 2003 (me) Review posted live • 2 July 2003 (yr) Original submission ## Author History Jean-Pierre Bouchard, MD; Laval University (2003-2012)Bernard Brais, MD, PhD (2020-present)Erik-Jan Kamsteeg, PhD (2012-present)Jean Mathieu, MD, FRCPC; Complexe Hospitalier de la Sagamie (2003-2012)Andrea Richter, PhD; University of Montreal (2003-2012)Yves Robitaille, MD, FCAP; University of Montreal (2003-2012)Matthis Synofzik, MD (2020-present)Bart P van de Warrenburg, MD, PhD (2012-present)Sascha Vermeer, MD, PhD (2012-present) ## Acknowledgments This project was supported, in part, via the European Union's Horizon 2020 research and innovation program by the BMBF under the frame of the E-Rare-3 network PREPARE (01GM1607 to MS, BvW, and BB) and grant 779257 "Solve-RD" (to MS and BvW). ## Revision History 2 January 2020 (ha) Comprehensive update posted live 11 October 2012 (me) Comprehensive update posted live 11 April 2007 (me) Comprehensive update posted live 3 January 2005 (me) Comprehensive update posted live 9 December 2003 (me) Review posted live 2 July 2003 (yr) Original submission • 2 January 2020 (ha) Comprehensive update posted live • 11 October 2012 (me) Comprehensive update posted live • 11 April 2007 (me) Comprehensive update posted live • 3 January 2005 (me) Comprehensive update posted live • 9 December 2003 (me) Review posted live • 2 July 2003 (yr) Original submission ## References ## Literature Cited	[ "V Ady, B Toscano-Márquez, M Nath, PK Chang, J Hui, A Cook, F Charron, R Larivière, B Brais, RA McKinney, AJ Watt. 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arterial-t	arterial-t	[ "Solute carrier family 2, facilitated glucose transporter member 10", "SLC2A10", "Arterial Tortuosity Syndrome" ]	Arterial Tortuosity Syndrome	Bert Callewaert, Anne De Paepe, Paul Coucke	Summary Arterial tortuosity syndrome (ATS) is characterized by widespread elongation and tortuosity of the aorta and mid-sized arteries as well as focal stenosis of segments of the pulmonary arteries and/or aorta combined with findings of a generalized connective tissue disorder, which may include soft or doughy hyperextensible skin, joint hypermobility, inguinal hernia, and diaphragmatic hernia. Skeletal findings include pectus excavatum or carinatum, arachnodactyly, scoliosis, knee/elbow contractures, and camptodactyly. The cardiovascular system is the major source of morbidity and mortality with increased risk at any age for aneurysm formation and dissection both at the aortic root and throughout the arterial tree, and for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs). The diagnosis of ATS is established in a proband with generalized arterial tortuosity and biallelic (homozygous or compound heterozygous) pathogenic variants in ATS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	## Diagnosis No formal diagnostic criteria have been established for arterial tortuosity syndrome (ATS). Arterial tortuosity syndrome Stenosis of the main and peripheral pulmonary arteries Focal stenosis of the aorta and large stenotic stretches Aortic and arterial aneurysms, dissections, and ischemic events Large-vein dilatation and tortuosity Blepharophimosis or periorbital fullness Downslanted palpebral fissures Convex nasal ridge Midface retrusion Micrognathia Large ears Long face High palate and dental crowding Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery Joint hypermobility Inguinal hernia Diaphragmatic hernia or sliding hernia Pectus excavatum/carinatum Arachnodactyly Scoliosis Knee/elbow contractures Camptodactyly The diagnosis of arterial tortuosity 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 [ 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 Depending on the testing method used for sequence analysis, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the testing method used, consultation with the lab is recommended regarding the need for additional testing such as gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Arterial Tortuosity Syndrome (ATS) 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. • Stenosis of the main and peripheral pulmonary arteries • Focal stenosis of the aorta and large stenotic stretches • Aortic and arterial aneurysms, dissections, and ischemic events • Large-vein dilatation and tortuosity • Stenosis of the main and peripheral pulmonary arteries • Focal stenosis of the aorta and large stenotic stretches • Aortic and arterial aneurysms, dissections, and ischemic events • Large-vein dilatation and tortuosity • Blepharophimosis or periorbital fullness • Downslanted palpebral fissures • Convex nasal ridge • Midface retrusion • Micrognathia • Large ears • Long face • High palate and dental crowding • Blepharophimosis or periorbital fullness • Downslanted palpebral fissures • Convex nasal ridge • Midface retrusion • Micrognathia • Large ears • Long face • High palate and dental crowding • Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery • Joint hypermobility • Inguinal hernia • Diaphragmatic hernia or sliding hernia • Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery • Joint hypermobility • Inguinal hernia • Diaphragmatic hernia or sliding hernia • Pectus excavatum/carinatum • Arachnodactyly • Scoliosis • Knee/elbow contractures • Camptodactyly • Pectus excavatum/carinatum • Arachnodactyly • Scoliosis • Knee/elbow contractures • Camptodactyly • Stenosis of the main and peripheral pulmonary arteries • Focal stenosis of the aorta and large stenotic stretches • Aortic and arterial aneurysms, dissections, and ischemic events • Large-vein dilatation and tortuosity • Blepharophimosis or periorbital fullness • Downslanted palpebral fissures • Convex nasal ridge • Midface retrusion • Micrognathia • Large ears • Long face • High palate and dental crowding • Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery • Joint hypermobility • Inguinal hernia • Diaphragmatic hernia or sliding hernia • Pectus excavatum/carinatum • Arachnodactyly • Scoliosis • Knee/elbow contractures • Camptodactyly ## Suggestive Findings Arterial tortuosity syndrome Stenosis of the main and peripheral pulmonary arteries Focal stenosis of the aorta and large stenotic stretches Aortic and arterial aneurysms, dissections, and ischemic events Large-vein dilatation and tortuosity Blepharophimosis or periorbital fullness Downslanted palpebral fissures Convex nasal ridge Midface retrusion Micrognathia Large ears Long face High palate and dental crowding Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery Joint hypermobility Inguinal hernia Diaphragmatic hernia or sliding hernia Pectus excavatum/carinatum Arachnodactyly Scoliosis Knee/elbow contractures Camptodactyly • Stenosis of the main and peripheral pulmonary arteries • Focal stenosis of the aorta and large stenotic stretches • Aortic and arterial aneurysms, dissections, and ischemic events • Large-vein dilatation and tortuosity • Stenosis of the main and peripheral pulmonary arteries • Focal stenosis of the aorta and large stenotic stretches • Aortic and arterial aneurysms, dissections, and ischemic events • Large-vein dilatation and tortuosity • Blepharophimosis or periorbital fullness • Downslanted palpebral fissures • Convex nasal ridge • Midface retrusion • Micrognathia • Large ears • Long face • High palate and dental crowding • Blepharophimosis or periorbital fullness • Downslanted palpebral fissures • Convex nasal ridge • Midface retrusion • Micrognathia • Large ears • Long face • High palate and dental crowding • Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery • Joint hypermobility • Inguinal hernia • Diaphragmatic hernia or sliding hernia • Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery • Joint hypermobility • Inguinal hernia • Diaphragmatic hernia or sliding hernia • Pectus excavatum/carinatum • Arachnodactyly • Scoliosis • Knee/elbow contractures • Camptodactyly • Pectus excavatum/carinatum • Arachnodactyly • Scoliosis • Knee/elbow contractures • Camptodactyly • Stenosis of the main and peripheral pulmonary arteries • Focal stenosis of the aorta and large stenotic stretches • Aortic and arterial aneurysms, dissections, and ischemic events • Large-vein dilatation and tortuosity • Blepharophimosis or periorbital fullness • Downslanted palpebral fissures • Convex nasal ridge • Midface retrusion • Micrognathia • Large ears • Long face • High palate and dental crowding • Soft or doughy hyperextensible skin with normal recoil on stretching, with or without loose skin folds and redundancy (as seen in cutis laxa syndromes) and atrophic scars, especially after surgery • Joint hypermobility • Inguinal hernia • Diaphragmatic hernia or sliding hernia • Pectus excavatum/carinatum • Arachnodactyly • Scoliosis • Knee/elbow contractures • Camptodactyly ## Establishing the Diagnosis The diagnosis of arterial tortuosity 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 [ 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 Depending on the testing method used for sequence analysis, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the testing method used, consultation with the lab is recommended regarding the need for additional testing such as gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Arterial Tortuosity Syndrome (ATS) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 Depending on the testing method used for sequence analysis, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no variant is detected by the testing method used, consultation with the lab is recommended regarding the need for additional testing such as gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications. For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Arterial Tortuosity Syndrome (ATS) See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics Arterial tortuosity syndrome (ATS) is characterized by widespread elongation and tortuosity of the aorta and mid-sized arteries as well as focal stenosis of segments of the pulmonary arteries and/or aorta combined with findings of a generalized connective tissue disorder. ATS is a highly variable disorder ranging from early mortality during infancy to limited manifestations in adulthood [ Most affected individuals are identified in early childhood, often because of a cardiac murmur or cyanosis. Subsequently manifestations of a generalized connective tissue disorder are often observed, prompting an echocardiogram that reveals aortic abnormalities with or without pulmonary artery stenosis. About 12% of all affected individuals are admitted to the neonatal intensive care unit because of a primary presentation with infant respiratory distress syndrome. Underlying causes may be diverse and include insufficient lung maturation, pulmonary hypertension, and/or diaphragmatic hernia. Few reports mention cardiorespiratory failure as the initial presentation during infancy or young childhood. Cutaneous (cutis laxa, stretchable skin) and gastrointestinal (pyloric stenosis, failure to thrive) manifestations have been infrequently reported as the initial presenting symptoms. Rare patients have been identified initially in adulthood, with joint aches and premature aging as the main presenting features [ To date, 106 individuals with ATS and biallelic pathogenic variants in Arterial Tortuosity Syndrome (ATS): Frequency of Select Features Percentages based on The risk is also increased at any age for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs). Although arterial dissections have been reported, it is unclear if thrombosis due to endothelial damage caused by increased shear stress on the wall of the tortuous arteries may have precipitated some of these ischemic events. Focal stenoses of the aorta and aortic branches are congenital and amenable to treatment (see Hypertension and ventricular hypertrophy have been reported in individuals and may require aggressive management [ Stenosis of the main and peripheral pulmonary arteries may lead to pulmonary hypertension [ Large-vein dilatation [ Valvular regurgitation and mitral valve prolapse [ A higher rate of Raynaud phenomenon and orthostatic hypotension is reported; the causal relation remains to be established [ Individuals often present with hypotonia and joint hypermobility and are at risk for sprains and luxations. Adults are at increased risk for joint pain and fatigue [ Diaphragmatic hernia and sliding hiatal hernias are reported in up to 50% of affected individuals [ Affected women are more prone to prolapse of the bladder, uterus, and rectum, especially following childbirth [ Osteopenia has been observed in rare individuals [Authors, unpublished data]. No genotype-phenotype correlations have been identified. Of note, in some reports "arterial tortuosity syndrome" refers to No reliable estimates of prevalence exist. ATS is considered rare (<1:1,000,000 live births). However, some authors suggest that it may be more frequent than estimated [ ATS occurs in all populations, but most reported cases to date are from Europe and the Middle East. • About 12% of all affected individuals are admitted to the neonatal intensive care unit because of a primary presentation with infant respiratory distress syndrome. Underlying causes may be diverse and include insufficient lung maturation, pulmonary hypertension, and/or diaphragmatic hernia. • Few reports mention cardiorespiratory failure as the initial presentation during infancy or young childhood. • Cutaneous (cutis laxa, stretchable skin) and gastrointestinal (pyloric stenosis, failure to thrive) manifestations have been infrequently reported as the initial presenting symptoms. • Rare patients have been identified initially in adulthood, with joint aches and premature aging as the main presenting features [ ## Clinical Description Arterial tortuosity syndrome (ATS) is characterized by widespread elongation and tortuosity of the aorta and mid-sized arteries as well as focal stenosis of segments of the pulmonary arteries and/or aorta combined with findings of a generalized connective tissue disorder. ATS is a highly variable disorder ranging from early mortality during infancy to limited manifestations in adulthood [ Most affected individuals are identified in early childhood, often because of a cardiac murmur or cyanosis. Subsequently manifestations of a generalized connective tissue disorder are often observed, prompting an echocardiogram that reveals aortic abnormalities with or without pulmonary artery stenosis. About 12% of all affected individuals are admitted to the neonatal intensive care unit because of a primary presentation with infant respiratory distress syndrome. Underlying causes may be diverse and include insufficient lung maturation, pulmonary hypertension, and/or diaphragmatic hernia. Few reports mention cardiorespiratory failure as the initial presentation during infancy or young childhood. Cutaneous (cutis laxa, stretchable skin) and gastrointestinal (pyloric stenosis, failure to thrive) manifestations have been infrequently reported as the initial presenting symptoms. Rare patients have been identified initially in adulthood, with joint aches and premature aging as the main presenting features [ To date, 106 individuals with ATS and biallelic pathogenic variants in Arterial Tortuosity Syndrome (ATS): Frequency of Select Features Percentages based on The risk is also increased at any age for ischemic vascular events involving cerebrovascular circulation (resulting in non-hemorrhagic stroke) and the abdominal arteries (resulting in infarctions of abdominal organs). Although arterial dissections have been reported, it is unclear if thrombosis due to endothelial damage caused by increased shear stress on the wall of the tortuous arteries may have precipitated some of these ischemic events. Focal stenoses of the aorta and aortic branches are congenital and amenable to treatment (see Hypertension and ventricular hypertrophy have been reported in individuals and may require aggressive management [ Stenosis of the main and peripheral pulmonary arteries may lead to pulmonary hypertension [ Large-vein dilatation [ Valvular regurgitation and mitral valve prolapse [ A higher rate of Raynaud phenomenon and orthostatic hypotension is reported; the causal relation remains to be established [ Individuals often present with hypotonia and joint hypermobility and are at risk for sprains and luxations. Adults are at increased risk for joint pain and fatigue [ Diaphragmatic hernia and sliding hiatal hernias are reported in up to 50% of affected individuals [ Affected women are more prone to prolapse of the bladder, uterus, and rectum, especially following childbirth [ Osteopenia has been observed in rare individuals [Authors, unpublished data]. • About 12% of all affected individuals are admitted to the neonatal intensive care unit because of a primary presentation with infant respiratory distress syndrome. Underlying causes may be diverse and include insufficient lung maturation, pulmonary hypertension, and/or diaphragmatic hernia. • Few reports mention cardiorespiratory failure as the initial presentation during infancy or young childhood. • Cutaneous (cutis laxa, stretchable skin) and gastrointestinal (pyloric stenosis, failure to thrive) manifestations have been infrequently reported as the initial presenting symptoms. • Rare patients have been identified initially in adulthood, with joint aches and premature aging as the main presenting features [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Nomenclature Of note, in some reports "arterial tortuosity syndrome" refers to ## Prevalence No reliable estimates of prevalence exist. ATS is considered rare (<1:1,000,000 live births). However, some authors suggest that it may be more frequent than estimated [ ATS occurs in all populations, but most reported cases to date are from Europe and the Middle East. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Arterial Tortuosity Syndrome Persons w/ AT is rarely present in Persons w/ hEDS: generalized joint hypermobility → repetitive joint luxations & chronic musculoskeletal pain; soft & hyperextensible skin; autonomic dysfunction vEDS: thin, translucent skin; atrophic scars, easy bruising; characteristic facial appearance (in some persons); arterial, intestinal, &/or uterine fragility Vascular dissection or rupture, GI perforation, or organ rupture are presenting signs in most adults w/vEDS. AT is absent in persons w/hEDS & vEDS. Skin & craniofacial features in vEDS are usually distinctive. Cutis laxa & systemic involvement, most commonly AT, aneurysms, & stenosis; retrognathia; joint laxity; arachnodactyly Severity ranges from perinatal lethality (due to cardiopulmonary failure) to manifestations limited to vascular & craniofacial systems Focal stenosis at aortic isthmus is more common in ARCL1B than in ATS. ARCL1B often presents w/more aggressive arterial phenotype w/rapid progression to aneurysms. Typical facial characteristics of ATS (e.g., blepharophimosis, convex nasal ridge, & long face) are often absent in ARCL1B. Osteopenia w/neonatal fractures Typical facial characteristics of ATS are absent Cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, & other evidence of generalized connective disorder incl inguinal hernias & hollow viscus diverticula (e.g., intestine, bladder) Supravalvar aortic stenosis occasionally observed Pulmonary emphysema or GI ruptures are often cause of death. Persons w/Marfan syndrome do not show manifest AT. Lens subluxation is not present in ATS. Persons w/kEDS do not present w/manifest tortuosity. Ocular fragility (a feature of Vascular findings (cerebral, thoracic, & abdominal arterial aneurysms, &/or dissections) Skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus) Persons w/LDS may have craniofacial manifestations (widely spaced eyes, cleft uvula/palate, craniosynostosis), findings usually not seen w/ATS. AT is often present in LDS but more often in ATS. Persons w/LDS present more frequently w/aneurysm of aortic root than persons w/ATS. AD = autosomal dominant; AR = autosomal recessive; AT = arterial tortuosity; ATS = arterial tortuosity syndrome; DiffDx = differential diagnosis; EDS = Ehlers-Danlos syndrome; GI = gastrointestinal; ID = intellectual disability; LDS = Loeys-Dietz syndrome; MOI = mode of inheritance; XL = X-linked "Occipital horns" are distinctive wedge-shaped calcifications at the sites of attachment of the trapezius muscle and the sternocleidomastoid muscle to the occipital bone. Hypermobile EDS is inherited in an autosomal dominant manner (the molecular basis of hEDS is unknown). Two reports mention arterial tortuosity syndrome in individuals previously misdiagnosed with EDS hypermobility type, one of whom was homozygous for the • Persons w/ • AT is rarely present in • Persons w/ • hEDS: generalized joint hypermobility → repetitive joint luxations & chronic musculoskeletal pain; soft & hyperextensible skin; autonomic dysfunction • vEDS: thin, translucent skin; atrophic scars, easy bruising; characteristic facial appearance (in some persons); arterial, intestinal, &/or uterine fragility • Vascular dissection or rupture, GI perforation, or organ rupture are presenting signs in most adults w/vEDS. • AT is absent in persons w/hEDS & vEDS. • Skin & craniofacial features in vEDS are usually distinctive. • Cutis laxa & systemic involvement, most commonly AT, aneurysms, & stenosis; retrognathia; joint laxity; arachnodactyly • Severity ranges from perinatal lethality (due to cardiopulmonary failure) to manifestations limited to vascular & craniofacial systems • Focal stenosis at aortic isthmus is more common in ARCL1B than in ATS. • ARCL1B often presents w/more aggressive arterial phenotype w/rapid progression to aneurysms. • Typical facial characteristics of ATS (e.g., blepharophimosis, convex nasal ridge, & long face) are often absent in ARCL1B. • Osteopenia w/neonatal fractures • Typical facial characteristics of ATS are absent • Cutis laxa, early childhood-onset pulmonary emphysema, peripheral pulmonary artery stenosis, & other evidence of generalized connective disorder incl inguinal hernias & hollow viscus diverticula (e.g., intestine, bladder) • Supravalvar aortic stenosis occasionally observed • Pulmonary emphysema or GI ruptures are often cause of death. • Persons w/Marfan syndrome do not show manifest AT. • Lens subluxation is not present in ATS. • Persons w/kEDS do not present w/manifest tortuosity. • Ocular fragility (a feature of • Vascular findings (cerebral, thoracic, & abdominal arterial aneurysms, &/or dissections) • Skeletal manifestations (pectus excavatum or pectus carinatum, scoliosis, joint laxity, arachnodactyly, talipes equinovarus) • Persons w/LDS may have craniofacial manifestations (widely spaced eyes, cleft uvula/palate, craniosynostosis), findings usually not seen w/ATS. • AT is often present in LDS but more often in ATS. • Persons w/LDS present more frequently w/aneurysm of aortic root than persons w/ATS. ## Management No clinical practice guidelines for arterial tortuosity syndrome (ATS) have been published. To establish the extent of disease and needs in an individual diagnosed with ATS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Arterial Tortuosity Syndrome ATS = arterial tortuosity syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse Individuals with ATS benefit from a coordinated approach from multidisciplinary specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon. If feasible, individuals with ATS should be managed in a medical center familiar with this condition. Treatment of Manifestations in Individuals with Arterial Tortuosity Syndrome Efficacy of these treatments has not been established in ATS. Caution is warranted when using blood pressure-lowering medications in presence of arterial stenosis (anatomic or functional due to severe tortuosity), esp renal artery stenosis, as such meds may confer risk for renal failure. No data available on aortic diameter at which intervention is appropriate Decision making should also incl assessment of family history or individual's personal assessment of risk vs benefit. Persons can & should maintain aerobic activity (e.g., swimming) in moderation. Persons w/ATS may have psychological issues, esp in adolescence, for which psychological guidance may be relevant. ATS = arterial tortuosity syndrome Recommended Surveillance for Individuals with Arterial Tortuosity Syndrome Every 3 mos until age 5 yrs Annually thereafter if diameters of aorta are w/in normal limits Annually from birth or time of diagnosis Under stable conditions (in absence of aneurysms, stenosis, or dilatation of aortic root), perform every 3 yrs in older children & adults. Baseline lung function at age 18 yrs Repeat exam based on symptomatology Avoid the following: Contact sports, competitive sports, and isometric exercise Scuba diving because of pressure differences and the need for positive pressure ventilation Agents that stimulate the cardiovascular system, including routine use of decongestants Use of tobacco, which increases cardiovascular and pulmonary risk and the likelihood of premature skin aging Sun tanning, which increases the likelihood of premature skin aging It is appropriate to evaluate the older and younger sibs of a proband with ATS in order to identify as early as possible those who would benefit from institution of If the If the pathogenic variants in the family are not known, at-risk sibs should be evaluated for signs of the disorder (clinically and with echocardiography or more advanced vascular imaging, as clinical symptoms may be very subtle) to clarify their genetic status. See Data on the management of women with arterial tortuosity syndrome during pregnancy and delivery are limited, with only three pregnancies reported (in 2 women) to date. All pregnancies had a good outcome; however, one woman experienced pelvic organ prolapse following the vaginal delivery of her first child [ Preconception counseling should include possible pregnancy-associated risks to the mother and medication-associated risks to the fetus. Currently, no data are available on a possible risk for pregnancy-associated uterine rupture (as is seen in Peripartum intensive monitoring is advised. Pregnancies should be followed by a high-risk obstetrician and a cardiologist familiar with this or related conditions. Increased surveillance of the aortic root and previously detected aneurysms during pregnancy and following delivery is recommended because of the increased risk for progressive dilatation. Echocardiography is suggested every two to three months from conception until six months post partum. Delivery should be planned in a center with experience with this or related conditions. It is currently unclear whether cæsarean section or vaginal delivery is preferable. Ideally, women with ATS who are planning a pregnancy should transition to a different antihypertensive medication (e.g., a beta-blocker) prior to conception. Women with ATS who become pregnant while taking an ACE-I or an ATIIR1 should be transitioned to a different antihypertensive medication as soon as the pregnancy is recognized. Women undergoing a non-valve-sparing aortic root replacement before pregnancy should be advised of the risk associated with anticoagulant therapy during pregnancy. See Search • Efficacy of these treatments has not been established in ATS. • Caution is warranted when using blood pressure-lowering medications in presence of arterial stenosis (anatomic or functional due to severe tortuosity), esp renal artery stenosis, as such meds may confer risk for renal failure. • No data available on aortic diameter at which intervention is appropriate • Decision making should also incl assessment of family history or individual's personal assessment of risk vs benefit. • Persons can & should maintain aerobic activity (e.g., swimming) in moderation. • Persons w/ATS may have psychological issues, esp in adolescence, for which psychological guidance may be relevant. • Every 3 mos until age 5 yrs • Annually thereafter if diameters of aorta are w/in normal limits • Annually from birth or time of diagnosis • Under stable conditions (in absence of aneurysms, stenosis, or dilatation of aortic root), perform every 3 yrs in older children & adults. • Baseline lung function at age 18 yrs • Repeat exam based on symptomatology • Contact sports, competitive sports, and isometric exercise • Scuba diving because of pressure differences and the need for positive pressure ventilation • Agents that stimulate the cardiovascular system, including routine use of decongestants • Use of tobacco, which increases cardiovascular and pulmonary risk and the likelihood of premature skin aging • Sun tanning, which increases the likelihood of premature skin aging • If the • If the pathogenic variants in the family are not known, at-risk sibs should be evaluated for signs of the disorder (clinically and with echocardiography or more advanced vascular imaging, as clinical symptoms may be very subtle) to clarify their genetic status. • Ideally, women with ATS who are planning a pregnancy should transition to a different antihypertensive medication (e.g., a beta-blocker) prior to conception. • Women with ATS who become pregnant while taking an ACE-I or an ATIIR1 should be transitioned to a different antihypertensive medication as soon as the pregnancy is recognized. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ATS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Arterial Tortuosity Syndrome ATS = arterial tortuosity syndrome; MOI = mode of inheritance Medical geneticist, certified genetic counselor, or certified advanced genetic nurse ## Treatment of Manifestations Individuals with ATS benefit from a coordinated approach from multidisciplinary specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, and cardiothoracic surgeon. If feasible, individuals with ATS should be managed in a medical center familiar with this condition. Treatment of Manifestations in Individuals with Arterial Tortuosity Syndrome Efficacy of these treatments has not been established in ATS. Caution is warranted when using blood pressure-lowering medications in presence of arterial stenosis (anatomic or functional due to severe tortuosity), esp renal artery stenosis, as such meds may confer risk for renal failure. No data available on aortic diameter at which intervention is appropriate Decision making should also incl assessment of family history or individual's personal assessment of risk vs benefit. Persons can & should maintain aerobic activity (e.g., swimming) in moderation. Persons w/ATS may have psychological issues, esp in adolescence, for which psychological guidance may be relevant. ATS = arterial tortuosity syndrome • Efficacy of these treatments has not been established in ATS. • Caution is warranted when using blood pressure-lowering medications in presence of arterial stenosis (anatomic or functional due to severe tortuosity), esp renal artery stenosis, as such meds may confer risk for renal failure. • No data available on aortic diameter at which intervention is appropriate • Decision making should also incl assessment of family history or individual's personal assessment of risk vs benefit. • Persons can & should maintain aerobic activity (e.g., swimming) in moderation. • Persons w/ATS may have psychological issues, esp in adolescence, for which psychological guidance may be relevant. ## Surveillance Recommended Surveillance for Individuals with Arterial Tortuosity Syndrome Every 3 mos until age 5 yrs Annually thereafter if diameters of aorta are w/in normal limits Annually from birth or time of diagnosis Under stable conditions (in absence of aneurysms, stenosis, or dilatation of aortic root), perform every 3 yrs in older children & adults. Baseline lung function at age 18 yrs Repeat exam based on symptomatology • Every 3 mos until age 5 yrs • Annually thereafter if diameters of aorta are w/in normal limits • Annually from birth or time of diagnosis • Under stable conditions (in absence of aneurysms, stenosis, or dilatation of aortic root), perform every 3 yrs in older children & adults. • Baseline lung function at age 18 yrs • Repeat exam based on symptomatology ## Agents/Circumstances to Avoid Avoid the following: Contact sports, competitive sports, and isometric exercise Scuba diving because of pressure differences and the need for positive pressure ventilation Agents that stimulate the cardiovascular system, including routine use of decongestants Use of tobacco, which increases cardiovascular and pulmonary risk and the likelihood of premature skin aging Sun tanning, which increases the likelihood of premature skin aging • Contact sports, competitive sports, and isometric exercise • Scuba diving because of pressure differences and the need for positive pressure ventilation • Agents that stimulate the cardiovascular system, including routine use of decongestants • Use of tobacco, which increases cardiovascular and pulmonary risk and the likelihood of premature skin aging • Sun tanning, which increases the likelihood of premature skin aging ## Evaluation of Relatives at Risk It is appropriate to evaluate the older and younger sibs of a proband with ATS in order to identify as early as possible those who would benefit from institution of If the If the pathogenic variants in the family are not known, at-risk sibs should be evaluated for signs of the disorder (clinically and with echocardiography or more advanced vascular imaging, as clinical symptoms may be very subtle) to clarify their genetic status. See • If the • If the pathogenic variants in the family are not known, at-risk sibs should be evaluated for signs of the disorder (clinically and with echocardiography or more advanced vascular imaging, as clinical symptoms may be very subtle) to clarify their genetic status. ## Pregnancy Management Data on the management of women with arterial tortuosity syndrome during pregnancy and delivery are limited, with only three pregnancies reported (in 2 women) to date. All pregnancies had a good outcome; however, one woman experienced pelvic organ prolapse following the vaginal delivery of her first child [ Preconception counseling should include possible pregnancy-associated risks to the mother and medication-associated risks to the fetus. Currently, no data are available on a possible risk for pregnancy-associated uterine rupture (as is seen in Peripartum intensive monitoring is advised. Pregnancies should be followed by a high-risk obstetrician and a cardiologist familiar with this or related conditions. Increased surveillance of the aortic root and previously detected aneurysms during pregnancy and following delivery is recommended because of the increased risk for progressive dilatation. Echocardiography is suggested every two to three months from conception until six months post partum. Delivery should be planned in a center with experience with this or related conditions. It is currently unclear whether cæsarean section or vaginal delivery is preferable. Ideally, women with ATS who are planning a pregnancy should transition to a different antihypertensive medication (e.g., a beta-blocker) prior to conception. Women with ATS who become pregnant while taking an ACE-I or an ATIIR1 should be transitioned to a different antihypertensive medication as soon as the pregnancy is recognized. Women undergoing a non-valve-sparing aortic root replacement before pregnancy should be advised of the risk associated with anticoagulant therapy during pregnancy. See • Ideally, women with ATS who are planning a pregnancy should transition to a different antihypertensive medication (e.g., a beta-blocker) prior to conception. • Women with ATS who become pregnant while taking an ACE-I or an ATIIR1 should be transitioned to a different antihypertensive medication as soon as the pregnancy is recognized. ## Therapies Under Investigation Search ## Genetic Counseling Arterial tortuosity syndrome (ATS) is inherited in an autosomal recessive manner. The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an 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 arterial tortuosity syndrome. 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., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for an • Heterozygotes (carriers) are asymptomatic and are not at risk of developing arterial tortuosity syndrome. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Arterial tortuosity syndrome (ATS) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an 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 arterial tortuosity syndrome. • The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • 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 arterial tortuosity syndrome. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Arterial Tortuosity Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Arterial Tortuosity Syndrome ( ## Molecular Pathogenesis ## Chapter Notes Bert Callewaert is an assistant professor at Ghent University, and pediatrician and clinical geneticist at the Center for Medical Genetics, Ghent University Hospital. He is a senior clinical investigator supported by the Research Foundation – Flanders. His research focuses on clinical aspects and mechanisms of disease in connective tissue disorders including the arterial tortuosity syndrome, cutis laxa syndromes, congenital contractural arachnodactyly, and familial thoracic aortic aneurysms. Paul Coucke is the supervisor of the connective tissue laboratory and head of the department at the Center for Medical Genetics. Anne De Paepe is a clinical geneticist at the Center for Medical Genetics. Dr Callewaert ([email protected]) is actively involved in clinical research regarding individuals with arterial tortuosity syndrome. He would be happy to communicate with persons who have any questions regarding diagnosis of arterial tortuosity syndrome or other considerations. Contact Dr Callewaert at [email protected] to inquire about the interpretation of Dr Callewaert ([email protected]) is also interested in hearing from clinicians treating families affected by arterial tortuosity syndrome in whom no causative variant has been identified through molecular genetic testing. Bert Callewaert is a senior clinical investigator of the Fund for Scientific Research-Flanders. 23 February 2023 (aa) Revision: added 14 July 2022 (blc) Revision: contact information for questions about arterial tortuosity syndrome added to 19 November 2020 (ha) Comprehensive update posted live 13 November 2014 (me) Review posted live 14 February 2014 (blc) Original submission • 23 February 2023 (aa) Revision: added • 14 July 2022 (blc) Revision: contact information for questions about arterial tortuosity syndrome added to • 19 November 2020 (ha) Comprehensive update posted live • 13 November 2014 (me) Review posted live • 14 February 2014 (blc) Original submission ## Author Notes Bert Callewaert is an assistant professor at Ghent University, and pediatrician and clinical geneticist at the Center for Medical Genetics, Ghent University Hospital. He is a senior clinical investigator supported by the Research Foundation – Flanders. His research focuses on clinical aspects and mechanisms of disease in connective tissue disorders including the arterial tortuosity syndrome, cutis laxa syndromes, congenital contractural arachnodactyly, and familial thoracic aortic aneurysms. Paul Coucke is the supervisor of the connective tissue laboratory and head of the department at the Center for Medical Genetics. Anne De Paepe is a clinical geneticist at the Center for Medical Genetics. Dr Callewaert ([email protected]) is actively involved in clinical research regarding individuals with arterial tortuosity syndrome. He would be happy to communicate with persons who have any questions regarding diagnosis of arterial tortuosity syndrome or other considerations. Contact Dr Callewaert at [email protected] to inquire about the interpretation of Dr Callewaert ([email protected]) is also interested in hearing from clinicians treating families affected by arterial tortuosity syndrome in whom no causative variant has been identified through molecular genetic testing. ## Acknowledgments Bert Callewaert is a senior clinical investigator of the Fund for Scientific Research-Flanders. ## Revision History 23 February 2023 (aa) Revision: added 14 July 2022 (blc) Revision: contact information for questions about arterial tortuosity syndrome added to 19 November 2020 (ha) Comprehensive update posted live 13 November 2014 (me) Review posted live 14 February 2014 (blc) Original submission • 23 February 2023 (aa) Revision: added • 14 July 2022 (blc) Revision: contact information for questions about arterial tortuosity syndrome added to • 19 November 2020 (ha) Comprehensive update posted live • 13 November 2014 (me) Review posted live • 14 February 2014 (blc) Original submission ## References ## Literature Cited Craniofacial findings in ATS A:VI-2, male age 12 years C:II-1, age 15 months (left) and 3 months (right) E:II-1, in infancy and age 35 years H:II-1, age 2 years I:II-1, age 6 years K:II-1, age 11 years Note characteristic features: Long face (A:VI-2, C:II-1, E:II-1, H:II-1, I:II-1, K:II-1) Aged appearance (E:II-1, K:II-1) Sagging cheeks (C:II-1, E:II-1, H:II-1, I:II-1, K:II-1) Large ears (A:VI-2, H:II-1, K:II-1) Widely spaced eyes (mild) (A:VI-2, C:II-1, E:II-1, I:II-1, K:II-1) Short palpebral fissures with periorbital fullness (A:VI-2, C:II-1, K:II-1) Downslanted palpebral fissures (C:II-1, E:II-1, I:II-1) Midface retrusion (A:VI-2, C:II-2, K:II-1) Micrognathia (A:VI-2, C:II-1, K:II-1) From	[ "CS Adamo, A Beyens, A Schiavinato, DR Keene, SF Tufa, M Mörgelin, J Brinckmann, T Sasaki, A Niehoff, M Dreiner, L Pottie, L Muiño-Mosquera, EY Gulec, A Gezdirici, P Braghetta, P Bonaldo, R Wagener, M Paulsson, H Bornaun, R De Rycke, M De Bruyne, F Baeke, WP Devine, B Gangaram, A Tam, M Balasubramanian, S Ellard, S Moore, S Symoens, J Shen, S Cole, U Schwarze, KW Holmes, SJ Hayflick, W Wiszniewski, S Nampoothiri, EC Davis, LY Sakai, G Sengle, B Callewaert. 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Mutations in the facilitative glucose transporter GLUT10 alter angiogenesis and cause arterial tortuosity syndrome.. Nat Genet. 2006;38:452-7", "C de Marcellus, V Baudouin, A Tanase, C Monet, L Perrin, G Deschenes, J Hogan. Severe neonatal hypertension revealing arterial tortuosity syndrome.. Kidney Int. 2018;93:526", "B Drera, A Guala, N Zoppi, R Gardella, P Franceschini, S Barlati, M. Colombi. Two novel SLC2A10/GLUT10 mutations in a patient with arterial tortuosity syndrome.. Am J Med Genet A. 2007b;143A:216-8", "JS Hardin, YA Zarate, B Callewaert, PH Phillips, DB Warner. Ophthalmic findings in patients with arterial tortuosity syndrome and carriers: a case series.. Ophthalmic Genet. 2018;39:29-34", "S Hasler, J Stürmer, C Kaufmann. Keratoglobus and deep stromal corneal opacification in a case of arterial tortuosity syndrome.. Klin Monbl Augenheilkd. 2011;228:345-6", "SJ Huang, LM Amendola, DL Sternen. Variation among DNA banking consent forms: points for clinicians to bank on.. 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arts	arts	[ "PRS Deficiency", "PRS Deficiency", "Charcot-Marie-Tooth Neuropathy X Type 5 (CMTX5)", "DFNX1 Nonsyndromic Sensorineural Hearing Loss (DFN2)", "Arts Syndrome", "Ribose-phosphate pyrophosphokinase 1", "PRPS1", "Phosphoribosylpyrophosphate Synthetase Deficiency" ]	Phosphoribosylpyrophosphate Synthetase Deficiency	Arjan PM de Brouwer, John Christodoulou	Summary Phosphoribosylpyrophosphate synthetase (PRS) deficiency, an X-linked disorder, is a phenotypic continuum comprising three disorders previously thought to be clinically distinct: Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural hearing loss (DFNX1). In affected males, the PRS deficiency phenotypic spectrum ranges from severe congenital profound sensorineural hearing loss, intellectual disability, delayed motor development, and progressive ophthalmologic involvement (retinal dystrophy and optic atrophy) to normal cognitive abilities and relatively later-onset, somewhat milder manifestations, such as mild sensorineural hearing loss, peripheral neuropathy, and gait ataxia. Heterozygous females can show isolated and/or milder manifestations in the PRS deficiency spectrum. To date, 40 families with PRS deficiency have been reported. The diagnosis of PRS deficiency is established in a male proband with suggestive findings and a hemizygous pathogenic variant in PRS deficiency is inherited in an X-linked manner. If the mother of the proband has a	With the current widespread use of multigene panels and comprehensive genomic testing based on an unbiased (i.e., not phenotype-driven) approach, it has become apparent that the phenotypic continuum associated with phosphoribosylpyrophosphate synthetase (PRS) deficiency is comprised of clusters encompassing three previously clinically distinct disorders – Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural hearing loss (DFNX1). PRS deficiency refers to this entire phenotypic spectrum and emphasizes the need to evaluate an individual with a PRS Deficiency: Disorders Previously Clinically Defined in the Phenotypical Continuum CMTX5 = Charcot-Marie-Tooth neuropathy X type 5; DFNX1 = X-linked nonsyndromic sensorineural hearing loss Females typically have a less severe presentation than males; the ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females. Also referred to as DFN2. Although postlingual progressive nonsyndromic hearing loss is typical, one family had congenital profound nonsyndromic hearing loss [ ## Diagnosis For the purposes of this No consensus clinical diagnostic criteria for phosphoribosylpyrophosphate synthetase (PRS) deficiency have been published. PRS deficiency Audiogram shapes are usually residual or flat [ Temporal bone imaging is normal [ Vestibular function is normal. Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ Optic neuronopathy/atrophy Fundoscopic examination shows bilateral optic disc pallor. Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. Retinal dystrophy [ Fundoscopic examination can show patches of retinal atrophy. Electroretinogram can show abnormal cone and rod responses. Note: (1) Serum uric acid concentration is not zero because the enzyme PRS-II, which has the same enzyme activity as the enzyme PRS-I, is active in tissues such as liver, resulting in purine nucleotide synthesis and uric acid production. (2) However, a low/normal serum uric acid concentration may be helpful in ruling out a diagnosis of Absent/low hypoxanthine concentration Normal range of concentration of other purines When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. 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 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 PRS 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 Data collectively provided for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Audiogram shapes are usually residual or flat [ • Temporal bone imaging is normal [ • Vestibular function is normal. • • Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ • Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ • Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ • Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ • • Optic neuronopathy/atrophy • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Retinal dystrophy [ • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Optic neuronopathy/atrophy • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Retinal dystrophy [ • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ • Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ • Optic neuronopathy/atrophy • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Retinal dystrophy [ • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Note: (1) Serum uric acid concentration is not zero because the enzyme PRS-II, which has the same enzyme activity as the enzyme PRS-I, is active in tissues such as liver, resulting in purine nucleotide synthesis and uric acid production. (2) However, a low/normal serum uric acid concentration may be helpful in ruling out a diagnosis of • Absent/low hypoxanthine concentration • Normal range of concentration of other purines • When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. • Absent/low hypoxanthine concentration • Normal range of concentration of other purines • When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. • Absent/low hypoxanthine concentration • Normal range of concentration of other purines • When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. ## Suggestive Findings PRS deficiency Audiogram shapes are usually residual or flat [ Temporal bone imaging is normal [ Vestibular function is normal. Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ Optic neuronopathy/atrophy Fundoscopic examination shows bilateral optic disc pallor. Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. Retinal dystrophy [ Fundoscopic examination can show patches of retinal atrophy. Electroretinogram can show abnormal cone and rod responses. Note: (1) Serum uric acid concentration is not zero because the enzyme PRS-II, which has the same enzyme activity as the enzyme PRS-I, is active in tissues such as liver, resulting in purine nucleotide synthesis and uric acid production. (2) However, a low/normal serum uric acid concentration may be helpful in ruling out a diagnosis of Absent/low hypoxanthine concentration Normal range of concentration of other purines When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. • Audiogram shapes are usually residual or flat [ • Temporal bone imaging is normal [ • Vestibular function is normal. • • Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ • Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ • Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ • Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ • • Optic neuronopathy/atrophy • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Retinal dystrophy [ • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Optic neuronopathy/atrophy • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Retinal dystrophy [ • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Motor nerve conduction velocities (NCVs) reveal delayed distal latencies and decreased amplitudes with relatively normal velocities (median motor NCV ≥38 m/s), consistent with an axonal neuropathy [ • Needle electromyography (EMG) revealed fibrillation potentials and neurogenic motor unit action potentials [ • Optic neuronopathy/atrophy • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Retinal dystrophy [ • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Fundoscopic examination shows bilateral optic disc pallor. • Visual evoked potentials demonstrate delayed latency and decreased amplitudes of P100. • Fundoscopic examination can show patches of retinal atrophy. • Electroretinogram can show abnormal cone and rod responses. • Note: (1) Serum uric acid concentration is not zero because the enzyme PRS-II, which has the same enzyme activity as the enzyme PRS-I, is active in tissues such as liver, resulting in purine nucleotide synthesis and uric acid production. (2) However, a low/normal serum uric acid concentration may be helpful in ruling out a diagnosis of • Absent/low hypoxanthine concentration • Normal range of concentration of other purines • When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. • Absent/low hypoxanthine concentration • Normal range of concentration of other purines • When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. • Absent/low hypoxanthine concentration • Normal range of concentration of other purines • When individuals with PRS deficiency are on a low-purine diet, the uric acid-to-creatinine ratio in urine may tend to be at the lower end of normal but not zero. ## Establishing the Diagnosis 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 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 PRS 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 Data collectively provided for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in PRS 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 Data collectively provided for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics The phenotype of phosphoribosylpyrophosphate synthetase (PRS) deficiency is now known to be a continuum encompassing three previously clinically defined disorders – Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural hearing loss (DFNX1). Arts syndrome (characterized by intellectual disability, hypotonia, ataxia, sensorineural hearing impairment, and progressive optic atrophy and/or retinopathy), CMTX5 (characterized by peripheral neuropathy, sensorineural hearing loss, and optic neuropathy), and DFNX1 were initially thought to represent distinct phenotypes. However, following the observation in a single family of a male with features of CMTX5 and Arts syndrome and a female with prelingual DFNX1, Subsequent reports confirmed this observation and further expanded the PRS deficiency phenotype: Detailed clinical and neurophysiologic examination of males diagnosed with Females heterozygous for a Thus, the phenotypic spectrum of PRS deficiency can range from profound congenital sensorineural hearing impairment, intellectual disability, delayed motor development, and progressive optic atrophy [ To date, 40 families have been identified with PRS deficiency [ Sural nerve biopsy showed the following: Loss of myelinated fibers without signs of demyelination or axonal degeneration in a boy age five years with Arts syndrome from the original Dutch family reported by Mild paranodal demyelination indicative of peripheral neuropathy in a boy age two years, who had absent lower limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy [ Heterozygous females can show isolated and/or milder manifestations, most notably late-onset (age >20 years) hearing impairment that can be either symmetric or asymmetric and ranges from mild to moderate [ In the wide and continuous spectrum of clinical manifestations associated with In females, who predictably have less severe manifestations, the ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome [ To date, 40 families with PRS deficiency have been identified worldwide deficiency [ Charcot-Marie-Tooth neuropathy X type 5 (CMTX5) was previously referred to as Rosenberg-Chutorian syndrome [ DFNX1 nonsyndromic hearing loss and deafness was previously referred to as DFN2 (OMIM • Detailed clinical and neurophysiologic examination of males diagnosed with • Females heterozygous for a • Loss of myelinated fibers without signs of demyelination or axonal degeneration in a boy age five years with Arts syndrome from the original Dutch family reported by • Mild paranodal demyelination indicative of peripheral neuropathy in a boy age two years, who had absent lower limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy [ ## Clinical Description The phenotype of phosphoribosylpyrophosphate synthetase (PRS) deficiency is now known to be a continuum encompassing three previously clinically defined disorders – Arts syndrome, Charcot-Marie-Tooth neuropathy X type 5 (CMTX5), and X-linked nonsyndromic sensorineural hearing loss (DFNX1). Arts syndrome (characterized by intellectual disability, hypotonia, ataxia, sensorineural hearing impairment, and progressive optic atrophy and/or retinopathy), CMTX5 (characterized by peripheral neuropathy, sensorineural hearing loss, and optic neuropathy), and DFNX1 were initially thought to represent distinct phenotypes. However, following the observation in a single family of a male with features of CMTX5 and Arts syndrome and a female with prelingual DFNX1, Subsequent reports confirmed this observation and further expanded the PRS deficiency phenotype: Detailed clinical and neurophysiologic examination of males diagnosed with Females heterozygous for a Thus, the phenotypic spectrum of PRS deficiency can range from profound congenital sensorineural hearing impairment, intellectual disability, delayed motor development, and progressive optic atrophy [ To date, 40 families have been identified with PRS deficiency [ Sural nerve biopsy showed the following: Loss of myelinated fibers without signs of demyelination or axonal degeneration in a boy age five years with Arts syndrome from the original Dutch family reported by Mild paranodal demyelination indicative of peripheral neuropathy in a boy age two years, who had absent lower limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy [ Heterozygous females can show isolated and/or milder manifestations, most notably late-onset (age >20 years) hearing impairment that can be either symmetric or asymmetric and ranges from mild to moderate [ • Detailed clinical and neurophysiologic examination of males diagnosed with • Females heterozygous for a • Loss of myelinated fibers without signs of demyelination or axonal degeneration in a boy age five years with Arts syndrome from the original Dutch family reported by • Mild paranodal demyelination indicative of peripheral neuropathy in a boy age two years, who had absent lower limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy [ ## Affected Males Sural nerve biopsy showed the following: Loss of myelinated fibers without signs of demyelination or axonal degeneration in a boy age five years with Arts syndrome from the original Dutch family reported by Mild paranodal demyelination indicative of peripheral neuropathy in a boy age two years, who had absent lower limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy [ • Loss of myelinated fibers without signs of demyelination or axonal degeneration in a boy age five years with Arts syndrome from the original Dutch family reported by • Mild paranodal demyelination indicative of peripheral neuropathy in a boy age two years, who had absent lower limb deep tendon reflexes and nerve conduction studies indicative of peripheral neuropathy [ ## Heterozygous Females Heterozygous females can show isolated and/or milder manifestations, most notably late-onset (age >20 years) hearing impairment that can be either symmetric or asymmetric and ranges from mild to moderate [ ## Genotype-Phenotype Correlations In the wide and continuous spectrum of clinical manifestations associated with In females, who predictably have less severe manifestations, the ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome [ ## Prevalence To date, 40 families with PRS deficiency have been identified worldwide deficiency [ ## Nomenclature Charcot-Marie-Tooth neuropathy X type 5 (CMTX5) was previously referred to as Rosenberg-Chutorian syndrome [ DFNX1 nonsyndromic hearing loss and deafness was previously referred to as DFN2 (OMIM ## Genetically Related (Allelic) Disorders ## Differential Diagnosis • • • • ## Management No clinical practice guidelines for phosphoribosylpyrophosphate synthetase (PRS) deficiency have been published. To establish the extent of disease and needs in an individual diagnosed with PRS deficiency, the evaluations summarized in PRS Deficiency: Recommended Evaluations Following Initial Diagnosis Otolaryngology eval Audiology eval To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Strength, motor skills, & presence/absence of tendon reflexes for signs of peripheral neuropathy; Balance & coordination for evidence of 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) Community or Social work involvement for parental support. ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for PRS deficiency. PRS Deficiency: Treatment of Manifestations See Genetic Hearing Loss Overview, Cochlear implantation in 2 affected males was assoc w/improved communication skills. Children: through early intervention programs &/or school district Adults: referral to low vision clinic &/or community vision services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or OT = occupational therapy; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations listed in PRS Deficiency: Recommended Surveillance For those not known to be affected: annually or per symptoms for clinical manifestations For those known to be affected: annually or per treating neurologist OT = occupational therapy; PT = physical therapy It is appropriate to clarify the genetic status of apparently asymptomatic older and younger male and female sibs of a proband in order to identify sibs at risk for hearing loss who may benefit from appropriate early support and management. See An anecdotal study suggested that co-therapy of SAM and nicotinamide riboside may be of additional clinical benefit [ Search • Otolaryngology eval • Audiology eval • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Strength, motor skills, & presence/absence of tendon reflexes for signs of peripheral neuropathy; • Balance & coordination for evidence of 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) • Community or • Social work involvement for parental support. • See Genetic Hearing Loss Overview, • Cochlear implantation in 2 affected males was assoc w/improved communication skills. • Children: through early intervention programs &/or school district • Adults: referral to low vision clinic &/or community vision services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • For those not known to be affected: annually or per symptoms for clinical manifestations • For those known to be affected: annually or per treating neurologist ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with PRS deficiency, the evaluations summarized in PRS Deficiency: Recommended Evaluations Following Initial Diagnosis Otolaryngology eval Audiology eval To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Strength, motor skills, & presence/absence of tendon reflexes for signs of peripheral neuropathy; Balance & coordination for evidence of 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) Community or Social work involvement for parental support. ADL = activities of daily living; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Otolaryngology eval • Audiology eval • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Strength, motor skills, & presence/absence of tendon reflexes for signs of peripheral neuropathy; • Balance & coordination for evidence of 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) • Community or • Social work involvement for parental support. ## Treatment of Manifestations There is no cure for PRS deficiency. PRS Deficiency: Treatment of Manifestations See Genetic Hearing Loss Overview, Cochlear implantation in 2 affected males was assoc w/improved communication skills. Children: through early intervention programs &/or school district Adults: referral to low vision clinic &/or community vision services Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or OT = occupational therapy; PT = physical therapy The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • See Genetic Hearing Loss Overview, • Cochlear implantation in 2 affected males was assoc w/improved communication skills. • Children: through early intervention programs &/or school district • Adults: referral to low vision clinic &/or community vision services • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## 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. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations listed in PRS Deficiency: Recommended Surveillance For those not known to be affected: annually or per symptoms for clinical manifestations For those known to be affected: annually or per treating neurologist OT = occupational therapy; PT = physical therapy • For those not known to be affected: annually or per symptoms for clinical manifestations • For those known to be affected: annually or per treating neurologist ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic older and younger male and female sibs of a proband in order to identify sibs at risk for hearing loss who may benefit from appropriate early support and management. See ## Therapies Under Investigation An anecdotal study suggested that co-therapy of SAM and nicotinamide riboside may be of additional clinical benefit [ Search ## Genetic Counseling Phosphoribosylpyrophosphate synthetase (PRS) deficiency is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a The frequency of Maternal germline mosaicism has not been reported to date but remains a possibility. Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. 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 Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit a If the proband represents a simplex case and if the 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 All of their daughters, who will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant (see Clinical Description, None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygous for this X-linked disorder may develop clinical findings related to the disorder (see Clinical Description, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • The frequency of • Maternal germline mosaicism has not been reported to date but remains a possibility. • The frequency of • Maternal germline mosaicism has not been reported to date but remains a possibility. • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • The frequency of • Maternal germline mosaicism has not been reported to date but remains a possibility. • 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 • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit a • 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 heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit 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 • All of their daughters, who will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant (see Clinical Description, • None of their sons. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a ## Mode of Inheritance Phosphoribosylpyrophosphate synthetase (PRS) deficiency is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a The frequency of Maternal germline mosaicism has not been reported to date but remains a possibility. Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. 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 Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit a If the proband represents a simplex case and if the 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 All of their daughters, who will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant (see Clinical Description, 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. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote, the affected male may have a • The frequency of • Maternal germline mosaicism has not been reported to date but remains a possibility. • The frequency of • Maternal germline mosaicism has not been reported to date but remains a possibility. • Molecular genetic testing of the mother is recommended to confirm her genetic status and to allow reliable recurrence risk assessment. • The frequency of • Maternal germline mosaicism has not been reported to date but remains a possibility. • 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 • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit a • Males who inherit the pathogenic variant will be affected. • Females who inherit the pathogenic variant will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit a • 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 heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant. The ratio of X-chromosome inactivation adds an additional variable in predicting clinical outcome in females who inherit 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 • All of their daughters, who will be heterozygotes and will be asymptomatic or show manifestations of PRS deficiency that are typically isolated and/or milder than manifestations in hemizygous males with the same pathogenic variant (see Clinical Description, • None of their sons. ## Heterozygote Detection Identification of female heterozygotes requires either prior identification of the Note: Females who are heterozygous for this X-linked disorder may develop clinical findings related to the disorder (see Clinical Description, ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having a • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of having 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 testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Department of Molecular Genetics University of Antwerp Antwerp Antwerpen B-2610 Belgium • • • • • • • • • • • • • • • • • Department of Molecular Genetics • University of Antwerp • Antwerp Antwerpen B-2610 • Belgium • • • • • • • • • • ## Molecular Genetics Phosphoribosylpyrophosphate Synthetase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Phosphoribosylpyrophosphate Synthetase Deficiency ( PRS-I enzyme activity is absent in erythrocytes (because PRS-I is the only isoform present); PRS-I enzyme activity is significantly lower in fibroblasts than in controls [ • PRS-I enzyme activity is absent in erythrocytes (because PRS-I is the only isoform present); • PRS-I enzyme activity is significantly lower in fibroblasts than in controls [ ## Molecular Pathogenesis PRS-I enzyme activity is absent in erythrocytes (because PRS-I is the only isoform present); PRS-I enzyme activity is significantly lower in fibroblasts than in controls [ • PRS-I enzyme activity is absent in erythrocytes (because PRS-I is the only isoform present); • PRS-I enzyme activity is significantly lower in fibroblasts than in controls [ ## Chapter Notes Contact Dr Arjan de Brouwer or Prof John Christodoulou to inquire about review of The authors are grateful to the families of the Dutch and Australian patients for providing samples used for biochemical and molecular analyses over a number of years. The research conducted at the Murdoch Children's Research Institute (MCRI) was supported by the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to JC is generously supported by The Royal Children's Hospital Foundation. Arjan PM de Brouwer, PhD (2008-present)John Christodoulou, MBBS, PhD (2008-present)John A Duley, PhD; University of Queensland (2008-2018) 8 June 2023 (bp) Comprehensive update posted live 22 March 2018 (sw) Comprehensive update posted live 29 March 2011 (cd) Revision: edits to Differential Diagnosis 4 January 2011 (cd) Revision: changes to Therapies Under Investigation 18 November 2010 (me) Comprehensive update posted live 21 October 2008 (me) Review posted live 3 June 2008 (apmb) Original submission • 8 June 2023 (bp) Comprehensive update posted live • 22 March 2018 (sw) Comprehensive update posted live • 29 March 2011 (cd) Revision: edits to Differential Diagnosis • 4 January 2011 (cd) Revision: changes to Therapies Under Investigation • 18 November 2010 (me) Comprehensive update posted live • 21 October 2008 (me) Review posted live • 3 June 2008 (apmb) Original submission ## Author Notes Contact Dr Arjan de Brouwer or Prof John Christodoulou to inquire about review of ## Acknowledgments The authors are grateful to the families of the Dutch and Australian patients for providing samples used for biochemical and molecular analyses over a number of years. The research conducted at the Murdoch Children's Research Institute (MCRI) was supported by the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to JC is generously supported by The Royal Children's Hospital Foundation. ## Author History Arjan PM de Brouwer, PhD (2008-present)John Christodoulou, MBBS, PhD (2008-present)John A Duley, PhD; University of Queensland (2008-2018) ## Revision History 8 June 2023 (bp) Comprehensive update posted live 22 March 2018 (sw) Comprehensive update posted live 29 March 2011 (cd) Revision: edits to Differential Diagnosis 4 January 2011 (cd) Revision: changes to Therapies Under Investigation 18 November 2010 (me) Comprehensive update posted live 21 October 2008 (me) Review posted live 3 June 2008 (apmb) Original submission • 8 June 2023 (bp) Comprehensive update posted live • 22 March 2018 (sw) Comprehensive update posted live • 29 March 2011 (cd) Revision: edits to Differential Diagnosis • 4 January 2011 (cd) Revision: changes to Therapies Under Investigation • 18 November 2010 (me) Comprehensive update posted live • 21 October 2008 (me) Review posted live • 3 June 2008 (apmb) Original submission ## References ## Literature Cited	[ "B Almoguera, S He, M Corton, P Fernandez-San Jose, F Blanco-Kelly, MI López-Molina, B García-Sandoval, J Del Val, Y Guo, L Tian, X Liu, L Guan, RJ Torres, JG Puig, H Hakonarson, X Xu, B Keating, C Ayuso. 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arvd	arvd	[ "Arrhythmogenic Right Ventricular Dysplasia (ARVD)", "Desmin", "Desmocollin-2", "Desmoglein-2", "Desmoplakin", "Junction plakoglobin", "Phospholamban", "Plakophilin-2", "Transmembrane protein 43", "DES", "DSC2", "DSG2", "DSP", "JUP", "PKP2", "PLN", "TMEM43", "Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC)", "Overview" ]	Arrhythmogenic Right Ventricular Cardiomyopathy Overview	Elizabeth McNally, Heather MacLeod, Lisa Dellefave-Castillo	Summary The purpose of this overview is to: Describe the Review the Provide an Review Inform	## Clinical Characteristics of Arrhythmogenic Right Ventricular Cardiomyopathy Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary cardiomyopathy that is often diagnosed after an individual presents with arrhythmia findings. Presenting manifestations include heart palpitations, syncope, or even sudden death. ARVC typically presents in adults (mean age of first presentation in one large cohort study was 36 ± 14 years [ ARVC typically affects the right ventricular apex, the base of the right ventricle, and the right ventricle outflow tract. The arrhythmias in ARVC most frequently arise from the right ventricle and have left bundle branch block morphology. The disease is progressive and is characterized by fibrofatty replacement of the myocardium. Pathology in ARVC may also extend to involve the left ventricle, resulting in regional left ventricular dysfunction. Note: There is a movement within clinical cardiology to merge ARVC with other arrhythmogenic cardiomyopathies because the left ventricle can become involved, or even become predominantly involved, especially in individuals with The concealed phase is the earliest phase and is without electrical, structural, or histologic changes as typically seen in ARVC. If scar formation is present, it can be so minimal that it goes undetected by cardiac MRI. However, affected individuals might experience sustained ventricular arrhythmias, and there is a potential risk of sudden cardiac death. An overt electrical disorder characterized by symptomatic arrhythmias including palpitations, syncope, and presyncope attributable to ventricular ectopy or sustained or nonsustained ventricular tachycardia Right ventricular failure A biventricular pump failure (resembling dilated cardiomyopathy) [ Diagnostic criteria for ARVC, initially proposed by an international task force [ A definite diagnosis of ARVC is Two major criteria; OR One major AND two minor criteria; OR Four minor criteria A borderline diagnosis of ARVC is considered in a proband with: One major AND one minor criterion; OR Three minor criteria from different categories A possible diagnosis of ARVC is considered in a proband with: One major criterion; OR Two minor criteria from different categories By 2D echo Regional RV akinesia, dyskinesia, or aneurysm; AND ONE of the following (end-diastole): Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m Fractional area change ≤33% By MRI Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND ONE of the following: Ratio of RV end-diastolic volume to BSA ≥110 mL/m RV ejection fraction ≤40% By RV angiography. Regional RV akinesia, dyskinesia, or aneurysm By 2D echo Regional RV akinesia or dyskinesia; AND ONE of the following (end-diastole): PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m Fractional area change >33% to ≤40% By MRI Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND ONE of the following: Ratio of RV end-diastolic volume to BSA ≥100 mL/m RV ejection fraction >40% to ≤45% Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG Filtered QRS duration (fQRS) ≥114 ms Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms Root-mean-square voltage of terminal 40 ms ≤20 uV Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis >500 ventricular extrasystoles per 24 hours (Holter) ARVC confirmed in a first-degree relative who meets 2010 Task Force Criteria [ ARVC confirmed pathologically at autopsy or surgery in a first-degree relative Identification of a pathogenic variant categorized as associated or probably associated with ARVC in the proband History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets 2010 Task Force Criteria [ Premature sudden death (age <35 years) due to suspected ARVC in a first-degree relative ARVC confirmed pathologically or by 2010 Task Force Criteria in second-degree relative • The concealed phase is the earliest phase and is without electrical, structural, or histologic changes as typically seen in ARVC. If scar formation is present, it can be so minimal that it goes undetected by cardiac MRI. However, affected individuals might experience sustained ventricular arrhythmias, and there is a potential risk of sudden cardiac death. • An overt electrical disorder characterized by symptomatic arrhythmias including palpitations, syncope, and presyncope attributable to ventricular ectopy or sustained or nonsustained ventricular tachycardia • Right ventricular failure • A biventricular pump failure (resembling dilated cardiomyopathy) [ • Two major criteria; OR • One major AND two minor criteria; OR • Four minor criteria • One major AND one minor criterion; OR • Three minor criteria from different categories • One major criterion; OR • Two minor criteria from different categories • By 2D echo • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • By MRI • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • By RV angiography. Regional RV akinesia, dyskinesia, or aneurysm • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • By 2D echo • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • By MRI • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • ARVC confirmed in a first-degree relative who meets 2010 Task Force Criteria [ • ARVC confirmed pathologically at autopsy or surgery in a first-degree relative • Identification of a pathogenic variant categorized as associated or probably associated with ARVC in the proband • History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets 2010 Task Force Criteria [ • Premature sudden death (age <35 years) due to suspected ARVC in a first-degree relative • ARVC confirmed pathologically or by 2010 Task Force Criteria in second-degree relative ## Clinical Description Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a primary cardiomyopathy that is often diagnosed after an individual presents with arrhythmia findings. Presenting manifestations include heart palpitations, syncope, or even sudden death. ARVC typically presents in adults (mean age of first presentation in one large cohort study was 36 ± 14 years [ ARVC typically affects the right ventricular apex, the base of the right ventricle, and the right ventricle outflow tract. The arrhythmias in ARVC most frequently arise from the right ventricle and have left bundle branch block morphology. The disease is progressive and is characterized by fibrofatty replacement of the myocardium. Pathology in ARVC may also extend to involve the left ventricle, resulting in regional left ventricular dysfunction. Note: There is a movement within clinical cardiology to merge ARVC with other arrhythmogenic cardiomyopathies because the left ventricle can become involved, or even become predominantly involved, especially in individuals with The concealed phase is the earliest phase and is without electrical, structural, or histologic changes as typically seen in ARVC. If scar formation is present, it can be so minimal that it goes undetected by cardiac MRI. However, affected individuals might experience sustained ventricular arrhythmias, and there is a potential risk of sudden cardiac death. An overt electrical disorder characterized by symptomatic arrhythmias including palpitations, syncope, and presyncope attributable to ventricular ectopy or sustained or nonsustained ventricular tachycardia Right ventricular failure A biventricular pump failure (resembling dilated cardiomyopathy) [ • The concealed phase is the earliest phase and is without electrical, structural, or histologic changes as typically seen in ARVC. If scar formation is present, it can be so minimal that it goes undetected by cardiac MRI. However, affected individuals might experience sustained ventricular arrhythmias, and there is a potential risk of sudden cardiac death. • An overt electrical disorder characterized by symptomatic arrhythmias including palpitations, syncope, and presyncope attributable to ventricular ectopy or sustained or nonsustained ventricular tachycardia • Right ventricular failure • A biventricular pump failure (resembling dilated cardiomyopathy) [ ## Diagnosis Diagnostic criteria for ARVC, initially proposed by an international task force [ A definite diagnosis of ARVC is Two major criteria; OR One major AND two minor criteria; OR Four minor criteria A borderline diagnosis of ARVC is considered in a proband with: One major AND one minor criterion; OR Three minor criteria from different categories A possible diagnosis of ARVC is considered in a proband with: One major criterion; OR Two minor criteria from different categories By 2D echo Regional RV akinesia, dyskinesia, or aneurysm; AND ONE of the following (end-diastole): Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m Fractional area change ≤33% By MRI Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND ONE of the following: Ratio of RV end-diastolic volume to BSA ≥110 mL/m RV ejection fraction ≤40% By RV angiography. Regional RV akinesia, dyskinesia, or aneurysm By 2D echo Regional RV akinesia or dyskinesia; AND ONE of the following (end-diastole): PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m Fractional area change >33% to ≤40% By MRI Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND ONE of the following: Ratio of RV end-diastolic volume to BSA ≥100 mL/m RV ejection fraction >40% to ≤45% Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG Filtered QRS duration (fQRS) ≥114 ms Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms Root-mean-square voltage of terminal 40 ms ≤20 uV Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis >500 ventricular extrasystoles per 24 hours (Holter) ARVC confirmed in a first-degree relative who meets 2010 Task Force Criteria [ ARVC confirmed pathologically at autopsy or surgery in a first-degree relative Identification of a pathogenic variant categorized as associated or probably associated with ARVC in the proband History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets 2010 Task Force Criteria [ Premature sudden death (age <35 years) due to suspected ARVC in a first-degree relative ARVC confirmed pathologically or by 2010 Task Force Criteria in second-degree relative • Two major criteria; OR • One major AND two minor criteria; OR • Four minor criteria • One major AND one minor criterion; OR • Three minor criteria from different categories • One major criterion; OR • Two minor criteria from different categories • By 2D echo • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • By MRI • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • By RV angiography. Regional RV akinesia, dyskinesia, or aneurysm • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • By 2D echo • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • By MRI • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • ARVC confirmed in a first-degree relative who meets 2010 Task Force Criteria [ • ARVC confirmed pathologically at autopsy or surgery in a first-degree relative • Identification of a pathogenic variant categorized as associated or probably associated with ARVC in the proband • History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets 2010 Task Force Criteria [ • Premature sudden death (age <35 years) due to suspected ARVC in a first-degree relative • ARVC confirmed pathologically or by 2010 Task Force Criteria in second-degree relative ## Imaging Findings: Global and/or Regional Cardiac Dysfunction and Structural Alterations By 2D echo Regional RV akinesia, dyskinesia, or aneurysm; AND ONE of the following (end-diastole): Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m Fractional area change ≤33% By MRI Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND ONE of the following: Ratio of RV end-diastolic volume to BSA ≥110 mL/m RV ejection fraction ≤40% By RV angiography. Regional RV akinesia, dyskinesia, or aneurysm By 2D echo Regional RV akinesia or dyskinesia; AND ONE of the following (end-diastole): PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m Fractional area change >33% to ≤40% By MRI Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND ONE of the following: Ratio of RV end-diastolic volume to BSA ≥100 mL/m RV ejection fraction >40% to ≤45% • By 2D echo • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • By MRI • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • By RV angiography. Regional RV akinesia, dyskinesia, or aneurysm • Regional RV akinesia, dyskinesia, or aneurysm; AND • ONE of the following (end-diastole): • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Parasternal long axis (PLAX) RV outflow tract (RVOT) ≥32 mm; corrected for body surface area (BSA) ≥19 mm/m • Parasternal short axis (PSAX) RVOT ≥36 mm; corrected for BSA ≥21 mm/m • Fractional area change ≤33% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • Ratio of RV end-diastolic volume to BSA ≥110 mL/m • RV ejection fraction ≤40% • By 2D echo • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • By MRI • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Regional RV akinesia or dyskinesia; AND • ONE of the following (end-diastole): • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • PLAX RVOT ≥29 mm to <32 mm; corrected for BSA ≥16 to <19 mm/m • PSAX RVOT ≥32 mm to <36 mm; corrected for BSA ≥18 to <21 mm/m • Fractional area change >33% to ≤40% • Regional RV akinesia or dyskinesia or dyssynchronous RV contraction; AND • ONE of the following: • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% • Ratio of RV end-diastolic volume to BSA ≥100 mL/m • RV ejection fraction >40% to ≤45% ## Endomyocardial Biopsy or Autopsy Findings ## EKG Findings Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG Filtered QRS duration (fQRS) ≥114 ms Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms Root-mean-square voltage of terminal 40 ms ≤20 uV Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis >500 ventricular extrasystoles per 24 hours (Holter) • • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • Inverted T waves in leads V1 and V2 in individuals age >14 years (in absence of complete right bundle branch block) or in V4, V5, or V6 • Inverted T waves in leads V1, V2, V3, and V4 in individuals age >14 years in the presence of complete right bundle branch block • • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • Late potential by signal-averaged EKG in at least one of three parameters in the absence of a QRS duration of ≥110 ms on standard EKG • Filtered QRS duration (fQRS) ≥114 ms • Duration of terminal QRS <40 uV (low-amplitude signal duration) ≥38 ms • Root-mean-square voltage of terminal 40 ms ≤20 uV • Terminal activation duration of QRS >55 ms measured from the nadir of the S wave to the end of the QRS, including R', in V1, V2, or V3 in the absence of complete right bundle branch block • • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) • Nonsustained or sustained ventricular tachycardia of RV outflow configuration, left bundle branch block morphology with inferior axis (positive QRS in leads II, III, and aVF and negative in lead aVL) or of unknown axis • >500 ventricular extrasystoles per 24 hours (Holter) ## Family History and Molecular Genetic Testing ARVC confirmed in a first-degree relative who meets 2010 Task Force Criteria [ ARVC confirmed pathologically at autopsy or surgery in a first-degree relative Identification of a pathogenic variant categorized as associated or probably associated with ARVC in the proband History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets 2010 Task Force Criteria [ Premature sudden death (age <35 years) due to suspected ARVC in a first-degree relative ARVC confirmed pathologically or by 2010 Task Force Criteria in second-degree relative • ARVC confirmed in a first-degree relative who meets 2010 Task Force Criteria [ • ARVC confirmed pathologically at autopsy or surgery in a first-degree relative • Identification of a pathogenic variant categorized as associated or probably associated with ARVC in the proband • History of ARVC in a first-degree relative in whom it is not possible or practical to determine whether the family member meets 2010 Task Force Criteria [ • Premature sudden death (age <35 years) due to suspected ARVC in a first-degree relative • ARVC confirmed pathologically or by 2010 Task Force Criteria in second-degree relative ## Genetic Causes of Arrhythmogenic Right Ventricular Cardiomyopathy A pathogenic variant in one of the genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) is identified in up to 66% of probands with a clinical diagnosis of ARVC (see Genes Associated with Arrhythmogenic Right Ventricular Cardiomyopathy (ClinGen Gene Validity Classifications: Definitive and Moderate) LV>RV involvement compared to Can present as myocarditis or sarcoidosis-like phenotype ARVC can be nonsyndromic or assoc w/mild palmoplantar keratoderma & woolly hair. Founder variant in Hutterite population Heterozygous variant causes nonsyndromic ARVC. Biallelic variants cause Naxos disease (ARVC w/palmoplantar keratoderma & peculiar woolly hair). ARVC = arrhythmogenic right ventricular cardiomyopathy; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; LV = left ventricle; RV = right ventricle; VT = ventricular tachycardia Genes are organized first by strength of ClinGen classification, then frequency of causation of ARVC, and then alphabetically. See Homozygosity for See Truncating variants in See ClinGen includes See Genes of Interest in the Differential Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy (ClinGen Gene Validity Classification: Limited) See Genes are organized alphabetically. • LV>RV involvement compared to • Can present as myocarditis or sarcoidosis-like phenotype • ARVC can be nonsyndromic or assoc w/mild palmoplantar keratoderma & woolly hair. • Founder variant in Hutterite population • Heterozygous variant causes nonsyndromic ARVC. • Biallelic variants cause Naxos disease (ARVC w/palmoplantar keratoderma & peculiar woolly hair). ## Evaluation Strategy to Identify the Genetic Cause of Arrhythmogenic Right Ventricular Cardiomyopathy Molecular genetic testing is recommended in individuals who both fulfill diagnostic criteria as well as those with suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) to (1) confirm the diagnosis of ARVC, as identification of an ARVC-related pathogenic variant is a major diagnostic criteria in the 2010 Task Force Criteria [ Note: American College of Cardiology / American Heart Association / Heart Rhythm Society (AHA/ACC/HRS) guideline for management of ventricular arrhythmias and prevention of sudden cardiac death recommend genetic counseling and molecular genetic testing for individuals with clinically diagnosed or suspected ARVC as a class IIa recommendation (i.e., a moderate level of evidence supports the recommendation is reasonable, can be useful/effective/beneficial, and the benefits outweigh the risks) [ Establishing the specific genetic cause of ARVC usually involves an evaluation with a cardiologist including medical history, physical examination, cardiology assessment, family history, and molecular genetic testing. Note: Molecular genetic testing should begin with a proband with a clinical diagnosis of ARVC or suspected ARVC rather than an unaffected family member; molecular testing of an affected individual will provide the most informative results [ The molecular cause of ARVC is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the known ARVC genes (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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. In individuals with a clinical diagnosis of ARVC consider a multigene panel (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click ## Medical Evaluation ## Molecular Genetic Testing The molecular cause of ARVC is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in one of the known ARVC genes (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 Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. In individuals with a clinical diagnosis of ARVC consider a multigene panel (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click ## Management of Arrhythmogenic Right Ventricular Cardiomyopathy This section provides information regarding risk assessment for arrhythmogenic right ventricular cardiomyopathy (ARVC), surveillance for cardiac involvement, and recommendations for medical and surgical management based (when possible) on the genetic cause. To establish the extent of disease and needs of an individual diagnosed with ARVC the following evaluations are recommended if not performed at the time of diagnosis: EKG Cardiac imaging. Cardiac MRI has improved yield compared to echocardiography, because cardiac MRI is superior in its ability to image the right ventricle and its ability to discern fibrofatty infiltration. Noninvasive monitoring. Cardiac rhythm can be monitored noninvasively through patch recorders that can record heart rate/rhythm data for up to 14 days. Event monitors can gather information for 30 days. Implantable loop recorders are useful for longer-term (three to five years) monitoring. These monitors can detect irregular atrial or ventricular rhythms including nonsustained ventricular tachycardia. Signal-averaged EKGs may also be useful [ Electrophysiology study to assess the risk for ventricular arrhythmias and determine if an implantable cardioverter-defibrillator may be indicated. Cardiac catheter ablation of tissue causing abnormal rhythms can be performed during the electrophysiology study (see EKG, annually or more frequently depending on symptoms Holter monitoring, event monitoring, implantable loop recorder Exercise stress testing Cardiac MRI, with frequency depending on symptoms and findings Echocardiogram, with frequency depending on symptoms and findings and degree of left ventricular involvement (and with knowledge that echocardiogram is insufficient for evaluating the right ventricle) Medical history, with attention to symptoms of arrhythmia, presyncope, syncope, and heart failure EKG, with consideration of signal-averaged EKG Holter monitoring Cardiac MRI Echocardiogram At-risk first-degree relatives with any abnormal clinical screening tests for cardiac involvement should be considered for repeat clinical screening in one year [ Affected individuals should be monitored by a cardiologist who is knowledgeable about ARVC. Management of individuals with ARVC is complicated by its variable course and the limited specificity of clinical findings to predict arrhythmia risk. Management should be individualized and based on the specific results of detailed clinical and genetic investigation. Treatment recommendations for ARVC can be found in an international task force consensus statement [ Management is focused on prevention of syncope, cardiac arrest, and sudden death (see Beta-blockers are considered first-line therapy [ Anti-arrhythmia agents including sotalol and amiodarone may also be effective [ A decrease of ventricular tachycardia burden has been observed after successful catheter ablation [ The primary treatment for ventricular tachycardia is implantable cardioverter-defibrillator placement, either transvenous or subcutaneous. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias [ Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation is rare. Education should be provided regarding risk of sudden death to affected adults and parents/caregivers of affected children. Prospective randomized trials have not been conducted in individuals with ARVC for the prevention of arrhythmias. Management relies on personalized recommendations based on clinical assessment. Prior history of sustained ventricular tachycardia or ventricular fibrillation Elevated burden of premature ventricular contractions (more than 1,000 in 24 hours) Nonsustained ventricular tachycardia A prior history of syncope Male sex. Males are more likely to be diagnosed and are 1.6 times more likely to have ventricular arrhythmias and to receive an appropriate shock from their ICD for ventricular arrhythmias than females [ Intense exercise [ Degree of myocardial involvement, defined as right ventricular ejection fraction ≤45% or >2 areas of regional dysfunction [ The AHA/ACC/HRS and Heart Rhythm Society (HRS) guidelines, which are based on experience and previously published reports, recommend ICD placement as a class I indication (i.e., procedure/treatment Individuals with ARVC are discouraged from participating in frequent, intense physical exercise and intense competitive athletic activity because of the strain caused on the right heart [ The majority of individuals with ARVC tolerate pregnancy well with no additional complications [ • EKG • Cardiac imaging. Cardiac MRI has improved yield compared to echocardiography, because cardiac MRI is superior in its ability to image the right ventricle and its ability to discern fibrofatty infiltration. • Noninvasive monitoring. Cardiac rhythm can be monitored noninvasively through patch recorders that can record heart rate/rhythm data for up to 14 days. Event monitors can gather information for 30 days. Implantable loop recorders are useful for longer-term (three to five years) monitoring. These monitors can detect irregular atrial or ventricular rhythms including nonsustained ventricular tachycardia. • Signal-averaged EKGs may also be useful [ • Electrophysiology study to assess the risk for ventricular arrhythmias and determine if an implantable cardioverter-defibrillator may be indicated. Cardiac catheter ablation of tissue causing abnormal rhythms can be performed during the electrophysiology study (see • EKG, annually or more frequently depending on symptoms • Holter monitoring, event monitoring, implantable loop recorder • Exercise stress testing • Cardiac MRI, with frequency depending on symptoms and findings • Echocardiogram, with frequency depending on symptoms and findings and degree of left ventricular involvement (and with knowledge that echocardiogram is insufficient for evaluating the right ventricle) • Medical history, with attention to symptoms of arrhythmia, presyncope, syncope, and heart failure • EKG, with consideration of signal-averaged EKG • Holter monitoring • Cardiac MRI • Echocardiogram • Management is focused on prevention of syncope, cardiac arrest, and sudden death (see • Beta-blockers are considered first-line therapy [ • Anti-arrhythmia agents including sotalol and amiodarone may also be effective [ • A decrease of ventricular tachycardia burden has been observed after successful catheter ablation [ • The primary treatment for ventricular tachycardia is implantable cardioverter-defibrillator placement, either transvenous or subcutaneous. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias [ • Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation is rare. • Education should be provided regarding risk of sudden death to affected adults and parents/caregivers of affected children. • Prior history of sustained ventricular tachycardia or ventricular fibrillation • Elevated burden of premature ventricular contractions (more than 1,000 in 24 hours) • Nonsustained ventricular tachycardia • A prior history of syncope • Male sex. Males are more likely to be diagnosed and are 1.6 times more likely to have ventricular arrhythmias and to receive an appropriate shock from their ICD for ventricular arrhythmias than females [ • Intense exercise [ • Degree of myocardial involvement, defined as right ventricular ejection fraction ≤45% or >2 areas of regional dysfunction [ ## Risk Assessment for ARVC To establish the extent of disease and needs of an individual diagnosed with ARVC the following evaluations are recommended if not performed at the time of diagnosis: EKG Cardiac imaging. Cardiac MRI has improved yield compared to echocardiography, because cardiac MRI is superior in its ability to image the right ventricle and its ability to discern fibrofatty infiltration. Noninvasive monitoring. Cardiac rhythm can be monitored noninvasively through patch recorders that can record heart rate/rhythm data for up to 14 days. Event monitors can gather information for 30 days. Implantable loop recorders are useful for longer-term (three to five years) monitoring. These monitors can detect irregular atrial or ventricular rhythms including nonsustained ventricular tachycardia. Signal-averaged EKGs may also be useful [ Electrophysiology study to assess the risk for ventricular arrhythmias and determine if an implantable cardioverter-defibrillator may be indicated. Cardiac catheter ablation of tissue causing abnormal rhythms can be performed during the electrophysiology study (see • EKG • Cardiac imaging. Cardiac MRI has improved yield compared to echocardiography, because cardiac MRI is superior in its ability to image the right ventricle and its ability to discern fibrofatty infiltration. • Noninvasive monitoring. Cardiac rhythm can be monitored noninvasively through patch recorders that can record heart rate/rhythm data for up to 14 days. Event monitors can gather information for 30 days. Implantable loop recorders are useful for longer-term (three to five years) monitoring. These monitors can detect irregular atrial or ventricular rhythms including nonsustained ventricular tachycardia. • Signal-averaged EKGs may also be useful [ • Electrophysiology study to assess the risk for ventricular arrhythmias and determine if an implantable cardioverter-defibrillator may be indicated. Cardiac catheter ablation of tissue causing abnormal rhythms can be performed during the electrophysiology study (see ## Surveillance for Cardiac Involvement EKG, annually or more frequently depending on symptoms Holter monitoring, event monitoring, implantable loop recorder Exercise stress testing Cardiac MRI, with frequency depending on symptoms and findings Echocardiogram, with frequency depending on symptoms and findings and degree of left ventricular involvement (and with knowledge that echocardiogram is insufficient for evaluating the right ventricle) Medical history, with attention to symptoms of arrhythmia, presyncope, syncope, and heart failure EKG, with consideration of signal-averaged EKG Holter monitoring Cardiac MRI Echocardiogram At-risk first-degree relatives with any abnormal clinical screening tests for cardiac involvement should be considered for repeat clinical screening in one year [ • EKG, annually or more frequently depending on symptoms • Holter monitoring, event monitoring, implantable loop recorder • Exercise stress testing • Cardiac MRI, with frequency depending on symptoms and findings • Echocardiogram, with frequency depending on symptoms and findings and degree of left ventricular involvement (and with knowledge that echocardiogram is insufficient for evaluating the right ventricle) • Medical history, with attention to symptoms of arrhythmia, presyncope, syncope, and heart failure • EKG, with consideration of signal-averaged EKG • Holter monitoring • Cardiac MRI • Echocardiogram ## Recommendations for Medical and Surgical Management of ARVC Affected individuals should be monitored by a cardiologist who is knowledgeable about ARVC. Management of individuals with ARVC is complicated by its variable course and the limited specificity of clinical findings to predict arrhythmia risk. Management should be individualized and based on the specific results of detailed clinical and genetic investigation. Treatment recommendations for ARVC can be found in an international task force consensus statement [ Management is focused on prevention of syncope, cardiac arrest, and sudden death (see Beta-blockers are considered first-line therapy [ Anti-arrhythmia agents including sotalol and amiodarone may also be effective [ A decrease of ventricular tachycardia burden has been observed after successful catheter ablation [ The primary treatment for ventricular tachycardia is implantable cardioverter-defibrillator placement, either transvenous or subcutaneous. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias [ Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation is rare. Education should be provided regarding risk of sudden death to affected adults and parents/caregivers of affected children. • Management is focused on prevention of syncope, cardiac arrest, and sudden death (see • Beta-blockers are considered first-line therapy [ • Anti-arrhythmia agents including sotalol and amiodarone may also be effective [ • A decrease of ventricular tachycardia burden has been observed after successful catheter ablation [ • The primary treatment for ventricular tachycardia is implantable cardioverter-defibrillator placement, either transvenous or subcutaneous. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias [ • Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation is rare. • Education should be provided regarding risk of sudden death to affected adults and parents/caregivers of affected children. ## Gene-Specific Management Recommendations ## General Management Recommendations for ARVC Treatment recommendations for ARVC can be found in an international task force consensus statement [ Management is focused on prevention of syncope, cardiac arrest, and sudden death (see Beta-blockers are considered first-line therapy [ Anti-arrhythmia agents including sotalol and amiodarone may also be effective [ A decrease of ventricular tachycardia burden has been observed after successful catheter ablation [ The primary treatment for ventricular tachycardia is implantable cardioverter-defibrillator placement, either transvenous or subcutaneous. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias [ Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation is rare. Education should be provided regarding risk of sudden death to affected adults and parents/caregivers of affected children. • Management is focused on prevention of syncope, cardiac arrest, and sudden death (see • Beta-blockers are considered first-line therapy [ • Anti-arrhythmia agents including sotalol and amiodarone may also be effective [ • A decrease of ventricular tachycardia burden has been observed after successful catheter ablation [ • The primary treatment for ventricular tachycardia is implantable cardioverter-defibrillator placement, either transvenous or subcutaneous. Risk-benefit analysis for device insertion and management should be balanced against clinical risk stratification for arrhythmias [ • Heart transplantation is considered when ARVC has progressed to right or left ventricular heart failure. Severe diffuse biventricular involvement simulating dilated cardiomyopathy and requiring heart transplantation is rare. • Education should be provided regarding risk of sudden death to affected adults and parents/caregivers of affected children. ## Prevention of Primary Manifestations Prospective randomized trials have not been conducted in individuals with ARVC for the prevention of arrhythmias. Management relies on personalized recommendations based on clinical assessment. Prior history of sustained ventricular tachycardia or ventricular fibrillation Elevated burden of premature ventricular contractions (more than 1,000 in 24 hours) Nonsustained ventricular tachycardia A prior history of syncope Male sex. Males are more likely to be diagnosed and are 1.6 times more likely to have ventricular arrhythmias and to receive an appropriate shock from their ICD for ventricular arrhythmias than females [ Intense exercise [ Degree of myocardial involvement, defined as right ventricular ejection fraction ≤45% or >2 areas of regional dysfunction [ The AHA/ACC/HRS and Heart Rhythm Society (HRS) guidelines, which are based on experience and previously published reports, recommend ICD placement as a class I indication (i.e., procedure/treatment • Prior history of sustained ventricular tachycardia or ventricular fibrillation • Elevated burden of premature ventricular contractions (more than 1,000 in 24 hours) • Nonsustained ventricular tachycardia • A prior history of syncope • Male sex. Males are more likely to be diagnosed and are 1.6 times more likely to have ventricular arrhythmias and to receive an appropriate shock from their ICD for ventricular arrhythmias than females [ • Intense exercise [ • Degree of myocardial involvement, defined as right ventricular ejection fraction ≤45% or >2 areas of regional dysfunction [ ## Agents/Circumstances to Avoid Individuals with ARVC are discouraged from participating in frequent, intense physical exercise and intense competitive athletic activity because of the strain caused on the right heart [ ## Pregnancy Management The majority of individuals with ARVC tolerate pregnancy well with no additional complications [ ## Genetic Risk Assessment and Evaluation of Relatives At-Risk A basic view of arrhythmogenic right ventricular cardiomyopathy (ARVC) genetic risk assessment for at-risk family members is presented in this section; issues that may be specific to a given family or genetic cause of nonsyndromic ARVC are not comprehensively addressed. Note: If a proband has a specific syndrome associated with ARVC (e.g., Naxos syndrome or Carvajal syndrome), counseling for that condition is indicated. Genetic risk assessment in families with syndromic ARVC is not discussed further in this section. Both Autosomal recessive Autosomal recessive Approximately 2%-4% of individuals with ARVC have more than one pathogenic variant. These individuals have either biallelic pathogenic variants in one gene (compound heterozygous or homozygous pathogenic variants) or double heterozygosity* for pathogenic variants in more than one ARVC-related gene [ * The presence of pathogenic variants in two different ARVC-related genes may be referred to in cardiology literature as "digenic ARVC." In genetics literature, the term "digenic" more typically refers to expression of a phenotype that requires the presence of pathogenic variants in two different genes. While additional genetic variants may modify outcome and result in more specific disease, nonsyndromic ARVC can be caused by the presence of one pathogenic variant in one ARVC-related gene. The majority of individuals diagnosed with autosomal dominant ARVC inherited a pathogenic variant from a heterozygous parent [ If a proband has two pathogenic variants in the same ARVC-related gene, both parents may be heterozygous. If a proband has pathogenic variants in two different ARVC-related genes, both parents may be heterozygous or, less commonly, one parent may have two pathogenic variants. Rarely, a proband with autosomal dominant ARVC may have the disorder as the result of a If the status of the parents is unknown: And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. Because ARVC may be asymptomatic, both the maternal and paternal lineages should be considered as possibly contributing to familial ARVC. If the proband has a known pathogenic variant that cannot be 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 one parent of the proband is heterozygous for an ARVC-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. If one parent of the proband has biallelic ARVC-related pathogenic variants, all sibs will inherit an ARVC-related pathogenic variant. If both parents of a proband are heterozygous for an ARVC-related pathogenic variant, sibs have a 75% chance of inheriting one or two ARVC-related pathogenic variants and a 25% chance of inheriting neither pathogenic variant. Sibs who inherit an ARVC-related pathogenic variant are at increased risk for ARVC and should undergo If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for ARVC (and Each child of an individual with one ARVC-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of an individual with biallelic pathogenic variants in one ARVC-related gene will inherit one pathogenic variant. It is appropriate to clarify the status of apparently asymptomatic relatives of an individual with ARVC in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures to reduce the risk of syncope, cardiac arrest, and sudden death. Clinical evaluation, genetic counseling, and targeted genetic testing of at-risk relatives (if the proband has a known ARVC-related pathogenic variant) constitute a class I recommendation in the American College of Cardiology / American Heart Association / Heart Rhythm Society (AHA/ACC/HRS) guideline for management of individuals with ventricular arrhythmias and the prevention of sudden cardiac death [ Note: Predictive testing should be offered in the context of formal genetic counseling. In order to appropriately assess the risk status of asymptomatic relatives of an individual with ARVC, it is important to ensure that: The proband has a clinical diagnosis of ARVC meeting the 2010 Task Force Criteria [ The pathogenic variant (or pathogenic variants) identified in the proband (if applicable) is in a known ARVC-related gene and represents the full genetic etiology of ARVC in the proband. If the proband meets 2010 ARVC Task Force Criteria and is identified as having a pathogenic variant in a gene not known to be associated with ARVC, then cascade genetic testing in family members is not reliable for ARVC risk assessment because the identified pathogenic variant may not represent the underlying cause of ARVC in the proband or may only partially account for the genetic risk of ARVC in the family. Cascade genetic testing can still be offered for the pathogenic variant identified in the proband, but a complete ARVC evaluation and risk assessment should still occur for all at-risk family members regardless of the results of genetic testing for the pathogenic variant identified in the proband. Identification of those individuals with a familial ARVC-related pathogenic variant(s) who have an increased lifetime risk for ARVC and should undergo Identification of individuals without the familial ARVC-related pathogenic variant(s) to be discharged from high-risk cardiac surveillance. Individuals without the familial ARVC-related pathogenic variant(s) can be discharged from high-risk cardiac surveillance ONLY when their ARVC-affected relative has had a detailed discussion with a cardiologist with expertise in ARVC genetics and when this cardiogenetic expert has deemed that the pathogenic gene variant identified in the affected relative is fully causative of their ARVC disease. If the pathogenic gene variant does not fully explain the proband's phenotype, then family members should continue cardiac screening (see • Autosomal recessive • Autosomal recessive • The majority of individuals diagnosed with autosomal dominant ARVC inherited a pathogenic variant from a heterozygous parent [ • If a proband has two pathogenic variants in the same ARVC-related gene, both parents may be heterozygous. If a proband has pathogenic variants in two different ARVC-related genes, both parents may be heterozygous or, less commonly, one parent may have two pathogenic variants. • Rarely, a proband with autosomal dominant ARVC may have the disorder as the result of a • If the status of the parents is unknown: • And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; • And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. • Because ARVC may be asymptomatic, both the maternal and paternal lineages should be considered as possibly contributing to familial ARVC. • And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; • And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. • If the proband has a known pathogenic variant that cannot be 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. • And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; • And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. • 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 one parent of the proband is heterozygous for an ARVC-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. • If one parent of the proband has biallelic ARVC-related pathogenic variants, all sibs will inherit an ARVC-related pathogenic variant. • If both parents of a proband are heterozygous for an ARVC-related pathogenic variant, sibs have a 75% chance of inheriting one or two ARVC-related pathogenic variants and a 25% chance of inheriting neither pathogenic variant. • Sibs who inherit an ARVC-related pathogenic variant are at increased risk for ARVC and should undergo • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for ARVC (and • Each child of an individual with one ARVC-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. • Each child of an individual with biallelic pathogenic variants in one ARVC-related gene will inherit one pathogenic variant. • The proband has a clinical diagnosis of ARVC meeting the 2010 Task Force Criteria [ • The pathogenic variant (or pathogenic variants) identified in the proband (if applicable) is in a known ARVC-related gene and represents the full genetic etiology of ARVC in the proband. • Identification of those individuals with a familial ARVC-related pathogenic variant(s) who have an increased lifetime risk for ARVC and should undergo • Identification of individuals without the familial ARVC-related pathogenic variant(s) to be discharged from high-risk cardiac surveillance. Individuals without the familial ARVC-related pathogenic variant(s) can be discharged from high-risk cardiac surveillance ONLY when their ARVC-affected relative has had a detailed discussion with a cardiologist with expertise in ARVC genetics and when this cardiogenetic expert has deemed that the pathogenic gene variant identified in the affected relative is fully causative of their ARVC disease. If the pathogenic gene variant does not fully explain the proband's phenotype, then family members should continue cardiac screening (see ## Genetic Risk Assessment Both Autosomal recessive Autosomal recessive Approximately 2%-4% of individuals with ARVC have more than one pathogenic variant. These individuals have either biallelic pathogenic variants in one gene (compound heterozygous or homozygous pathogenic variants) or double heterozygosity* for pathogenic variants in more than one ARVC-related gene [ * The presence of pathogenic variants in two different ARVC-related genes may be referred to in cardiology literature as "digenic ARVC." In genetics literature, the term "digenic" more typically refers to expression of a phenotype that requires the presence of pathogenic variants in two different genes. While additional genetic variants may modify outcome and result in more specific disease, nonsyndromic ARVC can be caused by the presence of one pathogenic variant in one ARVC-related gene. • Autosomal recessive • Autosomal recessive ## Risk to Family Members (Autosomal Dominant Inheritance) The majority of individuals diagnosed with autosomal dominant ARVC inherited a pathogenic variant from a heterozygous parent [ If a proband has two pathogenic variants in the same ARVC-related gene, both parents may be heterozygous. If a proband has pathogenic variants in two different ARVC-related genes, both parents may be heterozygous or, less commonly, one parent may have two pathogenic variants. Rarely, a proband with autosomal dominant ARVC may have the disorder as the result of a If the status of the parents is unknown: And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. Because ARVC may be asymptomatic, both the maternal and paternal lineages should be considered as possibly contributing to familial ARVC. If the proband has a known pathogenic variant that cannot be 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 one parent of the proband is heterozygous for an ARVC-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. If one parent of the proband has biallelic ARVC-related pathogenic variants, all sibs will inherit an ARVC-related pathogenic variant. If both parents of a proband are heterozygous for an ARVC-related pathogenic variant, sibs have a 75% chance of inheriting one or two ARVC-related pathogenic variants and a 25% chance of inheriting neither pathogenic variant. Sibs who inherit an ARVC-related pathogenic variant are at increased risk for ARVC and should undergo If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for ARVC (and Each child of an individual with one ARVC-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. Each child of an individual with biallelic pathogenic variants in one ARVC-related gene will inherit one pathogenic variant. • The majority of individuals diagnosed with autosomal dominant ARVC inherited a pathogenic variant from a heterozygous parent [ • If a proband has two pathogenic variants in the same ARVC-related gene, both parents may be heterozygous. If a proband has pathogenic variants in two different ARVC-related genes, both parents may be heterozygous or, less commonly, one parent may have two pathogenic variants. • Rarely, a proband with autosomal dominant ARVC may have the disorder as the result of a • If the status of the parents is unknown: • And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; • And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. • Because ARVC may be asymptomatic, both the maternal and paternal lineages should be considered as possibly contributing to familial ARVC. • And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; • And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. • If the proband has a known pathogenic variant that cannot be 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. • And a molecular diagnosis has been confirmed in the proband, targeted molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, clarify their need for cardiac surveillance, and inform recurrence risk assessment; • And a molecular diagnosis has not been confirmed in the proband, recommendations for the evaluation of parents include cardiac MRI or echocardiogram, EKG, and Holter monitoring. • 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 one parent of the proband is heterozygous for an ARVC-related pathogenic variant, the risk to the sibs of inheriting the pathogenic variant is 50%. • If one parent of the proband has biallelic ARVC-related pathogenic variants, all sibs will inherit an ARVC-related pathogenic variant. • If both parents of a proband are heterozygous for an ARVC-related pathogenic variant, sibs have a 75% chance of inheriting one or two ARVC-related pathogenic variants and a 25% chance of inheriting neither pathogenic variant. • Sibs who inherit an ARVC-related pathogenic variant are at increased risk for ARVC and should undergo • If the parents are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for ARVC (and • Each child of an individual with one ARVC-related pathogenic variant has a 50% chance of inheriting the pathogenic variant. • Each child of an individual with biallelic pathogenic variants in one ARVC-related gene will inherit one pathogenic variant. ## Evaluation of Relatives at Risk It is appropriate to clarify the status of apparently asymptomatic relatives of an individual with ARVC in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures to reduce the risk of syncope, cardiac arrest, and sudden death. Clinical evaluation, genetic counseling, and targeted genetic testing of at-risk relatives (if the proband has a known ARVC-related pathogenic variant) constitute a class I recommendation in the American College of Cardiology / American Heart Association / Heart Rhythm Society (AHA/ACC/HRS) guideline for management of individuals with ventricular arrhythmias and the prevention of sudden cardiac death [ Note: Predictive testing should be offered in the context of formal genetic counseling. In order to appropriately assess the risk status of asymptomatic relatives of an individual with ARVC, it is important to ensure that: The proband has a clinical diagnosis of ARVC meeting the 2010 Task Force Criteria [ The pathogenic variant (or pathogenic variants) identified in the proband (if applicable) is in a known ARVC-related gene and represents the full genetic etiology of ARVC in the proband. If the proband meets 2010 ARVC Task Force Criteria and is identified as having a pathogenic variant in a gene not known to be associated with ARVC, then cascade genetic testing in family members is not reliable for ARVC risk assessment because the identified pathogenic variant may not represent the underlying cause of ARVC in the proband or may only partially account for the genetic risk of ARVC in the family. Cascade genetic testing can still be offered for the pathogenic variant identified in the proband, but a complete ARVC evaluation and risk assessment should still occur for all at-risk family members regardless of the results of genetic testing for the pathogenic variant identified in the proband. Identification of those individuals with a familial ARVC-related pathogenic variant(s) who have an increased lifetime risk for ARVC and should undergo Identification of individuals without the familial ARVC-related pathogenic variant(s) to be discharged from high-risk cardiac surveillance. Individuals without the familial ARVC-related pathogenic variant(s) can be discharged from high-risk cardiac surveillance ONLY when their ARVC-affected relative has had a detailed discussion with a cardiologist with expertise in ARVC genetics and when this cardiogenetic expert has deemed that the pathogenic gene variant identified in the affected relative is fully causative of their ARVC disease. If the pathogenic gene variant does not fully explain the proband's phenotype, then family members should continue cardiac screening (see • The proband has a clinical diagnosis of ARVC meeting the 2010 Task Force Criteria [ • The pathogenic variant (or pathogenic variants) identified in the proband (if applicable) is in a known ARVC-related gene and represents the full genetic etiology of ARVC in the proband. • Identification of those individuals with a familial ARVC-related pathogenic variant(s) who have an increased lifetime risk for ARVC and should undergo • Identification of individuals without the familial ARVC-related pathogenic variant(s) to be discharged from high-risk cardiac surveillance. Individuals without the familial ARVC-related pathogenic variant(s) can be discharged from high-risk cardiac surveillance ONLY when their ARVC-affected relative has had a detailed discussion with a cardiologist with expertise in ARVC genetics and when this cardiogenetic expert has deemed that the pathogenic gene variant identified in the affected relative is fully causative of their ARVC disease. If the pathogenic gene variant does not fully explain the proband's phenotype, then family members should continue cardiac screening (see ## Resources The Johns Hopkins Hospital • • • • • • The Johns Hopkins Hospital • ## Chapter Notes 11 May 2023 (sw) Comprehensive update posted live; scope changed to overview 25 May 2017 (ha) Comprehensive update posted live 9 January 2014 (me) Comprehensive update posted live 12 December 2007 (me) Comprehensive update posted live 18 April 2005 (me) Review posted live 6 July 2004 (em) Original submission • 11 May 2023 (sw) Comprehensive update posted live; scope changed to overview • 25 May 2017 (ha) Comprehensive update posted live • 9 January 2014 (me) Comprehensive update posted live • 12 December 2007 (me) Comprehensive update posted live • 18 April 2005 (me) Review posted live • 6 July 2004 (em) Original submission ## Revision History 11 May 2023 (sw) Comprehensive update posted live; scope changed to overview 25 May 2017 (ha) Comprehensive update posted live 9 January 2014 (me) Comprehensive update posted live 12 December 2007 (me) Comprehensive update posted live 18 April 2005 (me) Review posted live 6 July 2004 (em) Original submission • 11 May 2023 (sw) Comprehensive update posted live; scope changed to overview • 25 May 2017 (ha) Comprehensive update posted live • 9 January 2014 (me) Comprehensive update posted live • 12 December 2007 (me) Comprehensive update posted live • 18 April 2005 (me) Review posted live • 6 July 2004 (em) Original submission ## References Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2018;15:e73-e189. [ Corrado D, van Tintelen PJ, McKenna WJ, Hauer RNW, Anastastakis A, Asimaki A, Basso C, Bauce B, Brunckhorst C, Bucciarelli-Ducci C, Duru F, Elliott P, Hamilton RM, Haugaa KH, James CA, Judge D, Link MS, Marchlinski FE, Mazzanti A, Mestroni L, Pantazis A, Pelliccia A, Marra MP, Pilichou K, Platonov PGA, Protonotarios A, Rampazzo A, Saffitz JE, Saguner AM, Schmied C, Sharma S, Tandri H, Te Riele ASJM, Thiene G, Tsatsopoulou A, Zareba W, Zorzi A, Wichter T, Marcus FI, Calkins H; International Experts. Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis. Eur Heart J. 2020;41:1414-29. [ Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic evaluation of cardiomyopathy-a Heart Failure Society of America practice guideline. J Card Fail. 2018;24:281-302. [ Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Safitz JE, Yoeger Sanborn DM, Steinberg JS, Tandri H, Theine G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31:806-14. [ Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM 3rd, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16:e301-e372. [ Wallace R, Calkins H. Risk stratification in arrhythmogenic right ventricular cardiomyopathy. Arrhythm Electrophysiol Rev. 2021;10:26-32. [ • Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2018;15:e73-e189. [ • Corrado D, van Tintelen PJ, McKenna WJ, Hauer RNW, Anastastakis A, Asimaki A, Basso C, Bauce B, Brunckhorst C, Bucciarelli-Ducci C, Duru F, Elliott P, Hamilton RM, Haugaa KH, James CA, Judge D, Link MS, Marchlinski FE, Mazzanti A, Mestroni L, Pantazis A, Pelliccia A, Marra MP, Pilichou K, Platonov PGA, Protonotarios A, Rampazzo A, Saffitz JE, Saguner AM, Schmied C, Sharma S, Tandri H, Te Riele ASJM, Thiene G, Tsatsopoulou A, Zareba W, Zorzi A, Wichter T, Marcus FI, Calkins H; International Experts. Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis. Eur Heart J. 2020;41:1414-29. [ • Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic evaluation of cardiomyopathy-a Heart Failure Society of America practice guideline. J Card Fail. 2018;24:281-302. [ • Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Safitz JE, Yoeger Sanborn DM, Steinberg JS, Tandri H, Theine G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31:806-14. [ • Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM 3rd, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16:e301-e372. [ • Wallace R, Calkins H. Risk stratification in arrhythmogenic right ventricular cardiomyopathy. Arrhythm Electrophysiol Rev. 2021;10:26-32. [ ## Published Guidelines / Consensus Statements Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2018;15:e73-e189. [ Corrado D, van Tintelen PJ, McKenna WJ, Hauer RNW, Anastastakis A, Asimaki A, Basso C, Bauce B, Brunckhorst C, Bucciarelli-Ducci C, Duru F, Elliott P, Hamilton RM, Haugaa KH, James CA, Judge D, Link MS, Marchlinski FE, Mazzanti A, Mestroni L, Pantazis A, Pelliccia A, Marra MP, Pilichou K, Platonov PGA, Protonotarios A, Rampazzo A, Saffitz JE, Saguner AM, Schmied C, Sharma S, Tandri H, Te Riele ASJM, Thiene G, Tsatsopoulou A, Zareba W, Zorzi A, Wichter T, Marcus FI, Calkins H; International Experts. Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis. Eur Heart J. 2020;41:1414-29. [ Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic evaluation of cardiomyopathy-a Heart Failure Society of America practice guideline. J Card Fail. 2018;24:281-302. [ Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Safitz JE, Yoeger Sanborn DM, Steinberg JS, Tandri H, Theine G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31:806-14. [ Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM 3rd, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16:e301-e372. [ Wallace R, Calkins H. Risk stratification in arrhythmogenic right ventricular cardiomyopathy. Arrhythm Electrophysiol Rev. 2021;10:26-32. [ • Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, Deal BJ, Dickfeld T, Field ME, Fonarow GC, Gillis AM, Granger CB, Hammill SC, Hlatky MA, Joglar JA, Kay GN, Matlock DD, Myerburg RJ, Page RL. 2017 AHA/ACC/HRS guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Heart Rhythm. 2018;15:e73-e189. [ • Corrado D, van Tintelen PJ, McKenna WJ, Hauer RNW, Anastastakis A, Asimaki A, Basso C, Bauce B, Brunckhorst C, Bucciarelli-Ducci C, Duru F, Elliott P, Hamilton RM, Haugaa KH, James CA, Judge D, Link MS, Marchlinski FE, Mazzanti A, Mestroni L, Pantazis A, Pelliccia A, Marra MP, Pilichou K, Platonov PGA, Protonotarios A, Rampazzo A, Saffitz JE, Saguner AM, Schmied C, Sharma S, Tandri H, Te Riele ASJM, Thiene G, Tsatsopoulou A, Zareba W, Zorzi A, Wichter T, Marcus FI, Calkins H; International Experts. Arrhythmogenic right ventricular cardiomyopathy: evaluation of the current diagnostic criteria and differential diagnosis. Eur Heart J. 2020;41:1414-29. [ • Hershberger RE, Givertz MM, Ho CY, Judge DP, Kantor PF, McBride KL, Morales A, Taylor MRG, Vatta M, Ware SM. Genetic evaluation of cardiomyopathy-a Heart Failure Society of America practice guideline. J Card Fail. 2018;24:281-302. [ • Marcus FI, McKenna WJ, Sherrill D, Basso C, Bauce B, Bluemke DA, Calkins H, Corrado D, Cox MGPJ, Daubert JP, Fontaine G, Gear K, Hauer R, Nava A, Picard MH, Protonotarios N, Safitz JE, Yoeger Sanborn DM, Steinberg JS, Tandri H, Theine G, Towbin JA, Tsatsopoulou A, Wichter T, Zareba W. Diagnosis of arrhythmogenic right ventricular cardiomyopathy/dysplasia: proposed modification of the Task Force Criteria. Eur Heart J. 2010;31:806-14. [ • Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, Daubert JP, de Chillou C, DePasquale EC, Desai MY, Estes NAM 3rd, Hua W, Indik JH, Ingles J, James CA, John RM, Judge DP, Keegan R, Krahn AD, Link MS, Marcus FI, McLeod CJ, Mestroni L, Priori SG, Saffitz JE, Sanatani S, Shimizu W, van Tintelen JP, Wilde AAM, Zareba W. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16:e301-e372. [ • Wallace R, Calkins H. Risk stratification in arrhythmogenic right ventricular cardiomyopathy. Arrhythm Electrophysiol Rev. 2021;10:26-32. [ ## Literature Cited	[]	18/4/2005	11/5/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
as-def	as-def	[ "ASNS Deficiency", "ASNS Deficiency", "Asparagine synthetase [glutamine-hydrolyzing]", "ASNS", "Asparagine Synthetase Deficiency" ]	Asparagine Synthetase Deficiency	Majid Alfadhel, Ayman W El-Hattab	Summary Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low cerebrospinal fluid (CSF) asparagine level can help the clinician in differentiating this disorder from others. In most cases age of onset of apnea, excessive irritability, and seizures is soon after birth. Affected individuals typically do not acquire any developmental milestones. Spastic quadriplegia can lead to severe contractures of the limbs and neurogenic scoliosis. Feeding difficulties (gastroesophageal reflux disease, frequent vomiting, swallowing dysfunction, and gastroesophageal incoordination) are a significant problem in most affected individuals. A majority have cortical blindness. MRI findings are nonspecific but may include generalized atrophy and simplified gyral pattern. The diagnosis of ASD is established in a proband by identification of biallelic pathogenic variants in At each visit: evaluation of developmental progress and growth; assessment for progression of spasticity, contractures, and scoliosis/kyphosis. Every six months: assessment of nutritional status through serum total protein, albumin, and prealbumin levels. Annually: ophthalmologic evaluation. As needed: EEG if there are concerns for new-onset seizure activity or progression of seizures; audiologic evaluation if there are concerns for hearing loss. Asparagine synthetase 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 Asparagine synthetase deficiency (ASD) Congenital and progressive microcephaly Severe global developmental delay Hypotonia followed by spastic quadriplegia, seizures, jitteriness, and hyperekplexia Intrauterine growth restriction with subsequent feeding difficulties, failure to thrive, and short stature Cortical blindness Generalized brain atrophy (100%) Simplified gyral pattern (81%) Cerebellar vermis hypoplasia (41%) Plasma acylcarnitine profile Creatine kinase (CK) level Total homocysteine, lactic acid, and ammonia levels Urine organic acids The diagnosis of ASD 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 For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Asparagine Synthetase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis has not identified any pathogenic variants to date. • Congenital and progressive microcephaly • Severe global developmental delay • Hypotonia followed by spastic quadriplegia, seizures, jitteriness, and hyperekplexia • Intrauterine growth restriction with subsequent feeding difficulties, failure to thrive, and short stature • Cortical blindness • Generalized brain atrophy (100%) • Simplified gyral pattern (81%) • Cerebellar vermis hypoplasia (41%) • Plasma acylcarnitine profile • Creatine kinase (CK) level • Total homocysteine, lactic acid, and ammonia levels • Urine organic acids • Plasma acylcarnitine profile • Creatine kinase (CK) level • Total homocysteine, lactic acid, and ammonia levels • Urine organic acids • Plasma acylcarnitine profile • Creatine kinase (CK) level • Total homocysteine, lactic acid, and ammonia levels • Urine organic acids • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Asparagine synthetase deficiency (ASD) Congenital and progressive microcephaly Severe global developmental delay Hypotonia followed by spastic quadriplegia, seizures, jitteriness, and hyperekplexia Intrauterine growth restriction with subsequent feeding difficulties, failure to thrive, and short stature Cortical blindness Generalized brain atrophy (100%) Simplified gyral pattern (81%) Cerebellar vermis hypoplasia (41%) Plasma acylcarnitine profile Creatine kinase (CK) level Total homocysteine, lactic acid, and ammonia levels Urine organic acids • Congenital and progressive microcephaly • Severe global developmental delay • Hypotonia followed by spastic quadriplegia, seizures, jitteriness, and hyperekplexia • Intrauterine growth restriction with subsequent feeding difficulties, failure to thrive, and short stature • Cortical blindness • Generalized brain atrophy (100%) • Simplified gyral pattern (81%) • Cerebellar vermis hypoplasia (41%) • Plasma acylcarnitine profile • Creatine kinase (CK) level • Total homocysteine, lactic acid, and ammonia levels • Urine organic acids • Plasma acylcarnitine profile • Creatine kinase (CK) level • Total homocysteine, lactic acid, and ammonia levels • Urine organic acids • Plasma acylcarnitine profile • Creatine kinase (CK) level • Total homocysteine, lactic acid, and ammonia levels • Urine organic acids ## Establishing the Diagnosis The diagnosis of ASD 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 For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Asparagine Synthetase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication analysis has not identified any pathogenic variants to date. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low CSF asparagine level can help differentiate this disorder from others with similar clinical findings [ The common clinical manifestations summarized in Clinical Manifestations of 22 Individuals with Asparagine Synthetase Deficiency Congenital microcephaly, apnea, excessive irritability, and seizures Head circumference is often 2 standard deviations (SD) below the mean at birth but may decline to 9 SD below the mean by early childhood. Congenital microcephaly, ranging between 26.5 and 33.4 cm (1-4 SD below the mean) Severe global developmental delay with no acquisition of developmental milestones [ Axial hypotonia followed by spastic quadriplegia [ The type of seizure is not specific and can include the following [ Generalized tonic-clonic (64%) Myoclonic (50%) Tonic (50%) Partial complex seizure (21%) Spasms (15%) that are refractory to anti-seizure medication EEG abnormalities are nonspecific [ Multiple independent spike foci most commonly (65%) Burst suppression Hypsarrhythmia Discontinuous EEG pattern Jitteriness and hyperekplexia are present in 78% and 35% of reported individuals, respectively. Delayed myelination (68%) Small pons Thin corpus callosum (55%) Enlarged ventricular system (50%) Left transverse sinus thrombosis and cerebral dysgenesis Blake's cyst and/or arachnoid cyst Bilateral caudate atrophy Increased lactate peak on MR spectroscopy in four individuals studied [ Note: CSF asparagine level was normal in one reported individual [ Recurrent aspiration has been reported in eight individuals. Many require nasogastric tube feeding or gastrostomy [ Intrauterine growth restriction [ Sensorineural hearing loss [ Frequent apneas necessitating mechanical ventilation, reported in nine affected individuals [ Diaphragmatic eventration [ Phrenic nerve palsy [ No genotype-phenotype correlations have been reported. ASD has been reported in 22 individuals from 14 families to date. Consanguinity was reported in 50% of families. Affected individuals from Saudi Arabia, United Arab Emirates, Canada, France, Japan, and India have been reported [ • Congenital microcephaly, ranging between 26.5 and 33.4 cm (1-4 SD below the mean) • Severe global developmental delay with no acquisition of developmental milestones [ • Axial hypotonia followed by spastic quadriplegia [ • The type of seizure is not specific and can include the following [ • Generalized tonic-clonic (64%) • Myoclonic (50%) • Tonic (50%) • Partial complex seizure (21%) • Spasms (15%) that are refractory to anti-seizure medication • Generalized tonic-clonic (64%) • Myoclonic (50%) • Tonic (50%) • Partial complex seizure (21%) • Spasms (15%) that are refractory to anti-seizure medication • EEG abnormalities are nonspecific [ • Multiple independent spike foci most commonly (65%) • Burst suppression • Hypsarrhythmia • Discontinuous EEG pattern • Multiple independent spike foci most commonly (65%) • Burst suppression • Hypsarrhythmia • Discontinuous EEG pattern • Jitteriness and hyperekplexia are present in 78% and 35% of reported individuals, respectively. • Generalized tonic-clonic (64%) • Myoclonic (50%) • Tonic (50%) • Partial complex seizure (21%) • Spasms (15%) that are refractory to anti-seizure medication • Multiple independent spike foci most commonly (65%) • Burst suppression • Hypsarrhythmia • Discontinuous EEG pattern • Delayed myelination (68%) • Small pons • Thin corpus callosum (55%) • Enlarged ventricular system (50%) • Left transverse sinus thrombosis and cerebral dysgenesis • Blake's cyst and/or arachnoid cyst • Bilateral caudate atrophy • Increased lactate peak on MR spectroscopy in four individuals studied [ • Intrauterine growth restriction [ • Sensorineural hearing loss [ • Frequent apneas necessitating mechanical ventilation, reported in nine affected individuals [ • Diaphragmatic eventration [ • Phrenic nerve palsy [ ## Clinical Description Asparagine synthetase deficiency (ASD) mainly presents as a triad of congenital microcephaly, severe developmental delay, and axial hypotonia followed by spastic quadriplegia. Low CSF asparagine level can help differentiate this disorder from others with similar clinical findings [ The common clinical manifestations summarized in Clinical Manifestations of 22 Individuals with Asparagine Synthetase Deficiency Congenital microcephaly, apnea, excessive irritability, and seizures Head circumference is often 2 standard deviations (SD) below the mean at birth but may decline to 9 SD below the mean by early childhood. Congenital microcephaly, ranging between 26.5 and 33.4 cm (1-4 SD below the mean) Severe global developmental delay with no acquisition of developmental milestones [ Axial hypotonia followed by spastic quadriplegia [ The type of seizure is not specific and can include the following [ Generalized tonic-clonic (64%) Myoclonic (50%) Tonic (50%) Partial complex seizure (21%) Spasms (15%) that are refractory to anti-seizure medication EEG abnormalities are nonspecific [ Multiple independent spike foci most commonly (65%) Burst suppression Hypsarrhythmia Discontinuous EEG pattern Jitteriness and hyperekplexia are present in 78% and 35% of reported individuals, respectively. Delayed myelination (68%) Small pons Thin corpus callosum (55%) Enlarged ventricular system (50%) Left transverse sinus thrombosis and cerebral dysgenesis Blake's cyst and/or arachnoid cyst Bilateral caudate atrophy Increased lactate peak on MR spectroscopy in four individuals studied [ Note: CSF asparagine level was normal in one reported individual [ Recurrent aspiration has been reported in eight individuals. Many require nasogastric tube feeding or gastrostomy [ Intrauterine growth restriction [ Sensorineural hearing loss [ Frequent apneas necessitating mechanical ventilation, reported in nine affected individuals [ Diaphragmatic eventration [ Phrenic nerve palsy [ • Congenital microcephaly, ranging between 26.5 and 33.4 cm (1-4 SD below the mean) • Severe global developmental delay with no acquisition of developmental milestones [ • Axial hypotonia followed by spastic quadriplegia [ • The type of seizure is not specific and can include the following [ • Generalized tonic-clonic (64%) • Myoclonic (50%) • Tonic (50%) • Partial complex seizure (21%) • Spasms (15%) that are refractory to anti-seizure medication • Generalized tonic-clonic (64%) • Myoclonic (50%) • Tonic (50%) • Partial complex seizure (21%) • Spasms (15%) that are refractory to anti-seizure medication • EEG abnormalities are nonspecific [ • Multiple independent spike foci most commonly (65%) • Burst suppression • Hypsarrhythmia • Discontinuous EEG pattern • Multiple independent spike foci most commonly (65%) • Burst suppression • Hypsarrhythmia • Discontinuous EEG pattern • Jitteriness and hyperekplexia are present in 78% and 35% of reported individuals, respectively. • Generalized tonic-clonic (64%) • Myoclonic (50%) • Tonic (50%) • Partial complex seizure (21%) • Spasms (15%) that are refractory to anti-seizure medication • Multiple independent spike foci most commonly (65%) • Burst suppression • Hypsarrhythmia • Discontinuous EEG pattern • Delayed myelination (68%) • Small pons • Thin corpus callosum (55%) • Enlarged ventricular system (50%) • Left transverse sinus thrombosis and cerebral dysgenesis • Blake's cyst and/or arachnoid cyst • Bilateral caudate atrophy • Increased lactate peak on MR spectroscopy in four individuals studied [ • Intrauterine growth restriction [ • Sensorineural hearing loss [ • Frequent apneas necessitating mechanical ventilation, reported in nine affected individuals [ • Diaphragmatic eventration [ • Phrenic nerve palsy [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been reported. ## Prevalence ASD has been reported in 22 individuals from 14 families to date. Consanguinity was reported in 50% of families. Affected individuals from Saudi Arabia, United Arab Emirates, Canada, France, Japan, and India have been reported [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of ASD is wide, and the cardinal features of spastic quadriplegia, microcephaly, and low asparagine level can aid clinicians in differentiating this disorder from the other related disorders. Note: Many chromosomal disorders present with features that overlap with asparagine synthetase deficiency; therefore, a chromosomal microarray could be considered. Differential Diagnosis of Asparagine Synthetase Deficiency (ASD) Normal CSF asparagine level No spastic quadriplegia Intrauterine growth restriction Sloping forehead Short stature Normal CSF asparagine level No spastic quadriplegia Cerebellar hypoplasia Simplified gyral pattern Spastic quadriplegia Lissencephaly & generalized polymicrogyria Normal CSF asparagine level Hypotonia Global DD Spastic quadriplegia Lissencephaly Dysmorphic features Normal CSF asparagine level Prenatal & postnatal growth restriction Dysmorphic features Syndactyly of 2nd & 3rd toes Postaxial polydactyly Congenital heart defect Hypospadias in males No spastic quadriplegia Low total cholesterol w/↑ 7-dehydrocholesterol Growth restriction DD Spastic quadriplegia Distinctive facial features Hirsutism Upper-limb reduction defects ranging from subtle phalangeal abnormalities to oligodactyly Neonatal seizure Global DD Spastic quadriplegia Low CSF serine & glycine level Cataract Nystagmus Neonatal seizure Failure to thrive Hypotonia DD Spastic quadriplegia Cerebellar hypoplasia Hepatopathy Hypoglycemia Protein-losing enteropathy Eye abnormalities Immunologic findings Skin abnormalities Skeletal findings Abnormal TIF Congenital microcephaly Severe DD Hypotonia Spastic quadriplegia Thin corpus callosum Delayed myelination AD = autosomal dominant; AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; MOI = mode of inheritance; TIF = transferrin isoelectrofocusing; XL = X-linked Lissencephaly-pachygyria spectrum of cortical malformation is characterized by smooth cortex with simplified gyration appearance. "Lissencephaly" refers to a brain without sulci. Pachygyria (focal or diffuse) is a mild expression of lissencephaly in which sulci are shallow and reduced in number. • Normal CSF asparagine level • No spastic quadriplegia • Intrauterine growth restriction • Sloping forehead • Short stature • Normal CSF asparagine level • No spastic quadriplegia • Cerebellar hypoplasia • Simplified gyral pattern • Spastic quadriplegia • Lissencephaly & generalized polymicrogyria • Normal CSF asparagine level • Hypotonia • Global DD • Spastic quadriplegia • Lissencephaly • Dysmorphic features • Normal CSF asparagine level • Prenatal & postnatal growth restriction • Dysmorphic features • Syndactyly of 2nd & 3rd toes • Postaxial polydactyly • Congenital heart defect • Hypospadias in males • No spastic quadriplegia • Low total cholesterol w/↑ 7-dehydrocholesterol • Growth restriction • DD • Spastic quadriplegia • Distinctive facial features • Hirsutism • Upper-limb reduction defects ranging from subtle phalangeal abnormalities to oligodactyly • Neonatal seizure • Global DD • Spastic quadriplegia • Low CSF serine & glycine level • Cataract • Nystagmus • Neonatal seizure • Failure to thrive • Hypotonia • DD • Spastic quadriplegia • Cerebellar hypoplasia • Hepatopathy • Hypoglycemia • Protein-losing enteropathy • Eye abnormalities • Immunologic findings • Skin abnormalities • Skeletal findings • Abnormal TIF • Congenital microcephaly • Severe DD • Hypotonia • Spastic quadriplegia • Thin corpus callosum • Delayed myelination ## Management To establish the extent of disease and needs in an individual diagnosed with asparagine synthetase deficiency (ASD), the following evaluations are recommended if they have not already been completed. Recommended Evaluations Following Initial Diagnosis of Asparagine Synthetase Deficiency GERD = gastroesophageal reflux The management of ASD requires a multidisciplinary team approach; treatment is primarily supportive. Note: Asparagine supplementation has not been effective and actually exacerbated seizures in affected individuals [ Treatment of Manifestations in Individuals with Asparagine Synthetase Deficiency 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). For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, 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. 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. Regular immunization to prevent life-threatening infections is indicated. Recommended Surveillance for Individuals with Asparagine Synthetase Deficiency Serum total protein, albumin, and prealbumin levels 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. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with asparagine synthetase deficiency (ASD), the following evaluations are recommended if they have not already been completed. Recommended Evaluations Following Initial Diagnosis of Asparagine Synthetase Deficiency GERD = gastroesophageal reflux ## Treatment of Manifestations The management of ASD requires a multidisciplinary team approach; treatment is primarily supportive. Note: Asparagine supplementation has not been effective and actually exacerbated seizures in affected individuals [ Treatment of Manifestations in Individuals with Asparagine Synthetase Deficiency 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). For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, 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. 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. ## Gross 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). For muscle tone abnormalities including hypertonia, consider involving appropriate specialists to aid in management of baclofen, 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. 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. ## Prevention of Secondary Complications Regular immunization to prevent life-threatening infections is indicated. ## Surveillance Recommended Surveillance for Individuals with Asparagine Synthetase Deficiency Serum total protein, albumin, and prealbumin levels ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Asparagine synthetase 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 the parents of an affected child. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., carriers of one • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of an affected child. ## Mode of Inheritance Asparagine synthetase 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 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 the parents of an affected child. • 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 the parents of an affected child. ## 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 Asparagine Synthetase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Asparagine Synthetase Deficiency ( ## Chapter Notes 20 September 2018 (mpa) Review posted live 8 January 2018 (ma) Original submission • 20 September 2018 (mpa) Review posted live • 8 January 2018 (ma) Original submission ## Revision History 20 September 2018 (mpa) Review posted live 8 January 2018 (ma) Original submission • 20 September 2018 (mpa) Review posted live • 8 January 2018 (ma) Original submission ## References ## Literature Cited	[]	20/9/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
asah1	asah1	[ "Farber Disease", "Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME)", "Spinal Muscular Atrophy without Epilepsy", "Progressive Adult-Onset Brachydactyly Due to Osteolysis", "Acid ceramidase", "ASAH1", "ASAH1-Related Disorders" ]		David A Dyment, Steffany AL Bennett, Jeffrey A Medin, Thierry Levade	Summary The spectrum of Classic FD is characterized by onset in the first weeks of life of painful, progressive deformity of the major joints; palpable subcutaneous nodules of joints and mechanical pressure points; and a hoarse cry resulting from granulomas of the larynx and epiglottis. Life expectancy is usually less than two years. In the other less common types of FD, onset, severity, and primary manifestations vary. SMA-PME is characterized by early-childhood-onset progressive lower motor neuron disease manifest typically between ages three and seven years as proximal lower-extremity weakness, followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss. Myoclonic epilepsy typically begins in late childhood after the onset of weakness and can include jerking of the upper limbs, action myoclonus, myoclonic status, and eyelid myoclonus. Other findings include generalized tremor, and cognitive decline. The time from disease onset to death from respiratory complications is usually five to 15 years. The diagnosis of an For FD: Management may include gastrostomy tube placement, surgical removal of oral and airway granulomas, and treatment of seizures as per standard practice. Hematopoietic stem cell transplantation may be an option in affected individuals who do not have significant neurologic involvement. For SMA-PME: Management may include standard treatment for hearing loss, scoliosis, seizures, and tremor. Weakness can be mitigated with the use of orthotics, wheelchairs, or other assistive devices. For FD: At each visit assess growth with emphasis on feeding and nutritional status; airway, joint mobility, and developmental milestones. For SMA-PME: At each visit monitor growth with emphasis on feeding and nutritional status, pulmonary function, back for evidence of scoliosis, strength, seizure control, functional capacity (e.g., mobility, communication); assess hearing annually.	Farber disease Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) Spinal muscular atrophy without epilepsy Progressive adult-onset brachydactyly due to osteolysis For synonyms and outdated names see For other genetic causes of this phenotype, see • Farber disease • Spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) • Spinal muscular atrophy without epilepsy • Progressive adult-onset brachydactyly due to osteolysis ## Diagnosis The following phenotypes of the Subcutaneous nodules located at pressure points and joints Swollen, painful joints with progressive limitation of range of motion resulting in contractures Hoarse voice/cry Normal motor and intellectual milestones Childhood-onset progressive, proximal muscle weakness at a mean age of five years Epilepsy characterized by myoclonic and atonic seizures that are refractory to treatment. Other seizure types include absence seizures and the occasional generalized tonic-clonic seizure. Electromyography (EMG): evidence of chronic denervation Electroencephalography (EEG): generalized polyspike and wave discharges Muscle biopsy: evidence of a neurogenic process; absence of mitochondrial-related pathology Absence of biallelic pathogenic variants in The diagnosis of an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Farber disease is relatively specific, young children with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders with lower motor neuron weakness and/or epilepsy, 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. One proband was a compound heterozygote for an intronic pathogenic variant ( One proband was a compound heterozygote for the recurrent pathogenic variant ( • Subcutaneous nodules located at pressure points and joints • Swollen, painful joints with progressive limitation of range of motion resulting in contractures • Hoarse voice/cry • Normal motor and intellectual milestones • Childhood-onset progressive, proximal muscle weakness at a mean age of five years • Epilepsy characterized by myoclonic and atonic seizures that are refractory to treatment. Other seizure types include absence seizures and the occasional generalized tonic-clonic seizure. • Electromyography (EMG): evidence of chronic denervation • Electroencephalography (EEG): generalized polyspike and wave discharges • Muscle biopsy: evidence of a neurogenic process; absence of mitochondrial-related pathology • Absence of biallelic pathogenic variants in • For an introduction to multigene panels click ## Suggestive Findings The following phenotypes of the Subcutaneous nodules located at pressure points and joints Swollen, painful joints with progressive limitation of range of motion resulting in contractures Hoarse voice/cry Normal motor and intellectual milestones Childhood-onset progressive, proximal muscle weakness at a mean age of five years Epilepsy characterized by myoclonic and atonic seizures that are refractory to treatment. Other seizure types include absence seizures and the occasional generalized tonic-clonic seizure. Electromyography (EMG): evidence of chronic denervation Electroencephalography (EEG): generalized polyspike and wave discharges Muscle biopsy: evidence of a neurogenic process; absence of mitochondrial-related pathology Absence of biallelic pathogenic variants in • Subcutaneous nodules located at pressure points and joints • Swollen, painful joints with progressive limitation of range of motion resulting in contractures • Hoarse voice/cry • Normal motor and intellectual milestones • Childhood-onset progressive, proximal muscle weakness at a mean age of five years • Epilepsy characterized by myoclonic and atonic seizures that are refractory to treatment. Other seizure types include absence seizures and the occasional generalized tonic-clonic seizure. • Electromyography (EMG): evidence of chronic denervation • Electroencephalography (EEG): generalized polyspike and wave discharges • Muscle biopsy: evidence of a neurogenic process; absence of mitochondrial-related pathology • Absence of biallelic pathogenic variants in ## Establishing the Diagnosis The diagnosis of an Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [ Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Farber disease is relatively specific, young children with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of an For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders with lower motor neuron weakness and/or epilepsy, 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. One proband was a compound heterozygote for an intronic pathogenic variant ( One proband was a compound heterozygote for the recurrent pathogenic variant ( • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of an 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 lower motor neuron weakness and/or epilepsy, 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. One proband was a compound heterozygote for an intronic pathogenic variant ( One proband was a compound heterozygote for the recurrent pathogenic variant ( ## Clinical Characteristics Furthermore, although to date SMA-PME and FD have been considered to be two distinct phenotypes with differences in age of onset and primary involvement of different organ systems, a girl with features of both phenotypes illustrates the phenotypic continuum of Farber disease in its classic form is an early-onset, progressive, and fatal disease. With better understanding of the natural history of FD over time, investigators have suggested categorization into several types based on age of onset, severity, and primary manifestations [ Neurologic involvement, reported in a significant proportion of children, can be difficult to assess given the extent of contractures and joint deformity. Many children with type 1 FD have a lower motor neuron disease that manifests as hypotonia and muscle atrophy; EMG studies show chronic denervation [ Other features can include a cherry red spot of the macula [ Infiltrative pulmonary disease causes respiratory insufficiency that typically results in death before age two years [ Life expectancy is to mid-childhood. Life expectancy is into the teen years [ Death occurs within the first days to weeks of life. Subcutaneous nodules can be present, but are usually mild. Lung infiltration and hepatosplenomegaly do not occur. SMA-PME is characterized by early-childhood onset of progressive proximal weakness followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss [ The lower motor neuron disease also involves the muscles of respiration; thus, recurrent aspiration pneumonias are common (6/16). Myoclonic seizures, which begin as jerking of the upper limbs, are more proximal than distal. Action myoclonus, myoclonic status, and eyelid myoclonus have also been reported [ Atonic seizures of the head and/or torso are also an early presenting seizure type. Absence seizures are observed in more than half of affected individuals [ Although reported, generalized tonic-clonic seizures are less common than the other types. Seizures vary in frequency from a few per day initially to a few per minute as the disease evolves. Over time, seizures become refractory to treatment. Brain MRI is normal. A decline in cognitive ability has been described in children in the last weeks of disease. In one child progressive cognitive decline was the first manifestation [ Two sibs in one family have been reported with childhood-onset A progressive adult-onset brachydactyly due to osteolysis has been reported in a single family with three affected family members who had progressive shortening of the fingers and toes due to severe osteolysis. Both reduced acid ceramidase activity and biallelic No obvious genotype-phenotype correlations have been observed in While recurrent pathogenic variants have been observed in the FD phenotype (e.g., There is a correlation in FD between age of death, in situ acid ceramidase activity, and the amount of ceramide accumulation [ Farber disease may also be referred to as "acid ceramidase deficiency," "Farber lipogranulomatosis," or "disseminated lipogranulomatosis." Spinal muscular atrophy with progressive myoclonic epilepsy may also be referred to as "myoclonus with progressive distal muscular atrophy." No known specific prevalence estimates exist for ## Clinical Description Furthermore, although to date SMA-PME and FD have been considered to be two distinct phenotypes with differences in age of onset and primary involvement of different organ systems, a girl with features of both phenotypes illustrates the phenotypic continuum of Farber disease in its classic form is an early-onset, progressive, and fatal disease. With better understanding of the natural history of FD over time, investigators have suggested categorization into several types based on age of onset, severity, and primary manifestations [ Neurologic involvement, reported in a significant proportion of children, can be difficult to assess given the extent of contractures and joint deformity. Many children with type 1 FD have a lower motor neuron disease that manifests as hypotonia and muscle atrophy; EMG studies show chronic denervation [ Other features can include a cherry red spot of the macula [ Infiltrative pulmonary disease causes respiratory insufficiency that typically results in death before age two years [ Life expectancy is to mid-childhood. Life expectancy is into the teen years [ Death occurs within the first days to weeks of life. Subcutaneous nodules can be present, but are usually mild. Lung infiltration and hepatosplenomegaly do not occur. SMA-PME is characterized by early-childhood onset of progressive proximal weakness followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss [ The lower motor neuron disease also involves the muscles of respiration; thus, recurrent aspiration pneumonias are common (6/16). Myoclonic seizures, which begin as jerking of the upper limbs, are more proximal than distal. Action myoclonus, myoclonic status, and eyelid myoclonus have also been reported [ Atonic seizures of the head and/or torso are also an early presenting seizure type. Absence seizures are observed in more than half of affected individuals [ Although reported, generalized tonic-clonic seizures are less common than the other types. Seizures vary in frequency from a few per day initially to a few per minute as the disease evolves. Over time, seizures become refractory to treatment. Brain MRI is normal. A decline in cognitive ability has been described in children in the last weeks of disease. In one child progressive cognitive decline was the first manifestation [ Two sibs in one family have been reported with childhood-onset A progressive adult-onset brachydactyly due to osteolysis has been reported in a single family with three affected family members who had progressive shortening of the fingers and toes due to severe osteolysis. Both reduced acid ceramidase activity and biallelic ## Farber Disease (FD) Farber disease in its classic form is an early-onset, progressive, and fatal disease. With better understanding of the natural history of FD over time, investigators have suggested categorization into several types based on age of onset, severity, and primary manifestations [ Neurologic involvement, reported in a significant proportion of children, can be difficult to assess given the extent of contractures and joint deformity. Many children with type 1 FD have a lower motor neuron disease that manifests as hypotonia and muscle atrophy; EMG studies show chronic denervation [ Other features can include a cherry red spot of the macula [ Infiltrative pulmonary disease causes respiratory insufficiency that typically results in death before age two years [ Life expectancy is to mid-childhood. Life expectancy is into the teen years [ Death occurs within the first days to weeks of life. Subcutaneous nodules can be present, but are usually mild. Lung infiltration and hepatosplenomegaly do not occur. ## Spinal Muscular Atrophy with Progressive Myoclonic Epilepsy (SMA-PME) SMA-PME is characterized by early-childhood onset of progressive proximal weakness followed by progressive myoclonic and atonic seizures, tremulousness/tremor, and sensorineural hearing loss [ The lower motor neuron disease also involves the muscles of respiration; thus, recurrent aspiration pneumonias are common (6/16). Myoclonic seizures, which begin as jerking of the upper limbs, are more proximal than distal. Action myoclonus, myoclonic status, and eyelid myoclonus have also been reported [ Atonic seizures of the head and/or torso are also an early presenting seizure type. Absence seizures are observed in more than half of affected individuals [ Although reported, generalized tonic-clonic seizures are less common than the other types. Seizures vary in frequency from a few per day initially to a few per minute as the disease evolves. Over time, seizures become refractory to treatment. Brain MRI is normal. A decline in cognitive ability has been described in children in the last weeks of disease. In one child progressive cognitive decline was the first manifestation [ Two sibs in one family have been reported with childhood-onset ## Progressive Adult-Onset Brachydactyly Due to Osteolysis A progressive adult-onset brachydactyly due to osteolysis has been reported in a single family with three affected family members who had progressive shortening of the fingers and toes due to severe osteolysis. Both reduced acid ceramidase activity and biallelic ## Genotype-Phenotype Correlations No obvious genotype-phenotype correlations have been observed in While recurrent pathogenic variants have been observed in the FD phenotype (e.g., There is a correlation in FD between age of death, in situ acid ceramidase activity, and the amount of ceramide accumulation [ ## Nomenclature Farber disease may also be referred to as "acid ceramidase deficiency," "Farber lipogranulomatosis," or "disseminated lipogranulomatosis." Spinal muscular atrophy with progressive myoclonic epilepsy may also be referred to as "myoclonus with progressive distal muscular atrophy." ## Prevalence No known specific prevalence estimates exist for ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Inherited Disorders to Consider in the Differential Diagnosis of AR = autosomal recessive; MERRF = ## Management To establish the extent of disease and needs in an individual diagnosed with an Recommended Evaluations Following Initial Diagnosis of an ADL = activities of daily living Recommended Evaluations Following Initial Diagnosis of an ADL = activities of daily living Treatment for those with FD and SMA-PME is symptomatic and multidisciplinary. There is no curative treatment; measures that can improve the individual's quality of life are summarized in Treatment of Manifestations in Individuals with ASM = anti-seizure medication Treatment of Manifestations in Individuals with Noninvasive ventilatory support (CPAP/BiPAP); Tracheostomy if ventilator dependent. OT = occupational therapist; PT = physical therapist Note: The following information represents typical management recommendations for individuals with adaptive disabilities in the United States; standard recommendations may vary from country to country. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. 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 guidelines have been published for the surveillance of Recommended Surveillance for Individuals with Surveillance relevant to the milder forms of Farber disease (i.e., type 1 FD and type 2 FD) Recommended Surveillance for Individuals with See Acid ceramidase cDNA introduced into mice in a viral vector has been shown to be expressed over an extended period of time [ Acid ceramidase introduced safely into in non-human, myelo-ablated primates using a lentiviral vector was successfully expressed in hematopoietic cells [ Human recombinant acid ceramidase reduced ceramide levels in the fibroblasts of an individual with Farber disease [ Recombinant acid ceramidase treatment of the mouse model resulted in no further accumulation of ceramide and improved survival [ Search • Noninvasive ventilatory support (CPAP/BiPAP); • Tracheostomy if ventilator dependent. • 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. • Human recombinant acid ceramidase reduced ceramide levels in the fibroblasts of an individual with Farber disease [ • Recombinant acid ceramidase treatment of the mouse model resulted in no further accumulation of ceramide and improved survival [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with an Recommended Evaluations Following Initial Diagnosis of an ADL = activities of daily living Recommended Evaluations Following Initial Diagnosis of an ADL = activities of daily living ## Treatment of Manifestations Treatment for those with FD and SMA-PME is symptomatic and multidisciplinary. There is no curative treatment; measures that can improve the individual's quality of life are summarized in Treatment of Manifestations in Individuals with ASM = anti-seizure medication Treatment of Manifestations in Individuals with Noninvasive ventilatory support (CPAP/BiPAP); Tracheostomy if ventilator dependent. OT = occupational therapist; PT = physical therapist Note: The following information represents typical management recommendations for individuals with adaptive disabilities in the United States; standard recommendations may vary from country to country. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. 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. • Noninvasive ventilatory support (CPAP/BiPAP); • Tracheostomy if ventilator dependent. • 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. ## Adaptive Disabilities Note: The following information represents typical management recommendations for individuals with adaptive disabilities in the United States; standard recommendations may vary from country to country. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies and to support parents in maximizing quality of life. 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 ## Surveillance No guidelines have been published for the surveillance of Recommended Surveillance for Individuals with Surveillance relevant to the milder forms of Farber disease (i.e., type 1 FD and type 2 FD) Recommended Surveillance for Individuals with ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Acid ceramidase cDNA introduced into mice in a viral vector has been shown to be expressed over an extended period of time [ Acid ceramidase introduced safely into in non-human, myelo-ablated primates using a lentiviral vector was successfully expressed in hematopoietic cells [ Human recombinant acid ceramidase reduced ceramide levels in the fibroblasts of an individual with Farber disease [ Recombinant acid ceramidase treatment of the mouse model resulted in no further accumulation of ceramide and improved survival [ Search • Human recombinant acid ceramidase reduced ceramide levels in the fibroblasts of an individual with Farber disease [ • Recombinant acid ceramidase treatment of the mouse model resulted in no further accumulation of ceramide and improved survival [ ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., carriers of one Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Sibs with the same two pathogenic variants would be expected to have the same (or very similar) phenotype. Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are 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. Sibs with the same two pathogenic variants would be expected to have the same (or very similar) phenotype. • 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 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. Sibs with the same two pathogenic variants would be expected to have the same (or very similar) phenotype. 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. Sibs with the same two pathogenic variants would be expected to have the same (or very similar) phenotype. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom • • • • • • • • United Kingdom • • • ## Molecular Genetics ASAH1-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ASAH1-Related Disorders ( Two reported gross deletions include: A 55-kb deletion including all of A 9,471-bp deletion including exons 3-5 (c.126-3941_382+1358del) [ Cellular ceramide levels, which are increased from two- to fivefold for Variants listed in the table have been provided by the authors. Acid ceramidase catalyzes the breakdown of ceramide into sphingosine and fatty acid within the acidic lysosome; it can also perform the reverse reaction and synthesize ceramide at neutral pH. The substrate, ceramide, is an important sphingolipid with a role in signal transmission and cell recognition [ • A 55-kb deletion including all of • A 9,471-bp deletion including exons 3-5 (c.126-3941_382+1358del) [ ## Chapter Notes Website: Website: Website: Website: The authors would like to acknowledge Dr Ed Schuchman for helpful discussion and advice. 29 March 2018 (bp) Review posted live 26 June 2017 (dad) Original submission • 29 March 2018 (bp) Review posted live • 26 June 2017 (dad) Original submission ## Author Notes Website: Website: Website: Website: ## Acknowledgments The authors would like to acknowledge Dr Ed Schuchman for helpful discussion and advice. ## Revision History 29 March 2018 (bp) Review posted live 26 June 2017 (dad) Original submission • 29 March 2018 (bp) Review posted live • 26 June 2017 (dad) Original submission ## References ## Literature Cited	[ "SK Abul-Haj, DG Martz, WF Douglas, LJ Geppert. Farber's disease. 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aspm-pm	aspm-pm	[ "ASPM Microcephalia Vera", "Microcephaly Primary Hereditary 5 (MCPH5)", "ASPM Microcephalia Vera", "Microcephaly Primary Hereditary (MCPH 5)", "Abnormal spindle-like microcephaly-associated protein", "ASPM", "ASPM Primary Microcephaly" ]		Alain Verloes, Séverine Drunat, Sandrine Passemard	Summary The diagnosis of	## Diagnosis Congenital microcephaly (usually identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth, and >3.5 SD below the mean before age one year Mild intrauterine growth restriction with postnatal catch up (Growth restriction does not persist after age two years.) No other congenital abnormalities Normal or subnormal motor development Usually mild intellectual disability (ID) with preserved memory but variable (range: borderline normal intellectual functioning to severe ID) Seizures (rare) Nonspecific facial features (i.e., narrow sloping forehead) Reduced brain volume that affects supratentorial structures, and, to a lesser extent, the cerebellum [ Commonly simplified gyral pattern with reduced gyrification index and surface of the cerebral cortex [ Mild lateral ventricle enlargement Corpus callosum dysplasia/hypoplasia [ Cortical dysplasia (rare), which can be bilateral polymicrogyria [ 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 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 Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. • Congenital microcephaly (usually identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth, and >3.5 SD below the mean before age one year • Mild intrauterine growth restriction with postnatal catch up (Growth restriction does not persist after age two years.) • No other congenital abnormalities • Normal or subnormal motor development • Usually mild intellectual disability (ID) with preserved memory but variable (range: borderline normal intellectual functioning to severe ID) • Seizures (rare) • Nonspecific facial features (i.e., narrow sloping forehead) • Reduced brain volume that affects supratentorial structures, and, to a lesser extent, the cerebellum [ • Commonly simplified gyral pattern with reduced gyrification index and surface of the cerebral cortex [ • Mild lateral ventricle enlargement • Corpus callosum dysplasia/hypoplasia [ • Cortical dysplasia (rare), which can be bilateral polymicrogyria [ ## Suggestive Findings Congenital microcephaly (usually identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth, and >3.5 SD below the mean before age one year Mild intrauterine growth restriction with postnatal catch up (Growth restriction does not persist after age two years.) No other congenital abnormalities Normal or subnormal motor development Usually mild intellectual disability (ID) with preserved memory but variable (range: borderline normal intellectual functioning to severe ID) Seizures (rare) Nonspecific facial features (i.e., narrow sloping forehead) Reduced brain volume that affects supratentorial structures, and, to a lesser extent, the cerebellum [ Commonly simplified gyral pattern with reduced gyrification index and surface of the cerebral cortex [ Mild lateral ventricle enlargement Corpus callosum dysplasia/hypoplasia [ Cortical dysplasia (rare), which can be bilateral polymicrogyria [ • Congenital microcephaly (usually identified before birth by ultrasound examination) with an occipitofrontal circumference ≥2 standard deviations (SD) below the mean at birth, and >3.5 SD below the mean before age one year • Mild intrauterine growth restriction with postnatal catch up (Growth restriction does not persist after age two years.) • No other congenital abnormalities • Normal or subnormal motor development • Usually mild intellectual disability (ID) with preserved memory but variable (range: borderline normal intellectual functioning to severe ID) • Seizures (rare) • Nonspecific facial features (i.e., narrow sloping forehead) • Reduced brain volume that affects supratentorial structures, and, to a lesser extent, the cerebellum [ • Commonly simplified gyral pattern with reduced gyrification index and surface of the cerebral cortex [ • Mild lateral ventricle enlargement • Corpus callosum dysplasia/hypoplasia [ • Cortical dysplasia (rare), which can be bilateral polymicrogyria [ ## 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 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 Data derived from the subscription-based professional view of Human Gene Mutation Database [ Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## 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 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics Individuals with Before age ten to 12 years, children are easily frustrated with learning activities and appear inattentive to others or to classroom activities. Inattentiveness (inability to listen to or carry out instructions), hyperkinesia (e.g., excessive movement, inability to sit still), and impulsiveness (no sense of danger) tend to appear at an early age and become more noticeable when children start school. Such behaviors are often considered more deleterious to functioning in a classroom than speech delay. After age 12 years, hyperactivity and impulsiveness disappear. Teenagers are calmer and more attentive. They can appear introverted. They become cheerful, affable, and cooperative [ Autistic features have not been described in EEG may be normal or show focal spikes. Findings that are rare, without a recurrent pattern, and are likely coincidental include: scoliosis (2 families [ No genotype-phenotype correlations have been identified. Age of onset is used to distinguish primary from secondary microcephaly. Primary microcephaly (PM) is congenital (present at birth) while secondary microcephaly refers to a normal OFC at birth followed by postnatal microcephaly. Microcephalia vera is a general term used to describe congenital microcephaly associated with neurologic features. A review of the literature in 2019 identified 685 individuals with ## Clinical Description Individuals with Before age ten to 12 years, children are easily frustrated with learning activities and appear inattentive to others or to classroom activities. Inattentiveness (inability to listen to or carry out instructions), hyperkinesia (e.g., excessive movement, inability to sit still), and impulsiveness (no sense of danger) tend to appear at an early age and become more noticeable when children start school. Such behaviors are often considered more deleterious to functioning in a classroom than speech delay. After age 12 years, hyperactivity and impulsiveness disappear. Teenagers are calmer and more attentive. They can appear introverted. They become cheerful, affable, and cooperative [ Autistic features have not been described in EEG may be normal or show focal spikes. Findings that are rare, without a recurrent pattern, and are likely coincidental include: scoliosis (2 families [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Nomenclature Age of onset is used to distinguish primary from secondary microcephaly. Primary microcephaly (PM) is congenital (present at birth) while secondary microcephaly refers to a normal OFC at birth followed by postnatal microcephaly. Microcephalia vera is a general term used to describe congenital microcephaly associated with neurologic features. ## Prevalence A review of the literature in 2019 identified 685 individuals with ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Monogenic disorders in the differential diagnosis of The three broad phenotypic categories of monogenic primary microcephaly include the following: Isolated PM in which the primary microcephaly is not associated with extracerebral malformations (e.g., PM with short stature (i.e., Seckel syndrome ); Syndromic PM, a heterogeneous group in which PM is associated with extracerebral anomalies and growth impairment (e.g., MCPH and Seckel syndrome may be further subdivided by the presence of cortical malformations and/or chorioretinopathy. Genes associated with the three broad phenotypic categories of PM (excluding those with a true clinically recognizable "syndromic gestalt" such as Although the three broad phenotypic categories have been valuable for clinical management and for differential diagnosis, this simple classification does not reflect underlying pathophysiologic mechanisms. Monogenic Disorders with Congenital Microcephaly and Intellectual Disability to Consider in the Differential Diagnosis of (AD) Short stature Inconstant anomalies of forearm Mammary hypoplasia in females Bilateral microtia & aplasia or hypoplasia of the patellae are characteristic but inconstant. ID uncommon Brain dysplasia of variable severity Fusion between caudate & putamen nuclei w/indistinct anterior arm of the internal capsule Neonatal seizures IUGR Severe short stature (>3 SD below the mean) Microcephaly may be disproportionate (in SD) compared to height. Beaked nose Sloping forehead IUGR w/subsequent very short stature Mild skeletal dysplasia Risk of brain hemorrhages IUGR w/subsequent short stature Brain malformations Ocular & auditory sensory deficit Encompass a spectrum of 3 phenotypes: primary MOPD type I, Roifman syndrome, & Lowry Wood syndrome Chorioretinopathy (inconstant) Chorioretinopathy & lymphedema (inconstant) ID uncommon Low CSF asparagine level Progressive encephalopathy w/cortical atrophy & seizures Low CSF serine level Neonatal seizures Distinctive facies: bitemporal narrowing, deep-set eyes, large simple ears, pointed nasal tip AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; IUGR = intrauterine growth restriction; MCPH = primary hereditary microcephaly; MOI = mode of inheritance; SD = standard deviation(s) Disorders are associated with intellectual disability unless otherwise noted. MCPH is inherited in an autosomal recessive manner with the exception of Meier-Gorlin syndrome is inherited in an autosomal recessive manner with the exception of Cortical dysplasia, complex, with other brain malformations (CDCBM) is inherited in an autosomal dominant manner with the exception of • Isolated PM in which the primary microcephaly is not associated with extracerebral malformations (e.g., • PM with short stature (i.e., Seckel syndrome *); • Syndromic PM, a heterogeneous group in which PM is associated with extracerebral anomalies and growth impairment (e.g., • Short stature • Inconstant anomalies of forearm • Mammary hypoplasia in females • Bilateral microtia & aplasia or hypoplasia of the patellae are characteristic but inconstant. • ID uncommon • Brain dysplasia of variable severity • Fusion between caudate & putamen nuclei w/indistinct anterior arm of the internal capsule • Neonatal seizures • IUGR • Severe short stature (>3 SD below the mean) • Microcephaly may be disproportionate (in SD) compared to height. • Beaked nose • Sloping forehead • IUGR w/subsequent very short stature • Mild skeletal dysplasia • Risk of brain hemorrhages • IUGR w/subsequent short stature • Brain malformations • Ocular & auditory sensory deficit • Encompass a spectrum of 3 phenotypes: primary MOPD type I, Roifman syndrome, & Lowry Wood syndrome • Chorioretinopathy (inconstant) • Chorioretinopathy & lymphedema (inconstant) • ID uncommon • Low CSF asparagine level • Progressive encephalopathy w/cortical atrophy & seizures • Low CSF serine level • Neonatal seizures • Distinctive facies: bitemporal narrowing, deep-set eyes, large simple ears, pointed nasal tip ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Consider an EEG. Review brain MRI for evidence of polymicrogyria, cortical dysplasia. To incl motor, adaptive, cognitive & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or online Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; FTT=failure to thrive; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy Treatment of Manifestations in Individuals with Usually responsive to mono or bi-therapy Education of parents/caregivers ADHD = attention-deficit/hyperactivity disorder; 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. 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. Consider evaluation for alternative means of communication (e.g., 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 (weight, height, OFC) Eval of nutritional status Monitor those w/seizures as clinically indicated. Assess for new manifestations incl new-onset seizures, spasticity, contractures (rare). OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy To be performed at each visit Use of methylphenidate should be limited, as it exacerbates hyperactivity [Author, personal data]. See Search • Consider an EEG. • Review brain MRI for evidence of polymicrogyria, cortical dysplasia. • To incl motor, adaptive, cognitive & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or online • Social work involvement for parental support. • Usually responsive to mono or bi-therapy • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. • Measurement of growth parameters (weight, height, OFC) • Eval of nutritional status • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl new-onset seizures, spasticity, contractures (rare). ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with Consider an EEG. Review brain MRI for evidence of polymicrogyria, cortical dysplasia. To incl motor, adaptive, cognitive & speech-language eval Eval for early intervention / special education Gross motor & fine motor skills Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) Community or online Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; FTT=failure to thrive; OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy • Consider an EEG. • Review brain MRI for evidence of polymicrogyria, cortical dysplasia. • To incl motor, adaptive, cognitive & speech-language eval • Eval for early intervention / special education • Gross motor & fine motor skills • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or online • Social work involvement for parental support. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Usually responsive to mono or bi-therapy Education of parents/caregivers ADHD = attention-deficit/hyperactivity disorder; 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. 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. Consider evaluation for alternative means of communication (e.g., 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 responsive to mono or bi-therapy • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. ## 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. ## Communication Issues Consider evaluation for alternative means of communication (e.g., ## Motor Dysfunction ## Social/Behavioral Concerns 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 (weight, height, OFC) Eval of nutritional status Monitor those w/seizures as clinically indicated. Assess for new manifestations incl new-onset seizures, spasticity, contractures (rare). OFC = occipitofrontal circumference; OT = occupational therapy; PT = physical therapy To be performed at each visit • Measurement of growth parameters (weight, height, OFC) • Eval of nutritional status • Monitor those w/seizures as clinically indicated. • Assess for new manifestations incl new-onset seizures, spasticity, contractures (rare). ## Agents/Circumstances to Avoid Use of methylphenidate should be limited, as it exacerbates hyperactivity [Author, personal data]. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an Heterozygotes (carriers) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with If both parents are known to be heterozygous for an Heterozygotes (carriers) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with 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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • Heterozygotes (carriers) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with • If both parents are known to be heterozygous for an • Heterozygotes (carriers) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance 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) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with If both parents are known to be heterozygous for an Heterozygotes (carriers) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with • 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) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with • If both parents are known to be heterozygous for an • Heterozygotes (carriers) may have mild microcephaly (2-3 SD below the mean) but do not have other clinical findings associated with ## 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 affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics ASPM Primary Microcephaly: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ASPM Primary Microcephaly ( The ASPM localizes to the centrosome in interphase, the spindle pole during metaphase, and the midbody during cytokinesis [ Recently, it has been shown that ASPM plays a role in centriole biogenesis and duplication during interphase, maintaining the number of centrioles and centrosomes over the course of several rapid cell cycles in neural progenitors. Notable Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The ASPM localizes to the centrosome in interphase, the spindle pole during metaphase, and the midbody during cytokinesis [ Recently, it has been shown that ASPM plays a role in centriole biogenesis and duplication during interphase, maintaining the number of centrioles and centrosomes over the course of several rapid cell cycles in neural progenitors. Notable Variants listed in the table have been provided by the authors. ## Chapter Notes 2 April 2020 (bp) Review posted live 13 May 2019 (av) Original submission • 2 April 2020 (bp) Review posted live • 13 May 2019 (av) Original submission ## Revision History 2 April 2020 (bp) Review posted live 13 May 2019 (av) Original submission • 2 April 2020 (bp) Review posted live • 13 May 2019 (av) Original submission ## References ## Literature Cited	[]	2/4/2020			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
asxl3	asxl3	[ "Bainbridge-Ropers Syndrome (BRPS)", "Bainbridge-Ropers Syndrome (BRPS)", "Putative Polycomb group protein ASXL3", "ASXL3", "ASXL3-Related Disorder" ]		Meena Balasubramanian, Schaida Schirwani	Summary The diagnosis of	## Diagnosis Formal clinical diagnostic criteria for Developmental delay (DD) or intellectual disability, typically in the moderate to severe range; AND Any of the following features presenting in infancy or childhood: Speech and language delay and/or absent speech Autism spectrum disorder or autistic traits Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth Feeding difficulties Hypotonia Poor postnatal growth Epilepsy including generalized tonic-clonic seizures and absence seizures Vision impairment including strabismus Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures The diagnosis of (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 From Most individuals so far reported with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. At least two individuals in a cohort with typical Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • Developmental delay (DD) or intellectual disability, typically in the moderate to severe range; AND • Any of the following features presenting in infancy or childhood: • Speech and language delay and/or absent speech • Autism spectrum disorder or autistic traits • Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth • Feeding difficulties • Hypotonia • Poor postnatal growth • Epilepsy including generalized tonic-clonic seizures and absence seizures • Vision impairment including strabismus • Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures • Speech and language delay and/or absent speech • Autism spectrum disorder or autistic traits • Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth • Feeding difficulties • Hypotonia • Poor postnatal growth • Epilepsy including generalized tonic-clonic seizures and absence seizures • Vision impairment including strabismus • Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures • Speech and language delay and/or absent speech • Autism spectrum disorder or autistic traits • Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth • Feeding difficulties • Hypotonia • Poor postnatal growth • Epilepsy including generalized tonic-clonic seizures and absence seizures • Vision impairment including strabismus • Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Developmental delay (DD) or intellectual disability, typically in the moderate to severe range; AND Any of the following features presenting in infancy or childhood: Speech and language delay and/or absent speech Autism spectrum disorder or autistic traits Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth Feeding difficulties Hypotonia Poor postnatal growth Epilepsy including generalized tonic-clonic seizures and absence seizures Vision impairment including strabismus Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures • Developmental delay (DD) or intellectual disability, typically in the moderate to severe range; AND • Any of the following features presenting in infancy or childhood: • Speech and language delay and/or absent speech • Autism spectrum disorder or autistic traits • Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth • Feeding difficulties • Hypotonia • Poor postnatal growth • Epilepsy including generalized tonic-clonic seizures and absence seizures • Vision impairment including strabismus • Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures • Speech and language delay and/or absent speech • Autism spectrum disorder or autistic traits • Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth • Feeding difficulties • Hypotonia • Poor postnatal growth • Epilepsy including generalized tonic-clonic seizures and absence seizures • Vision impairment including strabismus • Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures • Speech and language delay and/or absent speech • Autism spectrum disorder or autistic traits • Dysmorphic facial features including prominent forehead; highly arched eyebrows; synophrys, widely spaced eyes; downslanted palpebral fissures; long, tubular nose with prominent nasal bridge; wide mouth with full, everted vermilion of the lower lip; and crowded teeth • Feeding difficulties • Hypotonia • Poor postnatal growth • Epilepsy including generalized tonic-clonic seizures and absence seizures • Vision impairment including strabismus • Skeletal findings such as Marfanoid habitus, pectus excavatum, scoliosis, arachnodactyly, and joint flexion with contractures ## Establishing the Diagnosis The diagnosis of (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 From Most individuals so far reported with Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. At least two individuals in a cohort with typical Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics To date, 44 individuals from 40 families have been identified with a pathogenic variant in Select Features of 99% ASD = autism spectrum disorder; GTCS = generalized tonic-clonic seizures A majority of known individuals with Use of communication devices with expert speech and language therapy input can often be helpful in these individuals to develop alternate modes of communication, as it appears that receptive language skills may be better than expressive language skills in persons with this disorder. Less commonly, communication through gesture, sounds, words, and sentences has been described. Initial reports were of affected individuals with profound ID partly attributed to ascertainment bias; however, as more affected individuals have been identified, milder degrees of ID are being observed. The authors are aware of a father and son with a paternally inherited truncating Children with About half of affected individuals meet the formal clinical diagnostic criteria of an autism spectrum disorder (ASD), whereas others have autistic-like features. However, others are described as having a very friendly, placid personality. Other (more rarely) associated behaviors can include: Hand flapping Agitation Motor and/or vocal tics (Tourette syndrome) Hyperventilation episodes Teeth grinding (bruxism) Attention-deficit disorder (ADD) Pica Self-harm behaviors including self-biting, face scratching, and head banging Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. Swallow studies have shown impairment of oral stage of swallowing and oral sensorimotor feeding delay characterized by oral motor weakness, reduced mastication skills for age, and suspected oral hypersensitivity. This may result in delay in weaning and food refusal behavior. Affected individuals may also have a high arched palate. The severity of feeding difficulties varies considerably, with some affected children requiring long-term gastrostomy tube insertion while in others, feeding may be improved with the use of slow-flow nipples (see Although initial feeding issues may resolve with age, there may be ongoing difficulties with feeding as a result of food aversion, sensitivity to different food textures, and behavioral issues that may affect eating. Marfanoid habitus Pectus excavatum Joint hypermobility Pes planus Digital abnormalities including arachnodactyly, syndactyly, clinodactyly, contractures, and tapering fingers Postural scoliosis (possibly due to hypotonia) Delayed bone age Some affected individuals have problems with temperature regulation and are insensitive to cold/heat. Altered pain perception has been described in association with this condition but is not a consistent finding. No genotype-phenotype correlations for The prevalence of Affected individuals have been reported from all ethnicities and most have been identified in countries that undertake genomic testing in individuals with ID. • A majority of known individuals with • Use of communication devices with expert speech and language therapy input can often be helpful in these individuals to develop alternate modes of communication, as it appears that receptive language skills may be better than expressive language skills in persons with this disorder. • Less commonly, communication through gesture, sounds, words, and sentences has been described. • Initial reports were of affected individuals with profound ID partly attributed to ascertainment bias; however, as more affected individuals have been identified, milder degrees of ID are being observed. • The authors are aware of a father and son with a paternally inherited truncating • About half of affected individuals meet the formal clinical diagnostic criteria of an autism spectrum disorder (ASD), whereas others have autistic-like features. However, others are described as having a very friendly, placid personality. • Other (more rarely) associated behaviors can include: • Hand flapping • Agitation • Motor and/or vocal tics (Tourette syndrome) • Hyperventilation episodes • Teeth grinding (bruxism) • Attention-deficit disorder (ADD) • Pica • Self-harm behaviors including self-biting, face scratching, and head banging • Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. • Hand flapping • Agitation • Motor and/or vocal tics (Tourette syndrome) • Hyperventilation episodes • Teeth grinding (bruxism) • Attention-deficit disorder (ADD) • Pica • Self-harm behaviors including self-biting, face scratching, and head banging • Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. • Hand flapping • Agitation • Motor and/or vocal tics (Tourette syndrome) • Hyperventilation episodes • Teeth grinding (bruxism) • Attention-deficit disorder (ADD) • Pica • Self-harm behaviors including self-biting, face scratching, and head banging • Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. • Swallow studies have shown impairment of oral stage of swallowing and oral sensorimotor feeding delay characterized by oral motor weakness, reduced mastication skills for age, and suspected oral hypersensitivity. This may result in delay in weaning and food refusal behavior. Affected individuals may also have a high arched palate. • The severity of feeding difficulties varies considerably, with some affected children requiring long-term gastrostomy tube insertion while in others, feeding may be improved with the use of slow-flow nipples (see • Although initial feeding issues may resolve with age, there may be ongoing difficulties with feeding as a result of food aversion, sensitivity to different food textures, and behavioral issues that may affect eating. • Marfanoid habitus • Pectus excavatum • Joint hypermobility • Pes planus • Digital abnormalities including arachnodactyly, syndactyly, clinodactyly, contractures, and tapering fingers • Postural scoliosis (possibly due to hypotonia) • Delayed bone age • Some affected individuals have problems with temperature regulation and are insensitive to cold/heat. • Altered pain perception has been described in association with this condition but is not a consistent finding. ## Clinical Description To date, 44 individuals from 40 families have been identified with a pathogenic variant in Select Features of 99% ASD = autism spectrum disorder; GTCS = generalized tonic-clonic seizures A majority of known individuals with Use of communication devices with expert speech and language therapy input can often be helpful in these individuals to develop alternate modes of communication, as it appears that receptive language skills may be better than expressive language skills in persons with this disorder. Less commonly, communication through gesture, sounds, words, and sentences has been described. Initial reports were of affected individuals with profound ID partly attributed to ascertainment bias; however, as more affected individuals have been identified, milder degrees of ID are being observed. The authors are aware of a father and son with a paternally inherited truncating Children with About half of affected individuals meet the formal clinical diagnostic criteria of an autism spectrum disorder (ASD), whereas others have autistic-like features. However, others are described as having a very friendly, placid personality. Other (more rarely) associated behaviors can include: Hand flapping Agitation Motor and/or vocal tics (Tourette syndrome) Hyperventilation episodes Teeth grinding (bruxism) Attention-deficit disorder (ADD) Pica Self-harm behaviors including self-biting, face scratching, and head banging Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. Swallow studies have shown impairment of oral stage of swallowing and oral sensorimotor feeding delay characterized by oral motor weakness, reduced mastication skills for age, and suspected oral hypersensitivity. This may result in delay in weaning and food refusal behavior. Affected individuals may also have a high arched palate. The severity of feeding difficulties varies considerably, with some affected children requiring long-term gastrostomy tube insertion while in others, feeding may be improved with the use of slow-flow nipples (see Although initial feeding issues may resolve with age, there may be ongoing difficulties with feeding as a result of food aversion, sensitivity to different food textures, and behavioral issues that may affect eating. Marfanoid habitus Pectus excavatum Joint hypermobility Pes planus Digital abnormalities including arachnodactyly, syndactyly, clinodactyly, contractures, and tapering fingers Postural scoliosis (possibly due to hypotonia) Delayed bone age Some affected individuals have problems with temperature regulation and are insensitive to cold/heat. Altered pain perception has been described in association with this condition but is not a consistent finding. • A majority of known individuals with • Use of communication devices with expert speech and language therapy input can often be helpful in these individuals to develop alternate modes of communication, as it appears that receptive language skills may be better than expressive language skills in persons with this disorder. • Less commonly, communication through gesture, sounds, words, and sentences has been described. • Initial reports were of affected individuals with profound ID partly attributed to ascertainment bias; however, as more affected individuals have been identified, milder degrees of ID are being observed. • The authors are aware of a father and son with a paternally inherited truncating • About half of affected individuals meet the formal clinical diagnostic criteria of an autism spectrum disorder (ASD), whereas others have autistic-like features. However, others are described as having a very friendly, placid personality. • Other (more rarely) associated behaviors can include: • Hand flapping • Agitation • Motor and/or vocal tics (Tourette syndrome) • Hyperventilation episodes • Teeth grinding (bruxism) • Attention-deficit disorder (ADD) • Pica • Self-harm behaviors including self-biting, face scratching, and head banging • Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. • Hand flapping • Agitation • Motor and/or vocal tics (Tourette syndrome) • Hyperventilation episodes • Teeth grinding (bruxism) • Attention-deficit disorder (ADD) • Pica • Self-harm behaviors including self-biting, face scratching, and head banging • Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. • Hand flapping • Agitation • Motor and/or vocal tics (Tourette syndrome) • Hyperventilation episodes • Teeth grinding (bruxism) • Attention-deficit disorder (ADD) • Pica • Self-harm behaviors including self-biting, face scratching, and head banging • Onset of self-injurious behavior can be as early as age two years; some individuals display this behavior later in life. • Swallow studies have shown impairment of oral stage of swallowing and oral sensorimotor feeding delay characterized by oral motor weakness, reduced mastication skills for age, and suspected oral hypersensitivity. This may result in delay in weaning and food refusal behavior. Affected individuals may also have a high arched palate. • The severity of feeding difficulties varies considerably, with some affected children requiring long-term gastrostomy tube insertion while in others, feeding may be improved with the use of slow-flow nipples (see • Although initial feeding issues may resolve with age, there may be ongoing difficulties with feeding as a result of food aversion, sensitivity to different food textures, and behavioral issues that may affect eating. • Marfanoid habitus • Pectus excavatum • Joint hypermobility • Pes planus • Digital abnormalities including arachnodactyly, syndactyly, clinodactyly, contractures, and tapering fingers • Postural scoliosis (possibly due to hypotonia) • Delayed bone age • Some affected individuals have problems with temperature regulation and are insensitive to cold/heat. • Altered pain perception has been described in association with this condition but is not a consistent finding. ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Nomenclature ## Prevalence The prevalence of Affected individuals have been reported from all ethnicities and most have been identified in countries that undertake genomic testing in individuals with ID. ## Genetically Related (Allelic) Disorders All heterozygous pathogenic variants so far reported in association with Sporadic tumors (including parathyroid adenomas and prostate and pancreatic cancers) occurring as single tumors in the absence of any other findings of ## Differential Diagnosis Because the clinical presentation of Note: Heterozygous pathogenic variants ## Management Consensus clinical management 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 For persons age >12 mos: screen for concerns incl sleep disturbances, ADD, &/or features suggestive of ASD. To incl brain MRI Consider EEG if seizures are a concern. To incl assessment of: Gross motor & fine motor skills Contractures, pes planus, scoliosis & joint hypermobility 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 assess for malocclusion & hypodontia To assess for strabismus & ↓ vision To incl genetic counseling Community or Social work involvement for parental support; Home nursing referral. ADD = attention-deficit disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy Treatment of Manifestations in Individuals with 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 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; 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 whether any changes are needed. Special education law requires that children participating in an 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, and hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, and 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 & signs/symptoms of GERD or feeding aversion Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures & changes in tone. GERD = gastroesophageal disease; OT = occupational therapy; PT = physical therapy See Search • To incl brain MRI • Consider EEG if seizures are a concern. • Gross motor & fine motor skills • Contractures, pes planus, scoliosis & joint hypermobility • Mobility, activities of daily living, & 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. • 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 • 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, and hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, and 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 & signs/symptoms of GERD or feeding aversion • 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 Recommended Evaluations Following Initial Diagnosis in Individuals with To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education For persons age >12 mos: screen for concerns incl sleep disturbances, ADD, &/or features suggestive of ASD. To incl brain MRI Consider EEG if seizures are a concern. To incl assessment of: Gross motor & fine motor skills Contractures, pes planus, scoliosis & joint hypermobility 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 assess for malocclusion & hypodontia To assess for strabismus & ↓ vision To incl genetic counseling Community or Social work involvement for parental support; Home nursing referral. ADD = attention-deficit disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy • To incl brain MRI • Consider EEG if seizures are a concern. • Gross motor & fine motor skills • Contractures, pes planus, scoliosis & joint hypermobility • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with 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 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; 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 whether any changes are needed. Special education law requires that children participating in an 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, and hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, and 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 • 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, and hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, and 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, and hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, and 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, and hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, and 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 & signs/symptoms of GERD or feeding aversion Monitor those w/seizures as clinically indicated. Assess for new manifestations incl seizures & changes in tone. GERD = gastroesophageal disease; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & signs/symptoms of GERD or feeding aversion • 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 To date, most individuals with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of a 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. Sib recurrence due to presumed parental germline mosaicism has been reported in three families [ 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, most individuals with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of a 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. Sib recurrence due to presumed parental germline mosaicism has been reported in three families [ • 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 has been reported in three families [ • 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 has been reported in three families [ • 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 To date, most individuals with Rarely, individuals diagnosed with Molecular genetic testing is recommended for the parents of a 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. Sib recurrence due to presumed parental germline mosaicism has been reported in three families [ If a parent of the proband is heterozygous for the If the • To date, most individuals with • Rarely, individuals diagnosed with • Molecular genetic testing is recommended for the parents of a 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. Sib recurrence due to presumed parental germline mosaicism has been reported in three families [ • 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 has been reported in three families [ • 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 has been reported in three families [ • 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 United Kingdom • • • • • • United Kingdom • • • • ## Molecular Genetics ASXL3-Related Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ASXL3-Related Disorder ( Truncating pathogenic variants in Somatic missense variants in ## Molecular Pathogenesis Truncating pathogenic variants in ## Cancer and Benign Tumors Somatic missense variants in ## Chapter Notes Dr Balasubramanian's web page: In the area of pediatric dysmorphology / genomic medicine, the author has led several studies focused on genotype-phenotype correlation in newly identified genes from next-generation sequencing studies such as the Deciphering Developmental Disorders study and has several first/senior author papers published in this area in large cohorts of individuals with new syndromal diagnoses. The author has published the largest cohort of people so far with We would like to thank all the families and their clinicians who have thus far contributed to ongoing 5 November 2020 (ma) Review posted live 21 April 2020 (mb) Original submission • 5 November 2020 (ma) Review posted live • 21 April 2020 (mb) Original submission ## Author Notes Dr Balasubramanian's web page: In the area of pediatric dysmorphology / genomic medicine, the author has led several studies focused on genotype-phenotype correlation in newly identified genes from next-generation sequencing studies such as the Deciphering Developmental Disorders study and has several first/senior author papers published in this area in large cohorts of individuals with new syndromal diagnoses. The author has published the largest cohort of people so far with ## Acknowledgments We would like to thank all the families and their clinicians who have thus far contributed to ongoing ## Revision History 5 November 2020 (ma) Review posted live 21 April 2020 (mb) Original submission • 5 November 2020 (ma) Review posted live • 21 April 2020 (mb) Original submission ## References ## Literature Cited	[]	5/11/2020			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ataxia-telangiectas	ataxia-telangiectas	[ "Classic Ataxia-Telangiectasia", "Variant Ataxia-Telangiectasia", "Serine-protein kinase ATM", "ATM", "Ataxia-Telangiectasia" ]	Ataxia-Telangiectasia	Stefanie Veenhuis, Nienke van Os, Corry Weemaes, Erik-Jan Kamsteeg, Michèl Willemsen	Summary The phenotypic spectrum of ataxia-telangiectasia (A-T), a multisystem disorder, is a continuum ranging from classic A-T at the severe end and variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant A-T on this spectrum helps understand differences in disease course, rate of progression, and life expectancy. The diagnosis of A-T is established in a proband with suggestive findings and biallelic pathogenic variants in A-T is caused by biallelic pathogenic variants in	Ataxia-Telangiectasia: Phenotypic Spectrum A-T = ataxia-telangiectasia ## Diagnosis No consensus clinical diagnostic criteria for ataxia-telangiectasia (A-T) have been published. The two scenarios in which A-T may be considered are Newborn screening (NBS) for severe combined immunodeficiency (SCID), a severe but treatable immunologic disorder, relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots. Note: This chapter specifically focuses on A-T; for potential causes of decreased TREC levels in NBS other than classic A-T and SCID, see Newborns with an abnormal NBS for SCID Cerebellar ataxia (the presenting feature in most individuals) Extrapyramidal movement disorders (chorea, myoclonus, dystonia, tremor) Dysarthria Eye movement disorders (gaze-evoked nystagmus, oculomotor apraxia ) Oculocutaneous telangiectasias * In most individuals with classic A-T, abnormal eye movements and telangiectasias only occur some years after disease onset. Motor and sensory neuropathy generally develop at the end of the first decade of life. Cerebellar ataxia Extrapyramidal movement disorders (dystonia, chorea, myoclonus, tremor) Dysarthria Peripheral neuropathy; anterior horn disease in a minority of individuals Cancer in a young individual with an apparently static neurologic (motor) disorder ("cerebral palsy") The diagnosis of A-T 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 Ataxia-Telangiectasia 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/duplications/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 [ Several deep intronic variants outside of the exon and splice junction regions typically included by standard sequencing have been observed, including a deep intronic founder variant detected in the United Kingdom ( Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Alternatively, deletion/duplication analysis by using read depth or detecting breakpoints in exome and genome sequencing data is also possible. • Cerebellar ataxia (the presenting feature in most individuals) • Extrapyramidal movement disorders (chorea, myoclonus, dystonia, tremor) • Dysarthria • Eye movement disorders (gaze-evoked nystagmus, oculomotor apraxia ) • Oculocutaneous telangiectasias • • Cerebellar ataxia • Extrapyramidal movement disorders (dystonia, chorea, myoclonus, tremor) • Dysarthria • Peripheral neuropathy; anterior horn disease in a minority of individuals • Cancer in a young individual with an apparently static neurologic (motor) disorder ("cerebral palsy") ## Scenario 1: Abnormal Newborn Screening for Severe Combined Immunodeficiency Newborn screening (NBS) for severe combined immunodeficiency (SCID), a severe but treatable immunologic disorder, relies on the identification of reduced T-cell receptor excision circle (TREC) levels in blood spots. Note: This chapter specifically focuses on A-T; for potential causes of decreased TREC levels in NBS other than classic A-T and SCID, see Newborns with an abnormal NBS for SCID ## Scenario 2: Symptomatic Proband with Findings Suggestive of A-T Cerebellar ataxia (the presenting feature in most individuals) Extrapyramidal movement disorders (chorea, myoclonus, dystonia, tremor) Dysarthria Eye movement disorders (gaze-evoked nystagmus, oculomotor apraxia ) Oculocutaneous telangiectasias * In most individuals with classic A-T, abnormal eye movements and telangiectasias only occur some years after disease onset. Motor and sensory neuropathy generally develop at the end of the first decade of life. Cerebellar ataxia Extrapyramidal movement disorders (dystonia, chorea, myoclonus, tremor) Dysarthria Peripheral neuropathy; anterior horn disease in a minority of individuals Cancer in a young individual with an apparently static neurologic (motor) disorder ("cerebral palsy") • Cerebellar ataxia (the presenting feature in most individuals) • Extrapyramidal movement disorders (chorea, myoclonus, dystonia, tremor) • Dysarthria • Eye movement disorders (gaze-evoked nystagmus, oculomotor apraxia ) • Oculocutaneous telangiectasias • • Cerebellar ataxia • Extrapyramidal movement disorders (dystonia, chorea, myoclonus, tremor) • Dysarthria • Peripheral neuropathy; anterior horn disease in a minority of individuals • Cancer in a young individual with an apparently static neurologic (motor) disorder ("cerebral palsy") ## Classic A-T Cerebellar ataxia (the presenting feature in most individuals) Extrapyramidal movement disorders (chorea, myoclonus, dystonia, tremor) Dysarthria Eye movement disorders (gaze-evoked nystagmus, oculomotor apraxia ) Oculocutaneous telangiectasias * In most individuals with classic A-T, abnormal eye movements and telangiectasias only occur some years after disease onset. Motor and sensory neuropathy generally develop at the end of the first decade of life. • Cerebellar ataxia (the presenting feature in most individuals) • Extrapyramidal movement disorders (chorea, myoclonus, dystonia, tremor) • Dysarthria • Eye movement disorders (gaze-evoked nystagmus, oculomotor apraxia ) • Oculocutaneous telangiectasias • ## Variant A-T Cerebellar ataxia Extrapyramidal movement disorders (dystonia, chorea, myoclonus, tremor) Dysarthria Peripheral neuropathy; anterior horn disease in a minority of individuals Cancer in a young individual with an apparently static neurologic (motor) disorder ("cerebral palsy") • Cerebellar ataxia • Extrapyramidal movement disorders (dystonia, chorea, myoclonus, tremor) • Dysarthria • Peripheral neuropathy; anterior horn disease in a minority of individuals • Cancer in a young individual with an apparently static neurologic (motor) disorder ("cerebral palsy") ## Establishing the Diagnosis The diagnosis of A-T 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 Ataxia-Telangiectasia 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/duplications/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 [ Several deep intronic variants outside of the exon and splice junction regions typically included by standard sequencing have been observed, including a deep intronic founder variant detected in the United Kingdom ( Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Alternatively, deletion/duplication analysis by using read depth or detecting breakpoints in exome and genome sequencing data is also possible. ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ataxia-Telangiectasia 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/duplications/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 [ Several deep intronic variants outside of the exon and splice junction regions typically included by standard sequencing have been observed, including a deep intronic founder variant detected in the United Kingdom ( Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Alternatively, deletion/duplication analysis by using read depth or detecting breakpoints in exome and genome sequencing data is also possible. ## Clinical Characteristics Ataxia-telangiectasia (A-T) is often described has having a "classic A-T" phenotype and a "variant A-T" phenotype; however, these phenotypes are more of a continuum ranging from classic A-T at the severe end to variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant- A-T on this phenotypic spectrum helps understand differences in disease course, rate of progression, and life expectancy (see Ataxia-Telangiectasia: Comparison of Classic A-T and Variant A-T by Select Features Based on ++ = always present; + = usually present; ± = sometimes present; − rarely present; Ab = absent; ? = although this feature has not been systematically studied in individuals with variant A-T, the authors feel that this is very uncommon in these individuals During the first years after disease onset, motor abnormalities may appear to be stable because the natural acquisition of motor milestones in young children may appear to "compensate" for the (progressive) disease course [ Children have balance problems when they walk and show a rapid broad-based gait, with backward posturing of the arms and hands as a finding of dystonia. In addition, most children with classic A-T have extrapyramidal involvement such as dystonia, choreoathetosis, myoclonic jerks, and tremor. In the second or third decade, parkinsonism can occur [ After about age eight years children begin to show clinical signs of peripheral neuropathy, manifesting as a progressive sensorimotor neuropathy, decreased or loss of deep tendon reflexes, distal muscle weakness and atrophy, and impaired vibration sense [ After about age ten years most children with classic A-T require use a wheelchair to compensate for the cerebellar ataxia and extrapyramidal and peripheral nervous manifestations. With disease progression, speech problems occur in all individuals. Despite dysarthria, oral communication generally remains possible [ Dysphagia, which is common in young adults, makes eating frustrating and exhausting [ Oculomotor apraxia in individuals with classic A-T include gaze-evoked nystagmus, hypometric saccades, saccadic intrusions, convergence/accommodation, and vestibulo-ocular reflex abnormalities [ As the result of the complex eye movement disorders, visual fixation can be difficult and can, for example, affect reading [ About 10% of individuals with IgA and IgG deficiency have normal or elevated levels of IgM, the so-called hyper IgM phenotype [ A reduced selective polysaccharide antibody response can also occur, mostly in individuals with deficiencies of both IgA and IgG2 [ In contrast, mild sinopulmonary infections occur quite frequently and may aggravate pulmonary disease [ Viruses are the most common cause of respiratory tract infections during the first two years of life in both healthy children and children with A-T. Bacterial causes of respiratory tract infections are Recurrent respiratory tract infections can result in bronchiectasis and pleural abnormalities [ Interstitial lung disease, which commonly manifests as dry cough, tachypnea, hypoxemia, and dyspnea (in the absence of viral or bacterial infections), usually occurs in adolescence. Neuromuscular and central nervous system involvement can lead to dysphagia (commonly evident in the second decade) and chronic aspiration, aggravating existing lung disease [ Pulmonary disease progresses with increasing age and neurologic involvement. Individuals with the hyper IgM phenotype of classic A-T have a poorer prognosis than individuals with classic A-T, and most die before age 15 years due to respiratory failure [ The first manifestations of variant A-T can occur in childhood to adulthood. Most individuals have their first manifestations by age ten years. Cerebellar ataxia can be absent in variant A-T, in contrast to classic A-T. Extrapyramidal movement disorders are common, the most predominant of which are dystonia and dystonic tremor. Most individuals who have a purely extrapyramidal presentation tend to have a milder disease course [ Chorea and parkinsonism are rare in variant A-T. Most individuals with variant A-T have, in addition to central motor manifestations, signs and symptoms of an axonal sensorimotor polyneuropathy [ Rarely, individuals with variant A-T have anterior horn cell disease, which can either be one of the presenting features or can manifest during the disease course [ Although individuals heterozygous for a pathogenic In addition to this increased cancer risk, heterozygotes may also have an increased risk of developing cardiovascular disease, diabetes mellitus, and neurodegenerative disorders; however, systematic population studies to (quantitatively) investigate this issue are lacking [ In general, nonsense and/or frameshift variants lead to the classic A-T phenotype, whereas missense and splice site variants are more typically associated with variant A-T. Within families, phenotypes of affected individuals are generally similar [ Compound heterozygosity for Ataxia-telangiectasia was previously referred to as Louis-Bar syndrome. The reported incidence of A-T, a rare disorder, varies between 1:300,000 and 1:40,000. The estimated prevalence is 1-9:100,000 [ In the United States approximately 350 children with A-T are known to the patient organization A-T Children's Project (see Based on the incidence of A-T in the United States, the heterozygote frequency is estimated to be one in 200 persons [ Increased heterozygote frequencies have been reported in the following populations due to founder variants (see One in three to one in 15 in the Druze population in northern Israel [ One in 81 in the Moroccan and Tunisian Jewish population [ One in 36 in the Romani population in Spain [ • About 10% of individuals with IgA and IgG deficiency have normal or elevated levels of IgM, the so-called hyper IgM phenotype [ • A reduced selective polysaccharide antibody response can also occur, mostly in individuals with deficiencies of both IgA and IgG2 [ • • Compound heterozygosity for • One in three to one in 15 in the Druze population in northern Israel [ • One in 81 in the Moroccan and Tunisian Jewish population [ • One in 36 in the Romani population in Spain [ ## Clinical Description Ataxia-telangiectasia (A-T) is often described has having a "classic A-T" phenotype and a "variant A-T" phenotype; however, these phenotypes are more of a continuum ranging from classic A-T at the severe end to variant A-T at the milder end. Nonetheless, distinguishing between classic A-T and variant- A-T on this phenotypic spectrum helps understand differences in disease course, rate of progression, and life expectancy (see Ataxia-Telangiectasia: Comparison of Classic A-T and Variant A-T by Select Features Based on ++ = always present; + = usually present; ± = sometimes present; − rarely present; Ab = absent; ? = although this feature has not been systematically studied in individuals with variant A-T, the authors feel that this is very uncommon in these individuals During the first years after disease onset, motor abnormalities may appear to be stable because the natural acquisition of motor milestones in young children may appear to "compensate" for the (progressive) disease course [ Children have balance problems when they walk and show a rapid broad-based gait, with backward posturing of the arms and hands as a finding of dystonia. In addition, most children with classic A-T have extrapyramidal involvement such as dystonia, choreoathetosis, myoclonic jerks, and tremor. In the second or third decade, parkinsonism can occur [ After about age eight years children begin to show clinical signs of peripheral neuropathy, manifesting as a progressive sensorimotor neuropathy, decreased or loss of deep tendon reflexes, distal muscle weakness and atrophy, and impaired vibration sense [ After about age ten years most children with classic A-T require use a wheelchair to compensate for the cerebellar ataxia and extrapyramidal and peripheral nervous manifestations. With disease progression, speech problems occur in all individuals. Despite dysarthria, oral communication generally remains possible [ Dysphagia, which is common in young adults, makes eating frustrating and exhausting [ Oculomotor apraxia in individuals with classic A-T include gaze-evoked nystagmus, hypometric saccades, saccadic intrusions, convergence/accommodation, and vestibulo-ocular reflex abnormalities [ As the result of the complex eye movement disorders, visual fixation can be difficult and can, for example, affect reading [ About 10% of individuals with IgA and IgG deficiency have normal or elevated levels of IgM, the so-called hyper IgM phenotype [ A reduced selective polysaccharide antibody response can also occur, mostly in individuals with deficiencies of both IgA and IgG2 [ In contrast, mild sinopulmonary infections occur quite frequently and may aggravate pulmonary disease [ Viruses are the most common cause of respiratory tract infections during the first two years of life in both healthy children and children with A-T. Bacterial causes of respiratory tract infections are Recurrent respiratory tract infections can result in bronchiectasis and pleural abnormalities [ Interstitial lung disease, which commonly manifests as dry cough, tachypnea, hypoxemia, and dyspnea (in the absence of viral or bacterial infections), usually occurs in adolescence. Neuromuscular and central nervous system involvement can lead to dysphagia (commonly evident in the second decade) and chronic aspiration, aggravating existing lung disease [ Pulmonary disease progresses with increasing age and neurologic involvement. Individuals with the hyper IgM phenotype of classic A-T have a poorer prognosis than individuals with classic A-T, and most die before age 15 years due to respiratory failure [ The first manifestations of variant A-T can occur in childhood to adulthood. Most individuals have their first manifestations by age ten years. Cerebellar ataxia can be absent in variant A-T, in contrast to classic A-T. Extrapyramidal movement disorders are common, the most predominant of which are dystonia and dystonic tremor. Most individuals who have a purely extrapyramidal presentation tend to have a milder disease course [ Chorea and parkinsonism are rare in variant A-T. Most individuals with variant A-T have, in addition to central motor manifestations, signs and symptoms of an axonal sensorimotor polyneuropathy [ Rarely, individuals with variant A-T have anterior horn cell disease, which can either be one of the presenting features or can manifest during the disease course [ Although individuals heterozygous for a pathogenic In addition to this increased cancer risk, heterozygotes may also have an increased risk of developing cardiovascular disease, diabetes mellitus, and neurodegenerative disorders; however, systematic population studies to (quantitatively) investigate this issue are lacking [ • About 10% of individuals with IgA and IgG deficiency have normal or elevated levels of IgM, the so-called hyper IgM phenotype [ • A reduced selective polysaccharide antibody response can also occur, mostly in individuals with deficiencies of both IgA and IgG2 [ • ## Classic A-T During the first years after disease onset, motor abnormalities may appear to be stable because the natural acquisition of motor milestones in young children may appear to "compensate" for the (progressive) disease course [ Children have balance problems when they walk and show a rapid broad-based gait, with backward posturing of the arms and hands as a finding of dystonia. In addition, most children with classic A-T have extrapyramidal involvement such as dystonia, choreoathetosis, myoclonic jerks, and tremor. In the second or third decade, parkinsonism can occur [ After about age eight years children begin to show clinical signs of peripheral neuropathy, manifesting as a progressive sensorimotor neuropathy, decreased or loss of deep tendon reflexes, distal muscle weakness and atrophy, and impaired vibration sense [ After about age ten years most children with classic A-T require use a wheelchair to compensate for the cerebellar ataxia and extrapyramidal and peripheral nervous manifestations. With disease progression, speech problems occur in all individuals. Despite dysarthria, oral communication generally remains possible [ Dysphagia, which is common in young adults, makes eating frustrating and exhausting [ Oculomotor apraxia in individuals with classic A-T include gaze-evoked nystagmus, hypometric saccades, saccadic intrusions, convergence/accommodation, and vestibulo-ocular reflex abnormalities [ As the result of the complex eye movement disorders, visual fixation can be difficult and can, for example, affect reading [ About 10% of individuals with IgA and IgG deficiency have normal or elevated levels of IgM, the so-called hyper IgM phenotype [ A reduced selective polysaccharide antibody response can also occur, mostly in individuals with deficiencies of both IgA and IgG2 [ In contrast, mild sinopulmonary infections occur quite frequently and may aggravate pulmonary disease [ Viruses are the most common cause of respiratory tract infections during the first two years of life in both healthy children and children with A-T. Bacterial causes of respiratory tract infections are Recurrent respiratory tract infections can result in bronchiectasis and pleural abnormalities [ Interstitial lung disease, which commonly manifests as dry cough, tachypnea, hypoxemia, and dyspnea (in the absence of viral or bacterial infections), usually occurs in adolescence. Neuromuscular and central nervous system involvement can lead to dysphagia (commonly evident in the second decade) and chronic aspiration, aggravating existing lung disease [ Pulmonary disease progresses with increasing age and neurologic involvement. Individuals with the hyper IgM phenotype of classic A-T have a poorer prognosis than individuals with classic A-T, and most die before age 15 years due to respiratory failure [ • About 10% of individuals with IgA and IgG deficiency have normal or elevated levels of IgM, the so-called hyper IgM phenotype [ • A reduced selective polysaccharide antibody response can also occur, mostly in individuals with deficiencies of both IgA and IgG2 [ • ## Variant A-T The first manifestations of variant A-T can occur in childhood to adulthood. Most individuals have their first manifestations by age ten years. Cerebellar ataxia can be absent in variant A-T, in contrast to classic A-T. Extrapyramidal movement disorders are common, the most predominant of which are dystonia and dystonic tremor. Most individuals who have a purely extrapyramidal presentation tend to have a milder disease course [ Chorea and parkinsonism are rare in variant A-T. Most individuals with variant A-T have, in addition to central motor manifestations, signs and symptoms of an axonal sensorimotor polyneuropathy [ Rarely, individuals with variant A-T have anterior horn cell disease, which can either be one of the presenting features or can manifest during the disease course [ ## Heterozygotes Although individuals heterozygous for a pathogenic In addition to this increased cancer risk, heterozygotes may also have an increased risk of developing cardiovascular disease, diabetes mellitus, and neurodegenerative disorders; however, systematic population studies to (quantitatively) investigate this issue are lacking [ ## Genotype-Phenotype Correlations In general, nonsense and/or frameshift variants lead to the classic A-T phenotype, whereas missense and splice site variants are more typically associated with variant A-T. Within families, phenotypes of affected individuals are generally similar [ Compound heterozygosity for • Compound heterozygosity for ## Nomenclature Ataxia-telangiectasia was previously referred to as Louis-Bar syndrome. ## Prevalence The reported incidence of A-T, a rare disorder, varies between 1:300,000 and 1:40,000. The estimated prevalence is 1-9:100,000 [ In the United States approximately 350 children with A-T are known to the patient organization A-T Children's Project (see Based on the incidence of A-T in the United States, the heterozygote frequency is estimated to be one in 200 persons [ Increased heterozygote frequencies have been reported in the following populations due to founder variants (see One in three to one in 15 in the Druze population in northern Israel [ One in 81 in the Moroccan and Tunisian Jewish population [ One in 36 in the Romani population in Spain [ • One in three to one in 15 in the Druze population in northern Israel [ • One in 81 in the Moroccan and Tunisian Jewish population [ • One in 36 in the Romani population in Spain [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genetic disorders associated with eye findings and ataxia in the differential diagnosis of ataxia-telangiectasia (A-T) are listed in Genes of Interest in the Differential Diagnosis of Ataxia-Telangiectasia Hypoalbuminemia ↑ serum total cholesterol Generally normal serum AFP Pyramidal & sensory signs Optic atrophy Cardiomyopathy Normal serum AFP Hypoalbuminemia ↑ cholesterol Low plasma levels of vitamin E Pyramidal signs ↓ visual acuity Normal serum AFP Based on AFP = alpha-fetoprotein; A-T = ataxia-telangiectasia The disorders listed in this table are inherited in an autosomal recessive manner. • Hypoalbuminemia • ↑ serum total cholesterol • Generally normal serum AFP • Pyramidal & sensory signs • Optic atrophy • Cardiomyopathy • Normal serum AFP • Hypoalbuminemia • ↑ cholesterol • Low plasma levels of vitamin E • Pyramidal signs • ↓ visual acuity • Normal serum AFP ## Management Most of the guidelines recommended for the management of health-related problems in individuals with ataxia-telangiectasia (A-T) are expert and evidence based, due to a lack of clinical trials; see To establish the extent of disease and needs in an individual diagnosed with ataxia-telangiectasia (A-T), the evaluations summarized in Ataxia-Telangiectasia: Recommended Evaluations Following Initial Diagnosis Gross motor & fine motor skills Contractures & 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 aspiration risk & nutritional status Consider eval for gastrostomy tube placement if nutritional status is poor &/or if there is dysphagia &/or ↑ risk of aspiration. Eval for clinical manifestations of malignancy (e.g., lymphadenopathy) Laboratory tests to assess for hematologic malignancies (per annual screening; see For humoral & cellular immune defects; Whether immunoglobulin substitution therapy is indicated; Vaccination status. Assess for sinopulmonary infection. Determine need for prophylactic antibiotic treatment. Assess for pulmonary function Assess lung function when possible (often age >4 yrs). Assess length/height in children (using standard growth charts). Assess age-appropriate pubertal development. Screening for diabetes, cardiovascular disease, & hepatic disease in adolescents & adults Community or Social work involvement for parental support; Palliative care involvement &/or home nursing referral. ADL = activities of daily living; ATFS = Ataxia Telangiectasia Functioning Scale; A-T NEST = Ataxia-Telangiectasia Neurological Examination Scale Toolkit; ICARS = International Cooperative Ataxia Rating Scale; ID = intellectual disability; ILD = interstitial lung disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia Regarding interstitial lung disease (ILD), spirometry can detect restrictive lung disease. Decreased forced vital capacity (FVC) is possibly the result of abnormalities in respiratory muscle coordination or scoliosis. Helium dilution measurements can help discriminate between true restrictive lung disease and an inability to expire to residual volume. Although a lung biopsy can help confirm the diagnosis of ILD, the diagnostic benefits should be weighed against the risks of the procedure [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for ataxia-telangiectasia. The following discussion takes into consideration that distinctions between the findings in classic A-T and variant A-T are not always possible; thus, clinicians need to focus on the issues that are most relevant to each affected individual. For recommendations on the treatment of ataxia, chorea, myoclonus, and tremor, see Physical therapists can provide exercises to maintain muscle strength, overall condition, and activity and to prevent joint contractures. Necessary aids can include: Foot orthoses; A (wheel)chair to provide a good upright sitting position to reduce scoliosis and prevent choking; Standing frames. Occupational therapists can provide aids and devices for activities of daily living. Good nutritional status is required for optimal effectiveness of all other treatments in A-T. Individuals with A-T are often malnourished, as a result of the combination of physical difficulties with eating (i.e., oral-motor problems affecting chewing and swallowing), easy fatigability, and endocrine abnormalities that affect growth [ Practical tips such as attention to a good sitting position, use of a straw, thickening of thin liquids, and giving children easily chewable foods may help [ Gastrostomy placement early in the disease course can improve clinical outcomes [ Nystagmus and oculomotor apraxia generally do not require drug treatment. 4-aminopyridine did improve oculomotor and vestibular function in a small case series [ Acetyl-DL-leucine was shown to have an effect on downbeat nystagmus in a small study [ Treatment protocols for an individual with A-T with a malignancy should be individualized based on patient-related factors (such as mobility, lung function) and malignancy-related factors (such as type of malignancy and alternative treatment options). An IEP provides specially designed instruction and related services to children who qualify. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. As individuals with A-T have a severe disorder, attention should be paid to their emotional well-being [ Of note, in individuals with severe immunodeficiency, rubella vaccination should be avoided, as it can possibly increase the risk for granulomas [ In females with gonadal failure (in case of primary or secondary amenorrhea), estrogen supplementation can prevent osteoporosis [ Growth hormone treatment may be an option for children with severe growth failure [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Note the recommended surveillance is the same for individuals with classic A-T and variant A-T, with the exception that individuals who do not have evidence of lung disease at the time of the initial diagnosis do not require annual screening for pulmonary disease. Ataxia-Telangiectasia: Recommended Surveillance Eval by neurologist for response to therapy for existing findings & development of new findings If child has severe/profound ID, seek additional cause. Annually More frequently if problems are present or suspected Before becoming school age; once school age, annually More frequently if problems are present or suspected Annually More frequently if problems are present or suspected By pulmonologist Lung function testing (by spirometry) Annually for persons w/evidence of disease at time of initial diagnosis More frequently if problems are present or suspected Annually More frequently if problems are present or suspected Immediate referral to oncologist if malignancy is diagnosed or suspected Annually starting at age 25 yrs More frequently if problems are present or suspected Annually in childhood More frequently if problems are present or suspected Annually More frequently if problems are present or suspected Annually in adults More frequently if problems are present or suspected Annually More frequently if problems are present or suspected Hgb = hemoglobin; ID = intellectual disability; LDH = lactate dehydrogenase; SLP = speech-language pathologist Females heterozygous for the Females heterozygous for any other Radiation therapy at conventional doses is not contraindicated in females heterozygous for an To date, intensified screening for other types of cancer have not been recommended. To date, it is not recommended that heterozygotes avoid radiation therapy at conventional doses or diagnostic x-rays or CT scans. Heterozygotes should be made aware of lifestyle factors that contribute to cardiovascular diseases, but no specific screening has been recommended [ Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas [ Ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity [ Radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications [ It is appropriate to offer molecular genetic testing for the Sibs with biallelic Family members who are heterozygous for an See Currently, a multicenter randomized controlled trial with Search • Gross motor & fine motor skills • Contractures & 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 aspiration risk & nutritional status • Consider eval for gastrostomy tube placement if nutritional status is poor &/or if there is dysphagia &/or ↑ risk of aspiration. • Eval for clinical manifestations of malignancy (e.g., lymphadenopathy) • Laboratory tests to assess for hematologic malignancies (per annual screening; see • For humoral & cellular immune defects; • Whether immunoglobulin substitution therapy is indicated; • Vaccination status. • Assess for sinopulmonary infection. • Determine need for prophylactic antibiotic treatment. • Assess for pulmonary function • Assess lung function when possible (often age >4 yrs). • Assess length/height in children (using standard growth charts). • Assess age-appropriate pubertal development. • Screening for diabetes, cardiovascular disease, & hepatic disease in adolescents & adults • Community or • Social work involvement for parental support; • Palliative care involvement &/or home nursing referral. • Foot orthoses; • A (wheel)chair to provide a good upright sitting position to reduce scoliosis and prevent choking; • Standing frames. • 4-aminopyridine did improve oculomotor and vestibular function in a small case series [ • Acetyl-DL-leucine was shown to have an effect on downbeat nystagmus in a small study [ • An IEP provides specially designed instruction and related services to children who qualify. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who 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. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who 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. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Eval by neurologist for response to therapy for existing findings & development of new findings • If child has severe/profound ID, seek additional cause. • Annually • More frequently if problems are present or suspected • Before becoming school age; once school age, annually • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • By pulmonologist • Lung function testing (by spirometry) • Annually for persons w/evidence of disease at time of initial diagnosis • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • Immediate referral to oncologist if malignancy is diagnosed or suspected • Annually starting at age 25 yrs • More frequently if problems are present or suspected • Annually in childhood • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • Annually in adults • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • Females heterozygous for the • Females heterozygous for any other • Radiation therapy at conventional doses is not contraindicated in females heterozygous for an • To date, intensified screening for other types of cancer have not been recommended. • To date, it is not recommended that heterozygotes avoid radiation therapy at conventional doses or diagnostic x-rays or CT scans. • Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas [ • Ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity [ • Radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications [ • Sibs with biallelic • Family members who are heterozygous for an ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with ataxia-telangiectasia (A-T), the evaluations summarized in Ataxia-Telangiectasia: Recommended Evaluations Following Initial Diagnosis Gross motor & fine motor skills Contractures & 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 aspiration risk & nutritional status Consider eval for gastrostomy tube placement if nutritional status is poor &/or if there is dysphagia &/or ↑ risk of aspiration. Eval for clinical manifestations of malignancy (e.g., lymphadenopathy) Laboratory tests to assess for hematologic malignancies (per annual screening; see For humoral & cellular immune defects; Whether immunoglobulin substitution therapy is indicated; Vaccination status. Assess for sinopulmonary infection. Determine need for prophylactic antibiotic treatment. Assess for pulmonary function Assess lung function when possible (often age >4 yrs). Assess length/height in children (using standard growth charts). Assess age-appropriate pubertal development. Screening for diabetes, cardiovascular disease, & hepatic disease in adolescents & adults Community or Social work involvement for parental support; Palliative care involvement &/or home nursing referral. ADL = activities of daily living; ATFS = Ataxia Telangiectasia Functioning Scale; A-T NEST = Ataxia-Telangiectasia Neurological Examination Scale Toolkit; ICARS = International Cooperative Ataxia Rating Scale; ID = intellectual disability; ILD = interstitial lung disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia Regarding interstitial lung disease (ILD), spirometry can detect restrictive lung disease. Decreased forced vital capacity (FVC) is possibly the result of abnormalities in respiratory muscle coordination or scoliosis. Helium dilution measurements can help discriminate between true restrictive lung disease and an inability to expire to residual volume. Although a lung biopsy can help confirm the diagnosis of ILD, the diagnostic benefits should be weighed against the risks of the procedure [ Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Gross motor & fine motor skills • Contractures & 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 aspiration risk & nutritional status • Consider eval for gastrostomy tube placement if nutritional status is poor &/or if there is dysphagia &/or ↑ risk of aspiration. • Eval for clinical manifestations of malignancy (e.g., lymphadenopathy) • Laboratory tests to assess for hematologic malignancies (per annual screening; see • For humoral & cellular immune defects; • Whether immunoglobulin substitution therapy is indicated; • Vaccination status. • Assess for sinopulmonary infection. • Determine need for prophylactic antibiotic treatment. • Assess for pulmonary function • Assess lung function when possible (often age >4 yrs). • Assess length/height in children (using standard growth charts). • Assess age-appropriate pubertal development. • Screening for diabetes, cardiovascular disease, & hepatic disease in adolescents & adults • Community or • Social work involvement for parental support; • Palliative care involvement &/or home nursing referral. ## Treatment of Manifestations There is no cure for ataxia-telangiectasia. The following discussion takes into consideration that distinctions between the findings in classic A-T and variant A-T are not always possible; thus, clinicians need to focus on the issues that are most relevant to each affected individual. For recommendations on the treatment of ataxia, chorea, myoclonus, and tremor, see Physical therapists can provide exercises to maintain muscle strength, overall condition, and activity and to prevent joint contractures. Necessary aids can include: Foot orthoses; A (wheel)chair to provide a good upright sitting position to reduce scoliosis and prevent choking; Standing frames. Occupational therapists can provide aids and devices for activities of daily living. Good nutritional status is required for optimal effectiveness of all other treatments in A-T. Individuals with A-T are often malnourished, as a result of the combination of physical difficulties with eating (i.e., oral-motor problems affecting chewing and swallowing), easy fatigability, and endocrine abnormalities that affect growth [ Practical tips such as attention to a good sitting position, use of a straw, thickening of thin liquids, and giving children easily chewable foods may help [ Gastrostomy placement early in the disease course can improve clinical outcomes [ Nystagmus and oculomotor apraxia generally do not require drug treatment. 4-aminopyridine did improve oculomotor and vestibular function in a small case series [ Acetyl-DL-leucine was shown to have an effect on downbeat nystagmus in a small study [ Treatment protocols for an individual with A-T with a malignancy should be individualized based on patient-related factors (such as mobility, lung function) and malignancy-related factors (such as type of malignancy and alternative treatment options). An IEP provides specially designed instruction and related services to children who qualify. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. As individuals with A-T have a severe disorder, attention should be paid to their emotional well-being [ Of note, in individuals with severe immunodeficiency, rubella vaccination should be avoided, as it can possibly increase the risk for granulomas [ In females with gonadal failure (in case of primary or secondary amenorrhea), estrogen supplementation can prevent osteoporosis [ Growth hormone treatment may be an option for children with severe growth failure [ • Foot orthoses; • A (wheel)chair to provide a good upright sitting position to reduce scoliosis and prevent choking; • Standing frames. • 4-aminopyridine did improve oculomotor and vestibular function in a small case series [ • Acetyl-DL-leucine was shown to have an effect on downbeat nystagmus in a small study [ • An IEP provides specially designed instruction and related services to children who qualify. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who 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. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who 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. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Note the recommended surveillance is the same for individuals with classic A-T and variant A-T, with the exception that individuals who do not have evidence of lung disease at the time of the initial diagnosis do not require annual screening for pulmonary disease. Ataxia-Telangiectasia: Recommended Surveillance Eval by neurologist for response to therapy for existing findings & development of new findings If child has severe/profound ID, seek additional cause. Annually More frequently if problems are present or suspected Before becoming school age; once school age, annually More frequently if problems are present or suspected Annually More frequently if problems are present or suspected By pulmonologist Lung function testing (by spirometry) Annually for persons w/evidence of disease at time of initial diagnosis More frequently if problems are present or suspected Annually More frequently if problems are present or suspected Immediate referral to oncologist if malignancy is diagnosed or suspected Annually starting at age 25 yrs More frequently if problems are present or suspected Annually in childhood More frequently if problems are present or suspected Annually More frequently if problems are present or suspected Annually in adults More frequently if problems are present or suspected Annually More frequently if problems are present or suspected Hgb = hemoglobin; ID = intellectual disability; LDH = lactate dehydrogenase; SLP = speech-language pathologist Females heterozygous for the Females heterozygous for any other Radiation therapy at conventional doses is not contraindicated in females heterozygous for an To date, intensified screening for other types of cancer have not been recommended. To date, it is not recommended that heterozygotes avoid radiation therapy at conventional doses or diagnostic x-rays or CT scans. Heterozygotes should be made aware of lifestyle factors that contribute to cardiovascular diseases, but no specific screening has been recommended [ • Eval by neurologist for response to therapy for existing findings & development of new findings • If child has severe/profound ID, seek additional cause. • Annually • More frequently if problems are present or suspected • Before becoming school age; once school age, annually • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • By pulmonologist • Lung function testing (by spirometry) • Annually for persons w/evidence of disease at time of initial diagnosis • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • Immediate referral to oncologist if malignancy is diagnosed or suspected • Annually starting at age 25 yrs • More frequently if problems are present or suspected • Annually in childhood • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • Annually in adults • More frequently if problems are present or suspected • Annually • More frequently if problems are present or suspected • Females heterozygous for the • Females heterozygous for any other • Radiation therapy at conventional doses is not contraindicated in females heterozygous for an • To date, intensified screening for other types of cancer have not been recommended. • To date, it is not recommended that heterozygotes avoid radiation therapy at conventional doses or diagnostic x-rays or CT scans. ## Heterozygotes Females heterozygous for the Females heterozygous for any other Radiation therapy at conventional doses is not contraindicated in females heterozygous for an To date, intensified screening for other types of cancer have not been recommended. To date, it is not recommended that heterozygotes avoid radiation therapy at conventional doses or diagnostic x-rays or CT scans. Heterozygotes should be made aware of lifestyle factors that contribute to cardiovascular diseases, but no specific screening has been recommended [ • Females heterozygous for the • Females heterozygous for any other • Radiation therapy at conventional doses is not contraindicated in females heterozygous for an • To date, intensified screening for other types of cancer have not been recommended. • To date, it is not recommended that heterozygotes avoid radiation therapy at conventional doses or diagnostic x-rays or CT scans. ## Agents/Circumstances to Avoid Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas [ Ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity [ Radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications [ • Rubella vaccination should be avoided in individuals with severe immunodeficiency as it can possibly increase the risk for granulomas [ • Ionizing radiation (x-ray and gamma ray) is contraindicated, due to increased sensitivity [ • Radiation therapy is contraindicated because increased radiosensitivity may lead to very severe complications [ ## Evaluation of Relatives at Risk It is appropriate to offer molecular genetic testing for the Sibs with biallelic Family members who are heterozygous for an See • Sibs with biallelic • Family members who are heterozygous for an ## Therapies Under Investigation Currently, a multicenter randomized controlled trial with Search ## Genetic Counseling Ataxia-telangiectasia (A-T) is caused by biallelic pathogenic variants in The parents of an affected child are presumed to be heterozygous for an Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. Although individuals heterozygous for an If both parents are known to be heterozygous for an Sibs with biallelic Although individuals heterozygous for an Although most individuals with A-T do not reproduce, exceptions have been reported [ The offspring of an individual with A-T are obligate heterozygotes for a pathogenic variant in Heterozygote testing for at-risk relatives requires prior identification of the Although individuals with a heterozygous See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The 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. • Although individuals 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 • Sibs with biallelic • Although individuals heterozygous for an • Although most individuals with A-T do not reproduce, exceptions have been reported [ • The offspring of an individual with A-T are obligate heterozygotes for a pathogenic variant in • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance Ataxia-telangiectasia (A-T) is caused by biallelic pathogenic variants in ## 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. Although individuals heterozygous for an If both parents are known to be heterozygous for an Sibs with biallelic Although individuals heterozygous for an Although most individuals with A-T do not reproduce, exceptions have been reported [ The offspring of an individual with A-T are obligate heterozygotes for a pathogenic variant in • The parents of an affected child are presumed to be heterozygous for an • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • 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. • Although individuals 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 • Sibs with biallelic • Although individuals heterozygous for an • Although most individuals with A-T do not reproduce, exceptions have been reported [ • The offspring of an individual with A-T are obligate heterozygotes for a pathogenic variant in ## Heterozygote Detection Heterozygote testing for at-risk relatives requires prior identification of the Although individuals with a heterozygous ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are heterozygous, or are at risk of being heterozygous. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Ataxia-Telangiectasia Children's Project United Kingdom PO Box 8126 Gaithersburg MD 20898-8126 Netherlands Health Resources & Services Administration • • Ataxia-Telangiectasia Children's Project • • • United Kingdom • • • • • • • • • PO Box 8126 • Gaithersburg MD 20898-8126 • • • Netherlands • • • • • Health Resources & Services Administration • • • ## Molecular Genetics Ataxia-Telangiectasia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ataxia-Telangiectasia ( Individuals with classic A-T have no ATM kinase activity, whereas individuals with variant A-T have residual ATM kinase activity, and – compared to classic A-T – have a less severe disease course [ If a variant of uncertain significance (VUS) is identified, additional testing such as immunoblotting for ATM and/or functional analysis of ATM kinase activity is recommended. Intronic variant causing a pseudo-exon inclusion Founder variant in UK assoc w/variant A-T [ 4/6 persons homozygous for this variant had variant A-T & normal serum AFP levels [ Assoc w/high risk of breast cancer in homozygotes & heterozygotes [ Variants listed in the table have been provided by the authors. AFP = alpha-fetoprotein; A-T = ataxia-telangiectasia • Intronic variant causing a pseudo-exon inclusion • Founder variant in UK assoc w/variant A-T [ • 4/6 persons homozygous for this variant had variant A-T & normal serum AFP levels [ • Assoc w/high risk of breast cancer in homozygotes & heterozygotes [ ## Molecular Pathogenesis Individuals with classic A-T have no ATM kinase activity, whereas individuals with variant A-T have residual ATM kinase activity, and – compared to classic A-T – have a less severe disease course [ If a variant of uncertain significance (VUS) is identified, additional testing such as immunoblotting for ATM and/or functional analysis of ATM kinase activity is recommended. Intronic variant causing a pseudo-exon inclusion Founder variant in UK assoc w/variant A-T [ 4/6 persons homozygous for this variant had variant A-T & normal serum AFP levels [ Assoc w/high risk of breast cancer in homozygotes & heterozygotes [ Variants listed in the table have been provided by the authors. AFP = alpha-fetoprotein; A-T = ataxia-telangiectasia • Intronic variant causing a pseudo-exon inclusion • Founder variant in UK assoc w/variant A-T [ • 4/6 persons homozygous for this variant had variant A-T & normal serum AFP levels [ • Assoc w/high risk of breast cancer in homozygotes & heterozygotes [ ## Chapter Notes We want to thank all our colleagues from the multidisciplinary ataxia-telangiectasia (A-T) team at the Radboud University Medical Center for their cooperation. We also want to thank the Twan Foundation (Veenendaal, the Netherlands) for their financial support of A-T research and their social support of affected individuals and their families. Richard Gatti, MD; David Geffen School of Medicine at UCLA (1999-2023)Erik-Jan Kamsteeg, MD, PhD (2023-present)Susan Perlman, MD; David Geffen School of Medicine at UCLA (2016-2023)Nienke van Os, MD, PhD (2023-present)Stefanie Veenhuis, MD (2023-present)Corry Weemaes, MD, PhD (2023-present)Michèl Willemsen, MD, PhD (2023-present) 5 October 2023 (bp) Comprehensive update posted live 27 October 2016 (bp) Comprehensive update posted live 11 March 2010 (me) Comprehensive update posted live 15 February 2005 (me) Comprehensive update posted live 8 October 2002 (me) Comprehensive update posted live 19 March 1999 (pb) Review posted live 13 April 1998 (rg) Original submission • 5 October 2023 (bp) Comprehensive update posted live • 27 October 2016 (bp) Comprehensive update posted live • 11 March 2010 (me) Comprehensive update posted live • 15 February 2005 (me) Comprehensive update posted live • 8 October 2002 (me) Comprehensive update posted live • 19 March 1999 (pb) Review posted live • 13 April 1998 (rg) Original submission ## Acknowledgments We want to thank all our colleagues from the multidisciplinary ataxia-telangiectasia (A-T) team at the Radboud University Medical Center for their cooperation. We also want to thank the Twan Foundation (Veenendaal, the Netherlands) for their financial support of A-T research and their social support of affected individuals and their families. ## Author History Richard Gatti, MD; David Geffen School of Medicine at UCLA (1999-2023)Erik-Jan Kamsteeg, MD, PhD (2023-present)Susan Perlman, MD; David Geffen School of Medicine at UCLA (2016-2023)Nienke van Os, MD, PhD (2023-present)Stefanie Veenhuis, MD (2023-present)Corry Weemaes, MD, PhD (2023-present)Michèl Willemsen, MD, PhD (2023-present) ## Revision History 5 October 2023 (bp) Comprehensive update posted live 27 October 2016 (bp) Comprehensive update posted live 11 March 2010 (me) Comprehensive update posted live 15 February 2005 (me) Comprehensive update posted live 8 October 2002 (me) Comprehensive update posted live 19 March 1999 (pb) Review posted live 13 April 1998 (rg) Original submission • 5 October 2023 (bp) Comprehensive update posted live • 27 October 2016 (bp) Comprehensive update posted live • 11 March 2010 (me) Comprehensive update posted live • 15 February 2005 (me) Comprehensive update posted live • 8 October 2002 (me) Comprehensive update posted live • 19 March 1999 (pb) Review posted live • 13 April 1998 (rg) Original submission ## References ## Literature Cited	[]	19/3/1999	5/10/2023	10/4/2003	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ataxias	ataxias	[ "Alpha-tocopherol transfer protein", "Angiopoietin-related protein 3", "Anoctamin-10", "Apolipoprotein B-100", "Aprataxin", "Ataxin-1", "Ataxin-10", "Ataxin-2", "Ataxin-3", "Ataxin-7", "Ataxin-8", "Atrophin-1", "A-type voltage-gated potassium channel KCND3", "Atypical kinase ADCK3, mitochondrial", "Fibroblast growth factor 14", "Fragile X messenger ribonucleoprotein 1", "Frataxin, mitochondrial", "Inositol 1,4,5-trisphosphate-gated calcium channel ITPR1", "Microsomal triglyceride transfer protein large subunit", "Mitochondrial inner membrane m-AAA protease component AFG3L2", "Mitochondrial inner membrane m-AAA protease component paraplegin", "Nesprin-1", "Nucleolar protein 56", "Para-hydroxybenzoate--polyprenyltransferase, mitochondrial", "Probable helicase senataxin", "Protein BEAN1", "Protein kinase C gamma type", "Replication factor C subunit 1", "Sacsin", "Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform", "Serine-protein kinase ATM", "Spectrin beta chain, non-erythrocytic 2", "TATA-box-binding protein", "Ubiquinone biosynthesis protein COQ4 homolog, mitochondrial", "Voltage-dependent P/Q-type calcium channel subunit alpha-1A", "Voltage-gated potassium channel KCNC3", "Zinc finger homeobox protein 3", "AFG3L2", "ANGPTL3", "ANO10", "APOB", "APTX", "ATM", "ATN1", "ATXN1", "ATXN10", "ATXN2", "ATXN3", "ATXN7", "ATXN8", "ATXN8OS", "BEAN1", "CACNA1A", "COQ2", "COQ4", "COQ8A", "FGF14", "FMR1", "FXN", "ITPR1", "KCNC3", "KCND3", "MTTP", "NOP56", "PPP2R2B", "PRKCG", "RFC1", "SACS", "SETX", "SPG7", "SPTBN2", "SYNE1", "TBP", "TTPA", "ZFHX3", "Hereditary Ataxia", "Overview" ]	Hereditary Ataxia Overview	Susan Perlman	Summary The purpose of this overview is to: Briefly describe the Review common and notable Provide an Review Inform	## Clinical Characteristics of Primary Hereditary Ataxia For the purposes of this chapter, which deals exclusively with hereditary ataxias, the term "primary hereditary ataxia" has been used to designate hereditary ataxias for which an adult with ataxia or the caregivers of a child with ataxia would seek diagnosis and management from a neurologist as part of a multidisciplinary team. Use of the term "primary hereditary ataxia" is intended to exclude hereditary multisystem disorders in which ataxia may be observed, but is usually not the primary presenting manifestation. For the purposes of this overview the following categories of hereditary disorders in which ataxia may occur are not considered primary hereditary ataxias: Infantile-onset multisystem disorder Epileptic encephalopathy Presence of distinctive MRI findings: Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in Leukodystrophy Developmental delay / intellectual disability An inborn error of metabolism (e.g., Primary mitochondrial disorders (See Other complex multisystem disorders such as The manifestations of many of the more common primary hereditary ataxias discussed in The Most commonly, a slowly progressive gait disorder that appears unsteady and predisposes to unexpected falls; Disequilibrium ("dizziness"), which may lead to an evaluation for peripheral vestibular dysfunction; Hand and finger clumsiness or tremor, which may raise the possibility of essential tremor or even parkinsonism; Slurring of speech or unexpected choking, which could lead to an evaluation for Rarely, double vision, which could lead to an evaluation by an optometrist or ophthalmologist. At disease onset, these manifestations may be intermittent or evident only at certain times (e.g., later in the day, when tired, after consuming alcohol). The manifestations typically become constant and slowly worsen. Typical Wide-based, staggering walk with difficulty performing tandem gait; Truncal instability when sitting unsupported; Difficulty with target maneuvers of the upper extremities (dysmetria, terminal tremor); Slowed rapid alternating movements (dysdiadochokinesis); Dysarthria (slowed or slurred articulation, variable pitch and loudness, monotonous or "scanning" speech); Abnormal eye movements (saccade intrusions in primary gaze, nystagmus in horizontal or vertical gaze, saccade hypermetria). Alterations in descending frontal or parietal motor pathways (e.g., in normal pressure hydrocephalus); Brain stem changes that disrupt cerebellar pathways (e.g., in central vestibular dysfunction); Sensory pathway dysfunctions that alter input to the cerebellum (visual, peripheral vestibular, posterior column, peripheral sensory); Other sources of motor change, especially as they affect gait (weakness, rigidity, spasticity); Non-neurologic disorders (e.g., joint disease). Brain imaging (MRI, MRS, PET) confirms the presence of cerebellar atrophy or hypoplasia. Electronystagmography can document dysfunction in cerebellar, vestibular, or oculomotor pathways. Use of assistive devices for ambulation five to ten years after onset and ultimately to wheelchair dependence; Choking or falls resulting in, for example, head injury or hip fracture, which are common causes of morbidity and mortality; Infection and sepsis (from aspiration or other pneumonia, urinary tract infection, decubiti), especially prominent in the later stages of disease; Decline in self-care ability, increasing risk of falls, dependence on a feeding tube, and/or incontinence; The family or caregiver's need to consider more in-home care assistance or out-of-home placement. Affected individuals do not usually live longer than 25 years after manifestations emerge. See • Infantile-onset multisystem disorder • Epileptic encephalopathy • Presence of distinctive MRI findings: • Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in • Leukodystrophy • Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in • Leukodystrophy • Developmental delay / intellectual disability • An inborn error of metabolism (e.g., • Primary mitochondrial disorders (See • Other complex multisystem disorders such as • Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in • Leukodystrophy • Most commonly, a slowly progressive gait disorder that appears unsteady and predisposes to unexpected falls; • Disequilibrium ("dizziness"), which may lead to an evaluation for peripheral vestibular dysfunction; • Hand and finger clumsiness or tremor, which may raise the possibility of essential tremor or even parkinsonism; • Slurring of speech or unexpected choking, which could lead to an evaluation for • Rarely, double vision, which could lead to an evaluation by an optometrist or ophthalmologist. • Wide-based, staggering walk with difficulty performing tandem gait; • Truncal instability when sitting unsupported; • Difficulty with target maneuvers of the upper extremities (dysmetria, terminal tremor); • Slowed rapid alternating movements (dysdiadochokinesis); • Dysarthria (slowed or slurred articulation, variable pitch and loudness, monotonous or "scanning" speech); • Abnormal eye movements (saccade intrusions in primary gaze, nystagmus in horizontal or vertical gaze, saccade hypermetria). • Alterations in descending frontal or parietal motor pathways (e.g., in normal pressure hydrocephalus); • Brain stem changes that disrupt cerebellar pathways (e.g., in central vestibular dysfunction); • Sensory pathway dysfunctions that alter input to the cerebellum (visual, peripheral vestibular, posterior column, peripheral sensory); • Other sources of motor change, especially as they affect gait (weakness, rigidity, spasticity); • Non-neurologic disorders (e.g., joint disease). • Use of assistive devices for ambulation five to ten years after onset and ultimately to wheelchair dependence; • Choking or falls resulting in, for example, head injury or hip fracture, which are common causes of morbidity and mortality; • Infection and sepsis (from aspiration or other pneumonia, urinary tract infection, decubiti), especially prominent in the later stages of disease; • Decline in self-care ability, increasing risk of falls, dependence on a feeding tube, and/or incontinence; • The family or caregiver's need to consider more in-home care assistance or out-of-home placement. ## Excluded Categories For the purposes of this overview the following categories of hereditary disorders in which ataxia may occur are not considered primary hereditary ataxias: Infantile-onset multisystem disorder Epileptic encephalopathy Presence of distinctive MRI findings: Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in Leukodystrophy Developmental delay / intellectual disability An inborn error of metabolism (e.g., Primary mitochondrial disorders (See Other complex multisystem disorders such as • Infantile-onset multisystem disorder • Epileptic encephalopathy • Presence of distinctive MRI findings: • Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in • Leukodystrophy • Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in • Leukodystrophy • Developmental delay / intellectual disability • An inborn error of metabolism (e.g., • Primary mitochondrial disorders (See • Other complex multisystem disorders such as • Brain malformation (e.g., cerebellar hypoplasia, cerebellar vermis hypoplasia as in • Leukodystrophy ## Manifestations The manifestations of many of the more common primary hereditary ataxias discussed in The Most commonly, a slowly progressive gait disorder that appears unsteady and predisposes to unexpected falls; Disequilibrium ("dizziness"), which may lead to an evaluation for peripheral vestibular dysfunction; Hand and finger clumsiness or tremor, which may raise the possibility of essential tremor or even parkinsonism; Slurring of speech or unexpected choking, which could lead to an evaluation for Rarely, double vision, which could lead to an evaluation by an optometrist or ophthalmologist. At disease onset, these manifestations may be intermittent or evident only at certain times (e.g., later in the day, when tired, after consuming alcohol). The manifestations typically become constant and slowly worsen. Typical Wide-based, staggering walk with difficulty performing tandem gait; Truncal instability when sitting unsupported; Difficulty with target maneuvers of the upper extremities (dysmetria, terminal tremor); Slowed rapid alternating movements (dysdiadochokinesis); Dysarthria (slowed or slurred articulation, variable pitch and loudness, monotonous or "scanning" speech); Abnormal eye movements (saccade intrusions in primary gaze, nystagmus in horizontal or vertical gaze, saccade hypermetria). Alterations in descending frontal or parietal motor pathways (e.g., in normal pressure hydrocephalus); Brain stem changes that disrupt cerebellar pathways (e.g., in central vestibular dysfunction); Sensory pathway dysfunctions that alter input to the cerebellum (visual, peripheral vestibular, posterior column, peripheral sensory); Other sources of motor change, especially as they affect gait (weakness, rigidity, spasticity); Non-neurologic disorders (e.g., joint disease). Brain imaging (MRI, MRS, PET) confirms the presence of cerebellar atrophy or hypoplasia. Electronystagmography can document dysfunction in cerebellar, vestibular, or oculomotor pathways. Use of assistive devices for ambulation five to ten years after onset and ultimately to wheelchair dependence; Choking or falls resulting in, for example, head injury or hip fracture, which are common causes of morbidity and mortality; Infection and sepsis (from aspiration or other pneumonia, urinary tract infection, decubiti), especially prominent in the later stages of disease; Decline in self-care ability, increasing risk of falls, dependence on a feeding tube, and/or incontinence; The family or caregiver's need to consider more in-home care assistance or out-of-home placement. Affected individuals do not usually live longer than 25 years after manifestations emerge. See • Most commonly, a slowly progressive gait disorder that appears unsteady and predisposes to unexpected falls; • Disequilibrium ("dizziness"), which may lead to an evaluation for peripheral vestibular dysfunction; • Hand and finger clumsiness or tremor, which may raise the possibility of essential tremor or even parkinsonism; • Slurring of speech or unexpected choking, which could lead to an evaluation for • Rarely, double vision, which could lead to an evaluation by an optometrist or ophthalmologist. • Wide-based, staggering walk with difficulty performing tandem gait; • Truncal instability when sitting unsupported; • Difficulty with target maneuvers of the upper extremities (dysmetria, terminal tremor); • Slowed rapid alternating movements (dysdiadochokinesis); • Dysarthria (slowed or slurred articulation, variable pitch and loudness, monotonous or "scanning" speech); • Abnormal eye movements (saccade intrusions in primary gaze, nystagmus in horizontal or vertical gaze, saccade hypermetria). • Alterations in descending frontal or parietal motor pathways (e.g., in normal pressure hydrocephalus); • Brain stem changes that disrupt cerebellar pathways (e.g., in central vestibular dysfunction); • Sensory pathway dysfunctions that alter input to the cerebellum (visual, peripheral vestibular, posterior column, peripheral sensory); • Other sources of motor change, especially as they affect gait (weakness, rigidity, spasticity); • Non-neurologic disorders (e.g., joint disease). • Use of assistive devices for ambulation five to ten years after onset and ultimately to wheelchair dependence; • Choking or falls resulting in, for example, head injury or hip fracture, which are common causes of morbidity and mortality; • Infection and sepsis (from aspiration or other pneumonia, urinary tract infection, decubiti), especially prominent in the later stages of disease; • Decline in self-care ability, increasing risk of falls, dependence on a feeding tube, and/or incontinence; • The family or caregiver's need to consider more in-home care assistance or out-of-home placement. ## Causes of Hereditary Ataxia Note: Up to 40% of adults with late-onset cerebellar ataxia and no family history of ataxia will not have an identified genetic cause despite a comprehensive evaluation (see The causes of primary hereditary ataxia included in this overview are separated into nucleotide repeat disorders ( The nucleotide repeat disorders (see In nucleotide repeat disorders, a sequence of nucleotides is repeated a number of times in tandem within a gene (in an exon or intron) or near a gene. For a given gene, the size of the nucleotide repeats varies: smaller numbers of repeats are common and not associated with phenotypic abnormalities, whereas abnormally large numbers of repeats (uninterrupted or interrupted) may be associated with phenotypic abnormalities. All three modes of inheritance can be observed in nucleotide repeat disorders: autosomal dominant, autosomal recessive, and X-linked. Hereditary Ataxias Caused by Nucleotide Repeat Expansions Anticipation is prominent. More common in Japan Anticipation is more likely w/paternal transmission. Large Cuban founder population Anticipation may be more likely w/paternal transmission. Large Portuguese founder population Also known as Machado-Joseph disease Anticipation can occur w/paternal transmission. Large Mexican founder population Anticipation is not seen. See Differential diagnosis: Manifestations responsive to 4-aminopyridine Anticipation is not seen. Targeted therapy: omaveloxolone has been shown to slow progression of FRDA. Anticipation occurs almost exclusively w/maternal transmission. Most common X-linked ataxia; occurs in male & female premutation carriers DRPLA = dentatorubral-pallidoluysian atrophy; DTR = deep tendon reflex; FRDA = Friedreich ataxia; SCA = spinocerebellar ataxia Genes are listed in alphabetic order within prevalence categories. For more information see hyperlinked Nucleotide repeat expansions in Most Common Hereditary Ataxias (Excluding Nucleotide Repeat Disorders) Based on AD = autosomal dominant; ARCA = autosomal recessive cerebellar ataxia; MOI = mode of inheritance; SCA = spinocerebellar ataxia; SCAR = spinocerebellar ataxia, autosomal recessive; SPAX = spastic ataxia, autosomal recessive Genes are listed in alphabetic order. Allelic disorders include The disorder may occur as the result of a Allelic disorder: Allelic disorder: Allelic phenotype: arthrogryposis multiplex congenita (See Genetic Causes of Vitamin E Deficiency (Treatable with Vitamin E Replacement) Based on AR = autosomal recessive; DTR = deep tendon reflex; MOI = mode of inheritance Genes are listed in alphabetic order. Primary Coenzyme Q AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SNHL = sensorineural hearing loss; SRNS = steroid-resistant nephrotic syndrome Genes are listed in alphabetic order. Onset usually in infancy or early childhood • Anticipation is prominent. • More common in Japan • Anticipation is more likely w/paternal transmission. • Large Cuban founder population • Anticipation may be more likely w/paternal transmission. • Large Portuguese founder population • Also known as Machado-Joseph disease • Anticipation can occur w/paternal transmission. • Large Mexican founder population • Anticipation is not seen. • See • Differential diagnosis: • Manifestations responsive to 4-aminopyridine • Anticipation is not seen. • Targeted therapy: omaveloxolone has been shown to slow progression of FRDA. • Anticipation occurs almost exclusively w/maternal transmission. • Most common X-linked ataxia; occurs in male & female premutation carriers ## Nucleotide Repeat Disorders The nucleotide repeat disorders (see In nucleotide repeat disorders, a sequence of nucleotides is repeated a number of times in tandem within a gene (in an exon or intron) or near a gene. For a given gene, the size of the nucleotide repeats varies: smaller numbers of repeats are common and not associated with phenotypic abnormalities, whereas abnormally large numbers of repeats (uninterrupted or interrupted) may be associated with phenotypic abnormalities. All three modes of inheritance can be observed in nucleotide repeat disorders: autosomal dominant, autosomal recessive, and X-linked. Hereditary Ataxias Caused by Nucleotide Repeat Expansions Anticipation is prominent. More common in Japan Anticipation is more likely w/paternal transmission. Large Cuban founder population Anticipation may be more likely w/paternal transmission. Large Portuguese founder population Also known as Machado-Joseph disease Anticipation can occur w/paternal transmission. Large Mexican founder population Anticipation is not seen. See Differential diagnosis: Manifestations responsive to 4-aminopyridine Anticipation is not seen. Targeted therapy: omaveloxolone has been shown to slow progression of FRDA. Anticipation occurs almost exclusively w/maternal transmission. Most common X-linked ataxia; occurs in male & female premutation carriers DRPLA = dentatorubral-pallidoluysian atrophy; DTR = deep tendon reflex; FRDA = Friedreich ataxia; SCA = spinocerebellar ataxia Genes are listed in alphabetic order within prevalence categories. For more information see hyperlinked Nucleotide repeat expansions in • Anticipation is prominent. • More common in Japan • Anticipation is more likely w/paternal transmission. • Large Cuban founder population • Anticipation may be more likely w/paternal transmission. • Large Portuguese founder population • Also known as Machado-Joseph disease • Anticipation can occur w/paternal transmission. • Large Mexican founder population • Anticipation is not seen. • See • Differential diagnosis: • Manifestations responsive to 4-aminopyridine • Anticipation is not seen. • Targeted therapy: omaveloxolone has been shown to slow progression of FRDA. • Anticipation occurs almost exclusively w/maternal transmission. • Most common X-linked ataxia; occurs in male & female premutation carriers ## Molecular Mechanism In nucleotide repeat disorders, a sequence of nucleotides is repeated a number of times in tandem within a gene (in an exon or intron) or near a gene. For a given gene, the size of the nucleotide repeats varies: smaller numbers of repeats are common and not associated with phenotypic abnormalities, whereas abnormally large numbers of repeats (uninterrupted or interrupted) may be associated with phenotypic abnormalities. ## Inheritance Issues All three modes of inheritance can be observed in nucleotide repeat disorders: autosomal dominant, autosomal recessive, and X-linked. Hereditary Ataxias Caused by Nucleotide Repeat Expansions Anticipation is prominent. More common in Japan Anticipation is more likely w/paternal transmission. Large Cuban founder population Anticipation may be more likely w/paternal transmission. Large Portuguese founder population Also known as Machado-Joseph disease Anticipation can occur w/paternal transmission. Large Mexican founder population Anticipation is not seen. See Differential diagnosis: Manifestations responsive to 4-aminopyridine Anticipation is not seen. Targeted therapy: omaveloxolone has been shown to slow progression of FRDA. Anticipation occurs almost exclusively w/maternal transmission. Most common X-linked ataxia; occurs in male & female premutation carriers DRPLA = dentatorubral-pallidoluysian atrophy; DTR = deep tendon reflex; FRDA = Friedreich ataxia; SCA = spinocerebellar ataxia Genes are listed in alphabetic order within prevalence categories. For more information see hyperlinked Nucleotide repeat expansions in • Anticipation is prominent. • More common in Japan • Anticipation is more likely w/paternal transmission. • Large Cuban founder population • Anticipation may be more likely w/paternal transmission. • Large Portuguese founder population • Also known as Machado-Joseph disease • Anticipation can occur w/paternal transmission. • Large Mexican founder population • Anticipation is not seen. • See • Differential diagnosis: • Manifestations responsive to 4-aminopyridine • Anticipation is not seen. • Targeted therapy: omaveloxolone has been shown to slow progression of FRDA. • Anticipation occurs almost exclusively w/maternal transmission. • Most common X-linked ataxia; occurs in male & female premutation carriers ## Other Common Hereditary Ataxias Most Common Hereditary Ataxias (Excluding Nucleotide Repeat Disorders) Based on AD = autosomal dominant; ARCA = autosomal recessive cerebellar ataxia; MOI = mode of inheritance; SCA = spinocerebellar ataxia; SCAR = spinocerebellar ataxia, autosomal recessive; SPAX = spastic ataxia, autosomal recessive Genes are listed in alphabetic order. Allelic disorders include The disorder may occur as the result of a Allelic disorder: Allelic disorder: Allelic phenotype: arthrogryposis multiplex congenita (See ## Potentially Treatable Hereditary Ataxias Genetic Causes of Vitamin E Deficiency (Treatable with Vitamin E Replacement) Based on AR = autosomal recessive; DTR = deep tendon reflex; MOI = mode of inheritance Genes are listed in alphabetic order. Primary Coenzyme Q AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; SNHL = sensorineural hearing loss; SRNS = steroid-resistant nephrotic syndrome Genes are listed in alphabetic order. Onset usually in infancy or early childhood ## Evaluation Strategies to Identify the Genetic Cause of Hereditary Ataxia in a Proband Establishing a specific genetic cause of primary hereditary ataxia (as defined in this chapter): 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. Most of the common primary hereditary ataxias start similarly with an unsteady gait, imbalance or "dizziness," unexpected falls, clumsiness, and tremors. Distinctive features of the medical history that could suggest a specific diagnosis (see Age of onset: After age 50 years: SCA6 Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 Before age five years: ataxia-telangiectasia Infantile: SCA2, SCA7 Onset with episodic features: SCA6, the episodic ataxias Associated with: Retinopathy: SCA7 Seizure disorder: SCA10, infantile-onset SCA7, DRPLA Dementia: SCA2, SCA17, DRPLA Severe dizziness or vertigo: SCA3, SCA6, Muscle cramping: SCA2, SCA3 Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia Immunodeficiency or cancer: ataxia-telangiectasia All the primary hereditary ataxias have cerebellar features, but some have specific cerebellar or extracerebellar changes on examination that can suggest a specific diagnosis (see Early presence of slowed oculomotor saccades: SCA2, SCA7 Ophthalmoplegia: SCA1, SCA2, SCA3 Oculomotor apraxia: ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2 Fixation instability (saccade intrusions) in primary gaze: Friedreich ataxia Ocular conjunctival and skin telangiectases: ataxia-telangiectasia Downbeat nystagmus: SCA6 and episodic ataxia type 2 Central or peripheral vestibular involvement: SCA3, SCA6, Motor unit fasciculations: SCA2, SCA3 Peripheral neuropathy: SCA3, Spasticity: SCA1, SCA3, SCA7 Extrapyramidal signs: SCA1, SCA2, SCA3, SCA17, DRPLA Absent deep tendon reflexes and upgoing toes: Friedreich ataxia A three-generation family history should be taken with attention to relatives with manifestations of hereditary ataxia and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing, neuroimaging studies, and autopsy examinations. Findings in the family that may assist in narrowing the scope of relevant hereditary ataxias include the following: Earlier onset and increasing severity of disease in subsequent generations suggest an autosomal dominant nucleotide repeat disorder associated with anticipation (see An affected parent or grandparent suggests autosomal dominant inheritance. No male-to-male transmission of the disorder suggests X-linked inheritance. Affected sibs or consanguinity suggests autosomal recessive inheritance. Note: In communities with a high prevalence of an autosomal recessive ataxia (e.g., the Late-onset cerebellar ataxia in a grandfather who has a grandson with intellectual disability suggests Note: In the absence of a molecularly confirmed ataxia, reports of balance problems in a grandparent, parent, or sib do not necessarily indicate a shared genetic cause. Multifactorial and acquired cerebellar disorders, which are four to five times more common than inherited ataxias, can confuse a family history. Note that commercially available multigene panels that rely on sequence analysis alone will not identify these nucleotide repeat expansions; thus, specific assays are required to analyze the nucleotide repeat in each gene of interest. Options offered by some laboratories: A multigene "repeat expansion" panel to specifically identify nucleotide repeat expansions A multigene ataxia panel that combines both repeat expansion testing and sequence-based testing analysis For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, family history, and genomic/genetic testing. • Age of onset: • After age 50 years: SCA6 • Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 • Before age five years: ataxia-telangiectasia • Infantile: SCA2, SCA7 • After age 50 years: SCA6 • Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 • Before age five years: ataxia-telangiectasia • Infantile: SCA2, SCA7 • Onset with episodic features: SCA6, the episodic ataxias • Associated with: • Retinopathy: SCA7 • Seizure disorder: SCA10, infantile-onset SCA7, DRPLA • Dementia: SCA2, SCA17, DRPLA • Severe dizziness or vertigo: SCA3, SCA6, • Muscle cramping: SCA2, SCA3 • Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia • Immunodeficiency or cancer: ataxia-telangiectasia • Retinopathy: SCA7 • Seizure disorder: SCA10, infantile-onset SCA7, DRPLA • Dementia: SCA2, SCA17, DRPLA • Severe dizziness or vertigo: SCA3, SCA6, • Muscle cramping: SCA2, SCA3 • Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia • Immunodeficiency or cancer: ataxia-telangiectasia • After age 50 years: SCA6 • Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 • Before age five years: ataxia-telangiectasia • Infantile: SCA2, SCA7 • Retinopathy: SCA7 • Seizure disorder: SCA10, infantile-onset SCA7, DRPLA • Dementia: SCA2, SCA17, DRPLA • Severe dizziness or vertigo: SCA3, SCA6, • Muscle cramping: SCA2, SCA3 • Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia • Immunodeficiency or cancer: ataxia-telangiectasia • Early presence of slowed oculomotor saccades: SCA2, SCA7 • Ophthalmoplegia: SCA1, SCA2, SCA3 • Oculomotor apraxia: ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2 • Fixation instability (saccade intrusions) in primary gaze: Friedreich ataxia • Ocular conjunctival and skin telangiectases: ataxia-telangiectasia • Downbeat nystagmus: SCA6 and episodic ataxia type 2 • Central or peripheral vestibular involvement: SCA3, SCA6, • Motor unit fasciculations: SCA2, SCA3 • Peripheral neuropathy: SCA3, • Spasticity: SCA1, SCA3, SCA7 • Extrapyramidal signs: SCA1, SCA2, SCA3, SCA17, DRPLA • Absent deep tendon reflexes and upgoing toes: Friedreich ataxia • Earlier onset and increasing severity of disease in subsequent generations suggest an autosomal dominant nucleotide repeat disorder associated with anticipation (see • An affected parent or grandparent suggests autosomal dominant inheritance. • No male-to-male transmission of the disorder suggests X-linked inheritance. • Affected sibs or consanguinity suggests autosomal recessive inheritance. Note: In communities with a high prevalence of an autosomal recessive ataxia (e.g., the • Late-onset cerebellar ataxia in a grandfather who has a grandson with intellectual disability suggests • Note: In the absence of a molecularly confirmed ataxia, reports of balance problems in a grandparent, parent, or sib do not necessarily indicate a shared genetic cause. Multifactorial and acquired cerebellar disorders, which are four to five times more common than inherited ataxias, can confuse a family history. • A multigene "repeat expansion" panel to specifically identify nucleotide repeat expansions • A multigene ataxia panel that combines both repeat expansion testing and sequence-based testing analysis • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Medical History Most of the common primary hereditary ataxias start similarly with an unsteady gait, imbalance or "dizziness," unexpected falls, clumsiness, and tremors. Distinctive features of the medical history that could suggest a specific diagnosis (see Age of onset: After age 50 years: SCA6 Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 Before age five years: ataxia-telangiectasia Infantile: SCA2, SCA7 Onset with episodic features: SCA6, the episodic ataxias Associated with: Retinopathy: SCA7 Seizure disorder: SCA10, infantile-onset SCA7, DRPLA Dementia: SCA2, SCA17, DRPLA Severe dizziness or vertigo: SCA3, SCA6, Muscle cramping: SCA2, SCA3 Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia Immunodeficiency or cancer: ataxia-telangiectasia • Age of onset: • After age 50 years: SCA6 • Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 • Before age five years: ataxia-telangiectasia • Infantile: SCA2, SCA7 • After age 50 years: SCA6 • Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 • Before age five years: ataxia-telangiectasia • Infantile: SCA2, SCA7 • Onset with episodic features: SCA6, the episodic ataxias • Associated with: • Retinopathy: SCA7 • Seizure disorder: SCA10, infantile-onset SCA7, DRPLA • Dementia: SCA2, SCA17, DRPLA • Severe dizziness or vertigo: SCA3, SCA6, • Muscle cramping: SCA2, SCA3 • Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia • Immunodeficiency or cancer: ataxia-telangiectasia • Retinopathy: SCA7 • Seizure disorder: SCA10, infantile-onset SCA7, DRPLA • Dementia: SCA2, SCA17, DRPLA • Severe dizziness or vertigo: SCA3, SCA6, • Muscle cramping: SCA2, SCA3 • Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia • Immunodeficiency or cancer: ataxia-telangiectasia • After age 50 years: SCA6 • Before age 20 years: Friedreich ataxia, ataxia with oculomotor apraxia types 1 and 2 • Before age five years: ataxia-telangiectasia • Infantile: SCA2, SCA7 • Retinopathy: SCA7 • Seizure disorder: SCA10, infantile-onset SCA7, DRPLA • Dementia: SCA2, SCA17, DRPLA • Severe dizziness or vertigo: SCA3, SCA6, • Muscle cramping: SCA2, SCA3 • Scoliosis, pes cavus, cardiomyopathy: Friedreich ataxia • Immunodeficiency or cancer: ataxia-telangiectasia ## Physical Examination All the primary hereditary ataxias have cerebellar features, but some have specific cerebellar or extracerebellar changes on examination that can suggest a specific diagnosis (see Early presence of slowed oculomotor saccades: SCA2, SCA7 Ophthalmoplegia: SCA1, SCA2, SCA3 Oculomotor apraxia: ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2 Fixation instability (saccade intrusions) in primary gaze: Friedreich ataxia Ocular conjunctival and skin telangiectases: ataxia-telangiectasia Downbeat nystagmus: SCA6 and episodic ataxia type 2 Central or peripheral vestibular involvement: SCA3, SCA6, Motor unit fasciculations: SCA2, SCA3 Peripheral neuropathy: SCA3, Spasticity: SCA1, SCA3, SCA7 Extrapyramidal signs: SCA1, SCA2, SCA3, SCA17, DRPLA Absent deep tendon reflexes and upgoing toes: Friedreich ataxia • Early presence of slowed oculomotor saccades: SCA2, SCA7 • Ophthalmoplegia: SCA1, SCA2, SCA3 • Oculomotor apraxia: ataxia-telangiectasia, ataxia with oculomotor apraxia types 1 and 2 • Fixation instability (saccade intrusions) in primary gaze: Friedreich ataxia • Ocular conjunctival and skin telangiectases: ataxia-telangiectasia • Downbeat nystagmus: SCA6 and episodic ataxia type 2 • Central or peripheral vestibular involvement: SCA3, SCA6, • Motor unit fasciculations: SCA2, SCA3 • Peripheral neuropathy: SCA3, • Spasticity: SCA1, SCA3, SCA7 • Extrapyramidal signs: SCA1, SCA2, SCA3, SCA17, DRPLA • Absent deep tendon reflexes and upgoing toes: Friedreich ataxia ## Family History A three-generation family history should be taken with attention to relatives with manifestations of hereditary ataxia and documentation of relevant findings through direct examination or review of medical records, including results of molecular genetic testing, neuroimaging studies, and autopsy examinations. Findings in the family that may assist in narrowing the scope of relevant hereditary ataxias include the following: Earlier onset and increasing severity of disease in subsequent generations suggest an autosomal dominant nucleotide repeat disorder associated with anticipation (see An affected parent or grandparent suggests autosomal dominant inheritance. No male-to-male transmission of the disorder suggests X-linked inheritance. Affected sibs or consanguinity suggests autosomal recessive inheritance. Note: In communities with a high prevalence of an autosomal recessive ataxia (e.g., the Late-onset cerebellar ataxia in a grandfather who has a grandson with intellectual disability suggests Note: In the absence of a molecularly confirmed ataxia, reports of balance problems in a grandparent, parent, or sib do not necessarily indicate a shared genetic cause. Multifactorial and acquired cerebellar disorders, which are four to five times more common than inherited ataxias, can confuse a family history. • Earlier onset and increasing severity of disease in subsequent generations suggest an autosomal dominant nucleotide repeat disorder associated with anticipation (see • An affected parent or grandparent suggests autosomal dominant inheritance. • No male-to-male transmission of the disorder suggests X-linked inheritance. • Affected sibs or consanguinity suggests autosomal recessive inheritance. Note: In communities with a high prevalence of an autosomal recessive ataxia (e.g., the • Late-onset cerebellar ataxia in a grandfather who has a grandson with intellectual disability suggests • Note: In the absence of a molecularly confirmed ataxia, reports of balance problems in a grandparent, parent, or sib do not necessarily indicate a shared genetic cause. Multifactorial and acquired cerebellar disorders, which are four to five times more common than inherited ataxias, can confuse a family history. ## Molecular Genetic Testing Note that commercially available multigene panels that rely on sequence analysis alone will not identify these nucleotide repeat expansions; thus, specific assays are required to analyze the nucleotide repeat in each gene of interest. Options offered by some laboratories: A multigene "repeat expansion" panel to specifically identify nucleotide repeat expansions A multigene ataxia panel that combines both repeat expansion testing and sequence-based testing analysis For an introduction to multigene panels click For an introduction to comprehensive genomic testing click • A multigene "repeat expansion" panel to specifically identify nucleotide repeat expansions • A multigene ataxia panel that combines both repeat expansion testing and sequence-based testing analysis • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Management of Hereditary Ataxia To establish the extent of disease and needs of an individual diagnosed with a hereditary ataxia, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with a Hereditary Ataxia Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades, & smooth pursuit) UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperreflexia, amyotrophy, fasciculations) Vibration loss or polyneuropathy based on clinical findings Use standardized scale to establish baseline for ataxia (SARA). Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy. Brain MRI to evaluate presence & severity of cerebellar atrophy CCAS scale Psychiatrist, psychologist, neuropsychologist if needed. Community or Social work involvement for parental support Home nursing referral CCAS = cerebellar cognitive affective syndrome; EMG = electromyogram; LMN = lower motor neuron; NCS = nerve conduction study; OT = occupational therapy/therapist; PT = physical therapy/therapist; SARA = Scale for the Assessment and Rating of Ataxia; SLP = speech-language pathologist; UMN = upper motor neuron Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) The goals of supportive care are to maximize function and reduce complications. Depending on the clinical manifestations, affected individuals benefit from supportive care by a multidisciplinary team of specialists including neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech-language pathologists, pulmonologists, and mental health specialists. Treatment of Manifestations in Individuals with a Hereditary Ataxia 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 persons w/degenerative ataxias. Weight control to avoid obesity Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; UMN = upper motor neuron There are no published surveillance guidelines for hereditary ataxias in general. Recommended Surveillance for Individuals with a Hereditary Ataxia 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 the Assessment and Rating of Ataxia; UMN = upper motor neuron • Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades, & smooth pursuit) • UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperreflexia, amyotrophy, fasciculations) • Vibration loss or polyneuropathy based on clinical findings • Use standardized scale to establish baseline for ataxia (SARA). • Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy. • Brain MRI to evaluate presence & severity of cerebellar atrophy • CCAS scale • Psychiatrist, psychologist, neuropsychologist if needed. • Community or • Social work involvement for parental 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, muscle strengthening) to maintain mobility & function • OT to optimize ADL • Inpatient rehab w/OT/PT may improve ataxia & functional abilities in persons w/degenerative ataxias. • Weight control to avoid obesity • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) • 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 of an individual diagnosed with a hereditary ataxia, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with a Hereditary Ataxia Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades, & smooth pursuit) UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperreflexia, amyotrophy, fasciculations) Vibration loss or polyneuropathy based on clinical findings Use standardized scale to establish baseline for ataxia (SARA). Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy. Brain MRI to evaluate presence & severity of cerebellar atrophy CCAS scale Psychiatrist, psychologist, neuropsychologist if needed. Community or Social work involvement for parental support Home nursing referral CCAS = cerebellar cognitive affective syndrome; EMG = electromyogram; LMN = lower motor neuron; NCS = nerve conduction study; OT = occupational therapy/therapist; PT = physical therapy/therapist; SARA = Scale for the Assessment and Rating of Ataxia; SLP = speech-language pathologist; UMN = upper motor neuron Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades, & smooth pursuit) • UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperreflexia, amyotrophy, fasciculations) • Vibration loss or polyneuropathy based on clinical findings • Use standardized scale to establish baseline for ataxia (SARA). • Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy. • Brain MRI to evaluate presence & severity of cerebellar atrophy • CCAS scale • Psychiatrist, psychologist, neuropsychologist if needed. • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations The goals of supportive care are to maximize function and reduce complications. Depending on the clinical manifestations, affected individuals benefit from supportive care by a multidisciplinary team of specialists including neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech-language pathologists, pulmonologists, and mental health specialists. Treatment of Manifestations in Individuals with a Hereditary Ataxia 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 persons w/degenerative ataxias. Weight control to avoid obesity Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; UMN = upper motor neuron • 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 persons w/degenerative ataxias. • Weight control to avoid obesity • Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) ## Surveillance There are no published surveillance guidelines for hereditary ataxias in general. Recommended Surveillance for Individuals with a Hereditary Ataxia 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 the 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 ## Genetic Counseling of Family Members of an Individual with Hereditary Ataxia The hereditary ataxias included in this overview can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling and risk assessment depend on determination of the specific cause of an inherited ataxia in an individual. For hereditary ataxias that are nucleotide repeat disorders, select the relevant link to the The genetic counseling issues for the other common hereditary ataxias (see Most individuals diagnosed with autosomal dominant hereditary ataxia have an affected parent. Some individuals diagnosed with hereditary ataxia 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 identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with autosomal dominant hereditary ataxia may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before 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 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 pathogenic variant identified in the proband, the risk to sibs is 50%. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. (Note: Parental mosaicism has been reported in SCA29 [ If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for hereditary ataxia because of the possibility of age-related penetrance in a heterozygous parent or the possibility of parental germline mosaicism. The parents of an individual diagnosed with autosomal recessive hereditary ataxia are presumed to be heterozygous for a pathogenic variant. Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a 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 not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes (carriers) are not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an • Most individuals diagnosed with autosomal dominant hereditary ataxia have an affected parent. • Some individuals diagnosed with hereditary ataxia 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 identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with autosomal dominant hereditary ataxia may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before 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 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 pathogenic variant identified in the proband, the risk to sibs is 50%. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. (Note: Parental mosaicism has been reported in SCA29 [ • If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for hereditary ataxia because of the possibility of age-related penetrance in a heterozygous parent or the possibility of parental germline mosaicism. • The parents of an individual diagnosed with autosomal recessive hereditary ataxia are presumed to be heterozygous for a pathogenic variant. • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a 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 not at risk of developing autosomal recessive hereditary ataxia. (Note: 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 a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygotes (carriers) are not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an ## Mode of Inheritance The hereditary ataxias included in this overview can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Genetic counseling and risk assessment depend on determination of the specific cause of an inherited ataxia in an individual. For hereditary ataxias that are nucleotide repeat disorders, select the relevant link to the The genetic counseling issues for the other common hereditary ataxias (see ## Autosomal Dominant Inheritance – Risk to Family Members Most individuals diagnosed with autosomal dominant hereditary ataxia have an affected parent. Some individuals diagnosed with hereditary ataxia 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 identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. The family history of some individuals diagnosed with autosomal dominant hereditary ataxia may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before 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 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 pathogenic variant identified in the proband, the risk to sibs is 50%. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. (Note: Parental mosaicism has been reported in SCA29 [ If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for hereditary ataxia because of the possibility of age-related penetrance in a heterozygous parent or the possibility of parental germline mosaicism. • Most individuals diagnosed with autosomal dominant hereditary ataxia have an affected parent. • Some individuals diagnosed with hereditary ataxia 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 identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The family history of some individuals diagnosed with autosomal dominant hereditary ataxia may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before 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 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 pathogenic variant identified in the proband, the risk to sibs is 50%. • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism. (Note: Parental mosaicism has been reported in SCA29 [ • If the parents have not been tested for the pathogenic variant but are clinically unaffected, sibs are still presumed to be at increased risk for hereditary ataxia because of the possibility of age-related penetrance in a heterozygous parent or the possibility of parental germline mosaicism. ## Autosomal Recessive Inheritance – Risk to Family Members The parents of an individual diagnosed with autosomal recessive hereditary ataxia are presumed to be heterozygous for a pathogenic variant. Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a 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 not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an If both parents are known to be heterozygous for a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. Heterozygotes (carriers) are not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an • The parents of an individual diagnosed with autosomal recessive hereditary ataxia are presumed to be heterozygous for a pathogenic variant. • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a 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 not at risk of developing autosomal recessive hereditary ataxia. (Note: 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 a pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial pathogenic variants. • Heterozygotes (carriers) are not at risk of developing autosomal recessive hereditary ataxia. (Note: Individuals who are heterozygous for an ## Resources United Kingdom Spain Via Sara 12 16039 Italy Ataxia-Telangiectasia Children's Project United Kingdom Friedreich's Ataxia Research Alliance • • United Kingdom • • • • • Spain • • • Via Sara 12 • 16039 • Italy • • • Ataxia-Telangiectasia Children's Project • • • United Kingdom • • • Friedreich's Ataxia Research Alliance • • • ## Chapter Notes As a Clinical Professor of Neurology, Dr Perlman is involved in the diagnosis and treatment of cerebellar ataxia and other neurogenetic disorders. She conducts research on collaborative natural history, biomarker, and clinical trials in spinocerebellar ataxia, Friedreich ataxia, ataxia-telangiectasia, late-onset Tay-Sachs disease, and Huntington disease. Dr Perlman can be reached at: UCLA Neurology Services300 UCLA Medical Plaza, Suite B200, Los Angeles, CA, 90095Phone: 310-794-1195Fax: 310-794-7491Web page: The author acknowledges the following organizations and people: National Ataxia Foundation, sponsor of grants for collaborative natural history and biomarker studies Friedreich's Ataxia Research Alliance, sponsor of grants for collaborative natural history and biomarker studies The Smith Family Foundation, the Lapin Family Fund, the Bettencourt Fund, the John Paul Jr. Fund, and the Wapner Fund Our patients and their families, for their willingness to work with us and to share with us their ideas and hopes Thomas D Bird, MD; University of Washington (1998-2022)Susan Perlman, MD (2022-present) 20 February 2025 (bp) Revision: SCA4 added to 12 September 2024 (aa) Revision: deleted Hereditary Ataxias Caused by Nucleotide Repeat Expansions: Molecular Genetics table 16 November 2023 (bp) Revision: added 16 June 2022 (bp) Comprehensive update posted live 14 August 2014 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 27 June 2007 (me) Comprehensive update posted live 8 February 2005 (me) Comprehensive update posted live 27 February 2003 (me) Comprehensive update posted live 28 October 1998 (me) Overview posted live 23 June 1998 (tb) Original submission • National Ataxia Foundation, sponsor of grants for collaborative natural history and biomarker studies • Friedreich's Ataxia Research Alliance, sponsor of grants for collaborative natural history and biomarker studies • The Smith Family Foundation, the Lapin Family Fund, the Bettencourt Fund, the John Paul Jr. Fund, and the Wapner Fund • Our patients and their families, for their willingness to work with us and to share with us their ideas and hopes • 20 February 2025 (bp) Revision: SCA4 added to • 12 September 2024 (aa) Revision: deleted Hereditary Ataxias Caused by Nucleotide Repeat Expansions: Molecular Genetics table • 16 November 2023 (bp) Revision: added • 16 June 2022 (bp) Comprehensive update posted live • 14 August 2014 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 27 June 2007 (me) Comprehensive update posted live • 8 February 2005 (me) Comprehensive update posted live • 27 February 2003 (me) Comprehensive update posted live • 28 October 1998 (me) Overview posted live • 23 June 1998 (tb) Original submission ## Author Notes As a Clinical Professor of Neurology, Dr Perlman is involved in the diagnosis and treatment of cerebellar ataxia and other neurogenetic disorders. She conducts research on collaborative natural history, biomarker, and clinical trials in spinocerebellar ataxia, Friedreich ataxia, ataxia-telangiectasia, late-onset Tay-Sachs disease, and Huntington disease. Dr Perlman can be reached at: UCLA Neurology Services300 UCLA Medical Plaza, Suite B200, Los Angeles, CA, 90095Phone: 310-794-1195Fax: 310-794-7491Web page: ## Acknowledgments The author acknowledges the following organizations and people: National Ataxia Foundation, sponsor of grants for collaborative natural history and biomarker studies Friedreich's Ataxia Research Alliance, sponsor of grants for collaborative natural history and biomarker studies The Smith Family Foundation, the Lapin Family Fund, the Bettencourt Fund, the John Paul Jr. Fund, and the Wapner Fund Our patients and their families, for their willingness to work with us and to share with us their ideas and hopes • National Ataxia Foundation, sponsor of grants for collaborative natural history and biomarker studies • Friedreich's Ataxia Research Alliance, sponsor of grants for collaborative natural history and biomarker studies • The Smith Family Foundation, the Lapin Family Fund, the Bettencourt Fund, the John Paul Jr. Fund, and the Wapner Fund • Our patients and their families, for their willingness to work with us and to share with us their ideas and hopes ## Author History Thomas D Bird, MD; University of Washington (1998-2022)Susan Perlman, MD (2022-present) ## Revision History 20 February 2025 (bp) Revision: SCA4 added to 12 September 2024 (aa) Revision: deleted Hereditary Ataxias Caused by Nucleotide Repeat Expansions: Molecular Genetics table 16 November 2023 (bp) Revision: added 16 June 2022 (bp) Comprehensive update posted live 14 August 2014 (me) Comprehensive update posted live 17 February 2011 (me) Comprehensive update posted live 27 June 2007 (me) Comprehensive update posted live 8 February 2005 (me) Comprehensive update posted live 27 February 2003 (me) Comprehensive update posted live 28 October 1998 (me) Overview posted live 23 June 1998 (tb) Original submission • 20 February 2025 (bp) Revision: SCA4 added to • 12 September 2024 (aa) Revision: deleted Hereditary Ataxias Caused by Nucleotide Repeat Expansions: Molecular Genetics table • 16 November 2023 (bp) Revision: added • 16 June 2022 (bp) Comprehensive update posted live • 14 August 2014 (me) Comprehensive update posted live • 17 February 2011 (me) Comprehensive update posted live • 27 June 2007 (me) Comprehensive update posted live • 8 February 2005 (me) Comprehensive update posted live • 27 February 2003 (me) Comprehensive update posted live • 28 October 1998 (me) Overview posted live • 23 June 1998 (tb) Original submission ## Literature Cited Worldwide distribution of SCA subtypes[ Note: The data in (For a pdf version click Figure published courtesy of L Schöls, P Bauer, T Schmidt, T Schulte, O Reiss of University of Tübingen and Ruhr-University Bochum, Germany	[]	28/10/1998	16/6/2022	20/2/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
atn1-ndd	atn1-ndd	[ "ATN1-Related Neurodevelopmental Condition", "CHEDDA (Congenital Hypotonia, Epilepsy, Developmental Delay, Digit Abnormalities)", "CHEDDA (Congenital Hypotonia, Epilepsy, Developmental Delay, Digit Abnormalities)", "ATN1-Related Neurodevelopmental Condition", "Atrophin-1", "ATN1", "ATN1-Related Neurodevelopmental Disorder" ]		Chloe Whitton, Elizabeth Palmer, Fowzan Alkuraya	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Developmental delay (DD) or intellectual disability (ID) that is typically profound and rarely mild AND Any of the following presenting in infancy or childhood: Generalized hypotonia of infancy Severe feeding difficulties Respiratory complications such as obstructive and/or central apnea Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication Central vision impairment, strabismus, and/or hypermetropia Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads Congenital heart defects including atrial septal defects, patent foramen ovale, patent ductus arteriosus, and left or bilateral superior vena cava Congenital anomalies of the kidney and urinary tract (CAKUT), including renal hypoplasia or agenesis Genital anomalies such as bilateral or unilateral undescended testes Distinctive facial features including temporal alopecia (i.e., sparse hairline bitemporally), prominent ears, and a thin upper lip; see Figure 1 in Structural brain anomalies are common, including cerebellar hypoplasia, abnormalities of the corpus callosum, perisylvian polymicrogyria, and absent falx cerebri. For more details see Because 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 [ Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All variants reported to date are Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • Developmental delay (DD) or intellectual disability (ID) that is typically profound and rarely mild • AND • Any of the following presenting in infancy or childhood: • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Congenital heart defects including atrial septal defects, patent foramen ovale, patent ductus arteriosus, and left or bilateral superior vena cava • Congenital anomalies of the kidney and urinary tract (CAKUT), including renal hypoplasia or agenesis • Genital anomalies such as bilateral or unilateral undescended testes • Distinctive facial features including temporal alopecia (i.e., sparse hairline bitemporally), prominent ears, and a thin upper lip; see Figure 1 in • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Developmental delay (DD) or intellectual disability (ID) that is typically profound and rarely mild AND Any of the following presenting in infancy or childhood: Generalized hypotonia of infancy Severe feeding difficulties Respiratory complications such as obstructive and/or central apnea Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication Central vision impairment, strabismus, and/or hypermetropia Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads Congenital heart defects including atrial septal defects, patent foramen ovale, patent ductus arteriosus, and left or bilateral superior vena cava Congenital anomalies of the kidney and urinary tract (CAKUT), including renal hypoplasia or agenesis Genital anomalies such as bilateral or unilateral undescended testes Distinctive facial features including temporal alopecia (i.e., sparse hairline bitemporally), prominent ears, and a thin upper lip; see Figure 1 in Structural brain anomalies are common, including cerebellar hypoplasia, abnormalities of the corpus callosum, perisylvian polymicrogyria, and absent falx cerebri. For more details see Because • Developmental delay (DD) or intellectual disability (ID) that is typically profound and rarely mild • AND • Any of the following presenting in infancy or childhood: • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Congenital heart defects including atrial septal defects, patent foramen ovale, patent ductus arteriosus, and left or bilateral superior vena cava • Congenital anomalies of the kidney and urinary tract (CAKUT), including renal hypoplasia or agenesis • Genital anomalies such as bilateral or unilateral undescended testes • Distinctive facial features including temporal alopecia (i.e., sparse hairline bitemporally), prominent ears, and a thin upper lip; see Figure 1 in ## Clinical Findings Developmental delay (DD) or intellectual disability (ID) that is typically profound and rarely mild AND Any of the following presenting in infancy or childhood: Generalized hypotonia of infancy Severe feeding difficulties Respiratory complications such as obstructive and/or central apnea Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication Central vision impairment, strabismus, and/or hypermetropia Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads Congenital heart defects including atrial septal defects, patent foramen ovale, patent ductus arteriosus, and left or bilateral superior vena cava Congenital anomalies of the kidney and urinary tract (CAKUT), including renal hypoplasia or agenesis Genital anomalies such as bilateral or unilateral undescended testes Distinctive facial features including temporal alopecia (i.e., sparse hairline bitemporally), prominent ears, and a thin upper lip; see Figure 1 in • Developmental delay (DD) or intellectual disability (ID) that is typically profound and rarely mild • AND • Any of the following presenting in infancy or childhood: • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Generalized hypotonia of infancy • Severe feeding difficulties • Respiratory complications such as obstructive and/or central apnea • Epilepsy that is often consistent with a severe developmental and epileptic encephalopathy, and is either responsive or nonresponsive to anti-seizure medication • Central vision impairment, strabismus, and/or hypermetropia • Hearing impairment that is usually conductive, secondary to recurrent otitis media with effusions commonly requiring tympanostomy tubes; however, mild sensorineural hearing impairment has also been described • Hand and foot anomalies, most frequently overlapping toes, camptodactyly, and persistent fetal fingertip pads • Congenital heart defects including atrial septal defects, patent foramen ovale, patent ductus arteriosus, and left or bilateral superior vena cava • Congenital anomalies of the kidney and urinary tract (CAKUT), including renal hypoplasia or agenesis • Genital anomalies such as bilateral or unilateral undescended testes • Distinctive facial features including temporal alopecia (i.e., sparse hairline bitemporally), prominent ears, and a thin upper lip; see Figure 1 in ## Brain MRI Structural brain anomalies are common, including cerebellar hypoplasia, abnormalities of the corpus callosum, perisylvian polymicrogyria, and absent falx cerebri. For more details see ## Family History Because ## 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 [ Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click All variants reported to date are Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 To date, 18 individuals have been identified with Select Features of Based on CAKUT= congenital anomalies of the kidney and urinary tract; DD/ID = developmental delay / intellectual disability; GERD = gastroesophageal reflux disease Fine motor skills range from inability to grasp toys / small objects or bring hands to the midline to the ability to finger feed. In contrast, the girl with milder features has fine motor skills that are just below average. While some affected individuals can speak one or two words and communicate in gestures, most are nonverbal with no clear words. To date communication devices have not been reported to be particularly helpful, consistent with a profound developmental delay; however, caregivers thought that two individuals had more advanced receptive skills, and the girl with milder developmental delay was able to talk in short sentences at the age of 26 months. One individual had Lennox-Gastaut syndrome. While seizures were controlled in many individuals with a single ASM, others required two or more ASMs to achieve seizure control. Other findings contributing to respiratory difficulty in some individuals included Pierre Robin sequence, micrognathia, laryngomalacia, and asthma. Normal brain imaging findings appear to correlate with better neurodevelopmental outcome. In the five individuals with no major structural abnormalities, motor skills in four ranged from crawling, pulling to stand, taking a few steps, or, in one instance, walking unassisted, and at least four were able to grasp objects. Three individuals had no clear words, one had single words, and one speaks in short sentences. By contrast, of the 13 individuals with major structural abnormalities, two could stand with support, whereas the others had minimal motor skills (range: lack of head control to inability to roll to sitting with support); 12 individuals were nonverbal and one had a few single words. ASM = anti-seizure medication; DEE = developmental and epileptic encephalopathy Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) Arthrogryposis (1 individual) Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism Anorectal anomalies, including anteriorly placed anus No consistent genotype-phenotype correlations have been identified. Although more data are required, it is notable that the unique To date 18 individuals have been reported with • • Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. • Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. • Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see • Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) • Arthrogryposis (1 individual) • Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. • Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. • Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see • Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) • Arthrogryposis (1 individual) • • Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale • Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism • Anorectal anomalies, including anteriorly placed anus • Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale • Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism • Anorectal anomalies, including anteriorly placed anus • Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. • Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. • Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see • Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) • Arthrogryposis (1 individual) • Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale • Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism • Anorectal anomalies, including anteriorly placed anus ## Clinical Description To date, 18 individuals have been identified with Select Features of Based on CAKUT= congenital anomalies of the kidney and urinary tract; DD/ID = developmental delay / intellectual disability; GERD = gastroesophageal reflux disease Fine motor skills range from inability to grasp toys / small objects or bring hands to the midline to the ability to finger feed. In contrast, the girl with milder features has fine motor skills that are just below average. While some affected individuals can speak one or two words and communicate in gestures, most are nonverbal with no clear words. To date communication devices have not been reported to be particularly helpful, consistent with a profound developmental delay; however, caregivers thought that two individuals had more advanced receptive skills, and the girl with milder developmental delay was able to talk in short sentences at the age of 26 months. One individual had Lennox-Gastaut syndrome. While seizures were controlled in many individuals with a single ASM, others required two or more ASMs to achieve seizure control. Other findings contributing to respiratory difficulty in some individuals included Pierre Robin sequence, micrognathia, laryngomalacia, and asthma. Normal brain imaging findings appear to correlate with better neurodevelopmental outcome. In the five individuals with no major structural abnormalities, motor skills in four ranged from crawling, pulling to stand, taking a few steps, or, in one instance, walking unassisted, and at least four were able to grasp objects. Three individuals had no clear words, one had single words, and one speaks in short sentences. By contrast, of the 13 individuals with major structural abnormalities, two could stand with support, whereas the others had minimal motor skills (range: lack of head control to inability to roll to sitting with support); 12 individuals were nonverbal and one had a few single words. ASM = anti-seizure medication; DEE = developmental and epileptic encephalopathy Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) Arthrogryposis (1 individual) Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism Anorectal anomalies, including anteriorly placed anus • • Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. • Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. • Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see • Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) • Arthrogryposis (1 individual) • Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. • Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. • Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see • Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) • Arthrogryposis (1 individual) • • Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale • Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism • Anorectal anomalies, including anteriorly placed anus • Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale • Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism • Anorectal anomalies, including anteriorly placed anus • Scoliosis was reported in six of 18 individuals attributed to neuromuscular involvement rather than vertebral anomalies; however, no information is available on need for specific intervention. • Hip dysplasia was reported in five of 18 individuals; no information is available on the need for specific intervention. • Cervical stenosis was reported in two of six individuals on cervical spine MRI; no information is available on the need for specific intervention other than caution when manipulating the head and neck for airway management (see • Orofacial clefting: cleft palate (2 individuals); Pierre Robin sequence (1 individual), micrognathia (1 individual) • Arthrogryposis (1 individual) • Cardiac anomalies, including atrial and ventricular septal defects, anomalous drainage of the great veins, coarctation of the aorta, patent ductus arteriosus and foramen ovale • Urogenital anomalies, including unilateral renal hypoplasia or agenesis, vesicoureteric reflux, and cryptorchidism • Anorectal anomalies, including anteriorly placed anus ## Genotype-Phenotype Correlations No consistent genotype-phenotype correlations have been identified. Although more data are required, it is notable that the unique ## Nomenclature ## Prevalence To date 18 individuals have been reported with ## Genetically Related (Allelic) Conditions Similar to Unlike Of note, the identification of mosaic tetrasomy of 12p requires chromosome analysis of specific tissues; thus, routine molecular genetic testing of a blood sample would not be expected to suggest a diagnosis of PKS. • Similar to • Unlike ## Differential Diagnosis ## Management Although 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 program / IEP To incl brain MRI if not performed at time of diagnosis Consider EEG if seizures are a concern. Assess for cortical visual impairment. Screening for central & obstructive apnea in neonatal period Consider referral to sleep specialist &/or respiratory physician if respiratory &/or sleep symptoms occur. To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk. To incl EKG & echocardiogram Refer to cardiologist if concerns are identified. Craniocervical junction stenosis, preferably by spine MRI Scoliosis, hip dislocation Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl renal/abdominal ultrasound to assess for renal agenesis or hypoplasia Assess for cryptorchidism. Community or Social work involvement for parental support; Home nursing referral. IEP = individualized education plan; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in clinical genetics, neurology, ophthalmology, gastroenterology, cardiology, and general pediatrics (see Treatment of Manifestations in Individuals with Many ASMs may be effective; none has been demonstrated effective specifically for this condition. Education of parents/caregivers May require respiratory support, esp in neonatal period. Consider jaw distraction surgery if micrognathia is a component of obstructive sleep apnea. Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues & aspiration risk. May not require treatment Cardiology referral if structural heart defects detected or if otherwise indicated Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls For severe stenosis of the craniocervical junction: mgmt by neurosurgery &/or orthopedic specialists w/special attn during general anesthesia Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; DD/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. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Regular clinic visits are recommended because of the complexity of the medical and developmental issues associated with Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Orthopedics /PT & OT eval for development &/or progression of contractures &/or need for additional adaptive devices Screening for craniocervical junction stenosis & referral to neurosurgical team for advice on surveillance & mgmt OT = occupational therapy; PT = physical therapy In individuals with MRI-confirmed stenosis of the craniocervical junction, caution is required when manipulating the head and neck for airway management. See Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention program / IEP • To incl brain MRI if not performed at time of diagnosis • Consider EEG if seizures are a concern. • Assess for cortical visual impairment. • Screening for central & obstructive apnea in neonatal period • Consider referral to sleep specialist &/or respiratory physician if respiratory &/or sleep symptoms occur. • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk. • To incl EKG & echocardiogram • Refer to cardiologist if concerns are identified. • Craniocervical junction stenosis, preferably by spine MRI • Scoliosis, hip dislocation • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl renal/abdominal ultrasound to assess for renal agenesis or hypoplasia • Assess for cryptorchidism. • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for this condition. • Education of parents/caregivers • May require respiratory support, esp in neonatal period. • Consider jaw distraction surgery if micrognathia is a component of obstructive sleep apnea. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues & aspiration risk. • May not require treatment • Cardiology referral if structural heart defects detected or if otherwise indicated • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls • For severe stenosis of the craniocervical junction: mgmt by neurosurgery &/or orthopedic specialists w/special attn during general anesthesia • 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. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Orthopedics /PT & OT eval for development &/or progression of contractures &/or need for additional adaptive devices • Screening for craniocervical junction stenosis & referral to neurosurgical team for advice on surveillance & mgmt ## 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 program / IEP To incl brain MRI if not performed at time of diagnosis Consider EEG if seizures are a concern. Assess for cortical visual impairment. Screening for central & obstructive apnea in neonatal period Consider referral to sleep specialist &/or respiratory physician if respiratory &/or sleep symptoms occur. To incl eval of aspiration risk & nutritional status Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk. To incl EKG & echocardiogram Refer to cardiologist if concerns are identified. Craniocervical junction stenosis, preferably by spine MRI Scoliosis, hip dislocation Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl renal/abdominal ultrasound to assess for renal agenesis or hypoplasia Assess for cryptorchidism. Community or Social work involvement for parental support; Home nursing referral. IEP = individualized education plan; 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 program / IEP • To incl brain MRI if not performed at time of diagnosis • Consider EEG if seizures are a concern. • Assess for cortical visual impairment. • Screening for central & obstructive apnea in neonatal period • Consider referral to sleep specialist &/or respiratory physician if respiratory &/or sleep symptoms occur. • To incl eval of aspiration risk & nutritional status • Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk. • To incl EKG & echocardiogram • Refer to cardiologist if concerns are identified. • Craniocervical junction stenosis, preferably by spine MRI • Scoliosis, hip dislocation • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl renal/abdominal ultrasound to assess for renal agenesis or hypoplasia • Assess for cryptorchidism. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in clinical genetics, neurology, ophthalmology, gastroenterology, cardiology, and general pediatrics (see Treatment of Manifestations in Individuals with Many ASMs may be effective; none has been demonstrated effective specifically for this condition. Education of parents/caregivers May require respiratory support, esp in neonatal period. Consider jaw distraction surgery if micrognathia is a component of obstructive sleep apnea. Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues & aspiration risk. May not require treatment Cardiology referral if structural heart defects detected or if otherwise indicated Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls For severe stenosis of the craniocervical junction: mgmt by neurosurgery &/or orthopedic specialists w/special attn during general anesthesia Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; DD/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. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Many ASMs may be effective; none has been demonstrated effective specifically for this condition. • Education of parents/caregivers • May require respiratory support, esp in neonatal period. • Consider jaw distraction surgery if micrognathia is a component of obstructive sleep apnea. • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues & aspiration risk. • May not require treatment • Cardiology referral if structural heart defects detected or if otherwise indicated • Orthopedics / physical medicine & rehab / PT & OT incl stretching to help avoid contractures & falls • For severe stenosis of the craniocervical junction: mgmt by neurosurgery &/or orthopedic specialists w/special attn during general anesthesia • 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. ## Surveillance Regular clinic visits are recommended because of the complexity of the medical and developmental issues associated with Recommended Surveillance for Individuals with Measurement of growth parameters Eval of nutritional status & safety of oral intake Orthopedics /PT & OT eval for development &/or progression of contractures &/or need for additional adaptive devices Screening for craniocervical junction stenosis & referral to neurosurgical team for advice on surveillance & mgmt OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Orthopedics /PT & OT eval for development &/or progression of contractures &/or need for additional adaptive devices • Screening for craniocervical junction stenosis & referral to neurosurgical team for advice on surveillance & mgmt ## Agents/Circumstances to Avoid In individuals with MRI-confirmed stenosis of the craniocervical junction, caution is required when manipulating the head and neck for airway management. ## 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 in the germ cells only. If a parent of the proband is known to have the If the To date, individuals with Each child of an individual with The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the • If the • To date, individuals with • Each child of an individual with • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance ## Risk to Family Members All probands reported to date with Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If a parent of the proband is known to have the If the To date, individuals with Each child of an individual with • All probands reported to date with • Molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If a parent of the proband is known to have the • If the • To date, individuals with • Each child of an individual with ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Risk to future pregnancies is presumed to be low as the proband most likely has a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 ATN1-Related Neurodevelopmental Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for ATN1-Related Neurodevelopmental Disorder ( Although the role of ATN1 is incompletely understood, it appears to be a key nuclear transcriptional regulator involved in organ development in which the HX repeat motif plays a critical role [ ## Molecular Pathogenesis Although the role of ATN1 is incompletely understood, it appears to be a key nuclear transcriptional regulator involved in organ development in which the HX repeat motif plays a critical role [ ## Chapter Notes Dr Elizabeth Palmer ([email protected]) and Professor Fowzan Alkuraya ([email protected]) are actively involved in clinical research regarding individuals with Contact Dr Elizabeth Palmer and Professor Fowzan Alkuraya to inquire about review of Dr Elizabeth Palmer and Professor Alkuraya are also interested in hearing from clinicians treating families affected by CHEDDA ( We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition. 25 August 2022 (bp) Review posted live 26 May 2022 (ep) Original submission • 25 August 2022 (bp) Review posted live • 26 May 2022 (ep) Original submission ## Author Notes Dr Elizabeth Palmer ([email protected]) and Professor Fowzan Alkuraya ([email protected]) are actively involved in clinical research regarding individuals with Contact Dr Elizabeth Palmer and Professor Fowzan Alkuraya to inquire about review of Dr Elizabeth Palmer and Professor Alkuraya are also interested in hearing from clinicians treating families affected by CHEDDA ( ## Acknowledgments We would like to thank the patients, families, and clinicians who have participated in our previous publications delineating this condition. ## Revision History 25 August 2022 (bp) Review posted live 26 May 2022 (ep) Original submission • 25 August 2022 (bp) Review posted live • 26 May 2022 (ep) Original submission ## References ## Literature Cited	[ "EE Palmer, S Hong, F Al Zahrani, MO Hashem, FA Aleisa, HMJ Ahmed, T Kandula, R Macintosh, AE Minoche, C Puttick, V Gayevskiy, AP Drew, MJ Cowley, M Dinger, JA Rosenfeld, R Xiao, MT Cho, SF Yakubu, LB Henderson, MJ Guillen Sacoto, A Begtrup, M Hamad, M Shinawi, MV Andrews, MC Jones, K Lindstrom, RE Bristol, S Kayani, M Snyder, MM Villanueva, A Schteinschnaider, L Faivre, C Thauvin, A Vitobello, T Roscioli, EP Kirk, A Bye, J Merzaban, Ł Jaremko, M Jaremko, RK Sachdev, FS Alkuraya, ST Arold. De novo variants disrupting the HX repeat motif of ATN1 cause a recognizable non-progressive neurocognitive syndrome.. Am J Hum Genet. 2019;104:542-52", "EE Palmer, C Whitton, MO Hashem, RD Clark, S Ramanathan, LJ Starr, D Velasco, JK De Dios, E Singh, V Cormier-Daire, M Chopra, LH Rodan, C Nellaker, S Lakhani, EJ Mallack, K Panzer, A Sidhu, IM Wentzensen, D Lacombe, V Michaud, FS Alkuraya. CHEDDA syndrome is an underrecognized neurodevelopmental Condition with a highly restricted ATN1 mutation spectrum.. Clin Genet. 2021;100:468-77", "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", "M Shiyue, Z Xuan, X Jiaoli, F Xiaoge, L Zhi, J Zhipeng, Z Yaodong. Diagnosis of congenital hypotonia, epilepsy, developmental delay and digital (digital) deformity (CHEDDA) syndrome caused by ATN1 gene mutation by data reanalysis and literature review (with video).. China Clinical Case Results Database. 2022;04:E03953-E03953" ]	25/8/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
au-kline	au-kline	[ "HNRNPK-Related Neurodevelopmental Disorder", "Au-Kline-Okamoto Syndrome", "Okamoto Syndrome", "HNRNPK-Related Neurodevelopmental Disorder", "Au-Kline-Okamoto Syndrome", "Okamoto Syndrome", "Heterogeneous nuclear ribonucleoprotein K", "HNRNPK", "Au-Kline Syndrome" ]	Au-Kline Syndrome	Ping-Yee Billie Au, Vanda McNiven, Lindsay Phillips, A Micheil Innes, Antonie D Kline	Summary Au-Kline syndrome is characterized by developmental delay and hypotonia with moderate-to-severe intellectual disability, and typical facial features that include long palpebral fissures, ptosis, shallow orbits, large and deeply grooved tongue, broad nose with a wide nasal bridge, and downturned mouth. Congenital heart disease, hydronephrosis, palate abnormalities, and oligodontia are reported in the majority of affected individuals. Variable autonomic dysfunction (gastrointestinal dysmotility, high pain threshold, heat intolerance, recurrent fevers, abnormal sweating) is found in more than one third of affected individuals. Additional complications can include craniosynostosis, feeding difficulty, vision issues, hearing loss, osteopenia, and other skeletal anomalies. Epilepsy and brain malformations are rare. The diagnosis of Au-Kline syndrome is established in a proband by identification of a heterozygous pathogenic variant in Au-Kline syndrome is inherited in an autosomal dominant manner. All probands reported to date with Au-Kline syndrome have the disorder as a result of a	## Diagnosis Clinical diagnostic criteria for Au-Kline syndrome (AKS) have been proposed [ AKS Long palpebral fissures Ptosis Shallow orbits Deeply grooved tongue Broad nose with wide nasal bridge and thick alae nasi Downturned mouth, often described as an M-shaped Cupid's bow AND Global developmental delay or intellectual disability (defined as a DQ or IQ score below 70) Hypotonia A diagnosis is considered highly likely in an individual with at least five of the six characteristic facial features in addition to global developmental delay / intellectual disability and hypotonia [ Further supportive features may include: Craniosynostosis (Typically, sagittal and metopic sutures are affected; metopic ridging is common.) Palate abnormalities (e.g., cleft palate, high-arched palate, bifid uvula) Congenital heart malformations (e.g., ventricular septal defect, atrial septal defect, bicuspid aortic valve, and more complex malformations) Genitourinary anomalies (e.g., hydronephrosis, undescended testes) Skeletal anomalies (e.g., vertebral segmentation defects, scoliosis, congenital hip dysplasia) The diagnosis of AKS is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Au-Kline syndrome is often recognizable, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Au-Kline syndrome, molecular genetic testing approaches can include Note: Given the rarity of Au-Kline disorder, single-gene testing for For an introduction to multigene panels click When the diagnosis of Au-Kline syndrome is not considered because an individual has atypical phenotypic features or mild features that do not meet suggestive clinical diagnostic criteria, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Au-Kline 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. 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 • Long palpebral fissures • Ptosis • Shallow orbits • Deeply grooved tongue • Broad nose with wide nasal bridge and thick alae nasi • Downturned mouth, often described as an M-shaped Cupid's bow • Global developmental delay or intellectual disability (defined as a DQ or IQ score below 70) • Hypotonia • Craniosynostosis (Typically, sagittal and metopic sutures are affected; metopic ridging is common.) • Palate abnormalities (e.g., cleft palate, high-arched palate, bifid uvula) • Congenital heart malformations (e.g., ventricular septal defect, atrial septal defect, bicuspid aortic valve, and more complex malformations) • Genitourinary anomalies (e.g., hydronephrosis, undescended testes) • Skeletal anomalies (e.g., vertebral segmentation defects, scoliosis, congenital hip dysplasia) • Note: Given the rarity of Au-Kline disorder, single-gene testing for • For an introduction to multigene panels click ## Suggestive Findings AKS Long palpebral fissures Ptosis Shallow orbits Deeply grooved tongue Broad nose with wide nasal bridge and thick alae nasi Downturned mouth, often described as an M-shaped Cupid's bow AND Global developmental delay or intellectual disability (defined as a DQ or IQ score below 70) Hypotonia A diagnosis is considered highly likely in an individual with at least five of the six characteristic facial features in addition to global developmental delay / intellectual disability and hypotonia [ Further supportive features may include: Craniosynostosis (Typically, sagittal and metopic sutures are affected; metopic ridging is common.) Palate abnormalities (e.g., cleft palate, high-arched palate, bifid uvula) Congenital heart malformations (e.g., ventricular septal defect, atrial septal defect, bicuspid aortic valve, and more complex malformations) Genitourinary anomalies (e.g., hydronephrosis, undescended testes) Skeletal anomalies (e.g., vertebral segmentation defects, scoliosis, congenital hip dysplasia) • Long palpebral fissures • Ptosis • Shallow orbits • Deeply grooved tongue • Broad nose with wide nasal bridge and thick alae nasi • Downturned mouth, often described as an M-shaped Cupid's bow • Global developmental delay or intellectual disability (defined as a DQ or IQ score below 70) • Hypotonia • Craniosynostosis (Typically, sagittal and metopic sutures are affected; metopic ridging is common.) • Palate abnormalities (e.g., cleft palate, high-arched palate, bifid uvula) • Congenital heart malformations (e.g., ventricular septal defect, atrial septal defect, bicuspid aortic valve, and more complex malformations) • Genitourinary anomalies (e.g., hydronephrosis, undescended testes) • Skeletal anomalies (e.g., vertebral segmentation defects, scoliosis, congenital hip dysplasia) ## Establishing the Diagnosis The diagnosis of AKS is established in a proband by identification of a heterozygous pathogenic (or likely pathogenic) variant in Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Au-Kline syndrome is often recognizable, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Au-Kline syndrome, molecular genetic testing approaches can include Note: Given the rarity of Au-Kline disorder, single-gene testing for For an introduction to multigene panels click When the diagnosis of Au-Kline syndrome is not considered because an individual has atypical phenotypic features or mild features that do not meet suggestive clinical diagnostic criteria, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Au-Kline 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. 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: Given the rarity of Au-Kline disorder, single-gene testing for • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Au-Kline syndrome, molecular genetic testing approaches can include Note: Given the rarity of Au-Kline disorder, single-gene testing for For an introduction to multigene panels click • Note: Given the rarity of Au-Kline disorder, single-gene testing for • For an introduction to multigene panels click ## Option 2 When the diagnosis of Au-Kline syndrome is not considered because an individual has atypical phenotypic features or mild features that do not meet suggestive clinical diagnostic criteria, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Au-Kline 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. 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 To date, at least 75 individuals have been identified with a pathogenic variant in Select Features of Au-Kline Syndrome In a group of older individuals with loss-of-function pathogenic variants (ranging in age from eight years to young adulthood), independent ambulation was achieved by 5/11 individuals, although some still required assistive devices for longer distances. Nine out of 12 individuals used verbal communication, with 6/12 using mostly single words and 3/12 using phrases to communicate. Eight out of 11 individuals were able to use sign language or communication devices to supplement their communication. In nine older individuals with missense pathogenic variants, 8/9 were able to walk independently, with 6/9 achieving this skill before age three years. Six out of eight individuals in this group were able to speak in phrases. Many older children and adults are also able to use signs (sometimes up to several hundred) and devices to supplement their communication. Hypotonia has been reported in all known individuals with Au-Kline syndrome (AKS) and often persists into adulthood. Reflexes are typically reduced or absent. Some individuals have suspected neuropathy on exam, but formal nerve conduction studies / electromyography have not typically been pursued. Some individuals describe muscle weakness and/or easy fatigability. Muscle biopsy may be abnormal but has not been pursued in most individuals. Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. Several individuals have been diagnosed with autonomic dysfunction, presenting with gastrointestinal dysmotility, high pain threshold (37%), heat intolerance, recurrent fevers, and abnormal sweating. Sagittal and metopic sutures are typically affected, and many individuals have metopic ridging without obvious or confirmed synostosis. Approximately half of the individuals with craniosynostosis have required surgical intervention. However, it is unclear if surgical intervention improves cognitive outcome in individuals with AKS. Ventricular septal defects are the most common anomaly. Complex congenital heart defects are rarely reported. Aortic dilatation has been identified in three individuals; the natural history of aortic dilatation in AKS is unclear. Two affected individuals have had left ventricular non-compaction cardiomyopathy. Hydronephrosis is present in up to 52% of individuals with AKS (see Cryptorchidism is common in males. Most neonates with AKS have normal growth parameters. Approximately 30% of affected individuals demonstrate growth deficiency over time, affecting both height and weight. Age of onset of growth restriction has been variable, and the true incidence and degree of severity is unclear, as stature is also often affected by the presence of scoliosis. Occasionally, there may be mild microcephaly, which is usually noted by early childhood (see Overgrowth consisting of increased length and weight at birth has been described in two individuals; two other individuals have been reported to have obesity with increased weight versus height [ Thirty-nine percent of individuals with AKS have scoliosis, which can range from mild to severe and can require surgical intervention. Vertebral segmentation anomalies may be present and are more likely to be associated with severe scoliosis. Congenital hip dysplasia is observed in about one third of individuals with AKS. Talipes equinovarus and pes planus are also common. Some individuals have joint hypermobility, although joint dislocations have not been reported. Contractures are also occasionally reported, typically affecting large joints. Postaxial polydactyly has also been rarely reported. Hearing loss is present in approximately one quarter of affected individuals. Conductive hearing loss may be due to chronic middle ear effusion, but sensorineural hearing loss has been described in three individuals. Branchial defects have also been rarely reported. Myopia and hyperopia have both been reported in individuals with AKS. Optic nerve anomalies, including hypoplasia of the optic nerve or the presence of a coloboma, have been identified in four affected individuals. There is theoretical risk for exposure keratopathy in individuals with particularly shallow orbits and long palpebral fissures, but this has not been observed in individuals with AKS. Based on the limited number of reported individuals with AKS, it appears that individuals with missense pathogenic variants may have a reduced burden of major organ malformations compared to individuals with loss-of-function pathogenic variants [ General findings to date pertaining to specific features and genotype include the following: The disorder name " Okamoto syndrome was initially described in 1997, although the underlying molecular genetic etiology was unknown [ Prevalence is currently unknown. AKS is a rare disorder first described in 2015. The authors are aware of more than 75 affected individuals worldwide, with more than 40 individuals formally reported in the literature [ • In a group of older individuals with loss-of-function pathogenic variants (ranging in age from eight years to young adulthood), independent ambulation was achieved by 5/11 individuals, although some still required assistive devices for longer distances. • Nine out of 12 individuals used verbal communication, with 6/12 using mostly single words and 3/12 using phrases to communicate. • Eight out of 11 individuals were able to use sign language or communication devices to supplement their communication. • In nine older individuals with missense pathogenic variants, 8/9 were able to walk independently, with 6/9 achieving this skill before age three years. Six out of eight individuals in this group were able to speak in phrases. • Many older children and adults are also able to use signs (sometimes up to several hundred) and devices to supplement their communication. • Hypotonia has been reported in all known individuals with Au-Kline syndrome (AKS) and often persists into adulthood. • Reflexes are typically reduced or absent. • Some individuals have suspected neuropathy on exam, but formal nerve conduction studies / electromyography have not typically been pursued. • Some individuals describe muscle weakness and/or easy fatigability. • Muscle biopsy may be abnormal but has not been pursued in most individuals. • Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. • Muscle biopsy may be abnormal but has not been pursued in most individuals. • Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. • Several individuals have been diagnosed with autonomic dysfunction, presenting with gastrointestinal dysmotility, high pain threshold (37%), heat intolerance, recurrent fevers, and abnormal sweating. • Muscle biopsy may be abnormal but has not been pursued in most individuals. • Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. • Sagittal and metopic sutures are typically affected, and many individuals have metopic ridging without obvious or confirmed synostosis. • Approximately half of the individuals with craniosynostosis have required surgical intervention. However, it is unclear if surgical intervention improves cognitive outcome in individuals with AKS. • Ventricular septal defects are the most common anomaly. • Complex congenital heart defects are rarely reported. • Aortic dilatation has been identified in three individuals; the natural history of aortic dilatation in AKS is unclear. • Two affected individuals have had left ventricular non-compaction cardiomyopathy. • Hydronephrosis is present in up to 52% of individuals with AKS (see • Cryptorchidism is common in males. • Most neonates with AKS have normal growth parameters. • Approximately 30% of affected individuals demonstrate growth deficiency over time, affecting both height and weight. • Age of onset of growth restriction has been variable, and the true incidence and degree of severity is unclear, as stature is also often affected by the presence of scoliosis. • Occasionally, there may be mild microcephaly, which is usually noted by early childhood (see • Overgrowth consisting of increased length and weight at birth has been described in two individuals; two other individuals have been reported to have obesity with increased weight versus height [ • Thirty-nine percent of individuals with AKS have scoliosis, which can range from mild to severe and can require surgical intervention. • Vertebral segmentation anomalies may be present and are more likely to be associated with severe scoliosis. • Congenital hip dysplasia is observed in about one third of individuals with AKS. • Talipes equinovarus and pes planus are also common. • Some individuals have joint hypermobility, although joint dislocations have not been reported. • Contractures are also occasionally reported, typically affecting large joints. • Postaxial polydactyly has also been rarely reported. • Hearing loss is present in approximately one quarter of affected individuals. • Conductive hearing loss may be due to chronic middle ear effusion, but sensorineural hearing loss has been described in three individuals. • Branchial defects have also been rarely reported. • Myopia and hyperopia have both been reported in individuals with AKS. • Optic nerve anomalies, including hypoplasia of the optic nerve or the presence of a coloboma, have been identified in four affected individuals. • There is theoretical risk for exposure keratopathy in individuals with particularly shallow orbits and long palpebral fissures, but this has not been observed in individuals with AKS. ## Clinical Description To date, at least 75 individuals have been identified with a pathogenic variant in Select Features of Au-Kline Syndrome In a group of older individuals with loss-of-function pathogenic variants (ranging in age from eight years to young adulthood), independent ambulation was achieved by 5/11 individuals, although some still required assistive devices for longer distances. Nine out of 12 individuals used verbal communication, with 6/12 using mostly single words and 3/12 using phrases to communicate. Eight out of 11 individuals were able to use sign language or communication devices to supplement their communication. In nine older individuals with missense pathogenic variants, 8/9 were able to walk independently, with 6/9 achieving this skill before age three years. Six out of eight individuals in this group were able to speak in phrases. Many older children and adults are also able to use signs (sometimes up to several hundred) and devices to supplement their communication. Hypotonia has been reported in all known individuals with Au-Kline syndrome (AKS) and often persists into adulthood. Reflexes are typically reduced or absent. Some individuals have suspected neuropathy on exam, but formal nerve conduction studies / electromyography have not typically been pursued. Some individuals describe muscle weakness and/or easy fatigability. Muscle biopsy may be abnormal but has not been pursued in most individuals. Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. Several individuals have been diagnosed with autonomic dysfunction, presenting with gastrointestinal dysmotility, high pain threshold (37%), heat intolerance, recurrent fevers, and abnormal sweating. Sagittal and metopic sutures are typically affected, and many individuals have metopic ridging without obvious or confirmed synostosis. Approximately half of the individuals with craniosynostosis have required surgical intervention. However, it is unclear if surgical intervention improves cognitive outcome in individuals with AKS. Ventricular septal defects are the most common anomaly. Complex congenital heart defects are rarely reported. Aortic dilatation has been identified in three individuals; the natural history of aortic dilatation in AKS is unclear. Two affected individuals have had left ventricular non-compaction cardiomyopathy. Hydronephrosis is present in up to 52% of individuals with AKS (see Cryptorchidism is common in males. Most neonates with AKS have normal growth parameters. Approximately 30% of affected individuals demonstrate growth deficiency over time, affecting both height and weight. Age of onset of growth restriction has been variable, and the true incidence and degree of severity is unclear, as stature is also often affected by the presence of scoliosis. Occasionally, there may be mild microcephaly, which is usually noted by early childhood (see Overgrowth consisting of increased length and weight at birth has been described in two individuals; two other individuals have been reported to have obesity with increased weight versus height [ Thirty-nine percent of individuals with AKS have scoliosis, which can range from mild to severe and can require surgical intervention. Vertebral segmentation anomalies may be present and are more likely to be associated with severe scoliosis. Congenital hip dysplasia is observed in about one third of individuals with AKS. Talipes equinovarus and pes planus are also common. Some individuals have joint hypermobility, although joint dislocations have not been reported. Contractures are also occasionally reported, typically affecting large joints. Postaxial polydactyly has also been rarely reported. Hearing loss is present in approximately one quarter of affected individuals. Conductive hearing loss may be due to chronic middle ear effusion, but sensorineural hearing loss has been described in three individuals. Branchial defects have also been rarely reported. Myopia and hyperopia have both been reported in individuals with AKS. Optic nerve anomalies, including hypoplasia of the optic nerve or the presence of a coloboma, have been identified in four affected individuals. There is theoretical risk for exposure keratopathy in individuals with particularly shallow orbits and long palpebral fissures, but this has not been observed in individuals with AKS. • In a group of older individuals with loss-of-function pathogenic variants (ranging in age from eight years to young adulthood), independent ambulation was achieved by 5/11 individuals, although some still required assistive devices for longer distances. • Nine out of 12 individuals used verbal communication, with 6/12 using mostly single words and 3/12 using phrases to communicate. • Eight out of 11 individuals were able to use sign language or communication devices to supplement their communication. • In nine older individuals with missense pathogenic variants, 8/9 were able to walk independently, with 6/9 achieving this skill before age three years. Six out of eight individuals in this group were able to speak in phrases. • Many older children and adults are also able to use signs (sometimes up to several hundred) and devices to supplement their communication. • Hypotonia has been reported in all known individuals with Au-Kline syndrome (AKS) and often persists into adulthood. • Reflexes are typically reduced or absent. • Some individuals have suspected neuropathy on exam, but formal nerve conduction studies / electromyography have not typically been pursued. • Some individuals describe muscle weakness and/or easy fatigability. • Muscle biopsy may be abnormal but has not been pursued in most individuals. • Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. • Muscle biopsy may be abnormal but has not been pursued in most individuals. • Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. • Several individuals have been diagnosed with autonomic dysfunction, presenting with gastrointestinal dysmotility, high pain threshold (37%), heat intolerance, recurrent fevers, and abnormal sweating. • Muscle biopsy may be abnormal but has not been pursued in most individuals. • Histologic findings have not been consistent and have included type 1 fiber atrophy and mitochondrial complex 1 deficiency. • Sagittal and metopic sutures are typically affected, and many individuals have metopic ridging without obvious or confirmed synostosis. • Approximately half of the individuals with craniosynostosis have required surgical intervention. However, it is unclear if surgical intervention improves cognitive outcome in individuals with AKS. • Ventricular septal defects are the most common anomaly. • Complex congenital heart defects are rarely reported. • Aortic dilatation has been identified in three individuals; the natural history of aortic dilatation in AKS is unclear. • Two affected individuals have had left ventricular non-compaction cardiomyopathy. • Hydronephrosis is present in up to 52% of individuals with AKS (see • Cryptorchidism is common in males. • Most neonates with AKS have normal growth parameters. • Approximately 30% of affected individuals demonstrate growth deficiency over time, affecting both height and weight. • Age of onset of growth restriction has been variable, and the true incidence and degree of severity is unclear, as stature is also often affected by the presence of scoliosis. • Occasionally, there may be mild microcephaly, which is usually noted by early childhood (see • Overgrowth consisting of increased length and weight at birth has been described in two individuals; two other individuals have been reported to have obesity with increased weight versus height [ • Thirty-nine percent of individuals with AKS have scoliosis, which can range from mild to severe and can require surgical intervention. • Vertebral segmentation anomalies may be present and are more likely to be associated with severe scoliosis. • Congenital hip dysplasia is observed in about one third of individuals with AKS. • Talipes equinovarus and pes planus are also common. • Some individuals have joint hypermobility, although joint dislocations have not been reported. • Contractures are also occasionally reported, typically affecting large joints. • Postaxial polydactyly has also been rarely reported. • Hearing loss is present in approximately one quarter of affected individuals. • Conductive hearing loss may be due to chronic middle ear effusion, but sensorineural hearing loss has been described in three individuals. • Branchial defects have also been rarely reported. • Myopia and hyperopia have both been reported in individuals with AKS. • Optic nerve anomalies, including hypoplasia of the optic nerve or the presence of a coloboma, have been identified in four affected individuals. • There is theoretical risk for exposure keratopathy in individuals with particularly shallow orbits and long palpebral fissures, but this has not been observed in individuals with AKS. ## Genotype-Phenotype Correlations Based on the limited number of reported individuals with AKS, it appears that individuals with missense pathogenic variants may have a reduced burden of major organ malformations compared to individuals with loss-of-function pathogenic variants [ General findings to date pertaining to specific features and genotype include the following: ## Nomenclature The disorder name " Okamoto syndrome was initially described in 1997, although the underlying molecular genetic etiology was unknown [ ## Prevalence Prevalence is currently unknown. AKS is a rare disorder first described in 2015. The authors are aware of more than 75 affected individuals worldwide, with more than 40 individuals formally reported in the literature [ ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Au-Kline Syndrome Postnatal growth deficiency Congenital heart defects Genitourinary anomalies Elongated palpebral fissures, large, prominent ears, cleft palate, & dental anomalies ID (mild to moderate) Skeletal anomalies Arched & broad eyebrows; short columella w/depressed nasal tip Cleft lip or lip pits Immunodeficiency Craniosynostosis is rare. Short stature Genitourinary anomalies; cryptorchidism in males Coarse facial features Ptosis Prenatal cystic hygroma or ↑ nuchal translucency Absence of typical AKS facial gestalt DD of variable degree Hypertrophic cardiomyopathy Coagulation abnormalities Myelodysplasia Coarse facial features & macroglossia ID (mild to severe) Postaxial polydactyly Supernumerary nipples Vertebral anomalies Absence of typical AKS facial gestalt Typically affects males Pre- & postnatal overgrowth Polyhydramnios Macrostomia Aortic dilatation Sagittal craniosynostosis, shallow orbits, palate abnormalities, &/or bifid uvula ID (mild to moderate) Skeletal anomalies Absence of typical AKS facial gestalt Marfanoid body habitus Arachnodactyly & camptodactyly AD = autosomal dominant; AKS = Au-Kline syndrome; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Shallow orbits, coarse features, broad nasal ridge, open, downturned mouth with macroglossia, and a deeply grooved tongue would be more suggestive of AKS. Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in See Individuals with AKS caused by loss-of-function Of note, as individuals with • Postnatal growth deficiency • Congenital heart defects • Genitourinary anomalies • Elongated palpebral fissures, large, prominent ears, cleft palate, & dental anomalies • ID (mild to moderate) • Skeletal anomalies • Arched & broad eyebrows; short columella w/depressed nasal tip • Cleft lip or lip pits • Immunodeficiency • Craniosynostosis is rare. • Short stature • Genitourinary anomalies; cryptorchidism in males • Coarse facial features • Ptosis • Prenatal cystic hygroma or ↑ nuchal translucency • Absence of typical AKS facial gestalt • DD of variable degree • Hypertrophic cardiomyopathy • Coagulation abnormalities • Myelodysplasia • Coarse facial features & macroglossia • ID (mild to severe) • Postaxial polydactyly • Supernumerary nipples • Vertebral anomalies • Absence of typical AKS facial gestalt • Typically affects males • Pre- & postnatal overgrowth • Polyhydramnios • Macrostomia • Aortic dilatation • Sagittal craniosynostosis, shallow orbits, palate abnormalities, &/or bifid uvula • ID (mild to moderate) • Skeletal anomalies • Absence of typical AKS facial gestalt • Marfanoid body habitus • Arachnodactyly & camptodactyly ## Management No clinical practice guidelines for Au-Kline syndrome (AKS) have been published. To establish the extent of disease and needs in an individual diagnosed with AKS, the evaluations summarized in Au-Kline Syndrome: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Brain MRI could be considered if neurologic symptoms (e.g., seizure) are present. Consider EEG if seizures are a concern. Consider referral to neurologist. If there are feeding concerns or poor growth, consider GI referral & eval for dysmotility. Consider eval for gastrostomy tube placement in persons w/feeding difficulty & poor growth. Spine radiographs to assess for segmentation anomalies & scoliosis Hip ultrasound or radiograph depending on age Consider spine MRI to evaluate for spinal syrinx, as clinically indicated. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; AKS = Au-Kline syndrome; ASD = autism spectrum disorder; ENT = ear, nose, and throat; GI = gastrointestinal; T Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for AKS. 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 Au-Kline Syndrome: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; ENT = ear, nose, and throat; PT = physical therapy; SNHL = sensorineural hearing loss 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). Although autism spectrum disorder is uncommon in AKS, children may still 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. Anesthesia consultation is suggested prior to any sedation for surgery given potential airway issues from malocclusion and macroglossia. There is also potential risk that prolonged intubation and ventilation will be required, as occurred in one individual after surgery [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Au-Kline Syndrome: Recommended Surveillance Measurement of growth parameters Eval of nutritional status Per cardiologist Frequency of eval may depend on size of aortic root & arch. Periodic Frequency of bone densitometry may depend on severity & history of fracture. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; T The risk of developing scoliosis in adulthood is unclear. See Search • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Brain MRI could be considered if neurologic symptoms (e.g., seizure) are present. • Consider EEG if seizures are a concern. • Consider referral to neurologist. • If there are feeding concerns or poor growth, consider GI referral & eval for dysmotility. • Consider eval for gastrostomy tube placement in persons w/feeding difficulty & poor growth. • Spine radiographs to assess for segmentation anomalies & scoliosis • Hip ultrasound or radiograph depending on age • Consider spine MRI to evaluate for spinal syrinx, as clinically indicated. • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Measurement of growth parameters • Eval of nutritional status • Per cardiologist • Frequency of eval may depend on size of aortic root & arch. • Periodic • Frequency of bone densitometry may depend on severity & history of fracture. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with AKS, the evaluations summarized in Au-Kline Syndrome: Recommended Evaluations Following Initial Diagnosis To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Brain MRI could be considered if neurologic symptoms (e.g., seizure) are present. Consider EEG if seizures are a concern. Consider referral to neurologist. If there are feeding concerns or poor growth, consider GI referral & eval for dysmotility. Consider eval for gastrostomy tube placement in persons w/feeding difficulty & poor growth. Spine radiographs to assess for segmentation anomalies & scoliosis Hip ultrasound or radiograph depending on age Consider spine MRI to evaluate for spinal syrinx, as clinically indicated. Community or Social work involvement for parental support; Home nursing referral. ADHD = attention-deficit/hyperactivity disorder; AKS = Au-Kline syndrome; ASD = autism spectrum disorder; ENT = ear, nose, and throat; GI = gastrointestinal; T Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Brain MRI could be considered if neurologic symptoms (e.g., seizure) are present. • Consider EEG if seizures are a concern. • Consider referral to neurologist. • If there are feeding concerns or poor growth, consider GI referral & eval for dysmotility. • Consider eval for gastrostomy tube placement in persons w/feeding difficulty & poor growth. • Spine radiographs to assess for segmentation anomalies & scoliosis • Hip ultrasound or radiograph depending on age • Consider spine MRI to evaluate for spinal syrinx, as clinically indicated. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations There is no cure for AKS. 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 Au-Kline Syndrome: Treatment of Manifestations Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; ENT = ear, nose, and throat; PT = physical therapy; SNHL = sensorineural hearing loss 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). Although autism spectrum disorder is uncommon in AKS, children may still 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. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Although autism spectrum disorder is uncommon in AKS, children may still 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. ## Prevention of Secondary Complications Anesthesia consultation is suggested prior to any sedation for surgery given potential airway issues from malocclusion and macroglossia. There is also potential risk that prolonged intubation and ventilation will be required, as occurred in one individual after surgery [ ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Au-Kline Syndrome: Recommended Surveillance Measurement of growth parameters Eval of nutritional status Per cardiologist Frequency of eval may depend on size of aortic root & arch. Periodic Frequency of bone densitometry may depend on severity & history of fracture. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; T The risk of developing scoliosis in adulthood is unclear. • Measurement of growth parameters • Eval of nutritional status • Per cardiologist • Frequency of eval may depend on size of aortic root & arch. • Periodic • Frequency of bone densitometry may depend on severity & history of fracture. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Au-Kline syndrome (AKS) is an autosomal dominant disorder typically caused by a All probands reported to date with AKS whose parents have undergone molecular genetic testing 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 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. * Theoretically, a parent with somatic and germline mosaicism for an If the Theoretically, if a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to future sibs of inheriting the pathogenic variant is 50%. The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 AKS whose parents have undergone molecular genetic testing 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 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. • * Theoretically, 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. • * Theoretically, 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. • * Theoretically, a parent with somatic and germline mosaicism for an • If the • Theoretically, if a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to future sibs of inheriting the pathogenic variant is 50%. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 Au-Kline syndrome (AKS) is an autosomal dominant disorder typically caused by a ## Risk to Family Members All probands reported to date with AKS whose parents have undergone molecular genetic testing 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 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. * Theoretically, a parent with somatic and germline mosaicism for an If the Theoretically, if a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to future sibs of inheriting the pathogenic variant is 50%. • All probands reported to date with AKS whose parents have undergone molecular genetic testing 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 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. • * Theoretically, 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. • * Theoretically, 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. • * Theoretically, a parent with somatic and germline mosaicism for an • If the • Theoretically, if a parent of the proband is known to have the pathogenic variant identified in the proband, the risk to future sibs of inheriting the pathogenic variant is 50%. ## 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 Au-Kline Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Au-Kline Syndrome ( HnRNP K is involved with binding single-stranded DNA or RNA, which is mediated through its three KH domains. There are two consecutive KH domains at the N terminus (encoded by exons 4-7 and 9-10) and a third located at the C terminus (encoded by exons 15-16). HnRNP K also acts as a docking platform for interaction of kinases and signal transduction factors that have roles in nucleic acid-related cellular activities, implicating hnRNP K in chromatin remodeling, transcriptional regulation, and translational regulation [ Somatic pathogenic variants in ## Molecular Pathogenesis HnRNP K is involved with binding single-stranded DNA or RNA, which is mediated through its three KH domains. There are two consecutive KH domains at the N terminus (encoded by exons 4-7 and 9-10) and a third located at the C terminus (encoded by exons 15-16). HnRNP K also acts as a docking platform for interaction of kinases and signal transduction factors that have roles in nucleic acid-related cellular activities, implicating hnRNP K in chromatin remodeling, transcriptional regulation, and translational regulation [ ## Cancer and Benign Tumors Somatic pathogenic variants in ## Chapter Notes There is an Au-Kline syndrome (AKS) Facebook group for affected individuals and families. Additional support can also be found through the Dr Ping-Yee Billie Au ( We would like to acknowledge the individuals with AKS and their families. We would also like to acknowledge our large group of international collaborators who have contributed to case findings. We would further like to acknowledge the 1 February 2024 (ma) Comprehensive update posted live 18 April 2019 (sw) Review posted live 15 October 2018 (pyba) Original submission • 1 February 2024 (ma) Comprehensive update posted live • 18 April 2019 (sw) Review posted live • 15 October 2018 (pyba) Original submission ## Author Notes There is an Au-Kline syndrome (AKS) Facebook group for affected individuals and families. Additional support can also be found through the Dr Ping-Yee Billie Au ( ## Acknowledgments We would like to acknowledge the individuals with AKS and their families. We would also like to acknowledge our large group of international collaborators who have contributed to case findings. We would further like to acknowledge the ## Revision History 1 February 2024 (ma) Comprehensive update posted live 18 April 2019 (sw) Review posted live 15 October 2018 (pyba) Original submission • 1 February 2024 (ma) Comprehensive update posted live • 18 April 2019 (sw) Review posted live • 15 October 2018 (pyba) Original submission ## References ## Literature Cited Three individuals with Au-Kline syndrome A-C. Proband 1 at age 14 months, age eight years, and age 19 years. Note long palpebral fissures, prominent eyes and shallow orbits, broad nasal ridge, and M-shaped Cupid's bow to upper lip. D. High-arched palate with bifid uvula and deeply grooved tongue present in Proband 1 at age 19 years. E-G. Proband 2 at age 12 months, age eight years, and age 11 years. Note presence of metopic ridging, long palpebral fissures with subtle lateral eversion, and characteristic shape to nose and mouth. H-I. Proband 3 at age seven years. Note deep midline groove in the tongue. Adapted from	[]	18/4/2019	1/2/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
authors	authors	[]	GeneReviews Authors				[]				GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
aved	aved	[ "Ataxia with Isolated Vitamin E Deficiency", "AVED", "AVED", "Ataxia with Isolated Vitamin E Deficiency", "Alpha-tocopherol transfer protein", "TTPA", "Ataxia with Vitamin E Deficiency" ]	Ataxia with Vitamin E Deficiency	Markus Schuelke	Summary Untreated ataxia with vitamin E deficiency (AVED) generally manifests between ages five and 15 years. The first manifestations include progressive ataxia, clumsiness of the hands, loss of proprioception, and areflexia. Other features often observed are dysdiadochokinesia, dysarthria, positive Romberg sign, head titubation, decreased visual acuity, and positive Babinski sign. Although age of onset and disease course are more uniform within a given family, disease manifestations and their severity can vary even among sibs. When lifelong high-dose vitamin E supplementation is initiated in presymptomatic individuals, manifestations of AVED do not develop. The diagnosis of AVED is established in a proband with suggestive findings and biallelic pathogenic variants in AVED is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis No consensus clinical diagnostic criteria for ataxia with vitamin E deficiency (AVED) have been published. AVED Onset between ages five and 15 years Progressive cerebellar findings including the following: Gait ataxia Clumsiness of the hands Loss of proprioception (especially distal joint position and vibration sense) Dysdiadochokinesia Positive Romberg sign Head titubation Lower motor neuron involvement. Areflexia Upper motor neuron involvement. Positive Babinski sign Ophthalmologic involvement. Decreased visual acuity due to macular degeneration, pigmentary retinopathy Normal lipid and lipoprotein profile Very low plasma vitamin E (alpha-tocopherol, or α-tocopherol) concentration Note: There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories. In Because oxidation of α-tocopherol by air may invalidate test results, the following precautions with a blood sample should be taken: Centrifugation of the EDTA blood soon after venipuncture Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube Shipment of the sample to the test laboratory in dry ice No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED; even the presence of a severe neuropathy does not exclude the diagnosis of AVED. See Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20) and increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [ Cerebellar atrophy [ Small T Note: No radiologic findings are specific to or diagnostic of AVED. The diagnosis of AVED 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 Ataxia with Vitamin E Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A single whole-gene deletion has been reported [ • Onset between ages five and 15 years • Progressive cerebellar findings including the following: • Gait ataxia • Clumsiness of the hands • Loss of proprioception (especially distal joint position and vibration sense) • Dysdiadochokinesia • Positive Romberg sign • Head titubation • Gait ataxia • Clumsiness of the hands • Loss of proprioception (especially distal joint position and vibration sense) • Dysdiadochokinesia • Positive Romberg sign • Head titubation • Lower motor neuron involvement. Areflexia • Upper motor neuron involvement. Positive Babinski sign • Ophthalmologic involvement. Decreased visual acuity due to macular degeneration, pigmentary retinopathy • Gait ataxia • Clumsiness of the hands • Loss of proprioception (especially distal joint position and vibration sense) • Dysdiadochokinesia • Positive Romberg sign • Head titubation • Normal lipid and lipoprotein profile • Very low plasma vitamin E (alpha-tocopherol, or α-tocopherol) concentration • Note: There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories. • In • Because oxidation of α-tocopherol by air may invalidate test results, the following precautions with a blood sample should be taken: • Centrifugation of the EDTA blood soon after venipuncture • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube • Shipment of the sample to the test laboratory in dry ice • Centrifugation of the EDTA blood soon after venipuncture • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube • Shipment of the sample to the test laboratory in dry ice • Centrifugation of the EDTA blood soon after venipuncture • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube • Shipment of the sample to the test laboratory in dry ice • No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED; even the presence of a severe neuropathy does not exclude the diagnosis of AVED. See • Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20) and increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [ • Cerebellar atrophy [ • Small T ## Suggestive Findings AVED Onset between ages five and 15 years Progressive cerebellar findings including the following: Gait ataxia Clumsiness of the hands Loss of proprioception (especially distal joint position and vibration sense) Dysdiadochokinesia Positive Romberg sign Head titubation Lower motor neuron involvement. Areflexia Upper motor neuron involvement. Positive Babinski sign Ophthalmologic involvement. Decreased visual acuity due to macular degeneration, pigmentary retinopathy Normal lipid and lipoprotein profile Very low plasma vitamin E (alpha-tocopherol, or α-tocopherol) concentration Note: There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories. In Because oxidation of α-tocopherol by air may invalidate test results, the following precautions with a blood sample should be taken: Centrifugation of the EDTA blood soon after venipuncture Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube Shipment of the sample to the test laboratory in dry ice No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED; even the presence of a severe neuropathy does not exclude the diagnosis of AVED. See Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20) and increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [ Cerebellar atrophy [ Small T Note: No radiologic findings are specific to or diagnostic of AVED. • Onset between ages five and 15 years • Progressive cerebellar findings including the following: • Gait ataxia • Clumsiness of the hands • Loss of proprioception (especially distal joint position and vibration sense) • Dysdiadochokinesia • Positive Romberg sign • Head titubation • Gait ataxia • Clumsiness of the hands • Loss of proprioception (especially distal joint position and vibration sense) • Dysdiadochokinesia • Positive Romberg sign • Head titubation • Lower motor neuron involvement. Areflexia • Upper motor neuron involvement. Positive Babinski sign • Ophthalmologic involvement. Decreased visual acuity due to macular degeneration, pigmentary retinopathy • Gait ataxia • Clumsiness of the hands • Loss of proprioception (especially distal joint position and vibration sense) • Dysdiadochokinesia • Positive Romberg sign • Head titubation • Normal lipid and lipoprotein profile • Very low plasma vitamin E (alpha-tocopherol, or α-tocopherol) concentration • Note: There is no universal normal range of plasma vitamin E concentration, as it depends on the test method and varies among laboratories. • In • Because oxidation of α-tocopherol by air may invalidate test results, the following precautions with a blood sample should be taken: • Centrifugation of the EDTA blood soon after venipuncture • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube • Shipment of the sample to the test laboratory in dry ice • Centrifugation of the EDTA blood soon after venipuncture • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube • Shipment of the sample to the test laboratory in dry ice • Centrifugation of the EDTA blood soon after venipuncture • Quick separation of plasma from blood cells after centrifugation and subsequent flash freezing of the plasma in liquid nitrogen • Filling the space above the plasma with an inert gas (e.g., argon or nitrogen) • Protecting the sample from light by wrapping the container in aluminum foil, or using a black or light-shielded Eppendorf tube • Shipment of the sample to the test laboratory in dry ice • No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED; even the presence of a severe neuropathy does not exclude the diagnosis of AVED. See • Somatosensory evoked potentials show increased central conduction time between the segment C1 (N13b) and the sensorimotor cortex (N20) and increased latencies of the N20 (median nerve) and P40 (tibial nerve) waves. The P40 wave may be missing completely [ • Cerebellar atrophy [ • Small T ## Establishing the Diagnosis The diagnosis of AVED 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 Ataxia with Vitamin E Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A single whole-gene deletion has been reported [ ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Ataxia with Vitamin E Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. A single whole-gene deletion has been reported [ ## Clinical Characteristics The phenotype and disease severity of untreated ataxia with vitamin E deficiency (AVED) vary widely. Although age of onset and disease course tend to be more uniform within a given family, clinical findings and disease severity can vary among sibs [ When vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), manifestations of AVED do not develop (see Management, The following description of the phenotypic features associated with untreated individuals with AVED is based on findings in 132 individuals of North African descent [ Ataxia with Vitamin E Deficiency: Frequency of Select Features in Untreated Individuals Based on findings in 132 individuals of North African descent [ Tendon reflexes of the lower extremities are generally absent, and the plantar reflexes (Babinski sign) increase in intensity. Arm or cervical dystonia may be seen on rare occasion [ No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED. The following are the results from a neurophysiologic study of 45 individuals (from a cohort of 132 individuals) with AVED from North Africa that included median and peroneal nerve motor conduction velocity, compound muscle action potential, median and saphenous nerve sensory action potential, and sensory action potential [ 9% had normal findings. 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]). 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN). 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response). Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%). To date, only two pathogenic variants have shown clear-cut genotype-phenotype correlations: The pathogenic variant The pathogenic variant A less clear genotype-phenotype correlation can be seen for other pathogenic variants, particularly when homozygous. Preliminary genotype-phenotype correlations related to variant and age of onset of disease include: Pathogenic missense variants that cause substitutions in non- or semi-conserved amino acids (e.g., p.His101Gln, p.Ala120Thr, p.Arg192His, or p.Gly246Arg) are associated with a mild phenotype, whereas substitutions in highly conserved amino acids are associated with early onset and severe symptoms (e.g., p.Arg59Trp, p.Asp64Gly, p.Glu141Lys, p.Leu183Pro, p.Arg221Trp) (see AVED was first called "Friedreich ataxia phenotype with selective vitamin E deficiency" [ The Several restricted population-based studies have been performed. Of 29 individuals from Morocco with a Friedreich ataxia-like phenotype, 13 had AVED and the remainder had Friedreich ataxia [ In a population study in southeast Norway, 1 in 171 individuals with hereditary ataxia had AVED, suggesting a prevalence of 0.6:1,000,000 [ • 9% had normal findings. • 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]). • 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN). • 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response). • Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%). • The pathogenic variant • The pathogenic variant ## Clinical Description The phenotype and disease severity of untreated ataxia with vitamin E deficiency (AVED) vary widely. Although age of onset and disease course tend to be more uniform within a given family, clinical findings and disease severity can vary among sibs [ When vitamin E treatment is initiated in presymptomatic individuals (e.g., younger sibs of an index case), manifestations of AVED do not develop (see Management, The following description of the phenotypic features associated with untreated individuals with AVED is based on findings in 132 individuals of North African descent [ Ataxia with Vitamin E Deficiency: Frequency of Select Features in Untreated Individuals Based on findings in 132 individuals of North African descent [ Tendon reflexes of the lower extremities are generally absent, and the plantar reflexes (Babinski sign) increase in intensity. Arm or cervical dystonia may be seen on rare occasion [ No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED. The following are the results from a neurophysiologic study of 45 individuals (from a cohort of 132 individuals) with AVED from North Africa that included median and peroneal nerve motor conduction velocity, compound muscle action potential, median and saphenous nerve sensory action potential, and sensory action potential [ 9% had normal findings. 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]). 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN). 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response). Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%). • 9% had normal findings. • 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]). • 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN). • 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response). • Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%). ## Untreated Individuals Tendon reflexes of the lower extremities are generally absent, and the plantar reflexes (Babinski sign) increase in intensity. Arm or cervical dystonia may be seen on rare occasion [ No electrophysiologic findings (motor nerve conduction velocities, compound muscle action potentials, or nerve sensory action potentials) are specific to or diagnostic of AVED. The following are the results from a neurophysiologic study of 45 individuals (from a cohort of 132 individuals) with AVED from North Africa that included median and peroneal nerve motor conduction velocity, compound muscle action potential, median and saphenous nerve sensory action potential, and sensory action potential [ 9% had normal findings. 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]). 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN). 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response). Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%). • 9% had normal findings. • 47% had mild neuropathy (at least 1 parameter 70%-100% of lower limit of normal [LLN]). • 27% had moderate neuropathy (at least 1 parameter 30%-70% of LLN). • 17% had severe neuropathy (at least 1 parameter <30% of LLN or no response). • Neuropathy was either purely sensory (34%), purely motor (24%), or combined (42%). ## Genotype-Phenotype Correlations To date, only two pathogenic variants have shown clear-cut genotype-phenotype correlations: The pathogenic variant The pathogenic variant A less clear genotype-phenotype correlation can be seen for other pathogenic variants, particularly when homozygous. Preliminary genotype-phenotype correlations related to variant and age of onset of disease include: Pathogenic missense variants that cause substitutions in non- or semi-conserved amino acids (e.g., p.His101Gln, p.Ala120Thr, p.Arg192His, or p.Gly246Arg) are associated with a mild phenotype, whereas substitutions in highly conserved amino acids are associated with early onset and severe symptoms (e.g., p.Arg59Trp, p.Asp64Gly, p.Glu141Lys, p.Leu183Pro, p.Arg221Trp) (see • The pathogenic variant • The pathogenic variant ## Nomenclature AVED was first called "Friedreich ataxia phenotype with selective vitamin E deficiency" [ ## Prevalence The Several restricted population-based studies have been performed. Of 29 individuals from Morocco with a Friedreich ataxia-like phenotype, 13 had AVED and the remainder had Friedreich ataxia [ In a population study in southeast Norway, 1 in 171 individuals with hereditary ataxia had AVED, suggesting a prevalence of 0.6:1,000,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis ## Management No clinical practice guidelines for ataxia with vitamin E deficiency (AVED) have been published. To establish the extent of disease and needs of an individual diagnosed with a hereditary ataxia, the evaluations summarized in Hereditary Ataxia Overview, The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. With treatment, plasma vitamin E concentrations can become normal. No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes. The reported vitamin E dose ranges from 800 mg to 1,500 mg (or 40 mg/kg body weight in children) [ One of the following vitamin E preparations is used: The chemically manufactured racemic form, The naturally occurring form, It is currently unknown whether affected individuals should be treated with In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain [ The goals of supportive care in those with manifestations of AVED are to maximize function and reduce complications. Depending on the clinical manifestations, it is recommended that each individual be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech-language pathologists, pulmonologists, and mental health specialists (see Hereditary Ataxia Overview, For those on vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high-normal range. Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although α-tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Hereditary Ataxia Overview, Individuals with AVED should avoid: Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [ Occupations requiring quick responses or good balance. It is appropriate to clarify the genetic status of all sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease. See Because reduced vitamin E levels are associated with low fertility and embryo resorption in mice [ Search • The chemically manufactured racemic form, • The naturally occurring form, • Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [ • Occupations requiring quick responses or good balance. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with a hereditary ataxia, the evaluations summarized in Hereditary Ataxia Overview, ## Treatment of Manifestations The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. With treatment, plasma vitamin E concentrations can become normal. No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes. The reported vitamin E dose ranges from 800 mg to 1,500 mg (or 40 mg/kg body weight in children) [ One of the following vitamin E preparations is used: The chemically manufactured racemic form, The naturally occurring form, It is currently unknown whether affected individuals should be treated with In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain [ The goals of supportive care in those with manifestations of AVED are to maximize function and reduce complications. Depending on the clinical manifestations, it is recommended that each individual be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech-language pathologists, pulmonologists, and mental health specialists (see Hereditary Ataxia Overview, • The chemically manufactured racemic form, • The naturally occurring form, ## Targeted Therapy The treatment of choice for AVED is lifelong high-dose oral vitamin E supplementation. With treatment, plasma vitamin E concentrations can become normal. No large-scale therapeutic studies have been performed to determine optimal vitamin E dosage and to evaluate outcomes. The reported vitamin E dose ranges from 800 mg to 1,500 mg (or 40 mg/kg body weight in children) [ One of the following vitamin E preparations is used: The chemically manufactured racemic form, The naturally occurring form, It is currently unknown whether affected individuals should be treated with In older individuals, disease progression can be stopped, but deficits in proprioception and gait unsteadiness generally remain [ • The chemically manufactured racemic form, • The naturally occurring form, ## Supportive Care The goals of supportive care in those with manifestations of AVED are to maximize function and reduce complications. Depending on the clinical manifestations, it is recommended that each individual be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech-language pathologists, pulmonologists, and mental health specialists (see Hereditary Ataxia Overview, ## Surveillance For those on vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high-normal range. Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although α-tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Hereditary Ataxia Overview, ## Targeted Therapy For those on vitamin E therapy, the plasma vitamin E concentration should be measured at regular intervals (e.g., every 6 months), especially in children. Ideally the plasma vitamin E concentration should be maintained in the high-normal range. Some protocols call for measuring the total radical-trapping antioxidant parameter of plasma (TRAP). Although α-tocopherol only contributes 5%-10% to TRAP, this parameter appears to be the best surrogate marker for clinical improvement [ ## Symptomatic Individuals To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Hereditary Ataxia Overview, ## Agents/Circumstances to Avoid Individuals with AVED should avoid: Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [ Occupations requiring quick responses or good balance. • Smoking because it considerably lowers TRAP and reduces plasma vitamin E concentrations [ • Occupations requiring quick responses or good balance. ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of all sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of treatment. Timely treatment with vitamin E supplementation may completely avert the clinical manifestations of the disease. See ## Pregnancy Management Because reduced vitamin E levels are associated with low fertility and embryo resorption in mice [ ## Therapies Under Investigation Search ## Genetic Counseling Ataxia with vitamin E deficiency (AVED) 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 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 Clinical findings and disease severity can vary among affected sibs with the same 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: The moderately lowered plasma vitamin E concentration in heterozygotes is not a sensitive enough measure to distinguish between heterozygous carriers and non-carriers. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with AVED should be considered, particularly if both partners are of the same ethnic background (see 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 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 • Clinical findings and disease severity can vary among affected sibs with the same • 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 AVED should be considered, particularly if both partners are of the same ethnic background (see ## Mode of Inheritance Ataxia with vitamin E deficiency (AVED) 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 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 Clinical findings and disease severity can vary among affected 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 • 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 • Clinical findings and disease severity can vary among affected sibs with the same • 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: The moderately lowered plasma vitamin E concentration in heterozygotes is not a sensitive enough measure to distinguish between heterozygous carriers and non-carriers. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with AVED should be considered, particularly if both partners are of the same ethnic background (see • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for the reproductive partners of known carriers and for the reproductive partners of individuals affected with AVED should be considered, particularly if both partners are of the same ethnic background (see ## 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 • • • • • • United Kingdom • • • United Kingdom • • • ## Molecular Genetics Ataxia with Vitamin E Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ataxia with Vitamin E Deficiency ( Liver α-TTP incorporates α-tocopherol from the chylomicrons into very low-density lipoproteins (VLDLs), which are then secreted into the circulation [ Notable Variants listed in the table have been provided by the author. ## Molecular Pathogenesis Liver α-TTP incorporates α-tocopherol from the chylomicrons into very low-density lipoproteins (VLDLs), which are then secreted into the circulation [ Notable Variants listed in the table have been provided by the author. ## Chapter Notes 16 March 2023 (bp) Comprehensive update posted live 13 October 2016 (sw) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 4 September 2007 (me) Comprehensive update posted live 20 May 2005 (me) Review posted live 4 October 2004 (ms) Original submission • 16 March 2023 (bp) Comprehensive update posted live • 13 October 2016 (sw) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 4 September 2007 (me) Comprehensive update posted live • 20 May 2005 (me) Review posted live • 4 October 2004 (ms) Original submission ## Revision History 16 March 2023 (bp) Comprehensive update posted live 13 October 2016 (sw) Comprehensive update posted live 2 November 2010 (me) Comprehensive update posted live 4 September 2007 (me) Comprehensive update posted live 20 May 2005 (me) Review posted live 4 October 2004 (ms) Original submission • 16 March 2023 (bp) Comprehensive update posted live • 13 October 2016 (sw) Comprehensive update posted live • 2 November 2010 (me) Comprehensive update posted live • 4 September 2007 (me) Comprehensive update posted live • 20 May 2005 (me) Review posted live • 4 October 2004 (ms) Original submission ## Key Sections in this ## References ## Literature Cited	[]	20/5/2005	16/3/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
ayme-gripp	ayme-gripp	[ "Transcription factor Maf", "MAF", "Aymé-Gripp Syndrome" ]	Aymé-Gripp Syndrome	Shivarajan Manickavasagam Amudhavalli, Randi Gadea, Karen Gripp	Summary Aymé-Gripp syndrome is classically defined as the triad of bilateral early cataracts, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities. The facial features are often described as "Down syndrome-like" and include brachycephaly, flat facial appearance, short nose, long philtrum, narrow mouth, and low-set and posteriorly rotated ears. Hearing loss is often congenital. Other features may include postnatal short stature, seizure disorder, nonspecific brain abnormalities on head imaging, skeletal abnormalities, and joint limitations. A subset of individuals have been found to have pericarditis or pericardial effusion during the neonatal or infantile period. All affected individuals have had developmental delay, but the degree of cognitive impairment is extremely variable. Other features including gastrointestinal and endocrine abnormalities, ectodermal dysplasia (i.e., nail dystrophy and mammary gland hypoplasia), dental anomalies, and chronic glomerulopathy with proteinuria have been reported in rare affected individuals. The diagnosis of Aymé-Gripp syndrome is established in a proband with cataracts, sensorineural hearing loss, and suggestive facial features and a heterozygous pathogenic variant in a specific region of Aymé-Gripp syndrome is inherited in an autosomal dominant manner. Almost all individuals reported to date have been simplex cases (i.e., a single occurrence in a family) resulting from a	## Diagnosis Aymé-Gripp syndrome is classically defined as the triad of cataract, sensorineural hearing loss, and characteristic facial features in combination with neurodevelopmental abnormalities [ Aymé-Gripp syndrome Distinctive facial features ( Brachycephaly Flat facial appearance Short nose Long philtrum Narrow mouth Dental abnormalities (small, abnormally shaped teeth) Low-set and posteriorly rotated ears Sensorineural hearing loss Cataracts Developmental delay / intellectual disability Short stature Seizures (variable, from febrile seizures to epilepsy) Congenital radioulnar synostosis Pericardial effusion Mammary gland hypoplasia Ectodermal abnormalities (sparse scalp hair, dystrophic nails) Congenital radioulnar synostosis Radial head subluxation Chondrolysis of the hip (in a young adult) Carpal/tarsal long bone defects The diagnosis of Aymé-Gripp syndrome Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene is likely involved, whereas genomic testing does not. Because the phenotype of Aymé-Gripp syndrome is broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of Aymé-Gripp syndrome molecular genetic testing approaches can include Note: No exon/multiexon deletions/duplications have been reported to result in Aymé-Gripp syndrome. For an introduction to multigene panels click When the diagnosis of Aymé-Gripp syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aymé-Gripp 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 • Distinctive facial features ( • Brachycephaly • Flat facial appearance • Short nose • Long philtrum • Narrow mouth • Dental abnormalities (small, abnormally shaped teeth) • Low-set and posteriorly rotated ears • Brachycephaly • Flat facial appearance • Short nose • Long philtrum • Narrow mouth • Dental abnormalities (small, abnormally shaped teeth) • Low-set and posteriorly rotated ears • Sensorineural hearing loss • Cataracts • Developmental delay / intellectual disability • Short stature • Brachycephaly • Flat facial appearance • Short nose • Long philtrum • Narrow mouth • Dental abnormalities (small, abnormally shaped teeth) • Low-set and posteriorly rotated ears • Seizures (variable, from febrile seizures to epilepsy) • Congenital radioulnar synostosis • Pericardial effusion • Mammary gland hypoplasia • Ectodermal abnormalities (sparse scalp hair, dystrophic nails) • Congenital radioulnar synostosis • Radial head subluxation • Chondrolysis of the hip (in a young adult) • Carpal/tarsal long bone defects • Note: No exon/multiexon deletions/duplications have been reported to result in Aymé-Gripp syndrome. • For an introduction to multigene panels click ## Suggestive Findings Aymé-Gripp syndrome Distinctive facial features ( Brachycephaly Flat facial appearance Short nose Long philtrum Narrow mouth Dental abnormalities (small, abnormally shaped teeth) Low-set and posteriorly rotated ears Sensorineural hearing loss Cataracts Developmental delay / intellectual disability Short stature Seizures (variable, from febrile seizures to epilepsy) Congenital radioulnar synostosis Pericardial effusion Mammary gland hypoplasia Ectodermal abnormalities (sparse scalp hair, dystrophic nails) Congenital radioulnar synostosis Radial head subluxation Chondrolysis of the hip (in a young adult) Carpal/tarsal long bone defects • Distinctive facial features ( • Brachycephaly • Flat facial appearance • Short nose • Long philtrum • Narrow mouth • Dental abnormalities (small, abnormally shaped teeth) • Low-set and posteriorly rotated ears • Brachycephaly • Flat facial appearance • Short nose • Long philtrum • Narrow mouth • Dental abnormalities (small, abnormally shaped teeth) • Low-set and posteriorly rotated ears • Sensorineural hearing loss • Cataracts • Developmental delay / intellectual disability • Short stature • Brachycephaly • Flat facial appearance • Short nose • Long philtrum • Narrow mouth • Dental abnormalities (small, abnormally shaped teeth) • Low-set and posteriorly rotated ears • Seizures (variable, from febrile seizures to epilepsy) • Congenital radioulnar synostosis • Pericardial effusion • Mammary gland hypoplasia • Ectodermal abnormalities (sparse scalp hair, dystrophic nails) • Congenital radioulnar synostosis • Radial head subluxation • Chondrolysis of the hip (in a young adult) • Carpal/tarsal long bone defects ## Establishing the Diagnosis The diagnosis of Aymé-Gripp syndrome Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene is likely involved, whereas genomic testing does not. Because the phenotype of Aymé-Gripp syndrome is broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of Aymé-Gripp syndrome molecular genetic testing approaches can include Note: No exon/multiexon deletions/duplications have been reported to result in Aymé-Gripp syndrome. For an introduction to multigene panels click When the diagnosis of Aymé-Gripp syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aymé-Gripp 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 • Note: No exon/multiexon deletions/duplications have been reported to result in Aymé-Gripp syndrome. • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of Aymé-Gripp syndrome molecular genetic testing approaches can include Note: No exon/multiexon deletions/duplications have been reported to result in Aymé-Gripp syndrome. For an introduction to multigene panels click • Note: No exon/multiexon deletions/duplications have been reported to result in Aymé-Gripp syndrome. • For an introduction to multigene panels click ## Option 2 When the diagnosis of Aymé-Gripp syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Aymé-Gripp 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 ## Clinical Characteristics Individuals with Aymé-Gripp syndrome frequently have the triad of bilateral early cataracts, sensorineural hearing loss, and dysmorphic features that are often described as "Down syndrome-like" facies [ Features of Aymé-Gripp Syndrome DD = developmental delay Hearing loss is frequently bilateral and often diagnosed early in childhood. Hearing loss can vary from mild to severe, with a few affected individuals requiring hearing aids or cochlear implant. One affected individual, age 18 months at presentation, had bilateral retinal hemorrhage and optic disc anomaly [ One affected individual was reported to have bilateral cataracts diagnosed at age 14 months. This individual developed aphakic glaucoma and went blind at age two years [ Two affected parents were reported to have cataracts extracted after age 40 years [ Seizures have been reported in 15 of 21affected individuals, with five having febrile seizures [ Nonspecific brain abnormalities such as ventriculomegaly, Chiari 1 malformation, obstructive hydrocephalus, empty sella, and cerebral atrophy have been noted in slightly more than half of individuals who have undergone brain imaging. One individual was reported to have calcifications of the basal ganglia [ Congenital radioulnar synostosis, radial head subluxation, and shortened forearm as individual findings or in various combinations are the most common joint manifestations. Clino/campto/brachydactyly, pectus excavatum, scoliosis without vertebral anomalies, delayed skeletal maturation and carpal/tarsal bone defects, short fourth metatarsal, and hip joint chondrolysis have also been reported. Coronal craniosynostosis requiring surgical repair is reported as a rare feature. One affected individual was reported to have early fusion of the growth plates, spontaneous fractures, and exostosis [ Some affected adults have required hip replacement for hip joint chondrolysis. At least eight of 21 individuals have been noted to have pericarditis or pericardial effusion during the neonatal or infantile period: Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. Atrial septal defect and patent ductus arteriosus have been reported in a single individual each. Rare manifestations may include the following: Hiatal hernia and diaphragmatic hernia Transient hematuria Proteinuria and/or microalbuminuria (reported as a late-onset feature) Glomerulonephropathy Nephrotic syndrome (which did not recur after treatment with prednisone) Pathogenic variants causing Aymé-Gripp syndrome occur at serine, threonine, and proline residues in the N-terminal transactivation domain [ A subset of pathogenic variants in the C-terminal DNA binding domain have been associated with isolated congenital cataracts [ For this disorder, penetrance is felt to be 100%; however, there is variability in presentation as illustrated by a report from This disorder is rare and exact prevalence estimates are unknown. Only 21 individuals representing 19 families have been reported in the literature. • Hearing loss is frequently bilateral and often diagnosed early in childhood. • Hearing loss can vary from mild to severe, with a few affected individuals requiring hearing aids or cochlear implant. • One affected individual, age 18 months at presentation, had bilateral retinal hemorrhage and optic disc anomaly [ • One affected individual was reported to have bilateral cataracts diagnosed at age 14 months. This individual developed aphakic glaucoma and went blind at age two years [ • Two affected parents were reported to have cataracts extracted after age 40 years [ • Seizures have been reported in 15 of 21affected individuals, with five having febrile seizures [ • Nonspecific brain abnormalities such as ventriculomegaly, Chiari 1 malformation, obstructive hydrocephalus, empty sella, and cerebral atrophy have been noted in slightly more than half of individuals who have undergone brain imaging. One individual was reported to have calcifications of the basal ganglia [ • Congenital radioulnar synostosis, radial head subluxation, and shortened forearm as individual findings or in various combinations are the most common joint manifestations. • Clino/campto/brachydactyly, pectus excavatum, scoliosis without vertebral anomalies, delayed skeletal maturation and carpal/tarsal bone defects, short fourth metatarsal, and hip joint chondrolysis have also been reported. • Coronal craniosynostosis requiring surgical repair is reported as a rare feature. • One affected individual was reported to have early fusion of the growth plates, spontaneous fractures, and exostosis [ • Some affected adults have required hip replacement for hip joint chondrolysis. • At least eight of 21 individuals have been noted to have pericarditis or pericardial effusion during the neonatal or infantile period: • Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ • One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. • Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ • One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. • Atrial septal defect and patent ductus arteriosus have been reported in a single individual each. • Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ • One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. • Hiatal hernia and diaphragmatic hernia • Transient hematuria • Proteinuria and/or microalbuminuria (reported as a late-onset feature) • Glomerulonephropathy • Nephrotic syndrome (which did not recur after treatment with prednisone) • Pathogenic variants causing Aymé-Gripp syndrome occur at serine, threonine, and proline residues in the N-terminal transactivation domain [ • A subset of pathogenic variants in the C-terminal DNA binding domain have been associated with isolated congenital cataracts [ ## Clinical Description Individuals with Aymé-Gripp syndrome frequently have the triad of bilateral early cataracts, sensorineural hearing loss, and dysmorphic features that are often described as "Down syndrome-like" facies [ Features of Aymé-Gripp Syndrome DD = developmental delay Hearing loss is frequently bilateral and often diagnosed early in childhood. Hearing loss can vary from mild to severe, with a few affected individuals requiring hearing aids or cochlear implant. One affected individual, age 18 months at presentation, had bilateral retinal hemorrhage and optic disc anomaly [ One affected individual was reported to have bilateral cataracts diagnosed at age 14 months. This individual developed aphakic glaucoma and went blind at age two years [ Two affected parents were reported to have cataracts extracted after age 40 years [ Seizures have been reported in 15 of 21affected individuals, with five having febrile seizures [ Nonspecific brain abnormalities such as ventriculomegaly, Chiari 1 malformation, obstructive hydrocephalus, empty sella, and cerebral atrophy have been noted in slightly more than half of individuals who have undergone brain imaging. One individual was reported to have calcifications of the basal ganglia [ Congenital radioulnar synostosis, radial head subluxation, and shortened forearm as individual findings or in various combinations are the most common joint manifestations. Clino/campto/brachydactyly, pectus excavatum, scoliosis without vertebral anomalies, delayed skeletal maturation and carpal/tarsal bone defects, short fourth metatarsal, and hip joint chondrolysis have also been reported. Coronal craniosynostosis requiring surgical repair is reported as a rare feature. One affected individual was reported to have early fusion of the growth plates, spontaneous fractures, and exostosis [ Some affected adults have required hip replacement for hip joint chondrolysis. At least eight of 21 individuals have been noted to have pericarditis or pericardial effusion during the neonatal or infantile period: Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. Atrial septal defect and patent ductus arteriosus have been reported in a single individual each. Rare manifestations may include the following: Hiatal hernia and diaphragmatic hernia Transient hematuria Proteinuria and/or microalbuminuria (reported as a late-onset feature) Glomerulonephropathy Nephrotic syndrome (which did not recur after treatment with prednisone) • Hearing loss is frequently bilateral and often diagnosed early in childhood. • Hearing loss can vary from mild to severe, with a few affected individuals requiring hearing aids or cochlear implant. • One affected individual, age 18 months at presentation, had bilateral retinal hemorrhage and optic disc anomaly [ • One affected individual was reported to have bilateral cataracts diagnosed at age 14 months. This individual developed aphakic glaucoma and went blind at age two years [ • Two affected parents were reported to have cataracts extracted after age 40 years [ • Seizures have been reported in 15 of 21affected individuals, with five having febrile seizures [ • Nonspecific brain abnormalities such as ventriculomegaly, Chiari 1 malformation, obstructive hydrocephalus, empty sella, and cerebral atrophy have been noted in slightly more than half of individuals who have undergone brain imaging. One individual was reported to have calcifications of the basal ganglia [ • Congenital radioulnar synostosis, radial head subluxation, and shortened forearm as individual findings or in various combinations are the most common joint manifestations. • Clino/campto/brachydactyly, pectus excavatum, scoliosis without vertebral anomalies, delayed skeletal maturation and carpal/tarsal bone defects, short fourth metatarsal, and hip joint chondrolysis have also been reported. • Coronal craniosynostosis requiring surgical repair is reported as a rare feature. • One affected individual was reported to have early fusion of the growth plates, spontaneous fractures, and exostosis [ • Some affected adults have required hip replacement for hip joint chondrolysis. • At least eight of 21 individuals have been noted to have pericarditis or pericardial effusion during the neonatal or infantile period: • Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ • One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. • Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ • One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. • Atrial septal defect and patent ductus arteriosus have been reported in a single individual each. • Four affected individuals presented in the neonatal period with cardiac murmurs for which echocardiogram was performed, revealing pericardial effusion [ • One of these affected infants had persistent effusion and underwent effusion aspiration and eventually a pericardial window. • Hiatal hernia and diaphragmatic hernia • Transient hematuria • Proteinuria and/or microalbuminuria (reported as a late-onset feature) • Glomerulonephropathy • Nephrotic syndrome (which did not recur after treatment with prednisone) ## Genotype-Phenotype Correlations Pathogenic variants causing Aymé-Gripp syndrome occur at serine, threonine, and proline residues in the N-terminal transactivation domain [ A subset of pathogenic variants in the C-terminal DNA binding domain have been associated with isolated congenital cataracts [ • Pathogenic variants causing Aymé-Gripp syndrome occur at serine, threonine, and proline residues in the N-terminal transactivation domain [ • A subset of pathogenic variants in the C-terminal DNA binding domain have been associated with isolated congenital cataracts [ ## Penetrance For this disorder, penetrance is felt to be 100%; however, there is variability in presentation as illustrated by a report from ## Prevalence This disorder is rare and exact prevalence estimates are unknown. Only 21 individuals representing 19 families have been reported in the literature. ## Genetically Related (Allelic) Disorders Heterozygous pathogenic variants in ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Aymé-Gripp Syndrome Cataract Midface hypoplasia Short stature SNHL Absence of congenital radio ulnar synostosis, pericardial effusion, & ID/DD Distinct facial features (incl malar hypoplasia, broad or flat nasal bridge, & micro/retrognathia) Hearing loss ID/DD Joint contractures & camptodactyly Mid face hypoplasia Short stature Absence of cataract & pericardial effusion Distinct facial features (incl short palpebral fissures, deep-set eyes, maxillary underdevelopment, short philtrum, narrow mouth, & prognathism) Cataracts Flat facial appearance SNHL Abnormal liver function Brain anomalies such as cortical gyral anomalies, heterotopias, & subependymal cysts Large fontanelle AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; SNHL = sensorineural hearing loss Stickler syndrome caused by pathogenic variants Mild-to-moderate intellectual disability and developmental delay are common in Myhre syndrome; however, cognition can be within the normal range. Biallelic pathogenic variants in • Cataract • Midface hypoplasia • Short stature • SNHL • Absence of congenital radio ulnar synostosis, pericardial effusion, & ID/DD • Distinct facial features (incl malar hypoplasia, broad or flat nasal bridge, & micro/retrognathia) • Hearing loss • ID/DD • Joint contractures & camptodactyly • Mid face hypoplasia • Short stature • Absence of cataract & pericardial effusion • Distinct facial features (incl short palpebral fissures, deep-set eyes, maxillary underdevelopment, short philtrum, narrow mouth, & prognathism) • Cataracts • Flat facial appearance • SNHL • Abnormal liver function • Brain anomalies such as cortical gyral anomalies, heterotopias, & subependymal cysts • Large fontanelle ## Management To establish the extent of disease and needs in an individual diagnosed with Aymé-Gripp syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Aymé-Gripp Syndrome To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Community or Social work involvement for parental support. ASD = autism spectrum disorder Including a free T4 and TSH Treatment of this disorder is symptomatic and ideally involves multidisciplinary care, which may include an ophthalmologist, otolaryngologist, developmental and behavior specialist, speech therapist, occupational therapist, physiotherapist, orthopedist, endocrinologist, cardiologist, and neurologist, depending on the affected person's specific needs. Treatment of Manifestations in Individuals with Aymé-Gripp Syndrome Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; PT = physical therapy Cochlear implant has been used to treat severe hearing loss on occasion. 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. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). 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. Recommended Surveillance for Individuals with Aymé-Gripp Syndrome See Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support. • Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. • 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. • 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. • 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). ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Aymé-Gripp syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Aymé-Gripp Syndrome To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Community or Social work involvement for parental support. ASD = autism spectrum disorder Including a free T4 and TSH • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support. ## Treatment of Manifestations Treatment of this disorder is symptomatic and ideally involves multidisciplinary care, which may include an ophthalmologist, otolaryngologist, developmental and behavior specialist, speech therapist, occupational therapist, physiotherapist, orthopedist, endocrinologist, cardiologist, and neurologist, depending on the affected person's specific needs. Treatment of Manifestations in Individuals with Aymé-Gripp Syndrome Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; DD = developmental delay; ID = intellectual disability; PT = physical therapy Cochlear implant has been used to treat severe hearing loss on occasion. 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. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). 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. • Many different ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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. • 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. • 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. • 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). ## 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. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • 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. • 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. • 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. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and is typically performed one on one with a board-certified behavior analyst. ## Surveillance Recommended Surveillance for Individuals with Aymé-Gripp Syndrome ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Aymé-Gripp syndrome is inherited in an autosomal dominant manner. Most individuals diagnosed with Aymé-Gripp syndrome have the disorder as the result of a The proportion of cases caused by a In two families reported to date, a proband with Aymé-Gripp syndrome had the disorder as the result of an Molecular genetic testing is recommended for the parents of a proband who has an identifiable If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the pathogenic variant was most likely Although almost all individuals with Aymé-Gripp syndrome represent simplex cases (i.e., the only affected individual in the family), the family history may appear to be negative due to failure to recognize features of the disorder in mildly affected family members. 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 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, 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 Aymé-Gripp syndrome have the disorder as the result of a • The proportion of cases caused by a • In two families reported to date, a proband with Aymé-Gripp syndrome had the disorder as the result of an • Molecular genetic testing is recommended for the parents of a proband who has an identifiable • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the pathogenic variant was most likely • Although almost all individuals with Aymé-Gripp syndrome represent simplex cases (i.e., the only affected individual in the family), the family history may appear to be negative due to failure to recognize features of the disorder in mildly affected family members. 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 • 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 Aymé-Gripp syndrome is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with Aymé-Gripp syndrome have the disorder as the result of a The proportion of cases caused by a In two families reported to date, a proband with Aymé-Gripp syndrome had the disorder as the result of an Molecular genetic testing is recommended for the parents of a proband who has an identifiable If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the pathogenic variant was most likely Although almost all individuals with Aymé-Gripp syndrome represent simplex cases (i.e., the only affected individual in the family), the family history may appear to be negative due to failure to recognize features of the disorder in mildly affected family members. 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 If the parents have not been tested for the • Most individuals diagnosed with Aymé-Gripp syndrome have the disorder as the result of a • The proportion of cases caused by a • In two families reported to date, a proband with Aymé-Gripp syndrome had the disorder as the result of an • Molecular genetic testing is recommended for the parents of a proband who has an identifiable • If the pathogenic variant found in the proband cannot be detected in leukocyte DNA of either parent, the pathogenic variant was most likely • Although almost all individuals with Aymé-Gripp syndrome represent simplex cases (i.e., the only affected individual in the family), the family history may appear to be negative due to failure to recognize features of the disorder in mildly affected family members. 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 • 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources Speaking out for People with Intellectual and Developmental Disabilities • • • • • • • • • • • • • • • Speaking out for People with Intellectual and Developmental Disabilities • ## Molecular Genetics Ayme-Gripp Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Ayme-Gripp Syndrome ( MAF has a C-terminal extended homology region, a b-ZIP domain mediating DNA binding, and an N-terminal transactivation domain required for transcriptional and regulatory activity [ Impaired phosphorylation of the GSK3 binding sites affects MAF ubiquitination, and in turn, this impairs protein degradation [ ## Molecular Pathogenesis MAF has a C-terminal extended homology region, a b-ZIP domain mediating DNA binding, and an N-terminal transactivation domain required for transcriptional and regulatory activity [ Impaired phosphorylation of the GSK3 binding sites affects MAF ubiquitination, and in turn, this impairs protein degradation [ ## Chapter Notes 6 February 2020 (ma) Review posted live 7 March 2019 (sma) Original submission • 6 February 2020 (ma) Review posted live • 7 March 2019 (sma) Original submission ## Revision History 6 February 2020 (ma) Review posted live 7 March 2019 (sma) Original submission • 6 February 2020 (ma) Review posted live • 7 March 2019 (sma) Original submission ## References ## Literature Cited Individuals with a molecularly confirmed diagnosis of Aymé-Gripp syndrome with characteristic facial features including midface retrusion, high forehead, flat nasal bridge, long philtrum, and thin vermillion of the upper lip Individual 1 shown at age three years (1a), four years (1b) and seven years (1c). Note the progression of the facial phenotype. Individual 2 is an affected adult (age unknown). From	[ "E Alkhunaizi, RK Koenekoop, C Saint-Martin, L Russell. Maternally inherited MAF variant associated with variable expression of Aymé-Gripp syndrome.. Am J Med Genet A. 2019;179:2233-6", "SM Amudhavalli, R Hanson, B Angle, K Bontempo, KW Gripp. Further delineation of Aymé-Gripp syndrome and use of automated facial analysis tool.. Am J Med Genet A. 2018;176:1648-56", "D Anand, SA Agrawal, A Slavotinek, SA Lachke. Mutation update of transcription factor genes FOXE3,HSF4, MAF, and PITX3 causing cataracts and other developmental ocular defects.. Hum Mutat. 2018;39:471-94", "S Aymé, N Philip. Apparently new syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation.. Am J Med Genet. 1997;70:333-5", "KW Gripp, L Nicholson, CI Scott. Apparently new syndrome of congenital cataracts, sensorineural deafness, Down syndrome-like facial appearance, short stature, and mental retardation.. Am J Med Genet. 1996;61:382-6", "RV Jamieson, R Perveen, B Kerr, M Carette, J Yardley, E Heon, MG Wirth, V van Heyningen, D Donnai, F Munier, GC Black. Domain disruption and mutation of the bZIP transcription factor, MAF, associated with cataract, ocular anterior segment dysgenesis and coloboma.. Hum Mol Genet. 2002;11:33-42", "S Javadiyan, JE Craig, S Sharma, KM Lower, T Casey, E Haan, E Souzeau, KP Burdon. Novel missense mutation in the bZIP transcription factor, MAF, associated with congenital cataract, developmental delay, seizures and hearing loss (Aymé-Gripp syndrome).. BMC Med Genet. 2017;18:52", "M Niceta, D Barbuti, N Gupta, C Ruggiero, EF Tizzano, L Graul-Neumann, S Barresi, G Nishimura, I Valenzuela, FL Grondona, P Fernandez Alvarez, C Leoni, C Zweier, A Tzschach, E Stellacci, A Del Fattore, B Dallapiccola, G Zampino, M Tartaglia. Skeletal abnormalities are common features in Aymé-Gripp syndrome.. Clin Genet. 2020;97:362-9", "M Niceta, E Stellacci, KW Gripp, G Zampino, M Kousi, M Anselmi, A Traversa, A Ciolfi, D Stabley, A Bruselles, V Caputo. Mutations impairing GSK3-mediated MAF phosphorylation cause cataract, deafness, intellectual disability, seizures, and a Down syndrome-like facies.. Am J Hum Genet. 2015;96:816-25", "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" ]	6/2/2020			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
b-thal	b-thal	[ "Cooley's Anemia", "Mediterranean Anemia", "Cooley's Anemia", "Mediterranean Anemia", "Beta-Thalassemia Minor", "Beta-Thalassemia Intermedia", "Beta-Thalassemia Major", "Hemoglobin subunit beta", "HBB", "Beta-Thalassemia" ]	Beta-Thalassemia	Arielle L Langer	Summary Beta-thalassemia (β-thalassemia) has two clinically significant forms, β-thalassemia major and β-thalassemia intermedia, caused by absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain). Individuals with β-thalassemia major present between ages six and 24 months with pallor due to severe anemia, poor weight gain, stunted growth, mild jaundice, and hepatosplenomegaly. Feeding problems, diarrhea, irritability, and recurrent bouts of fever may occur. Treatment with regular red blood cell transfusions and iron chelation therapy allows for normal growth and development and improves prognosis. Long-term complications associated with iron overload include stunted growth, dilated cardiomyopathy, liver disease, and endocrinopathies. Individuals with β-thalassemia intermedia have a more variable age of presentation due to milder anemia that does not require regular red blood cell transfusions from early childhood. Additional clinical features may include jaundice, cholelithiasis, hepatosplenomegaly, skeletal changes (long bone deformities, characteristic craniofacial features, and osteoporosis), leg ulcers, pulmonary hypertension, extramedullary masses of hyperplastic erythroid marrow, and increased risk of thrombotic complications. Individuals with β-thalassemia intermedia are at risk for iron overload secondary to increased intestinal absorption of iron as a result of dysregulation of iron metabolism caused by ineffective erythropoiesis. The diagnosis of β-thalassemia is established in a proband older than age 12 months by identification of microcytic hypochromic anemia, absence of iron deficiency, anisopoikilocytosis with nucleated red blood cells on peripheral blood smear, and decreased or complete absence of hemoglobin A (HbA) and increased hemoglobin A For β-thalassemia intermedia, splenectomy, folic acid supplementation, red blood cell transfusions as needed, and iron chelation. Some individuals can benefit from HbF induction with hydroxyurea. Luspatercept may also be used to ameliorate anemia with variable efficacy. Cholecystectomy for biliary colic; vitamin D supplementation, regular physical activity, and bisphosphonates for osteoporosis; referral for treatment of pulmonary hypertension; anticoagulation for unprovoked venous thromboembolism. Beta-thalassemia major and β-thalassemia intermedia are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Beta-thalassemia major Beta-thalassemia intermedia Beta-thalassemia minor: heterozygote (carrier) for β-thalassemia • Beta-thalassemia major • Beta-thalassemia intermedia • Beta-thalassemia minor: heterozygote (carrier) for β-thalassemia ## Diagnosis Pallor Poor weight gain Stunted growth Mild jaundice Hepatosplenomegaly Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) Increased hemoglobin A Absence of iron deficiency Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear The diagnosis of β-thalassemia The diagnosis of β-thalassemia Complete absence of HbA on newborn screening (diagnostic of β Biallelic pathogenic (or likely pathogenic) variants in Note: (1) The reduction of HbA levels in infants with β Red Blood Cell Indices in Beta-Thalassemia HbA. Two alpha globin chains and two beta globin chains (α HbF. Two alpha globin chains and two gamma globin chains (α HbA The hemoglobin pattern in β-thalassemia varies by β-thalassemia type (see Hemoglobin Patterns in Beta-Thalassemia (Age >12 Months) HbA = hemoglobin A; HbA Hemoglobin electrophoresis and HPLC also detect other hemoglobinopathies (S, C, E, O The recommended molecular genetic testing approach for β-thalassemia is Sequence analysis of Note: Analysis of Note: Targeted analysis for pathogenic variants can be performed first in individuals of specific at-risk populations (see Molecular Genetic Testing Used in Beta-Thalassemia 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. • • Pallor • Poor weight gain • Stunted growth • Mild jaundice • Hepatosplenomegaly • Pallor • Poor weight gain • Stunted growth • Mild jaundice • Hepatosplenomegaly • • Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) • Increased hemoglobin A • Absence of iron deficiency • Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear • Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) • Increased hemoglobin A • Absence of iron deficiency • Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear • Pallor • Poor weight gain • Stunted growth • Mild jaundice • Hepatosplenomegaly • Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) • Increased hemoglobin A • Absence of iron deficiency • Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear • Complete absence of HbA on newborn screening (diagnostic of β • Biallelic pathogenic (or likely pathogenic) variants in • Note: (1) The reduction of HbA levels in infants with β • HbA. Two alpha globin chains and two beta globin chains (α • HbF. Two alpha globin chains and two gamma globin chains (α • HbA ## Suggestive Findings Pallor Poor weight gain Stunted growth Mild jaundice Hepatosplenomegaly Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) Increased hemoglobin A Absence of iron deficiency Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear • • Pallor • Poor weight gain • Stunted growth • Mild jaundice • Hepatosplenomegaly • Pallor • Poor weight gain • Stunted growth • Mild jaundice • Hepatosplenomegaly • • Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) • Increased hemoglobin A • Absence of iron deficiency • Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear • Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) • Increased hemoglobin A • Absence of iron deficiency • Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear • Pallor • Poor weight gain • Stunted growth • Mild jaundice • Hepatosplenomegaly • Reduced (or absent) hemoglobin A (HbA) on newborn screening (i.e., through hemoglobin electrophoresis, isoelectric focusing, or high-performance liquid chromatography [HPLC] on newborn blood spots) • Increased hemoglobin A • Absence of iron deficiency • Severe microcytic hypochromic anemia with anisopoikilocytosis and nucleated red blood cells on peripheral blood smear ## Establishing the Diagnosis The diagnosis of β-thalassemia The diagnosis of β-thalassemia Complete absence of HbA on newborn screening (diagnostic of β Biallelic pathogenic (or likely pathogenic) variants in Note: (1) The reduction of HbA levels in infants with β Red Blood Cell Indices in Beta-Thalassemia HbA. Two alpha globin chains and two beta globin chains (α HbF. Two alpha globin chains and two gamma globin chains (α HbA The hemoglobin pattern in β-thalassemia varies by β-thalassemia type (see Hemoglobin Patterns in Beta-Thalassemia (Age >12 Months) HbA = hemoglobin A; HbA Hemoglobin electrophoresis and HPLC also detect other hemoglobinopathies (S, C, E, O The recommended molecular genetic testing approach for β-thalassemia is Sequence analysis of Note: Analysis of Note: Targeted analysis for pathogenic variants can be performed first in individuals of specific at-risk populations (see Molecular Genetic Testing Used in Beta-Thalassemia 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. • Complete absence of HbA on newborn screening (diagnostic of β • Biallelic pathogenic (or likely pathogenic) variants in • Note: (1) The reduction of HbA levels in infants with β • HbA. Two alpha globin chains and two beta globin chains (α • HbF. Two alpha globin chains and two gamma globin chains (α • HbA ## Hematologic Findings Red Blood Cell Indices in Beta-Thalassemia HbA. Two alpha globin chains and two beta globin chains (α HbF. Two alpha globin chains and two gamma globin chains (α HbA The hemoglobin pattern in β-thalassemia varies by β-thalassemia type (see Hemoglobin Patterns in Beta-Thalassemia (Age >12 Months) HbA = hemoglobin A; HbA Hemoglobin electrophoresis and HPLC also detect other hemoglobinopathies (S, C, E, O • HbA. Two alpha globin chains and two beta globin chains (α • HbF. Two alpha globin chains and two gamma globin chains (α • HbA ## Molecular Genetic Testing The recommended molecular genetic testing approach for β-thalassemia is Sequence analysis of Note: Analysis of Note: Targeted analysis for pathogenic variants can be performed first in individuals of specific at-risk populations (see Molecular Genetic Testing Used in Beta-Thalassemia 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 Beta-thalassemia (β-thalassemia) has two clinically significant forms, β-thalassemia major and β-thalassemia intermedia, caused by absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain). Individuals with β-thalassemia major usually come to medical attention within the first two years of life; they subsequently require regular red blood cell transfusions to survive. Individuals with β-thalassemia intermedia have a more variable age of presentation due to milder anemia that does not require regular red blood cell transfusions from early childhood. Affected infants have progressive pallor, poor weight gain, and stunted growth. Feeding problems, diarrhea, irritability, recurrent fever, and progressive enlargement of the abdomen caused by hepatosplenomegaly may occur. If the diagnosis of β-thalassemia major is established by age 24 months and red blood cell transfusions that maintain a minimum hemoglobin concentration of 9.5-10.5 g/dL are initiated, growth and development progress normally until at least age ten to 11 years. Complications of iron overload include the following: In children, stunted growth and failure of sexual maturation In adults, involvement of the heart (arrhythmias, dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrinopathies (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands) Complications of iron chelation include the following: Ocular toxicity (primarily with deferoxamine) Hearing loss Liver injury (primarily with deferasirox) Proteinuria (only with deferasirox) Impaired renal filtration Agranulocytosis (only with deferiprone) Injection site reaction (only with deferoxamine) Other possible complications include the following: Hypersplenism Chronic hepatitis due to hepatitis B and/or hepatitis C infection acquired from transfusion HIV infection acquired from transfusion Venous thrombosis, especially in individuals who have undergone splenectomy Cholelithiasis due to the formation of pigment gallstones in the setting of chronic hemolysis Osteoporosis, a common complication in adults; its origin is multifactorial, making it difficult to manage Hepatocellular carcinoma secondary to chronic hepatitis and cirrhosis [ Stunted growth Pallor Jaundice Poor musculature Hepatosplenomegaly Leg ulcers, which are thought to reflect a similar physiology to pulmonary hypertension and relate to nitric oxide depletion in the setting of chronic hemolysis Development of paraspinal masses from extramedullary hematopoiesis Skeletal changes that result from expansion of the bone marrow, including the following: Deformities of the long bones of the legs Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) Osteoporosis Individuals who do not receive red blood cell transfusions usually die in the first two decades. Individuals who have been poorly transfused are also at risk of complications of iron overload, as are those who do not receive iron chelation. Clinical features of β-thalassemia intermedia include pallor, jaundice, cardiac disease, cholelithiasis, hepatosplenomegaly, moderate-to-severe skeletal changes (long bone deformities, craniofacial changes, and osteopenia/osteoporosis), leg ulcers, pulmonary hypertension (often clinically silent until advanced and much more common than in individuals with β-thalassemia major), extramedullary masses of hyperplastic erythroid marrow, and thrombotic complications [ By definition, red blood cell transfusions are not continuously required from childhood, but may become regularly needed over time or due to complications (e.g., pulmonary hypertension, paraspinal extramedullary hematopoiesis). Iron overload occurs mainly from increased intestinal absorption of iron caused by hepcidin deficiency (a peptide produced by hepatocytes that plays a central role in the regulation of iron homeostasis). Hepcidin deficiency is driven by the elaboration of erythroferrone during ineffective erythropoiesis. The complications of iron overload present later in individuals with β-thalassemia intermedia but may be as severe as those seen in individuals with β-thalassemia major. The clinical severity of the β-thalassemia depends on the extent of alpha/non-alpha globin chain imbalance (i.e., ratio of alpha globin chains to beta globin chains or gamma globin chains). The nonassembled alpha globin chains that result from unbalanced alpha/non-alpha globin chain synthesis precipitate in the form of inclusions. These inclusions damage erythroid precursors in the bone marrow and the spleen, causing ineffective erythropoiesis. Some β Biallelic β β β Biallelic β Note: The clinical severity associated with β Heterozygous Heterozygosity for some Double heterozygosity for an Clinical presentation in individuals with compound heterozygosity for a β-thalassemia-related Clinical severity of β-thalassemia may be ameliorated by coinheritance of pathogenic variants in The coinheritance of some genetic determinants able to sustain a continuous production of gamma globin chains (hereditary persistence of fetal hemoglobin [HPFH]) in adult life may also reduce the extent of alpha/non-alpha globin chain imbalance and may result in a milder phenotype. δβ Deletions that remove only the 5' region of the HPFH due to single-nucleotide variants in The NM_000559.3:c.-249C>T Other genetic loci not linked to the The A study of 890 individuals with β-thalassemia reported that three factors – the type of pathogenic variant in Beta-thalassemia includes three main forms: Beta-thalassemia major, also referred as Cooley's anemia, Mediterranean anemia, or transfusion-dependent thalassemia (TDT); Beta-thalassemia intermedia; and Beta-thalassemia minor, also called β-thalassemia carrier, β-thalassemia trait, or heterozygous β-thalassemia. Non-transfusion-dependent thalassemia (NTDT) is a term used to designate individuals with thalassemia (alpha or beta) who do not require regular red blood cell transfusions for survival; NTDT encompasses β-thalassemia intermedia, hemoglobin E/β-thalassemia (mild and moderate forms), and α-thalassemia intermedia (hemoglobin H disease). Some individuals with NTDT develop complications that necessitate initiating regular red blood cell transfusions and are then characterized as having TDT. Note: Individuals with β-thalassemia major by definition have TDT. Beta-thalassemia is more prevalent in populations from the Mediterranean, the Middle East, Central and Southeast Asia, and the Indian subcontinent. It is also common in populations of African descent. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia. The increased frequency of β-thalassemia in these regions is most likely related to selective pressure from malaria. This distribution is quite similar to that of endemic • Affected infants have progressive pallor, poor weight gain, and stunted growth. • Feeding problems, diarrhea, irritability, recurrent fever, and progressive enlargement of the abdomen caused by hepatosplenomegaly may occur. • If the diagnosis of β-thalassemia major is established by age 24 months and red blood cell transfusions that maintain a minimum hemoglobin concentration of 9.5-10.5 g/dL are initiated, growth and development progress normally until at least age ten to 11 years. • In children, stunted growth and failure of sexual maturation • In adults, involvement of the heart (arrhythmias, dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrinopathies (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands) • Ocular toxicity (primarily with deferoxamine) • Hearing loss • Liver injury (primarily with deferasirox) • Proteinuria (only with deferasirox) • Impaired renal filtration • Agranulocytosis (only with deferiprone) • Injection site reaction (only with deferoxamine) • Hypersplenism • Chronic hepatitis due to hepatitis B and/or hepatitis C infection acquired from transfusion • HIV infection acquired from transfusion • Venous thrombosis, especially in individuals who have undergone splenectomy • Cholelithiasis due to the formation of pigment gallstones in the setting of chronic hemolysis • Osteoporosis, a common complication in adults; its origin is multifactorial, making it difficult to manage • Hepatocellular carcinoma secondary to chronic hepatitis and cirrhosis [ • Stunted growth • Pallor • Jaundice • Poor musculature • Hepatosplenomegaly • Leg ulcers, which are thought to reflect a similar physiology to pulmonary hypertension and relate to nitric oxide depletion in the setting of chronic hemolysis • Development of paraspinal masses from extramedullary hematopoiesis • Skeletal changes that result from expansion of the bone marrow, including the following: • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis • Some β • Biallelic β • β • β • Biallelic β • Heterozygosity for some • Double heterozygosity for an • δβ • Deletions that remove only the 5' region of the • δβ • Deletions that remove only the 5' region of the • HPFH due to single-nucleotide variants in • The NM_000559.3:c.-249C>T • The NM_000559.3:c.-249C>T • δβ • Deletions that remove only the 5' region of the • The NM_000559.3:c.-249C>T • The • Beta-thalassemia major, also referred as Cooley's anemia, Mediterranean anemia, or transfusion-dependent thalassemia (TDT); • Beta-thalassemia intermedia; and • Beta-thalassemia minor, also called β-thalassemia carrier, β-thalassemia trait, or heterozygous β-thalassemia. ## Clinical Description Beta-thalassemia (β-thalassemia) has two clinically significant forms, β-thalassemia major and β-thalassemia intermedia, caused by absent or reduced synthesis of the hemoglobin subunit beta (beta globin chain). Individuals with β-thalassemia major usually come to medical attention within the first two years of life; they subsequently require regular red blood cell transfusions to survive. Individuals with β-thalassemia intermedia have a more variable age of presentation due to milder anemia that does not require regular red blood cell transfusions from early childhood. Affected infants have progressive pallor, poor weight gain, and stunted growth. Feeding problems, diarrhea, irritability, recurrent fever, and progressive enlargement of the abdomen caused by hepatosplenomegaly may occur. If the diagnosis of β-thalassemia major is established by age 24 months and red blood cell transfusions that maintain a minimum hemoglobin concentration of 9.5-10.5 g/dL are initiated, growth and development progress normally until at least age ten to 11 years. Complications of iron overload include the following: In children, stunted growth and failure of sexual maturation In adults, involvement of the heart (arrhythmias, dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrinopathies (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands) Complications of iron chelation include the following: Ocular toxicity (primarily with deferoxamine) Hearing loss Liver injury (primarily with deferasirox) Proteinuria (only with deferasirox) Impaired renal filtration Agranulocytosis (only with deferiprone) Injection site reaction (only with deferoxamine) Other possible complications include the following: Hypersplenism Chronic hepatitis due to hepatitis B and/or hepatitis C infection acquired from transfusion HIV infection acquired from transfusion Venous thrombosis, especially in individuals who have undergone splenectomy Cholelithiasis due to the formation of pigment gallstones in the setting of chronic hemolysis Osteoporosis, a common complication in adults; its origin is multifactorial, making it difficult to manage Hepatocellular carcinoma secondary to chronic hepatitis and cirrhosis [ Stunted growth Pallor Jaundice Poor musculature Hepatosplenomegaly Leg ulcers, which are thought to reflect a similar physiology to pulmonary hypertension and relate to nitric oxide depletion in the setting of chronic hemolysis Development of paraspinal masses from extramedullary hematopoiesis Skeletal changes that result from expansion of the bone marrow, including the following: Deformities of the long bones of the legs Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) Osteoporosis Individuals who do not receive red blood cell transfusions usually die in the first two decades. Individuals who have been poorly transfused are also at risk of complications of iron overload, as are those who do not receive iron chelation. Clinical features of β-thalassemia intermedia include pallor, jaundice, cardiac disease, cholelithiasis, hepatosplenomegaly, moderate-to-severe skeletal changes (long bone deformities, craniofacial changes, and osteopenia/osteoporosis), leg ulcers, pulmonary hypertension (often clinically silent until advanced and much more common than in individuals with β-thalassemia major), extramedullary masses of hyperplastic erythroid marrow, and thrombotic complications [ By definition, red blood cell transfusions are not continuously required from childhood, but may become regularly needed over time or due to complications (e.g., pulmonary hypertension, paraspinal extramedullary hematopoiesis). Iron overload occurs mainly from increased intestinal absorption of iron caused by hepcidin deficiency (a peptide produced by hepatocytes that plays a central role in the regulation of iron homeostasis). Hepcidin deficiency is driven by the elaboration of erythroferrone during ineffective erythropoiesis. The complications of iron overload present later in individuals with β-thalassemia intermedia but may be as severe as those seen in individuals with β-thalassemia major. • Affected infants have progressive pallor, poor weight gain, and stunted growth. • Feeding problems, diarrhea, irritability, recurrent fever, and progressive enlargement of the abdomen caused by hepatosplenomegaly may occur. • If the diagnosis of β-thalassemia major is established by age 24 months and red blood cell transfusions that maintain a minimum hemoglobin concentration of 9.5-10.5 g/dL are initiated, growth and development progress normally until at least age ten to 11 years. • In children, stunted growth and failure of sexual maturation • In adults, involvement of the heart (arrhythmias, dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrinopathies (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands) • Ocular toxicity (primarily with deferoxamine) • Hearing loss • Liver injury (primarily with deferasirox) • Proteinuria (only with deferasirox) • Impaired renal filtration • Agranulocytosis (only with deferiprone) • Injection site reaction (only with deferoxamine) • Hypersplenism • Chronic hepatitis due to hepatitis B and/or hepatitis C infection acquired from transfusion • HIV infection acquired from transfusion • Venous thrombosis, especially in individuals who have undergone splenectomy • Cholelithiasis due to the formation of pigment gallstones in the setting of chronic hemolysis • Osteoporosis, a common complication in adults; its origin is multifactorial, making it difficult to manage • Hepatocellular carcinoma secondary to chronic hepatitis and cirrhosis [ • Stunted growth • Pallor • Jaundice • Poor musculature • Hepatosplenomegaly • Leg ulcers, which are thought to reflect a similar physiology to pulmonary hypertension and relate to nitric oxide depletion in the setting of chronic hemolysis • Development of paraspinal masses from extramedullary hematopoiesis • Skeletal changes that result from expansion of the bone marrow, including the following: • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis ## Beta-Thalassemia Major Affected infants have progressive pallor, poor weight gain, and stunted growth. Feeding problems, diarrhea, irritability, recurrent fever, and progressive enlargement of the abdomen caused by hepatosplenomegaly may occur. If the diagnosis of β-thalassemia major is established by age 24 months and red blood cell transfusions that maintain a minimum hemoglobin concentration of 9.5-10.5 g/dL are initiated, growth and development progress normally until at least age ten to 11 years. Complications of iron overload include the following: In children, stunted growth and failure of sexual maturation In adults, involvement of the heart (arrhythmias, dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrinopathies (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands) Complications of iron chelation include the following: Ocular toxicity (primarily with deferoxamine) Hearing loss Liver injury (primarily with deferasirox) Proteinuria (only with deferasirox) Impaired renal filtration Agranulocytosis (only with deferiprone) Injection site reaction (only with deferoxamine) Other possible complications include the following: Hypersplenism Chronic hepatitis due to hepatitis B and/or hepatitis C infection acquired from transfusion HIV infection acquired from transfusion Venous thrombosis, especially in individuals who have undergone splenectomy Cholelithiasis due to the formation of pigment gallstones in the setting of chronic hemolysis Osteoporosis, a common complication in adults; its origin is multifactorial, making it difficult to manage Hepatocellular carcinoma secondary to chronic hepatitis and cirrhosis [ Stunted growth Pallor Jaundice Poor musculature Hepatosplenomegaly Leg ulcers, which are thought to reflect a similar physiology to pulmonary hypertension and relate to nitric oxide depletion in the setting of chronic hemolysis Development of paraspinal masses from extramedullary hematopoiesis Skeletal changes that result from expansion of the bone marrow, including the following: Deformities of the long bones of the legs Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) Osteoporosis Individuals who do not receive red blood cell transfusions usually die in the first two decades. Individuals who have been poorly transfused are also at risk of complications of iron overload, as are those who do not receive iron chelation. • Affected infants have progressive pallor, poor weight gain, and stunted growth. • Feeding problems, diarrhea, irritability, recurrent fever, and progressive enlargement of the abdomen caused by hepatosplenomegaly may occur. • If the diagnosis of β-thalassemia major is established by age 24 months and red blood cell transfusions that maintain a minimum hemoglobin concentration of 9.5-10.5 g/dL are initiated, growth and development progress normally until at least age ten to 11 years. • In children, stunted growth and failure of sexual maturation • In adults, involvement of the heart (arrhythmias, dilated cardiomyopathy), liver (fibrosis and cirrhosis), and endocrinopathies (resulting in diabetes mellitus and insufficiency of the parathyroid, thyroid, pituitary, and, less commonly, adrenal glands) • Ocular toxicity (primarily with deferoxamine) • Hearing loss • Liver injury (primarily with deferasirox) • Proteinuria (only with deferasirox) • Impaired renal filtration • Agranulocytosis (only with deferiprone) • Injection site reaction (only with deferoxamine) • Hypersplenism • Chronic hepatitis due to hepatitis B and/or hepatitis C infection acquired from transfusion • HIV infection acquired from transfusion • Venous thrombosis, especially in individuals who have undergone splenectomy • Cholelithiasis due to the formation of pigment gallstones in the setting of chronic hemolysis • Osteoporosis, a common complication in adults; its origin is multifactorial, making it difficult to manage • Hepatocellular carcinoma secondary to chronic hepatitis and cirrhosis [ • Stunted growth • Pallor • Jaundice • Poor musculature • Hepatosplenomegaly • Leg ulcers, which are thought to reflect a similar physiology to pulmonary hypertension and relate to nitric oxide depletion in the setting of chronic hemolysis • Development of paraspinal masses from extramedullary hematopoiesis • Skeletal changes that result from expansion of the bone marrow, including the following: • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis • Deformities of the long bones of the legs • Typical craniofacial changes (frontal bossing, malar prominence, depressed nasal bridge, tendency toward upslanted palpebral fissures, and hypertrophy of the maxillae, which tends to expose the upper teeth) • Osteoporosis ## Beta-Thalassemia Intermedia Clinical features of β-thalassemia intermedia include pallor, jaundice, cardiac disease, cholelithiasis, hepatosplenomegaly, moderate-to-severe skeletal changes (long bone deformities, craniofacial changes, and osteopenia/osteoporosis), leg ulcers, pulmonary hypertension (often clinically silent until advanced and much more common than in individuals with β-thalassemia major), extramedullary masses of hyperplastic erythroid marrow, and thrombotic complications [ By definition, red blood cell transfusions are not continuously required from childhood, but may become regularly needed over time or due to complications (e.g., pulmonary hypertension, paraspinal extramedullary hematopoiesis). Iron overload occurs mainly from increased intestinal absorption of iron caused by hepcidin deficiency (a peptide produced by hepatocytes that plays a central role in the regulation of iron homeostasis). Hepcidin deficiency is driven by the elaboration of erythroferrone during ineffective erythropoiesis. The complications of iron overload present later in individuals with β-thalassemia intermedia but may be as severe as those seen in individuals with β-thalassemia major. ## Genotype-Phenotype Correlations The clinical severity of the β-thalassemia depends on the extent of alpha/non-alpha globin chain imbalance (i.e., ratio of alpha globin chains to beta globin chains or gamma globin chains). The nonassembled alpha globin chains that result from unbalanced alpha/non-alpha globin chain synthesis precipitate in the form of inclusions. These inclusions damage erythroid precursors in the bone marrow and the spleen, causing ineffective erythropoiesis. Some β Biallelic β β β Biallelic β Note: The clinical severity associated with β Heterozygous Heterozygosity for some Double heterozygosity for an Clinical presentation in individuals with compound heterozygosity for a β-thalassemia-related Clinical severity of β-thalassemia may be ameliorated by coinheritance of pathogenic variants in The coinheritance of some genetic determinants able to sustain a continuous production of gamma globin chains (hereditary persistence of fetal hemoglobin [HPFH]) in adult life may also reduce the extent of alpha/non-alpha globin chain imbalance and may result in a milder phenotype. δβ Deletions that remove only the 5' region of the HPFH due to single-nucleotide variants in The NM_000559.3:c.-249C>T Other genetic loci not linked to the The A study of 890 individuals with β-thalassemia reported that three factors – the type of pathogenic variant in • Some β • Biallelic β • β • β • Biallelic β • Heterozygosity for some • Double heterozygosity for an • δβ • Deletions that remove only the 5' region of the • δβ • Deletions that remove only the 5' region of the • HPFH due to single-nucleotide variants in • The NM_000559.3:c.-249C>T • The NM_000559.3:c.-249C>T • δβ • Deletions that remove only the 5' region of the • The NM_000559.3:c.-249C>T • The ## Heterozygous Heterozygous Heterozygosity for some Double heterozygosity for an Clinical presentation in individuals with compound heterozygosity for a β-thalassemia-related • Heterozygosity for some • Double heterozygosity for an ## Ameliorating Genetic Factors Clinical severity of β-thalassemia may be ameliorated by coinheritance of pathogenic variants in The coinheritance of some genetic determinants able to sustain a continuous production of gamma globin chains (hereditary persistence of fetal hemoglobin [HPFH]) in adult life may also reduce the extent of alpha/non-alpha globin chain imbalance and may result in a milder phenotype. δβ Deletions that remove only the 5' region of the HPFH due to single-nucleotide variants in The NM_000559.3:c.-249C>T Other genetic loci not linked to the The A study of 890 individuals with β-thalassemia reported that three factors – the type of pathogenic variant in • δβ • Deletions that remove only the 5' region of the • δβ • Deletions that remove only the 5' region of the • HPFH due to single-nucleotide variants in • The NM_000559.3:c.-249C>T • The NM_000559.3:c.-249C>T • δβ • Deletions that remove only the 5' region of the • The NM_000559.3:c.-249C>T • The ## Nomenclature Beta-thalassemia includes three main forms: Beta-thalassemia major, also referred as Cooley's anemia, Mediterranean anemia, or transfusion-dependent thalassemia (TDT); Beta-thalassemia intermedia; and Beta-thalassemia minor, also called β-thalassemia carrier, β-thalassemia trait, or heterozygous β-thalassemia. Non-transfusion-dependent thalassemia (NTDT) is a term used to designate individuals with thalassemia (alpha or beta) who do not require regular red blood cell transfusions for survival; NTDT encompasses β-thalassemia intermedia, hemoglobin E/β-thalassemia (mild and moderate forms), and α-thalassemia intermedia (hemoglobin H disease). Some individuals with NTDT develop complications that necessitate initiating regular red blood cell transfusions and are then characterized as having TDT. Note: Individuals with β-thalassemia major by definition have TDT. • Beta-thalassemia major, also referred as Cooley's anemia, Mediterranean anemia, or transfusion-dependent thalassemia (TDT); • Beta-thalassemia intermedia; and • Beta-thalassemia minor, also called β-thalassemia carrier, β-thalassemia trait, or heterozygous β-thalassemia. ## Prevalence Beta-thalassemia is more prevalent in populations from the Mediterranean, the Middle East, Central and Southeast Asia, and the Indian subcontinent. It is also common in populations of African descent. The highest incidences are reported in Cyprus (14%), Sardinia (12%), and Southeast Asia. The increased frequency of β-thalassemia in these regions is most likely related to selective pressure from malaria. This distribution is quite similar to that of endemic ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Few conditions share similarities with β-thalassemia major and β-thalassemia intermedia. The genetic sideroblastic anemias are easily differentiated from β-thalassemia because of ring sideroblasts in the bone marrow and variably elevated serum concentration of erythrocyte protoporphyrin. They do not result in increased hemoglobin A Congenital dyserythropoietic anemias do not have high HbA A few acquired conditions associated with high HbF (juvenile chronic myeloid leukemia, aplastic anemia) may be mistaken for β-thalassemia, even though they have very characteristic hematologic features. Rarely, severe iron deficiency can be mistaken for β-thalassemia intermedia due to microcytosis. This should be readily distinguishable by both the lack of hemolysis and laboratory evidence of iron deficiency such as decreased ferritin. • The genetic sideroblastic anemias are easily differentiated from β-thalassemia because of ring sideroblasts in the bone marrow and variably elevated serum concentration of erythrocyte protoporphyrin. They do not result in increased hemoglobin A • Congenital dyserythropoietic anemias do not have high HbA • A few acquired conditions associated with high HbF (juvenile chronic myeloid leukemia, aplastic anemia) may be mistaken for β-thalassemia, even though they have very characteristic hematologic features. • Rarely, severe iron deficiency can be mistaken for β-thalassemia intermedia due to microcytosis. This should be readily distinguishable by both the lack of hemolysis and laboratory evidence of iron deficiency such as decreased ferritin. ## Management Comprehensive reviews of the management of beta-thalassemia (β-thalassemia) major and β-thalassemia intermedia have been published by the Thalassemia International Federation [ To establish the extent of disease and needs in an individual diagnosed with β-thalassemia, the evaluations summarized in Beta-Thalassemia: Recommended Evaluations Following Initial Diagnosis Hemoglobin electrophoresis Molecular analysis to determine globin genotype To determine if person has β-thalassemia major or β-thalassemia intermedia Those w/Hb <7 g/dL (excluding all other contributory causes, e.g., infections), or presence of manifestations of β-thalassemia major, regardless of Hb level, are diagnosed w/thalassemia major Facial changes Stunted growth Fractures Hepatosplenomegaly Hb = hemoglobin; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ Before starting red blood cell transfusions, the following are recommended: hepatitis B vaccination; extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy; and serum immunoglobulin determination, which detects individuals with IgA deficiency, who need special (repeatedly washed) blood unit preparation before each transfusion. An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ The need for and timing of Development of Individuals with β-thalassemia intermedia may develop Recommendations for clinical and laboratory evaluations for individuals with β-thalassemia major have been provided by the Thalassemia International Federation [ Beta-Thalassemia Major: Recommended Surveillance Serum ALT Serum ferritin Liver ultrasound Serum alpha-fetoprotein for early detection of hepatocarcinoma Serum creatinine, creatinine clearance, &/or plasma cystatin C levels Urine protein ALT = alanine transaminase; CBC = complete blood count Serum ferritin is not always reliable for evaluating iron burden because it is influenced by other factors, the most important being the extent of liver damage. Beta-Thalassemia Intermedia: Recommended Surveillance Serum ALT Serum ferritin Liver ultrasound Serum alpha-fetoprotein for early detection of hepatocarcinoma Serum creatinine, creatinine clearance, &/or plasma cystatin C levels Urine protein ALT = alanine transaminase; CBC = complete blood count Serum ferritin is not always reliable for evaluating iron burden because it is influenced by other factors, the most important being the extent of liver damage. The following should be avoided: Alcohol consumption, which in individuals with liver disease has a synergistic effect with iron-induced liver damage Iron-containing preparations Exposure to infection It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual as early as possible. Early detection allows prompt, appropriate treatment and monitoring. For newborn sibs, For sibs older than 12 months in whom absent or reduced hemoglobin A (HbA) was not detected on newborn screening* (or who did not undergo newborn screening), initial screening can be quickly accomplished with a complete blood count, as the absence of microcytosis rules out all forms of β-thalassemia. Sibs with microcytosis should have a hemoglobin electrophoresis and may merit additional testing (e.g., * In the United States, infants with biallelic β See Pregnancy in women with β-thalassemia usually has a favorable outcome in those followed by a multidisciplinary team but requires collaboration and preparation to avoid complications [ Women with β-thalassemia intermedia who had never previously received a red blood cell transfusion or who had received a minimal quantity of blood are reported to be at risk of alloimmunization anemia if red blood cell transfusions are required during pregnancy and therefore are also at increased risk for hemolytic disease of the fetus and newborn [ Therapeutic strategies aimed at improving iron dysregulation such as minihepcidin, TMPRSS6, and ferroportin inhibitors are showing promise [ Preliminary results for Search • Hemoglobin electrophoresis • Molecular analysis to determine globin genotype • To determine if person has β-thalassemia major or β-thalassemia intermedia • Those w/Hb <7 g/dL (excluding all other contributory causes, e.g., infections), or presence of manifestations of β-thalassemia major, regardless of Hb level, are diagnosed w/thalassemia major • Facial changes • Stunted growth • Fractures • Hepatosplenomegaly • The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ • The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ • Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ • Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. • Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ • An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T • While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ • Serum ALT • Serum ferritin • Liver ultrasound • Serum alpha-fetoprotein for early detection of hepatocarcinoma • Serum creatinine, creatinine clearance, &/or plasma cystatin C levels • Urine protein • Serum ALT • Serum ferritin • Liver ultrasound • Serum alpha-fetoprotein for early detection of hepatocarcinoma • Serum creatinine, creatinine clearance, &/or plasma cystatin C levels • Urine protein • Alcohol consumption, which in individuals with liver disease has a synergistic effect with iron-induced liver damage • Iron-containing preparations • Exposure to infection • For newborn sibs, • For sibs older than 12 months in whom absent or reduced hemoglobin A (HbA) was not detected on newborn screening* (or who did not undergo newborn screening), initial screening can be quickly accomplished with a complete blood count, as the absence of microcytosis rules out all forms of β-thalassemia. Sibs with microcytosis should have a hemoglobin electrophoresis and may merit additional testing (e.g., ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with β-thalassemia, the evaluations summarized in Beta-Thalassemia: Recommended Evaluations Following Initial Diagnosis Hemoglobin electrophoresis Molecular analysis to determine globin genotype To determine if person has β-thalassemia major or β-thalassemia intermedia Those w/Hb <7 g/dL (excluding all other contributory causes, e.g., infections), or presence of manifestations of β-thalassemia major, regardless of Hb level, are diagnosed w/thalassemia major Facial changes Stunted growth Fractures Hepatosplenomegaly Hb = hemoglobin; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Hemoglobin electrophoresis • Molecular analysis to determine globin genotype • To determine if person has β-thalassemia major or β-thalassemia intermedia • Those w/Hb <7 g/dL (excluding all other contributory causes, e.g., infections), or presence of manifestations of β-thalassemia major, regardless of Hb level, are diagnosed w/thalassemia major • Facial changes • Stunted growth • Fractures • Hepatosplenomegaly ## Treatment of Manifestations The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ Before starting red blood cell transfusions, the following are recommended: hepatitis B vaccination; extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy; and serum immunoglobulin determination, which detects individuals with IgA deficiency, who need special (repeatedly washed) blood unit preparation before each transfusion. An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ The need for and timing of Development of Individuals with β-thalassemia intermedia may develop • The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ • The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ • Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ • Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. • Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ • An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T • While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ ## Targeted Therapies The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ • The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ • The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ • Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ • Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. • Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ ## The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ • The ideal donor is a human leukocyte antigen (HLA)-matched sib. Individuals without an HLA-matched sib could also benefit from haploidentical mother-to-child transplantation, the results of which appear encouraging [ • The outcome of HSCT is related to pretransplantation clinical manifestations (presence of hepatomegaly, extent of liver fibrosis, and magnitude of cardiac and liver iron accumulation). In children who lack these pretransplantation risk factors, the disease-free survival rate is greater than 90%. Adults with β-thalassemia are at increased risk for transplant-related toxicity due to an advanced phase of the disease and have a two-year overall survival rate of 80% and a two-year event-free survival rate of 76% with current treatment protocols [ • Individuals with limited iron overload who receive HSCT from an unrelated donor selected based on stringent criteria of HLA compatibility have results that are comparable to HSCT from an HLA-matched sib donor [ • Severe acute graft-versus-host disease (GVHD) may occur in 9% of individuals, with a lower risk observed in those with an HLA-matched sib donor. • Cord blood transplantation remains an alternative for individuals seeking curative therapy without other donor options. Treatment with related donor cord blood was associated with a low risk of GVHD and a good chance of cure [ ## Supportive Care Before starting red blood cell transfusions, the following are recommended: hepatitis B vaccination; extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy; and serum immunoglobulin determination, which detects individuals with IgA deficiency, who need special (repeatedly washed) blood unit preparation before each transfusion. An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ The need for and timing of Development of Individuals with β-thalassemia intermedia may develop • An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T • While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ ## Before starting red blood cell transfusions, the following are recommended: hepatitis B vaccination; extensive red blood cell antigen typing, including Rh, Kell, Kidd, and Duffy; and serum immunoglobulin determination, which detects individuals with IgA deficiency, who need special (repeatedly washed) blood unit preparation before each transfusion. An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ • An open-label single-arm prospective Phase II study evaluated combination DFX-DFO in individuals with severe transfusional myocardial iron deposition followed by optional switch to DFX monotherapy when achieving myocardial T • While large-scale studies have not been conducted, the combination of DFX and deferiprone has been shown to be safe and effective in repeated case series [ ## The need for and timing of Development of Individuals with β-thalassemia intermedia may develop ## Surveillance Recommendations for clinical and laboratory evaluations for individuals with β-thalassemia major have been provided by the Thalassemia International Federation [ Beta-Thalassemia Major: Recommended Surveillance Serum ALT Serum ferritin Liver ultrasound Serum alpha-fetoprotein for early detection of hepatocarcinoma Serum creatinine, creatinine clearance, &/or plasma cystatin C levels Urine protein ALT = alanine transaminase; CBC = complete blood count Serum ferritin is not always reliable for evaluating iron burden because it is influenced by other factors, the most important being the extent of liver damage. Beta-Thalassemia Intermedia: Recommended Surveillance Serum ALT Serum ferritin Liver ultrasound Serum alpha-fetoprotein for early detection of hepatocarcinoma Serum creatinine, creatinine clearance, &/or plasma cystatin C levels Urine protein ALT = alanine transaminase; CBC = complete blood count Serum ferritin is not always reliable for evaluating iron burden because it is influenced by other factors, the most important being the extent of liver damage. • Serum ALT • Serum ferritin • Liver ultrasound • Serum alpha-fetoprotein for early detection of hepatocarcinoma • Serum creatinine, creatinine clearance, &/or plasma cystatin C levels • Urine protein • Serum ALT • Serum ferritin • Liver ultrasound • Serum alpha-fetoprotein for early detection of hepatocarcinoma • Serum creatinine, creatinine clearance, &/or plasma cystatin C levels • Urine protein ## Agents/Circumstances to Avoid The following should be avoided: Alcohol consumption, which in individuals with liver disease has a synergistic effect with iron-induced liver damage Iron-containing preparations Exposure to infection • Alcohol consumption, which in individuals with liver disease has a synergistic effect with iron-induced liver damage • Iron-containing preparations • Exposure to infection ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger sibs of an affected individual as early as possible. Early detection allows prompt, appropriate treatment and monitoring. For newborn sibs, For sibs older than 12 months in whom absent or reduced hemoglobin A (HbA) was not detected on newborn screening* (or who did not undergo newborn screening), initial screening can be quickly accomplished with a complete blood count, as the absence of microcytosis rules out all forms of β-thalassemia. Sibs with microcytosis should have a hemoglobin electrophoresis and may merit additional testing (e.g., * In the United States, infants with biallelic β See • For newborn sibs, • For sibs older than 12 months in whom absent or reduced hemoglobin A (HbA) was not detected on newborn screening* (or who did not undergo newborn screening), initial screening can be quickly accomplished with a complete blood count, as the absence of microcytosis rules out all forms of β-thalassemia. Sibs with microcytosis should have a hemoglobin electrophoresis and may merit additional testing (e.g., ## Pregnancy Management Pregnancy in women with β-thalassemia usually has a favorable outcome in those followed by a multidisciplinary team but requires collaboration and preparation to avoid complications [ Women with β-thalassemia intermedia who had never previously received a red blood cell transfusion or who had received a minimal quantity of blood are reported to be at risk of alloimmunization anemia if red blood cell transfusions are required during pregnancy and therefore are also at increased risk for hemolytic disease of the fetus and newborn [ ## Therapies Under Investigation Therapeutic strategies aimed at improving iron dysregulation such as minihepcidin, TMPRSS6, and ferroportin inhibitors are showing promise [ Preliminary results for Search ## Genetic Counseling Beta-thalassemia (β-thalassemia) major and β-thalassemia intermedia are inherited in an autosomal recessive manner. The parents of an individual with β-thalassemia are typically heterozygous for one Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment. If both If the If 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. Heterozygotes (carriers) are typically clinically asymptomatic but have microcytosis and either mild anemia or no anemia. Carriers are often referred to as having β-thalassemia minor. Rarely, a heterozygous If both parents are known to be heterozygous for an If one parent is known to be heterozygous for an The clinical severity of β-thalassemia in sibs who inherit biallelic The familial pathogenic variants segregating in the family (see The presence of Heterozygotes (carriers) are typically clinically asymptomatic but occasionally slightly anemic. Carriers are often referred to as having β-thalassemia minor. Rarely, a heterozygous Does not have an Is heterozygous for an Is also affected with β-thalassemia,* all offspring will have biallelic * Beta-thalassemia can be found around the world but is more prevalent in populations from the Mediterranean, the Middle East, Central and Southeast Asia, and the Indian subcontinent. It is also common in populations of African descent (see Carrier testing for at-risk relatives can be done by hematologic and/or (if the pathogenic variants have been identified in an affected family member) molecular genetic testing. See Population screening relies on hematologic analysis. When the hematologic analysis indicates a β-thalassemia carrier state, molecular genetic testing of Individuals who should be considered for carrier detection: Family members (See Gamete donors Members of populations with a higher prevalence of β-thalassemia (See Of note, the American College of Medical Genetics and Genomics includes β-thalassemia among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [ Carriers are often identified by analysis of red blood cell indices (see Hematologic Findings in individuals with Beta-Thalassemia Minor (Carrier) Adapted from Hemoglobin Analysis in Beta-Thalassemia Minor (Carrier) HbA = hemoglobin A; HbA Coinheritance of Coinheritance of delta-thalassemia (δ-thalassemia), which reduces to normal the increased HbA Confusion of α-thalassemia carriers with β-thalassemia carriers can occur, resulting from microcytosis and hypochromia. However, α-thalassemia carriers are easily distinguished by normal HbA β When the hematologic analysis is abnormal, molecular genetic testing of See Management, A thorough overview of the issues involved in β-thalassemia prevention is provided in The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Once both An indeterminate-risk pregnancy is one in which: One parent is a definite heterozygote, and the other parent has a β-thalassemia-like hematologic picture, but no The mother is a known heterozygote, and the clinical/genetic status of the father is unknown or the father is unavailable for testing, especially if the father belongs to a population at risk. Options for noninvasive prenatal 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. • The parents of an individual with β-thalassemia are typically heterozygous for one • Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment. • If both • If the • If both • If the • If 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. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are typically clinically asymptomatic but have microcytosis and either mild anemia or no anemia. Carriers are often referred to as having β-thalassemia minor. • Rarely, a heterozygous • Rarely, a heterozygous • If both • If 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 pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Rarely, a heterozygous • If both parents are known to be heterozygous for an • If one parent is known to be heterozygous for an • The clinical severity of β-thalassemia in sibs who inherit biallelic • The familial pathogenic variants segregating in the family (see • The presence of • The familial pathogenic variants segregating in the family (see • The presence of • Heterozygotes (carriers) are typically clinically asymptomatic but occasionally slightly anemic. Carriers are often referred to as having β-thalassemia minor. • Rarely, a heterozygous • Rarely, a heterozygous • The familial pathogenic variants segregating in the family (see • The presence of • Rarely, a heterozygous • Does not have an • Is heterozygous for an • Is also affected with β-thalassemia,* all offspring will have biallelic • Family members (See • Gamete donors • Members of populations with a higher prevalence of β-thalassemia (See • Coinheritance of • Coinheritance of delta-thalassemia (δ-thalassemia), which reduces to normal the increased HbA • Confusion of α-thalassemia carriers with β-thalassemia carriers can occur, resulting from microcytosis and hypochromia. However, α-thalassemia carriers are easily distinguished by normal HbA • β • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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. • One parent is a definite heterozygote, and the other parent has a β-thalassemia-like hematologic picture, but no • The mother is a known heterozygote, and the clinical/genetic status of the father is unknown or the father is unavailable for testing, especially if the father belongs to a population at risk. ## Mode of Inheritance Beta-thalassemia (β-thalassemia) major and β-thalassemia intermedia are inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an individual with β-thalassemia are typically heterozygous for one Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment. If both If the If 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. Heterozygotes (carriers) are typically clinically asymptomatic but have microcytosis and either mild anemia or no anemia. Carriers are often referred to as having β-thalassemia minor. Rarely, a heterozygous If both parents are known to be heterozygous for an If one parent is known to be heterozygous for an The clinical severity of β-thalassemia in sibs who inherit biallelic The familial pathogenic variants segregating in the family (see The presence of Heterozygotes (carriers) are typically clinically asymptomatic but occasionally slightly anemic. Carriers are often referred to as having β-thalassemia minor. Rarely, a heterozygous Does not have an Is heterozygous for an Is also affected with β-thalassemia,* all offspring will have biallelic * Beta-thalassemia can be found around the world but is more prevalent in populations from the Mediterranean, the Middle East, Central and Southeast Asia, and the Indian subcontinent. It is also common in populations of African descent (see • The parents of an individual with β-thalassemia are typically heterozygous for one • Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment. • If both • If the • If both • If the • If 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. • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes (carriers) are typically clinically asymptomatic but have microcytosis and either mild anemia or no anemia. Carriers are often referred to as having β-thalassemia minor. • Rarely, a heterozygous • Rarely, a heterozygous • If both • If 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 pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband. • Rarely, a heterozygous • If both parents are known to be heterozygous for an • If one parent is known to be heterozygous for an • The clinical severity of β-thalassemia in sibs who inherit biallelic • The familial pathogenic variants segregating in the family (see • The presence of • The familial pathogenic variants segregating in the family (see • The presence of • Heterozygotes (carriers) are typically clinically asymptomatic but occasionally slightly anemic. Carriers are often referred to as having β-thalassemia minor. • Rarely, a heterozygous • Rarely, a heterozygous • The familial pathogenic variants segregating in the family (see • The presence of • Rarely, a heterozygous • Does not have an • Is heterozygous for an • Is also affected with β-thalassemia,* all offspring will have biallelic ## Carrier Detection Carrier testing for at-risk relatives can be done by hematologic and/or (if the pathogenic variants have been identified in an affected family member) molecular genetic testing. See ## Population Screening Population screening relies on hematologic analysis. When the hematologic analysis indicates a β-thalassemia carrier state, molecular genetic testing of Individuals who should be considered for carrier detection: Family members (See Gamete donors Members of populations with a higher prevalence of β-thalassemia (See Of note, the American College of Medical Genetics and Genomics includes β-thalassemia among those disorders for which carrier screening should be offered to all individuals who are pregnant or planning a pregnancy [ Carriers are often identified by analysis of red blood cell indices (see Hematologic Findings in individuals with Beta-Thalassemia Minor (Carrier) Adapted from Hemoglobin Analysis in Beta-Thalassemia Minor (Carrier) HbA = hemoglobin A; HbA Coinheritance of Coinheritance of delta-thalassemia (δ-thalassemia), which reduces to normal the increased HbA Confusion of α-thalassemia carriers with β-thalassemia carriers can occur, resulting from microcytosis and hypochromia. However, α-thalassemia carriers are easily distinguished by normal HbA β When the hematologic analysis is abnormal, molecular genetic testing of • Family members (See • Gamete donors • Members of populations with a higher prevalence of β-thalassemia (See • Coinheritance of • Coinheritance of delta-thalassemia (δ-thalassemia), which reduces to normal the increased HbA • Confusion of α-thalassemia carriers with β-thalassemia carriers can occur, resulting from microcytosis and hypochromia. However, α-thalassemia carriers are easily distinguished by normal HbA • β ## Hematologic Testing Carriers are often identified by analysis of red blood cell indices (see Hematologic Findings in individuals with Beta-Thalassemia Minor (Carrier) Adapted from Hemoglobin Analysis in Beta-Thalassemia Minor (Carrier) HbA = hemoglobin A; HbA Coinheritance of Coinheritance of delta-thalassemia (δ-thalassemia), which reduces to normal the increased HbA Confusion of α-thalassemia carriers with β-thalassemia carriers can occur, resulting from microcytosis and hypochromia. However, α-thalassemia carriers are easily distinguished by normal HbA β • Coinheritance of • Coinheritance of delta-thalassemia (δ-thalassemia), which reduces to normal the increased HbA • Confusion of α-thalassemia carriers with β-thalassemia carriers can occur, resulting from microcytosis and hypochromia. However, α-thalassemia carriers are easily distinguished by normal HbA • β ## Molecular Genetic Testing When the hematologic analysis is abnormal, molecular genetic testing of ## Related Genetic Counseling Issues See Management, A thorough overview of the issues involved in β-thalassemia prevention is provided in The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 both An indeterminate-risk pregnancy is one in which: One parent is a definite heterozygote, and the other parent has a β-thalassemia-like hematologic picture, but no The mother is a known heterozygote, and the clinical/genetic status of the father is unknown or the father is unavailable for testing, especially if the father belongs to a population at risk. Options for noninvasive prenatal 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. • One parent is a definite heterozygote, and the other parent has a β-thalassemia-like hematologic picture, but no • The mother is a known heterozygote, and the clinical/genetic status of the father is unknown or the father is unavailable for testing, especially if the father belongs to a population at risk. ## Resources Cyprus Health Resources & Services Administration United Kingdom • • • • • • Cyprus • • • Health Resources & Services Administration • • • United Kingdom • ## Molecular Genetics Beta-Thalassemia: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Beta-Thalassemia ( Almost 300 β β Complex β-thalassemias (delta-beta-thalassemia and gamma-delta-beta-thalassemia) resulting from various contiguous deletions within the Beta-thalassemia caused by deletion of the LCR (leaving Population-specific pathogenic variants are common (see Mild β One of 6 common pathogenic variants in African & African American populations Mild β One of 6 common pathogenic variants in Mediterranean population Mild β One of 6 common pathogenic variants in African & African American populations One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population Mild β One of 6 common pathogenic variants in Middle Eastern population One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population Hb Malay Mild β One of 6 common pathogenic variants in Taiwanese population Mild β One of 6 common pathogenic variants in African & African American populations Hb Knossos Silent β One of 6 common pathogenic variants in African & African American populations One of 6 common pathogenic variants in Middle Eastern & Taiwanese populations Mild β One of 6 common pathogenic variants in Mediterranean population One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions Variant nomenclature following current guidelines has been provided. However, because the initiation methionine is not part of the mature beta globin protein, the long-standing convention of numbering the amino acids is to begin with the next amino acid (Val). For consistency with the literature and the Globin Gene Server ( Nucleotide substitution activates a splice site. • β • β • Complex β-thalassemias (delta-beta-thalassemia and gamma-delta-beta-thalassemia) resulting from various contiguous deletions within the • Beta-thalassemia caused by deletion of the LCR (leaving • Mild β • One of 6 common pathogenic variants in African & African American populations • Mild β • One of 6 common pathogenic variants in Mediterranean population • Mild β • One of 6 common pathogenic variants in African & African American populations • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population • Mild β • One of 6 common pathogenic variants in Middle Eastern population • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population • Hb Malay • Mild β • One of 6 common pathogenic variants in Taiwanese population • Mild β • One of 6 common pathogenic variants in African & African American populations • Hb Knossos • Silent β • One of 6 common pathogenic variants in African & African American populations • One of 6 common pathogenic variants in Middle Eastern & Taiwanese populations • Mild β • One of 6 common pathogenic variants in Mediterranean population • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population ## Molecular Pathogenesis Almost 300 β β Complex β-thalassemias (delta-beta-thalassemia and gamma-delta-beta-thalassemia) resulting from various contiguous deletions within the Beta-thalassemia caused by deletion of the LCR (leaving Population-specific pathogenic variants are common (see Mild β One of 6 common pathogenic variants in African & African American populations Mild β One of 6 common pathogenic variants in Mediterranean population Mild β One of 6 common pathogenic variants in African & African American populations One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population Mild β One of 6 common pathogenic variants in Middle Eastern population One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population Hb Malay Mild β One of 6 common pathogenic variants in Taiwanese population Mild β One of 6 common pathogenic variants in African & African American populations Hb Knossos Silent β One of 6 common pathogenic variants in African & African American populations One of 6 common pathogenic variants in Middle Eastern & Taiwanese populations Mild β One of 6 common pathogenic variants in Mediterranean population One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population One of 4 common pathogenic variants in Chinese population One of 6 common pathogenic variants in Taiwanese population Variants listed in the table have been provided by the author. Variant designation that does not conform to current naming conventions Variant nomenclature following current guidelines has been provided. However, because the initiation methionine is not part of the mature beta globin protein, the long-standing convention of numbering the amino acids is to begin with the next amino acid (Val). For consistency with the literature and the Globin Gene Server ( Nucleotide substitution activates a splice site. • β • β • Complex β-thalassemias (delta-beta-thalassemia and gamma-delta-beta-thalassemia) resulting from various contiguous deletions within the • Beta-thalassemia caused by deletion of the LCR (leaving • Mild β • One of 6 common pathogenic variants in African & African American populations • Mild β • One of 6 common pathogenic variants in Mediterranean population • Mild β • One of 6 common pathogenic variants in African & African American populations • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population • Mild β • One of 6 common pathogenic variants in Middle Eastern population • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population • Hb Malay • Mild β • One of 6 common pathogenic variants in Taiwanese population • Mild β • One of 6 common pathogenic variants in African & African American populations • Hb Knossos • Silent β • One of 6 common pathogenic variants in African & African American populations • One of 6 common pathogenic variants in Middle Eastern & Taiwanese populations • Mild β • One of 6 common pathogenic variants in Mediterranean population • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population • One of 4 common pathogenic variants in Chinese population • One of 6 common pathogenic variants in Taiwanese population ## Chapter Notes Arielle L Langer, MD, MPH, is the director of the Thalassemia Program at Brigham and Women's Hospital and Dana Farber Cancer Institute. Her research interests include the impact of thalassemia on pregnancy. Inquiries can be sent to: Arielle L Langer MD MPHDivision of HematologyBrigham and Women's Hospital75 Francis StBoston, MA 02115Email: The author would like to thank the Foundation for Women and Girls with Blood Disorders (FWGBD) for funding to support research on beta-thalassemia minor in pregnancy, as well as the Thalassemia International Federation and Cooley's Anemia Foundation for their tireless work to support clinicians and patients. Antonio Cao, MD; Consiglio Nazionale delle Ricerche (2000-2012)Renzo Galanello, MD; Ospedale Regionale Microcitemie (2000-2013)Arielle L Langer, MD, MPH (2023-present)Raffaella Origa, MD; Università degli Studi di Cagliari (2013-2023) 8 February 2024 (aa) Revision: CRISPR gene therapy exagamglogene autotemcel (exa-cel) approved by FDA 20 July 2023 (sw) Comprehensive update posted live 25 January 2018 (ha) Comprehensive update posted live 14 May 2015 (me) Comprehensive update posted live 24 January 2013 (me) Comprehensive update posted live 17 June 2010 (me) Comprehensive update posted live 23 October 2007 (me) Comprehensive update posted live 19 June 2005 (me) Comprehensive update posted live 18 March 2003 (tk) Comprehensive update posted live 28 September 2000 (me) Review posted live March 2000 (ac) Original submission • 8 February 2024 (aa) Revision: CRISPR gene therapy exagamglogene autotemcel (exa-cel) approved by FDA • 20 July 2023 (sw) Comprehensive update posted live • 25 January 2018 (ha) Comprehensive update posted live • 14 May 2015 (me) Comprehensive update posted live • 24 January 2013 (me) Comprehensive update posted live • 17 June 2010 (me) Comprehensive update posted live • 23 October 2007 (me) Comprehensive update posted live • 19 June 2005 (me) Comprehensive update posted live • 18 March 2003 (tk) Comprehensive update posted live • 28 September 2000 (me) Review posted live • March 2000 (ac) Original submission ## Author Notes Arielle L Langer, MD, MPH, is the director of the Thalassemia Program at Brigham and Women's Hospital and Dana Farber Cancer Institute. Her research interests include the impact of thalassemia on pregnancy. Inquiries can be sent to: Arielle L Langer MD MPHDivision of HematologyBrigham and Women's Hospital75 Francis StBoston, MA 02115Email: ## Acknowledgments The author would like to thank the Foundation for Women and Girls with Blood Disorders (FWGBD) for funding to support research on beta-thalassemia minor in pregnancy, as well as the Thalassemia International Federation and Cooley's Anemia Foundation for their tireless work to support clinicians and patients. ## Author History Antonio Cao, MD; Consiglio Nazionale delle Ricerche (2000-2012)Renzo Galanello, MD; Ospedale Regionale Microcitemie (2000-2013)Arielle L Langer, MD, MPH (2023-present)Raffaella Origa, MD; Università degli Studi di Cagliari (2013-2023) ## Revision History 8 February 2024 (aa) Revision: CRISPR gene therapy exagamglogene autotemcel (exa-cel) approved by FDA 20 July 2023 (sw) Comprehensive update posted live 25 January 2018 (ha) Comprehensive update posted live 14 May 2015 (me) Comprehensive update posted live 24 January 2013 (me) Comprehensive update posted live 17 June 2010 (me) Comprehensive update posted live 23 October 2007 (me) Comprehensive update posted live 19 June 2005 (me) Comprehensive update posted live 18 March 2003 (tk) Comprehensive update posted live 28 September 2000 (me) Review posted live March 2000 (ac) Original submission • 8 February 2024 (aa) Revision: CRISPR gene therapy exagamglogene autotemcel (exa-cel) approved by FDA • 20 July 2023 (sw) Comprehensive update posted live • 25 January 2018 (ha) Comprehensive update posted live • 14 May 2015 (me) Comprehensive update posted live • 24 January 2013 (me) Comprehensive update posted live • 17 June 2010 (me) Comprehensive update posted live • 23 October 2007 (me) Comprehensive update posted live • 19 June 2005 (me) Comprehensive update posted live • 18 March 2003 (tk) Comprehensive update posted live • 28 September 2000 (me) Review posted live • March 2000 (ac) Original submission ## Key Sections in this ## References ## Literature Cited	[]	28/9/2000	20/7/2023	8/2/2024	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bachmann-bupp	bachmann-bupp	[ "ODC1-Related Neurodevelopmental Disorder", "ODC1-Related Neurodevelopmental Disorder", "Ornithine decarboxylase", "ODC1", "Bachmann-Bupp Syndrome" ]	Bachmann-Bupp Syndrome	Caleb Bupp, Julianne Michael, Elizabeth VanSickle, Surender Rajasekaran, André Stephan Bachmann	Summary Bachmann-Bupp syndrome (BABS) is characterized by a distinctive type of alopecia, global developmental delay in the moderate to severe range, hypotonia, nonspecific dysmorphic features, behavioral abnormalities (autism spectrum disorder, attention-deficit/hyperactivity disorder) and feeding difficulties. Hair is typically present at birth but may be sparse and of an unexpected color with subsequent loss of hair in large clumps within the first few weeks of life. Rare findings may include seizures with onset in later childhood and conductive hearing loss. The finding of abnormal polyamine pathway metabolites (including increased N-acetylputrescine) on metabolomic profiling is suggestive of a diagnosis of BABS. The diagnosis is established in a proband with suggestive findings and a heterozygous pathogenic variant in BABS is expressed in an autosomal dominant manner and typically caused by a	## Diagnosis No consensus clinical diagnostic criteria for Bachmann-Bupp syndrome (BABS) have been published. BABS Prenatal history of polyhydramnios An unusual pattern of noncongenital alopecia due to sudden-onset hair loss shortly after birth with congenitally absent or sparse eyebrows and eyelashes Developmental delay, typically in the moderate to severe range Hypotonia Macrocephaly, defined as OFC of >97 Macrosomia (defined as weight and length >95 Recurrent follicular cysts Nonspecific white matter hyperintensities Cystic lesions, primarily in the periventricular region but occasionally in other areas, potentially associated with in utero intraventricular hemorrhage The diagnosis of BABS 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 supportive laboratory findings suggest the diagnosis of BABS, 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 developmental delay and growth abnormalities, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Bachmann-Bupp 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. As this condition is thought to be due to a gain of function, it is not anticipated that whole-exon or gene deletions or duplications will lead to this phenotype (see • Prenatal history of polyhydramnios • An unusual pattern of noncongenital alopecia due to sudden-onset hair loss shortly after birth with congenitally absent or sparse eyebrows and eyelashes • Developmental delay, typically in the moderate to severe range • Hypotonia • Macrocephaly, defined as OFC of >97 • Macrosomia (defined as weight and length >95 • Recurrent follicular cysts • Nonspecific white matter hyperintensities • Cystic lesions, primarily in the periventricular region but occasionally in other areas, potentially associated with in utero intraventricular hemorrhage • For an introduction to multigene panels click ## Suggestive Findings BABS Prenatal history of polyhydramnios An unusual pattern of noncongenital alopecia due to sudden-onset hair loss shortly after birth with congenitally absent or sparse eyebrows and eyelashes Developmental delay, typically in the moderate to severe range Hypotonia Macrocephaly, defined as OFC of >97 Macrosomia (defined as weight and length >95 Recurrent follicular cysts Nonspecific white matter hyperintensities Cystic lesions, primarily in the periventricular region but occasionally in other areas, potentially associated with in utero intraventricular hemorrhage • Prenatal history of polyhydramnios • An unusual pattern of noncongenital alopecia due to sudden-onset hair loss shortly after birth with congenitally absent or sparse eyebrows and eyelashes • Developmental delay, typically in the moderate to severe range • Hypotonia • Macrocephaly, defined as OFC of >97 • Macrosomia (defined as weight and length >95 • Recurrent follicular cysts • Nonspecific white matter hyperintensities • Cystic lesions, primarily in the periventricular region but occasionally in other areas, potentially associated with in utero intraventricular hemorrhage ## Establishing the Diagnosis The diagnosis of BABS 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 supportive laboratory findings suggest the diagnosis of BABS, 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 developmental delay and growth abnormalities, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Bachmann-Bupp 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. As this condition is thought to be due to a gain of function, it is not anticipated that whole-exon or gene deletions or duplications will lead to this phenotype (see • For an introduction to multigene panels click ## Option 1 When the phenotypic and supportive laboratory findings suggest the diagnosis of BABS, 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 developmental delay and growth abnormalities, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Bachmann-Bupp 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. As this condition is thought to be due to a gain of function, it is not anticipated that whole-exon or gene deletions or duplications will lead to this phenotype (see ## Clinical Characteristics To date, nine individuals from nine families have been reported with a pathogenic variant in Bachmann-Bupp Syndrome: Frequency of Select Features One reported case was of a late-term stillbirth; thus, some features pertaining to this person are unknown [ Hair is typically present at birth but is sometimes sparse and sometimes has atypical color (darker or lighter than anticipated). Loss of hair, if present, begins in the first few weeks of life with hair falling out in large clumps. Absent or sparse eyebrows and eyelashes are typically congenital. Some affected individuals undergo regrowth of scalp hair that usually remains sparse, although one affected individual had full, thick hair with no reported loss of hair postnatally but absent eyebrows and eyelashes. Behavioral concerns evolved in one affected individual treated with difluoromethylornithine (DFMO) (see It is unclear whether DFMO treatment accelerated the development of autistic symptoms that would have developed in any case (although more slowly) without treatment, or whether the treatment itself affected brain function through the alteration of polyamine levels. Macrosomia at birth has been reported; in four of five affected individuals measured, length was >95% percentile, and in two of five weight was >95% percentile. However, growth parameters tend to normalize with age: at later childhood examination, only two of eight had height >95% percentile and none had weight >95% percentile. Gain-of-function variants located in the C terminus are associated with BABS. For example, pathogenic variants resulting in a premature termination codon within the last exon, escaping nonsense-mediated decay and causing a gain-of-function terminus, are associated with BABS. Loss-of-function variants may be enriched with neurologic phenotypes (see Bachmann-Bupp syndrome may also be referred to as The prevalence of Bachmann-Bupp syndrome is unknown. Nine affected individuals have been reported in the literature to date. Three additional affected individuals are known to these authors but have not been reported in the medical literature. • Hair is typically present at birth but is sometimes sparse and sometimes has atypical color (darker or lighter than anticipated). • Loss of hair, if present, begins in the first few weeks of life with hair falling out in large clumps. • Absent or sparse eyebrows and eyelashes are typically congenital. • Some affected individuals undergo regrowth of scalp hair that usually remains sparse, although one affected individual had full, thick hair with no reported loss of hair postnatally but absent eyebrows and eyelashes. • Behavioral concerns evolved in one affected individual treated with difluoromethylornithine (DFMO) (see • It is unclear whether DFMO treatment accelerated the development of autistic symptoms that would have developed in any case (although more slowly) without treatment, or whether the treatment itself affected brain function through the alteration of polyamine levels. ## Clinical Description To date, nine individuals from nine families have been reported with a pathogenic variant in Bachmann-Bupp Syndrome: Frequency of Select Features One reported case was of a late-term stillbirth; thus, some features pertaining to this person are unknown [ Hair is typically present at birth but is sometimes sparse and sometimes has atypical color (darker or lighter than anticipated). Loss of hair, if present, begins in the first few weeks of life with hair falling out in large clumps. Absent or sparse eyebrows and eyelashes are typically congenital. Some affected individuals undergo regrowth of scalp hair that usually remains sparse, although one affected individual had full, thick hair with no reported loss of hair postnatally but absent eyebrows and eyelashes. Behavioral concerns evolved in one affected individual treated with difluoromethylornithine (DFMO) (see It is unclear whether DFMO treatment accelerated the development of autistic symptoms that would have developed in any case (although more slowly) without treatment, or whether the treatment itself affected brain function through the alteration of polyamine levels. Macrosomia at birth has been reported; in four of five affected individuals measured, length was >95% percentile, and in two of five weight was >95% percentile. However, growth parameters tend to normalize with age: at later childhood examination, only two of eight had height >95% percentile and none had weight >95% percentile. • Hair is typically present at birth but is sometimes sparse and sometimes has atypical color (darker or lighter than anticipated). • Loss of hair, if present, begins in the first few weeks of life with hair falling out in large clumps. • Absent or sparse eyebrows and eyelashes are typically congenital. • Some affected individuals undergo regrowth of scalp hair that usually remains sparse, although one affected individual had full, thick hair with no reported loss of hair postnatally but absent eyebrows and eyelashes. • Behavioral concerns evolved in one affected individual treated with difluoromethylornithine (DFMO) (see • It is unclear whether DFMO treatment accelerated the development of autistic symptoms that would have developed in any case (although more slowly) without treatment, or whether the treatment itself affected brain function through the alteration of polyamine levels. ## Genotype-Phenotype Correlations Gain-of-function variants located in the C terminus are associated with BABS. For example, pathogenic variants resulting in a premature termination codon within the last exon, escaping nonsense-mediated decay and causing a gain-of-function terminus, are associated with BABS. Loss-of-function variants may be enriched with neurologic phenotypes (see ## Nomenclature Bachmann-Bupp syndrome may also be referred to as ## Prevalence The prevalence of Bachmann-Bupp syndrome is unknown. Nine affected individuals have been reported in the literature to date. Three additional affected individuals are known to these authors but have not been reported in the medical literature. ## Genetically Related (Allelic) Disorders It is unclear whether loss-of-function variants in ## Differential Diagnosis Selected Genetic Disorders in the Differential Diagnosis of Bachmann-Bupp Syndrome Ectodermal dysplasia is not typically assoc w/DD or hypotonia. Alopecia is congenital in most ectodermal dysplasia. BABS is not assoc w/dental issues. Only 1 person w/BABS was reported to have ↓ sweating. AD = autosomal dominant; AR = autosomal recessive; BABS = Bachmann-Bupp syndrome; DD = developmental delay; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked • Ectodermal dysplasia is not typically assoc w/DD or hypotonia. Alopecia is congenital in most ectodermal dysplasia. • BABS is not assoc w/dental issues. Only 1 person w/BABS was reported to have ↓ sweating. ## Management No clinical practice guidelines for Bachmann-Bupp syndrome (BABS) have been published. To establish the extent of disease and needs in an individual diagnosed with BABS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Bachmann-Bupp Syndrome To incl eval for aspiration risk, nutritional status, & signs & symptoms of constipation May require use of special nipple &/or nasogastric tube in infancy Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Use of community or Need for social work involvement for parental support; Need for home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BABS = Bachmann-Bupp syndrome; EEG = electroencephalogram; MOI = mode of inheritance; MRI = magnetic resonance imaging Medical geneticist, certified genetic counselor, certified advanced genetic nurse An experimental targeted treatment for BABS is being investigated (see Supportive Treatment of Manifestations in Individuals with Bachmann-Bupp Syndrome Feeding therapy Special nipple or nasogastric tube may be required. Gastrostomy tube placement may be considered for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for BABS. In 1 person, epilepsy was refractory to multiple ASMs, ketogenic diet, & vagal nerve stimulators. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability 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. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with Bachmann-Bupp Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy See Experimental Targeted Treatment of Manifestations in Individuals with Bachmann-Bupp Syndrome Escalating 500 mg/m 1000 mg/m This dosing strategy was used for 3 patients w/BABS under FDA-approved Single Patient IND based on previous data from pediatric dosing for neuroblastoma treatment. Future treatment strategies for DFMO may be influenced by ongoing safety & efficacy data. BID = twice a day; FDA = Food and Drug Administration; IND = investigational new drug Also called eflornithine Search • To incl eval for aspiration risk, nutritional status, & signs & symptoms of constipation • May require use of special nipple &/or nasogastric tube in infancy • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. • Feeding therapy • Special nipple or nasogastric tube may be required. • Gastrostomy tube placement may be considered for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for BABS. • In 1 person, epilepsy was refractory to multiple ASMs, ketogenic diet, & vagal nerve stimulators. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Escalating 500 mg/m • 1000 mg/m • This dosing strategy was used for 3 patients w/BABS under FDA-approved Single Patient IND based on previous data from pediatric dosing for neuroblastoma treatment. • Future treatment strategies for DFMO may be influenced by ongoing safety & efficacy data. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with BABS, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Bachmann-Bupp Syndrome To incl eval for aspiration risk, nutritional status, & signs & symptoms of constipation May require use of special nipple &/or nasogastric tube in infancy Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education Use of community or Need for social work involvement for parental support; Need for home nursing referral. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BABS = Bachmann-Bupp syndrome; EEG = electroencephalogram; MOI = mode of inheritance; MRI = magnetic resonance imaging Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl eval for aspiration risk, nutritional status, & signs & symptoms of constipation • May require use of special nipple &/or nasogastric tube in infancy • Consider eval for gastric tube placement in those w/dysphagia &/or aspiration risk. • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • Use of community or • Need for social work involvement for parental support; • Need for home nursing referral. ## Treatment of Manifestations An experimental targeted treatment for BABS is being investigated (see Supportive Treatment of Manifestations in Individuals with Bachmann-Bupp Syndrome Feeding therapy Special nipple or nasogastric tube may be required. Gastrostomy tube placement may be considered for persistent feeding issues. Many ASMs may be effective; none has been demonstrated effective specifically for BABS. In 1 person, epilepsy was refractory to multiple ASMs, ketogenic diet, & vagal nerve stimulators. Education of parents/caregivers Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability 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. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Feeding therapy • Special nipple or nasogastric tube may be required. • Gastrostomy tube placement may be considered for persistent feeding issues. • Many ASMs may be effective; none has been demonstrated effective specifically for BABS. • In 1 person, epilepsy was refractory to multiple ASMs, ketogenic diet, & vagal nerve stimulators. • Education of parents/caregivers • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • 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. Individualized education plan (IEP) services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Individualized education plan (IEP) services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public-school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with Bachmann-Bupp Syndrome Measurement of growth parameters Eval of nutritional status & safety of oral intake ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Experimental Targeted Treatment of Manifestations in Individuals with Bachmann-Bupp Syndrome Escalating 500 mg/m 1000 mg/m This dosing strategy was used for 3 patients w/BABS under FDA-approved Single Patient IND based on previous data from pediatric dosing for neuroblastoma treatment. Future treatment strategies for DFMO may be influenced by ongoing safety & efficacy data. BID = twice a day; FDA = Food and Drug Administration; IND = investigational new drug Also called eflornithine Search • Escalating 500 mg/m • 1000 mg/m • This dosing strategy was used for 3 patients w/BABS under FDA-approved Single Patient IND based on previous data from pediatric dosing for neuroblastoma treatment. • Future treatment strategies for DFMO may be influenced by ongoing safety & efficacy data. ## Genetic Counseling Bachmann-Bupp syndrome (BABS) is an autosomal dominant disorder typically caused by a All probands reported to date with BABS whose parents have also undergone molecular genetic testing have the disorder as the result of 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 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the If a parent of the proband is known to have the Each child of an individual with BABS has a 50% chance of inheriting the To date, individuals with BABS are not known to reproduce; however, many are not yet of reproductive 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 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 BABS whose parents have also undergone molecular genetic testing have the disorder as the result of 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 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If the • If a parent of the proband is known to have the • Each child of an individual with BABS has a 50% chance of inheriting the • To date, individuals with BABS are not known to reproduce; however, many are not yet of reproductive 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 parents of affected individuals. ## Mode of Inheritance Bachmann-Bupp syndrome (BABS) is an autosomal dominant disorder typically caused by a ## Risk to Family Members All probands reported to date with BABS whose parents have also undergone molecular genetic testing have the disorder as the result of 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 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the If a parent of the proband is known to have the Each child of an individual with BABS has a 50% chance of inheriting the To date, individuals with BABS are not known to reproduce; however, many are not yet of reproductive age. • All probands reported to date with BABS whose parents have also undergone molecular genetic testing have the disorder as the result of 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 pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • If the • If a parent of the proband is known to have the • Each child of an individual with BABS has a 50% chance of inheriting the • To date, individuals with BABS are not known to reproduce; however, many are not yet of reproductive age. ## 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 See • • • • ## Molecular Genetics Bachmann-Bupp Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Bachmann-Bupp Syndrome ( The polyamine metabolic pathway and associated genetic disorders ODC and polyamines are intrinsically involved in the regulation of embryogenesis, organogenesis, and tumorigenesis. This occurs through tight regulation of putrescine, spermidine, and spermine, all of which control cell division and proliferation. Spermidine is substrate to eIF5A and essential for its hypusination (activation) and therefore directly affects eIF5A-mediated protein translation events. Many polyamine pathway-linked genes including Figure and legend republished from When intracellular putrescine and other polyamine levels are elevated, these metabolites are acetylated. Acetylated polyamines are shuttled out of the cell in an attempt to regain homeostasis, resulting in elevated plasma N-acetylputrescine. In cell experiments using high-performance liquid chromatography (HPLC), increased putrescine is observed because HPLC is not able to separate putrescine from N-acetylputrescine; however, mass spectrometry does have this capability. A transgenic mouse model created in 1995 in which a C-terminally deleted ODC (p.Pro427Ter) protein was overexpressed showed higher ODC enzyme levels and increased polyamine metabolites [ Due to its role in regulating cell growth and proliferation, the polyamine pathway and ODC are known to be involved in neoplastic cell growth, specifically in neuroblastoma and in breast, colon, lung, prostate, and skin cancers [ ## Molecular Pathogenesis The polyamine metabolic pathway and associated genetic disorders ODC and polyamines are intrinsically involved in the regulation of embryogenesis, organogenesis, and tumorigenesis. This occurs through tight regulation of putrescine, spermidine, and spermine, all of which control cell division and proliferation. Spermidine is substrate to eIF5A and essential for its hypusination (activation) and therefore directly affects eIF5A-mediated protein translation events. Many polyamine pathway-linked genes including Figure and legend republished from When intracellular putrescine and other polyamine levels are elevated, these metabolites are acetylated. Acetylated polyamines are shuttled out of the cell in an attempt to regain homeostasis, resulting in elevated plasma N-acetylputrescine. In cell experiments using high-performance liquid chromatography (HPLC), increased putrescine is observed because HPLC is not able to separate putrescine from N-acetylputrescine; however, mass spectrometry does have this capability. A transgenic mouse model created in 1995 in which a C-terminally deleted ODC (p.Pro427Ter) protein was overexpressed showed higher ODC enzyme levels and increased polyamine metabolites [ ## Cancer and Benign Tumors Due to its role in regulating cell growth and proliferation, the polyamine pathway and ODC are known to be involved in neoplastic cell growth, specifically in neuroblastoma and in breast, colon, lung, prostate, and skin cancers [ ## Chapter Notes The Caleb Bupp, MD, FACMGDivision Chief, Medical Genetics and GenomicsSpectrum Health and Helen DeVos Children's Hospital25 Michigan Street NE, Suite 2000Grand Rapids, Michigan [email protected] André S Bachmann, MS, PHDProfessor of Pediatrics and Associate Chair for ResearchDepartment of Pediatrics and Human Development, College of Human MedicineMichigan State University400 Monroe Ave NWGrand Rapids, Michigan [email protected]. Research interests: polyamines, ODC, DFMO, natural products drug discovery, proteasome inhibitors, pediatric cancer, neuroblastoma, medical genetics, Bachmann-Bupp syndrome, Synder-Robinson syndrome, preclinical & clinical trial studies The authors acknowledge the research support of the Spectrum Health Michigan State University Alliance Corporation for this work. The authors would like to thank all individuals with BABS and their families for sharing their medical and personal stories. They are the true experts and based upon their knowledge we have been able to write this 25 August 2022 (ma) Review posted live 7 January 2022 (cb) Original submission • 25 August 2022 (ma) Review posted live • 7 January 2022 (cb) Original submission ## Author Notes The Caleb Bupp, MD, FACMGDivision Chief, Medical Genetics and GenomicsSpectrum Health and Helen DeVos Children's Hospital25 Michigan Street NE, Suite 2000Grand Rapids, Michigan [email protected] André S Bachmann, MS, PHDProfessor of Pediatrics and Associate Chair for ResearchDepartment of Pediatrics and Human Development, College of Human MedicineMichigan State University400 Monroe Ave NWGrand Rapids, Michigan [email protected]. Research interests: polyamines, ODC, DFMO, natural products drug discovery, proteasome inhibitors, pediatric cancer, neuroblastoma, medical genetics, Bachmann-Bupp syndrome, Synder-Robinson syndrome, preclinical & clinical trial studies ## Acknowledgments The authors acknowledge the research support of the Spectrum Health Michigan State University Alliance Corporation for this work. The authors would like to thank all individuals with BABS and their families for sharing their medical and personal stories. They are the true experts and based upon their knowledge we have been able to write this ## Revision History 25 August 2022 (ma) Review posted live 7 January 2022 (cb) Original submission • 25 August 2022 (ma) Review posted live • 7 January 2022 (cb) Original submission ## References ## Literature Cited	[ "LG Biesecker, MP Adam, FS Alkuraya, AR Amemiya, MJ Bamshad, AE Beck, JT Bennett, LM Bird, JC Carey, B Chung, RD Clark, TC Cox, C Curry, MBP Dinulos, WB Dobyns, PF Giampietro, KM Girisha, IA Glass, JM Graham, KW Gripp, CR Haldeman-Englert, BD Hall, AM Innes, JM Kalish, KM Keppler-Noreuil, K Kosaki, BA Kozel, GM Mirzaa, JJ Mulvihill, MJM Nowaczyk, RA Pagon, K Retterer, AF Rope, PA Sanchez-Lara, LH Seaver, JT Shieh, AM Slavotinek, AK Sobering, CA Stevens, DA Stevenson, TY Tan, WH Tan, AC Tsai, DD Weaver, MS Williams, E Zackai, YA Zarate. A dyadic approach to the delineation of diagnostic entities in clinical genomics.. Am J Hum Genet. 2021;108:8-15", "CP Bupp, CR Schultz, KL Uhl, S Rajasekaran, AS Bachmann. Novel de novo pathogenic variant in the ODC1 gene in a girl with developmental delay, alopecia, and dysmorphic features.. Am J Med Genet A. 2018;176:2548-53", "EC Lewis, JM Kraveka, W Ferguson, D Eslin, VI Brown, G Bergendahl, W Roberts, RK Wada, J Oesterheld, D Mitchell, J Foley, P Zage, J Rawwas, M Rich, E Lorenzi, K Broglio, D Berry, GL Saulnier Sholler. A subset analysis of a phase II trial evaluating the use of DFMO as maintenance therapy for high-risk neuroblastoma.. Int J Cancer. 2020;147:3152-9", "L Megosh, SK Gilmour, D Rosson, AP Soler, M Blessing, JA Sawicki, TG O'Brien. Increased frequency of spontaneous skin tumors in transgenic mice which overexpress ornithine decarboxylase.. Cancer Research. 1995;55:4205-9", "SL Nowotarski, PM Woster, RA Casero. Polyamines and cancer: implications for chemotherapy and chemoprevention.. Expert Rev Mol Med. 2013;15", "JW Prokop, CP Bupp, A Frisch, SM Bilinovich, DB Campbell, D Vogt, CR Schultz, KL Uhl, E VanSickle, S Rajasekaran, AS Bachmann. Emerging Role of ODC1 in Neurodevelopmental Disorders and Brain Development.. Genes (Basel) 2021;12:470", "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 Rajasekaran, CP Bupp, M Leimanis, A Shukla, C Russell, E Gleason, E VanSickle, Y Edgerly, B Wittman, JW Prokop, AS Bachmann. Repurposing a pre-existing drug to treat a rare disease: Eflornithine used in a patient with ODC1 gain-of-function variant.. eLife. 2021;10", "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", "LH Rodan, K Anyane-Yeboa, K Chong, JS Klein Wassink-Ruiter, A Wilson, L Smith, SV Kothare, F Rajabi, S Blaser, M Ni, RJ DeBerardinis, A Poduri, GT Berry. Gain-of-function variants in the ODC1 gene cause a syndromic neurodevelopmental disorder associated with macrocephaly, alopecia, dysmorphic features, and neuroimaging abnormalities.. Am J Med Genet A. 2018;176:2554-60", "GL Saulnier Sholler, EW Gerner, G Bergendahl, RB MacArthur, A VanderWerff, T Ashikaga, JP Bond, W Ferguson, W Roberts, RK Wada, D Eslin, JM Kraveka, J Kaplan, D Mitchell, NS Parikh, K Neville, L Sender, T Higgins, M Kawakita, K Hiramatsu, SS Moriya, AS Bachmann. A Phase I trial of DFMO targeting polyamine addiction in patients with relapsed/refractory neuroblastoma.. PLoS One. 2015;10", "CR Schultz, CP Bupp, S Rajasekaran, AS Bachmann. Biochemical features of primary cells from a pediatric patient with a gain-of-function ODC1 genetic mutation.. Biochem J. 2019;476:2047-57", "AP Soler, G Gilliard, LC Megosh, TG O'Brien. Modulation of murine hair follicle function by alterations in ornithine decarboxylase activity.. J Invest Dermatol. 1996;106:1108-13", "EA VanSickle, J Michael, AS Bachmann, S Rajasekaran, JW Prokop, R Kuzniecky, FC Hofstede, K Steindl, A Rauch, MH Lipson, CP Bupp. Expanding the phenotype: Four new cases and hope for treatment in Bachmann-Bupp syndrome.. Am J Med Genet A. 2021;185:3485-93" ]	25/8/2022			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bap1-tpds	bap1-tpds	[ "BAP1 Cancer Syndrome", "Cutaneous/Ocular Melanoma, Atypical Melanocytic Proliferations, and Other Internal Neoplasms (COMMON Syndrome)", "BAP1 Cancer Syndrome", "Cutaneous/Ocular Melanoma, Atypical Melanocytic Proliferations, and Other Internal Neoplasms (COMMON Syndrome)", "Ubiquitin carboxyl-terminal hydrolase BAP1", "BAP1", "BAP1 Tumor Predisposition Syndrome" ]		Robert Pilarski, Lindsey Byrne, Maria I Carlo, Helen Hanson, Colleen Cebulla, Mohamed Abdel-Rahman	Summary The diagnosis of	## Diagnosis No diagnostic criteria have been published for Two or more confirmed One * Excluding two basal cell cancers and/or cutaneous melanomas, given their high frequency in the general population Confirmed Uveal (eye) melanoma (UM) Malignant mesothelioma (MMe) Cutaneous melanoma (CM) Renal cell carcinoma (RCC) Basal cell carcinoma (BCC), meningioma, and cholangiocarcinoma, which appear to be less common manifestations of Unconfirmed tumors include the following (in alphabetic order): Breast cancer Colon polyps and colon cancer Hepatocellular carcinoma Neuroendocrine tumors Non-small cell lung adenocarcinoma Onychopapilloma Ovarian sex cord-stromal tumors Thyroid cancer Urinary bladder 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 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. • Two or more confirmed • One • Uveal (eye) melanoma (UM) • Malignant mesothelioma (MMe) • Cutaneous melanoma (CM) • Renal cell carcinoma (RCC) • Basal cell carcinoma (BCC), meningioma, and cholangiocarcinoma, which appear to be less common manifestations of • Breast cancer • Colon polyps and colon cancer • Hepatocellular carcinoma • Neuroendocrine tumors • Non-small cell lung adenocarcinoma • Onychopapilloma • Ovarian sex cord-stromal tumors • Thyroid cancer • Urinary bladder cancer • For an introduction to multigene panels click ## Suggestive Findings Two or more confirmed One * Excluding two basal cell cancers and/or cutaneous melanomas, given their high frequency in the general population Confirmed Uveal (eye) melanoma (UM) Malignant mesothelioma (MMe) Cutaneous melanoma (CM) Renal cell carcinoma (RCC) Basal cell carcinoma (BCC), meningioma, and cholangiocarcinoma, which appear to be less common manifestations of Unconfirmed tumors include the following (in alphabetic order): Breast cancer Colon polyps and colon cancer Hepatocellular carcinoma Neuroendocrine tumors Non-small cell lung adenocarcinoma Onychopapilloma Ovarian sex cord-stromal tumors Thyroid cancer Urinary bladder cancer • Two or more confirmed • One • Uveal (eye) melanoma (UM) • Malignant mesothelioma (MMe) • Cutaneous melanoma (CM) • Renal cell carcinoma (RCC) • Basal cell carcinoma (BCC), meningioma, and cholangiocarcinoma, which appear to be less common manifestations of • Breast cancer • Colon polyps and colon cancer • Hepatocellular carcinoma • Neuroendocrine tumors • Non-small cell lung adenocarcinoma • Onychopapilloma • Ovarian sex cord-stromal tumors • Thyroid cancer • Urinary bladder 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 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 In contrast to survival in persons with Growing evidence suggests that Note: Nail abnormalities are also reported. A single-center prospective cohort study of 47 individuals with Breast cancer [ Colon polyps and colon cancers Neuroendocrine tumors [ Non-small cell lung adenocarcinoma [ Thyroid cancer [ Urinary bladder carcinoma. One individual was reported with a Some The penetrance of Atypical Spitz tumors Nevoid melanoma-like melanocytic proliferations (NEMMP) [ Melanocytic BAPoma The prevalence of The prevalence of • Breast cancer [ • Colon polyps and colon cancers • Neuroendocrine tumors [ • Non-small cell lung adenocarcinoma [ • Thyroid cancer [ • Urinary bladder carcinoma. One individual was reported with a • Atypical Spitz tumors • Nevoid melanoma-like melanocytic proliferations (NEMMP) [ • Melanocytic • BAPoma ## Clinical Description In contrast to survival in persons with Growing evidence suggests that Note: Nail abnormalities are also reported. A single-center prospective cohort study of 47 individuals with Breast cancer [ Colon polyps and colon cancers Neuroendocrine tumors [ Non-small cell lung adenocarcinoma [ Thyroid cancer [ Urinary bladder carcinoma. One individual was reported with a • Breast cancer [ • Colon polyps and colon cancers • Neuroendocrine tumors [ • Non-small cell lung adenocarcinoma [ • Thyroid cancer [ • Urinary bladder carcinoma. One individual was reported with a ## Tumors with Definitive Evidence of Association with In contrast to survival in persons with Growing evidence suggests that ## Tumors with Moderate Evidence of Association with Note: Nail abnormalities are also reported. A single-center prospective cohort study of 47 individuals with ## Tumors with Limited Evidence of Association with Breast cancer [ Colon polyps and colon cancers Neuroendocrine tumors [ Non-small cell lung adenocarcinoma [ Thyroid cancer [ Urinary bladder carcinoma. One individual was reported with a • Breast cancer [ • Colon polyps and colon cancers • Neuroendocrine tumors [ • Non-small cell lung adenocarcinoma [ • Thyroid cancer [ • Urinary bladder carcinoma. One individual was reported with a ## Genotype-Phenotype Correlations Some ## Penetrance The penetrance of ## Nomenclature Atypical Spitz tumors Nevoid melanoma-like melanocytic proliferations (NEMMP) [ Melanocytic BAPoma • Atypical Spitz tumors • Nevoid melanoma-like melanocytic proliferations (NEMMP) [ • Melanocytic • BAPoma ## Prevalence The prevalence of The prevalence of ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Germline pathogenic variants in genes other than Genes to Consider in the Differential Diagnosis Renal tumors: hybrid oncocytic, chromophobe, oncocytoma, papillary, & clear cell RCC Cutaneous: fibrofolliculomas Pulmonary: lung cysts, spontaneous pneumothoraces CM = cutaneous melanoma; MMe = malignant mesothelioma; RCC = renal cell carcinoma; UM = uveal melanoma Monogenic disorders included in this table are inherited in an autosomal dominant manner. • Renal tumors: hybrid oncocytic, chromophobe, oncocytoma, papillary, & clear cell RCC • Cutaneous: fibrofolliculomas • Pulmonary: lung cysts, spontaneous pneumothoraces ## Management Clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with Full-body skin exam incl nails by dermatologist specializing in melanoma w/eval for subungual tumors Consider total body photography in those w/large number of lesions. Dilated eye exam & baseline dilated fundus imaging Referral to ophthalmologist specializing in mgmt of UM (ocular oncologist) for any suspected lesion Abdominal & respiratory clinical exam w/further investigation for any clinical manifestations of MMe Abdominal MRI combined w/RCC screening Beginning at age 30 yrs Abdominal MRI combined w/RCC eval beginning at age 30 yrs Consider chest & pelvic MRI as part of clinical trial. Beginning at age 30 yrs Combined w/MMe eval where undertaken Medical geneticist, certified genetic counselor, or 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 Excision of lesions suggestive of BIMT is debated. Excision & treatment of other suspicious melanocytic lesions, CM, & BCC per established clinical guidelines Excision biopsy of BIMT is suggested but not universally recommended for asymptomatic, stable lesions. Excision should be reserved for clinically suspicious lesions (growing/changing) or when there is diagnostic uncertainty. MMe w/germline Sunglasses with high UVA and UVB protection can reduce risk of cancer on the eyelids, but data regarding the benefit of sunglasses for UM are lacking. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, international consensus recommendations for surveillance have not been established; however, several groups have proposed variations of the recommendations summarized in Full-body skin exam by dermatologist specializing in melanoma Biopsy of BIMT is not recommended unless lesions grow or change in shape or color. Clinical eval for manifestations of pleurisy (pleural inflammation), peritonitis, ascites, &/or pleural effusion: chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, upper body & face edema, abdominal pain, nausea, vomiting, &/or constipation Note: (1) Avoid routine surveillance w/chest radiograph or CT. (2) No consensus on screening modalities exists. Clinical eval for manifestations of RCC (e.g., flank pain, hematuria) Abdominal ultrasound/MRI w/diffusion-weighted sequences Clinical exam annually beginning at age 30 yrs Ultrasound (every 2 yrs) alternating w/MRI (every 2 yrs) so that imaging is done annually beginning at age 30 yrs BIMT = Some physicians recommend spiral chest CT for asymptomatic persons with a history of asbestos exposure; others do not, given the possible increased risk of cancer from radiation. exposure. Avoid the following: Arc welding Asbestos (including naturally occurring tremolite and erionite) Smoking Unnecessary and prolonged sun exposure Routine chest radiographs and CT examinations It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the Predictive genetic testing for a known familial pathogenic variant in Note: If at-risk first-degree relatives are not able to (or choose not to) undergo molecular genetic testing for a known familial See Currently no open treatment trials specifically target individuals with One National Cancer Institute (NCI)-sponsored trial ( Another NCI Phase II study is currently investigating the rate of stabilization or disease improvement from investigational decitabine/cedazuridine (INQOVI) treatment in individuals with One study undertook saturation genome editing (SGE) of Search • Full-body skin exam incl nails by dermatologist specializing in melanoma w/eval for subungual tumors • Consider total body photography in those w/large number of lesions. • Dilated eye exam & baseline dilated fundus imaging • Referral to ophthalmologist specializing in mgmt of UM (ocular oncologist) for any suspected lesion • Abdominal & respiratory clinical exam w/further investigation for any clinical manifestations of MMe • Abdominal MRI combined w/RCC screening • Beginning at age 30 yrs • Abdominal MRI combined w/RCC eval beginning at age 30 yrs • Consider chest & pelvic MRI as part of clinical trial. • Beginning at age 30 yrs • Combined w/MMe eval where undertaken • Excision of lesions suggestive of BIMT is debated. • Excision & treatment of other suspicious melanocytic lesions, CM, & BCC per established clinical guidelines • Excision biopsy of BIMT is suggested but not universally recommended for asymptomatic, stable lesions. • Excision should be reserved for clinically suspicious lesions (growing/changing) or when there is diagnostic uncertainty. • MMe w/germline • Full-body skin exam by dermatologist specializing in melanoma • Biopsy of BIMT is not recommended unless lesions grow or change in shape or color. • Clinical eval for manifestations of pleurisy (pleural inflammation), peritonitis, ascites, &/or pleural effusion: chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, upper body & face edema, abdominal pain, nausea, vomiting, &/or constipation • Note: (1) Avoid routine surveillance w/chest radiograph or CT. (2) No consensus on screening modalities exists. • Clinical eval for manifestations of RCC (e.g., flank pain, hematuria) • Abdominal ultrasound/MRI w/diffusion-weighted sequences • Clinical exam annually beginning at age 30 yrs • Ultrasound (every 2 yrs) alternating w/MRI (every 2 yrs) so that imaging is done annually beginning at age 30 yrs • Arc welding • Asbestos (including naturally occurring tremolite and erionite) • Smoking • Unnecessary and prolonged sun exposure • Routine chest radiographs and CT examinations ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Full-body skin exam incl nails by dermatologist specializing in melanoma w/eval for subungual tumors Consider total body photography in those w/large number of lesions. Dilated eye exam & baseline dilated fundus imaging Referral to ophthalmologist specializing in mgmt of UM (ocular oncologist) for any suspected lesion Abdominal & respiratory clinical exam w/further investigation for any clinical manifestations of MMe Abdominal MRI combined w/RCC screening Beginning at age 30 yrs Abdominal MRI combined w/RCC eval beginning at age 30 yrs Consider chest & pelvic MRI as part of clinical trial. Beginning at age 30 yrs Combined w/MMe eval where undertaken Medical geneticist, certified genetic counselor, or certified advanced genetic nurse • Full-body skin exam incl nails by dermatologist specializing in melanoma w/eval for subungual tumors • Consider total body photography in those w/large number of lesions. • Dilated eye exam & baseline dilated fundus imaging • Referral to ophthalmologist specializing in mgmt of UM (ocular oncologist) for any suspected lesion • Abdominal & respiratory clinical exam w/further investigation for any clinical manifestations of MMe • Abdominal MRI combined w/RCC screening • Beginning at age 30 yrs • Abdominal MRI combined w/RCC eval beginning at age 30 yrs • Consider chest & pelvic MRI as part of clinical trial. • Beginning at age 30 yrs • Combined w/MMe eval where undertaken ## 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 Excision of lesions suggestive of BIMT is debated. Excision & treatment of other suspicious melanocytic lesions, CM, & BCC per established clinical guidelines Excision biopsy of BIMT is suggested but not universally recommended for asymptomatic, stable lesions. Excision should be reserved for clinically suspicious lesions (growing/changing) or when there is diagnostic uncertainty. MMe w/germline • Excision of lesions suggestive of BIMT is debated. • Excision & treatment of other suspicious melanocytic lesions, CM, & BCC per established clinical guidelines • Excision biopsy of BIMT is suggested but not universally recommended for asymptomatic, stable lesions. • Excision should be reserved for clinically suspicious lesions (growing/changing) or when there is diagnostic uncertainty. • MMe w/germline ## Prevention of Primary Manifestations Sunglasses with high UVA and UVB protection can reduce risk of cancer on the eyelids, but data regarding the benefit of sunglasses for UM are lacking. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, international consensus recommendations for surveillance have not been established; however, several groups have proposed variations of the recommendations summarized in Full-body skin exam by dermatologist specializing in melanoma Biopsy of BIMT is not recommended unless lesions grow or change in shape or color. Clinical eval for manifestations of pleurisy (pleural inflammation), peritonitis, ascites, &/or pleural effusion: chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, upper body & face edema, abdominal pain, nausea, vomiting, &/or constipation Note: (1) Avoid routine surveillance w/chest radiograph or CT. (2) No consensus on screening modalities exists. Clinical eval for manifestations of RCC (e.g., flank pain, hematuria) Abdominal ultrasound/MRI w/diffusion-weighted sequences Clinical exam annually beginning at age 30 yrs Ultrasound (every 2 yrs) alternating w/MRI (every 2 yrs) so that imaging is done annually beginning at age 30 yrs BIMT = Some physicians recommend spiral chest CT for asymptomatic persons with a history of asbestos exposure; others do not, given the possible increased risk of cancer from radiation. exposure. • Full-body skin exam by dermatologist specializing in melanoma • Biopsy of BIMT is not recommended unless lesions grow or change in shape or color. • Clinical eval for manifestations of pleurisy (pleural inflammation), peritonitis, ascites, &/or pleural effusion: chest pain, cough, fever, shortness of breath, dysphagia, hoarseness, weight loss, upper body & face edema, abdominal pain, nausea, vomiting, &/or constipation • Note: (1) Avoid routine surveillance w/chest radiograph or CT. (2) No consensus on screening modalities exists. • Clinical eval for manifestations of RCC (e.g., flank pain, hematuria) • Abdominal ultrasound/MRI w/diffusion-weighted sequences • Clinical exam annually beginning at age 30 yrs • Ultrasound (every 2 yrs) alternating w/MRI (every 2 yrs) so that imaging is done annually beginning at age 30 yrs ## Agents/Circumstances to Avoid Avoid the following: Arc welding Asbestos (including naturally occurring tremolite and erionite) Smoking Unnecessary and prolonged sun exposure Routine chest radiographs and CT examinations • Arc welding • Asbestos (including naturally occurring tremolite and erionite) • Smoking • Unnecessary and prolonged sun exposure • Routine chest radiographs and CT examinations ## Evaluation of Relatives at Risk It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual by molecular genetic testing for the Predictive genetic testing for a known familial pathogenic variant in Note: If at-risk first-degree relatives are not able to (or choose not to) undergo molecular genetic testing for a known familial See ## Therapies Under Investigation Currently no open treatment trials specifically target individuals with One National Cancer Institute (NCI)-sponsored trial ( Another NCI Phase II study is currently investigating the rate of stabilization or disease improvement from investigational decitabine/cedazuridine (INQOVI) treatment in individuals with One study undertook saturation genome editing (SGE) of Search ## Genetic Counseling To date, 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 evaluate their genetic status, inform recurrence risk assessment, and determine their need for If the germline The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. The family history of some individuals diagnosed with If a parent of the proband has the germline An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see The types of 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 a germline 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, 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 evaluate their genetic status, inform recurrence risk assessment, and determine their need for • If the germline • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The family history of some individuals diagnosed with • 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 the germline • An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see • The types of • An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see • The types of • If the • If the parents have not been tested for the • An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see • The types 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 To date, 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 evaluate their genetic status, inform recurrence risk assessment, and determine their need for If the germline The proband has a The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. The family history of some individuals diagnosed with If a parent of the proband has the germline An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see The types of If the If the parents have not been tested for the • To date, 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 evaluate their genetic status, inform recurrence risk assessment, and determine their need for • If the germline • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • The family history of some individuals diagnosed with • 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 the germline • An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see • The types of • An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see • The types of • If the • If the parents have not been tested for the • An accurate estimate of penetrance in heterozygous individuals cannot be determined at this time (see • The types 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 a germline 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 BAP1 Tumor Predisposition Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for BAP1 Tumor Predisposition Syndrome ( Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis Variants listed in the table have been provided by the authors. ## Chapter Notes Authors' The research of Dr Abdel-Rahman and Dr Cebulla is focused on identifying and characterizing hereditary causes of uveal melanoma. They were one of three groups coreporting on the identification of Dr Carlo's research is on the genetics of renal cancer. Dr Hanson is the lead author of the manuscript on the European guidelines for management of Mohamed Abdel-Rahman, MD, PhD (2016-present)Lindsey Byrne, MS, CGC (2024-present)Maria I Carlo, MD (2020-present)Colleen Cebulla, MD, PhD (2016-present)Helen Hanson, MD (2024-present)Robert Pilarski, MS, LGC, MSW (2016-present)Karan Rai, BS; The Ohio State University (2016-2020) 5 December 2024 (sw) Comprehensive update posted live 17 September 2020 (sw) Comprehensive update posted live 13 October 2016 (bp) Review posted live 3 May 2016 (rp) Original submission • 5 December 2024 (sw) Comprehensive update posted live • 17 September 2020 (sw) Comprehensive update posted live • 13 October 2016 (bp) Review posted live • 3 May 2016 (rp) Original submission ## Author Notes Authors' The research of Dr Abdel-Rahman and Dr Cebulla is focused on identifying and characterizing hereditary causes of uveal melanoma. They were one of three groups coreporting on the identification of Dr Carlo's research is on the genetics of renal cancer. Dr Hanson is the lead author of the manuscript on the European guidelines for management of ## Author History Mohamed Abdel-Rahman, MD, PhD (2016-present)Lindsey Byrne, MS, CGC (2024-present)Maria I Carlo, MD (2020-present)Colleen Cebulla, MD, PhD (2016-present)Helen Hanson, MD (2024-present)Robert Pilarski, MS, LGC, MSW (2016-present)Karan Rai, BS; The Ohio State University (2016-2020) ## Revision History 5 December 2024 (sw) Comprehensive update posted live 17 September 2020 (sw) Comprehensive update posted live 13 October 2016 (bp) Review posted live 3 May 2016 (rp) Original submission • 5 December 2024 (sw) Comprehensive update posted live • 17 September 2020 (sw) Comprehensive update posted live • 13 October 2016 (bp) Review posted live • 3 May 2016 (rp) Original submission ## References ## Literature Cited	[]	13/10/2016	5/12/2024	24/3/2022	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
baraitser-winter	baraitser-winter	[ "Actin, cytoplasmic 1", "Actin, cytoplasmic 2", "ACTB", "ACTG1", "Baraitser-Winter Cerebrofrontofacial Syndrome" ]	Baraitser-Winter Cerebrofrontofacial Syndrome	Alain Verloes, Séverine Drunat, Daniela Pilz, Nataliya Di Donato	Summary Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations. Seizures, congenital heart defects, renal malformations, and gastrointestinal dysfunction are also common. The diagnosis of BWCFF syndrome is established in a proband with suggestive findings and a heterozygous missense pathogenic variant in either BWCFF syndrome is an autosomal dominant disorder. Most individuals with BWCFF syndrome reported to date have the disorder as the result of a	## Diagnosis No consensus clinical diagnostic criteria for Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome have been published. BWCFF syndrome Typical craniofacial features (widely spaced eyes, bulbous nose with broad nasal tip and prominent nasal bridge, congenital nonmyopathic ptosis, prominent metopic ridge, and highly arched eyebrows) Developmental delay / intellectual disability Variably present findings: Ocular coloboma Wasting of the muscles of the shoulder girdle Sensorineural hearing loss The diagnosis of BWCFF syndrome 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 variant of uncertain significance does not establish or rule out the diagnosis of this disorder. 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 Baraitser-Winter Cerebrofrontofacial Syndrome BWCFF = Baraitser-Winter cerebrofrontofacial; NA = not applicable 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 Human Gene Mutation Database [ Deletions and duplications of either All pathogenic variants reported to date are gain-of-function missense variants in Estimate based on authors' experience • Typical craniofacial features (widely spaced eyes, bulbous nose with broad nasal tip and prominent nasal bridge, congenital nonmyopathic ptosis, prominent metopic ridge, and highly arched eyebrows) • Developmental delay / intellectual disability • Ocular coloboma • Wasting of the muscles of the shoulder girdle • Sensorineural hearing loss ## Suggestive Findings BWCFF syndrome Typical craniofacial features (widely spaced eyes, bulbous nose with broad nasal tip and prominent nasal bridge, congenital nonmyopathic ptosis, prominent metopic ridge, and highly arched eyebrows) Developmental delay / intellectual disability Variably present findings: Ocular coloboma Wasting of the muscles of the shoulder girdle Sensorineural hearing loss • Typical craniofacial features (widely spaced eyes, bulbous nose with broad nasal tip and prominent nasal bridge, congenital nonmyopathic ptosis, prominent metopic ridge, and highly arched eyebrows) • Developmental delay / intellectual disability • Ocular coloboma • Wasting of the muscles of the shoulder girdle • Sensorineural hearing loss ## Establishing the Diagnosis The diagnosis of BWCFF syndrome 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 variant of uncertain significance does not establish or rule out the diagnosis of this disorder. 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 Baraitser-Winter Cerebrofrontofacial Syndrome BWCFF = Baraitser-Winter cerebrofrontofacial; NA = not applicable 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 Human Gene Mutation Database [ Deletions and duplications of either All pathogenic variants reported to date are gain-of-function missense variants in Estimate based on authors' experience ## Option 1 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Baraitser-Winter Cerebrofrontofacial Syndrome BWCFF = Baraitser-Winter cerebrofrontofacial; NA = not applicable 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 Human Gene Mutation Database [ Deletions and duplications of either All pathogenic variants reported to date are gain-of-function missense variants in Estimate based on authors' experience ## Clinical Characteristics Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations [ Significant variation in clinical features is observed, and some individuals whose diagnosis was made through identification of a pathogenic variant on gene panel or exome analyses (rather than on clinical suspicion) are expected to show milder or incomplete phenotypes ( Baraitser-Winter Cerebrofrontofacial Syndrome: Frequency of Select Features Prominent metopic ridging or trigonocephaly (65%) Widely spaced eyes (95%) Bilateral ptosis (90%) Highly arched eyebrows (90%) Ocular coloboma (30%); may be assoc w/microphthalmia (<10%) Small ears w/↑ posterior angulation, anteverted pinnae, overfolded, thick helix, & underdeveloped antihelix (73%) Wide, short, thick, & upturned nose, w/large, flat tip (85%) Long, smooth philtrum (84%) Wide mouth w/downturned corners & everted vermilion of lower lip (45%) Cleft lip & palate (10%) Mild-to-moderate developmental delay w/mild intellectual disability Delays profound if severe lissencephaly present Rare individuals w/normal intelligence Pachygyria (frontal or predominantly central) &/or subcortical band heterotopia (61%) Periventricular heterotopias (2%) Corpus callosum abnormality (20%) Typically assoc w/structural brain anomalies Age dependent Manifests from 1st mos of life to 24 yrs Peculiar stance, joint contractures, & pterygia observed in some persons Contractures & muscle wasting may progress w/time. Can be progressive May be assoc w/inner ear malformation Hydronephrosis (23%) Structural renal malformation (10%) Micropenis, cryptorchidism, & hypospadias (rare) Frequent chronic constipation (requiring daily medication) & reflux disease Occasional vomiting, diarrhea, feeding difficulties, failure to thrive Several persons required tube feeding & PEG. Rare anomalies incl intestinal malrotation, duodenal atresia, & bowel pseudo-obstruction PEG = percutaneous endoscopic gastrostomy Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus), lagophthalmos, and euryblepharon; appearance may resemble the ocular findings in Highly arched eyebrows in continuity of the lateral edges of the nose Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia Wide, short, thick, and upturned nose, with a large, flat tip, a thick columella, anteverted, thick nares, and a median grove (in the most severe cases) Prominent nasal bridge, flat in its middle part Long and smooth philtrum and thin vermilion border of the upper lip Wide mouth with downturned corners, everted vermilion of the lower lip Cleft lip and palate In children with normal brain structure, motor delay is common, but otherwise development is only mildly to moderately delayed. ID is usually mild. Rare individuals with normal intelligence have also been reported. Among those with a cortical malformation, development is always delayed. ID varied from profound in those with severe and diffuse lissencephaly to mild ID in some with anterior pachygyria or periventricular heterotopia. Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly [ Subcortical band and/or periventricular heterotopias; Short, thick, or absent corpus callosum [ Chiari malformation [ Epilepsy, of no specific type and of variable severity, is present in 50% of individuals, often in conjunction with structural cerebral anomalies. Variable muscular hypotonia, particularly of the upper body, is frequent and may result in progressive scoliosis beginning from age eight to 10 years. Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis, anteverted shoulders, and slightly flexed elbows and knees, which may be associated with limited joint movement. Axillary and popliteal pterygia may be present at birth. A few have congenital arthrogryposis multiplex congenita. Increasingly difficult ambulation is seen in some adults, which may indicate a slowly progressive myopathic process with slowly progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility and develop late-onset spinal deformity (kyphosis, scoliosis). Normal or low intrauterine growth; moderate short stature is observed in 50% of teenagers and adults. Head circumference is typically low normal at birth, although several individuals with severe prenatal microcephaly have been reported [ Constipation (either chronic or occasional) is the most frequently observed GI finding. Rarely, bowel pseudo-obstruction occurs. Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and small children. Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been reported in several children. Structural malformations include duodenal atresia and intestinal malrotation; one individual developed liver cirrhosis. Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects, abnormal aortic valve, aortic stenosis, mitral valve regurgitation, and tricuspid regurgitation have been identified. Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication, and hypospadias. Musculoskeletal features include broad thumbs and hallux (rarely, duplication of the hallux and/or thumbs). Cutaneous lymphoma was diagnosed at age 19 years in an individual with BWCFF syndrome and a germline Precursor B-cell acute lymphatic leukemia developed at age eight years in a child with BWCFF syndrome and a germline Acute myeloid leukemia, M5 subtype developed at age 21 years in an individual with BWCFF syndrome and a germline Although phenotypic expression of BWCFF syndrome is remarkably variable, even among unrelated individuals harboring an identical pathogenic variant, two pathogenic variants have been found in those with the most severe presentation of the BWCFF syndrome clinical spectrum, including microcephaly and pachygyria, profound intellectual disability, and epilepsy along with variable anomalies of other systems. These variants are The penetrance of BWCFF syndrome appears to be complete, but no single clinical manifestation is constant. Cerebrofrontofacial syndrome type 1 and type 3 and Fryns-Aftimos syndrome represent the severe end of the BWCFF syndrome spectrum. As the same pathogenic variant can lead to any of those three phenotypes, those entities are not considered allelic disorders, but rather part of the phenotypic spectrum of BWCFF syndrome. BWCFF syndrome is rare. Slightly fewer than 100 individuals with a molecularly confirmed diagnosis have been documented to date. However, considering the phenotypic variability, it may be underdiagnosed. • Prominent metopic ridging or trigonocephaly (65%) • Widely spaced eyes (95%) • Bilateral ptosis (90%) • Highly arched eyebrows (90%) • Ocular coloboma (30%); may be assoc w/microphthalmia (<10%) • Small ears w/↑ posterior angulation, anteverted pinnae, overfolded, thick helix, & underdeveloped antihelix (73%) • Wide, short, thick, & upturned nose, w/large, flat tip (85%) • Long, smooth philtrum (84%) • Wide mouth w/downturned corners & everted vermilion of lower lip (45%) • Cleft lip & palate (10%) • Mild-to-moderate developmental delay w/mild intellectual disability • Delays profound if severe lissencephaly present • Rare individuals w/normal intelligence • Pachygyria (frontal or predominantly central) &/or subcortical band heterotopia (61%) • Periventricular heterotopias (2%) • Corpus callosum abnormality (20%) • Typically assoc w/structural brain anomalies • Age dependent • Manifests from 1st mos of life to 24 yrs • Peculiar stance, joint contractures, & pterygia observed in some persons • Contractures & muscle wasting may progress w/time. • Can be progressive • May be assoc w/inner ear malformation • Hydronephrosis (23%) • Structural renal malformation (10%) • Micropenis, cryptorchidism, & hypospadias (rare) • Frequent chronic constipation (requiring daily medication) & reflux disease • Occasional vomiting, diarrhea, feeding difficulties, failure to thrive • Several persons required tube feeding & PEG. • Rare anomalies incl intestinal malrotation, duodenal atresia, & bowel pseudo-obstruction • Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus), lagophthalmos, and euryblepharon; appearance may resemble the ocular findings in • Highly arched eyebrows in continuity of the lateral edges of the nose • Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia • Wide, short, thick, and upturned nose, with a large, flat tip, a thick columella, anteverted, thick nares, and a median grove (in the most severe cases) • Prominent nasal bridge, flat in its middle part • Long and smooth philtrum and thin vermilion border of the upper lip • Wide mouth with downturned corners, everted vermilion of the lower lip • Cleft lip and palate • In children with normal brain structure, motor delay is common, but otherwise development is only mildly to moderately delayed. ID is usually mild. Rare individuals with normal intelligence have also been reported. • Among those with a cortical malformation, development is always delayed. ID varied from profound in those with severe and diffuse lissencephaly to mild ID in some with anterior pachygyria or periventricular heterotopia. • Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly [ • Subcortical band and/or periventricular heterotopias; • Short, thick, or absent corpus callosum [ • Chiari malformation [ • Epilepsy, of no specific type and of variable severity, is present in 50% of individuals, often in conjunction with structural cerebral anomalies. • Variable muscular hypotonia, particularly of the upper body, is frequent and may result in progressive scoliosis beginning from age eight to 10 years. • Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis, anteverted shoulders, and slightly flexed elbows and knees, which may be associated with limited joint movement. Axillary and popliteal pterygia may be present at birth. A few have congenital arthrogryposis multiplex congenita. • Increasingly difficult ambulation is seen in some adults, which may indicate a slowly progressive myopathic process with slowly progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility and develop late-onset spinal deformity (kyphosis, scoliosis). • Normal or low intrauterine growth; moderate short stature is observed in 50% of teenagers and adults. • Head circumference is typically low normal at birth, although several individuals with severe prenatal microcephaly have been reported [ • Constipation (either chronic or occasional) is the most frequently observed GI finding. Rarely, bowel pseudo-obstruction occurs. • Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and small children. • Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been reported in several children. • Structural malformations include duodenal atresia and intestinal malrotation; one individual developed liver cirrhosis. • Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects, abnormal aortic valve, aortic stenosis, mitral valve regurgitation, and tricuspid regurgitation have been identified. • Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication, and hypospadias. • Musculoskeletal features include broad thumbs and hallux (rarely, duplication of the hallux and/or thumbs). • Cutaneous lymphoma was diagnosed at age 19 years in an individual with BWCFF syndrome and a germline • Precursor B-cell acute lymphatic leukemia developed at age eight years in a child with BWCFF syndrome and a germline • Acute myeloid leukemia, M5 subtype developed at age 21 years in an individual with BWCFF syndrome and a germline ## Clinical Description Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is a multiple congenital anomaly syndrome characterized by typical craniofacial features and intellectual disability. Many (but not all) affected individuals have pachygyria that is predominantly frontal, wasting of the shoulder girdle muscles, and sensory impairment due to iris or retinal coloboma and/or sensorineural deafness. Intellectual disability, which is common but variable, is related to the severity of the brain malformations [ Significant variation in clinical features is observed, and some individuals whose diagnosis was made through identification of a pathogenic variant on gene panel or exome analyses (rather than on clinical suspicion) are expected to show milder or incomplete phenotypes ( Baraitser-Winter Cerebrofrontofacial Syndrome: Frequency of Select Features Prominent metopic ridging or trigonocephaly (65%) Widely spaced eyes (95%) Bilateral ptosis (90%) Highly arched eyebrows (90%) Ocular coloboma (30%); may be assoc w/microphthalmia (<10%) Small ears w/↑ posterior angulation, anteverted pinnae, overfolded, thick helix, & underdeveloped antihelix (73%) Wide, short, thick, & upturned nose, w/large, flat tip (85%) Long, smooth philtrum (84%) Wide mouth w/downturned corners & everted vermilion of lower lip (45%) Cleft lip & palate (10%) Mild-to-moderate developmental delay w/mild intellectual disability Delays profound if severe lissencephaly present Rare individuals w/normal intelligence Pachygyria (frontal or predominantly central) &/or subcortical band heterotopia (61%) Periventricular heterotopias (2%) Corpus callosum abnormality (20%) Typically assoc w/structural brain anomalies Age dependent Manifests from 1st mos of life to 24 yrs Peculiar stance, joint contractures, & pterygia observed in some persons Contractures & muscle wasting may progress w/time. Can be progressive May be assoc w/inner ear malformation Hydronephrosis (23%) Structural renal malformation (10%) Micropenis, cryptorchidism, & hypospadias (rare) Frequent chronic constipation (requiring daily medication) & reflux disease Occasional vomiting, diarrhea, feeding difficulties, failure to thrive Several persons required tube feeding & PEG. Rare anomalies incl intestinal malrotation, duodenal atresia, & bowel pseudo-obstruction PEG = percutaneous endoscopic gastrostomy Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus), lagophthalmos, and euryblepharon; appearance may resemble the ocular findings in Highly arched eyebrows in continuity of the lateral edges of the nose Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia Wide, short, thick, and upturned nose, with a large, flat tip, a thick columella, anteverted, thick nares, and a median grove (in the most severe cases) Prominent nasal bridge, flat in its middle part Long and smooth philtrum and thin vermilion border of the upper lip Wide mouth with downturned corners, everted vermilion of the lower lip Cleft lip and palate In children with normal brain structure, motor delay is common, but otherwise development is only mildly to moderately delayed. ID is usually mild. Rare individuals with normal intelligence have also been reported. Among those with a cortical malformation, development is always delayed. ID varied from profound in those with severe and diffuse lissencephaly to mild ID in some with anterior pachygyria or periventricular heterotopia. Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly [ Subcortical band and/or periventricular heterotopias; Short, thick, or absent corpus callosum [ Chiari malformation [ Epilepsy, of no specific type and of variable severity, is present in 50% of individuals, often in conjunction with structural cerebral anomalies. Variable muscular hypotonia, particularly of the upper body, is frequent and may result in progressive scoliosis beginning from age eight to 10 years. Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis, anteverted shoulders, and slightly flexed elbows and knees, which may be associated with limited joint movement. Axillary and popliteal pterygia may be present at birth. A few have congenital arthrogryposis multiplex congenita. Increasingly difficult ambulation is seen in some adults, which may indicate a slowly progressive myopathic process with slowly progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility and develop late-onset spinal deformity (kyphosis, scoliosis). Normal or low intrauterine growth; moderate short stature is observed in 50% of teenagers and adults. Head circumference is typically low normal at birth, although several individuals with severe prenatal microcephaly have been reported [ Constipation (either chronic or occasional) is the most frequently observed GI finding. Rarely, bowel pseudo-obstruction occurs. Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and small children. Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been reported in several children. Structural malformations include duodenal atresia and intestinal malrotation; one individual developed liver cirrhosis. Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects, abnormal aortic valve, aortic stenosis, mitral valve regurgitation, and tricuspid regurgitation have been identified. Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication, and hypospadias. Musculoskeletal features include broad thumbs and hallux (rarely, duplication of the hallux and/or thumbs). Cutaneous lymphoma was diagnosed at age 19 years in an individual with BWCFF syndrome and a germline Precursor B-cell acute lymphatic leukemia developed at age eight years in a child with BWCFF syndrome and a germline Acute myeloid leukemia, M5 subtype developed at age 21 years in an individual with BWCFF syndrome and a germline • Prominent metopic ridging or trigonocephaly (65%) • Widely spaced eyes (95%) • Bilateral ptosis (90%) • Highly arched eyebrows (90%) • Ocular coloboma (30%); may be assoc w/microphthalmia (<10%) • Small ears w/↑ posterior angulation, anteverted pinnae, overfolded, thick helix, & underdeveloped antihelix (73%) • Wide, short, thick, & upturned nose, w/large, flat tip (85%) • Long, smooth philtrum (84%) • Wide mouth w/downturned corners & everted vermilion of lower lip (45%) • Cleft lip & palate (10%) • Mild-to-moderate developmental delay w/mild intellectual disability • Delays profound if severe lissencephaly present • Rare individuals w/normal intelligence • Pachygyria (frontal or predominantly central) &/or subcortical band heterotopia (61%) • Periventricular heterotopias (2%) • Corpus callosum abnormality (20%) • Typically assoc w/structural brain anomalies • Age dependent • Manifests from 1st mos of life to 24 yrs • Peculiar stance, joint contractures, & pterygia observed in some persons • Contractures & muscle wasting may progress w/time. • Can be progressive • May be assoc w/inner ear malformation • Hydronephrosis (23%) • Structural renal malformation (10%) • Micropenis, cryptorchidism, & hypospadias (rare) • Frequent chronic constipation (requiring daily medication) & reflux disease • Occasional vomiting, diarrhea, feeding difficulties, failure to thrive • Several persons required tube feeding & PEG. • Rare anomalies incl intestinal malrotation, duodenal atresia, & bowel pseudo-obstruction • Long, often downslanted palpebral fissures (with or without epicanthal folds or epicanthus inversus), lagophthalmos, and euryblepharon; appearance may resemble the ocular findings in • Highly arched eyebrows in continuity of the lateral edges of the nose • Uni- or bilateral ocular coloboma that may extend from the iris to the macula, sometimes with microphthalmia • Wide, short, thick, and upturned nose, with a large, flat tip, a thick columella, anteverted, thick nares, and a median grove (in the most severe cases) • Prominent nasal bridge, flat in its middle part • Long and smooth philtrum and thin vermilion border of the upper lip • Wide mouth with downturned corners, everted vermilion of the lower lip • Cleft lip and palate • In children with normal brain structure, motor delay is common, but otherwise development is only mildly to moderately delayed. ID is usually mild. Rare individuals with normal intelligence have also been reported. • Among those with a cortical malformation, development is always delayed. ID varied from profound in those with severe and diffuse lissencephaly to mild ID in some with anterior pachygyria or periventricular heterotopia. • Frontal or predominantly central pachygyria; more rarely, severe lissencephaly or microlissencephaly [ • Subcortical band and/or periventricular heterotopias; • Short, thick, or absent corpus callosum [ • Chiari malformation [ • Epilepsy, of no specific type and of variable severity, is present in 50% of individuals, often in conjunction with structural cerebral anomalies. • Variable muscular hypotonia, particularly of the upper body, is frequent and may result in progressive scoliosis beginning from age eight to 10 years. • Many affected individuals, especially teenagers and adults, have a peculiar stance with kyphosis, anteverted shoulders, and slightly flexed elbows and knees, which may be associated with limited joint movement. Axillary and popliteal pterygia may be present at birth. A few have congenital arthrogryposis multiplex congenita. • Increasingly difficult ambulation is seen in some adults, which may indicate a slowly progressive myopathic process with slowly progressive, generalized muscle weakness. Some adults may become dependent on a wheelchair for mobility and develop late-onset spinal deformity (kyphosis, scoliosis). • Normal or low intrauterine growth; moderate short stature is observed in 50% of teenagers and adults. • Head circumference is typically low normal at birth, although several individuals with severe prenatal microcephaly have been reported [ • Constipation (either chronic or occasional) is the most frequently observed GI finding. Rarely, bowel pseudo-obstruction occurs. • Frequent vomiting and gastroesophageal reflux disease have been reported occasionally in newborns and small children. • Severe feeding difficulties requiring nasogastric tube feeding with subsequent feeding tube have been reported in several children. • Structural malformations include duodenal atresia and intestinal malrotation; one individual developed liver cirrhosis. • Cardiovascular malformations such as patent ductus arteriosus, ventricular or atrial septal defects, abnormal aortic valve, aortic stenosis, mitral valve regurgitation, and tricuspid regurgitation have been identified. • Genitourinary abnormalities can include hydronephrosis, horseshoe or ectopic kidneys, renal duplication, and hypospadias. • Musculoskeletal features include broad thumbs and hallux (rarely, duplication of the hallux and/or thumbs). • Cutaneous lymphoma was diagnosed at age 19 years in an individual with BWCFF syndrome and a germline • Precursor B-cell acute lymphatic leukemia developed at age eight years in a child with BWCFF syndrome and a germline • Acute myeloid leukemia, M5 subtype developed at age 21 years in an individual with BWCFF syndrome and a germline ## Genotype-Phenotype Correlations Although phenotypic expression of BWCFF syndrome is remarkably variable, even among unrelated individuals harboring an identical pathogenic variant, two pathogenic variants have been found in those with the most severe presentation of the BWCFF syndrome clinical spectrum, including microcephaly and pachygyria, profound intellectual disability, and epilepsy along with variable anomalies of other systems. These variants are ## Penetrance The penetrance of BWCFF syndrome appears to be complete, but no single clinical manifestation is constant. ## Nomenclature Cerebrofrontofacial syndrome type 1 and type 3 and Fryns-Aftimos syndrome represent the severe end of the BWCFF syndrome spectrum. As the same pathogenic variant can lead to any of those three phenotypes, those entities are not considered allelic disorders, but rather part of the phenotypic spectrum of BWCFF syndrome. ## Prevalence BWCFF syndrome is rare. Slightly fewer than 100 individuals with a molecularly confirmed diagnosis have been documented to date. However, considering the phenotypic variability, it may be underdiagnosed. ## Genetically Related (Allelic) Disorders Note: Variants in Allelic Disorders BWCFF = Baraitser-Winter cerebrofrontofacial; CHD = congenital heart defect; DD = developmental delay; ID = intellectual disability; LoF = loss of function ## Differential Diagnosis Disorders to consider in the differential diagnosis of Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome are summarized in Selected Disorders in the Differential Diagnosis of Baraitser-Winter Cerebrofrontofacial Syndrome AD = autosomal dominant; AR = autosomal recessive; BWCFF = Baraitser-Winter cerebrofrontofacial; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Genes are organized first by frequency of causation of Noonan syndrome and then alphabetically. Recent reports have implicated several additional genes associated with a Noonan syndrome-like phenotype in fewer than ten individuals each, including Noonan syndrome is most often inherited in an autosomal dominant manner. Noonan syndrome caused by pathogenic variants in ## Management No clinical practice guidelines for Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome have been published. To establish the extent of disease and needs in an individual diagnosed with BWCFF syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Baraitser-Winter Cerebrofrontofacial Syndrome To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl brain MRI Consider EEG if brain MRI anomaly &/or seizures present. Abdominal ultrasound &, if necessary, assess GI motility. Assess for feeding difficulties. Community or Social work involvement for parental support; Home nursing referral. BWCFF = Baraitser-Winter cerebrofrontofacial; MOI = mode of inheritance Note that individuals diagnosed via molecular genetic testing with a pathogenic Medical geneticist, certified genetic counselor, certified advanced genetic nurse No specific treatment for BWCFF syndrome exists. Management recommendations are detailed in Treatment of Manifestations in Individuals with Baraitser-Winter Cerebrofrontofacial Syndrome Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; GI = gastrointestinal; 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. Intensive and regular 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 Baraitser-Winter Cerebrofrontofacial Syndrome Note: The risk of malignancies is not established for BWCFF syndrome, and thus no regular surveillance is recommended. However, screening for hematologic malignancies must be considered in case of physical deterioration or unexplained chronic fever. See Search • To incl motor, adaptive, cognitive, & speech/language eval • Eval for early intervention / special education • To incl brain MRI • Consider EEG if brain MRI anomaly &/or seizures present. • Abdominal ultrasound &, if necessary, assess GI motility. • Assess for feeding difficulties. • Community or • Social work involvement for parental support; • Home nursing referral. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • Intensive and regular physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with BWCFF syndrome, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with Baraitser-Winter Cerebrofrontofacial Syndrome To incl motor, adaptive, cognitive, & speech/language eval Eval for early intervention / special education To incl brain MRI Consider EEG if brain MRI anomaly &/or seizures present. Abdominal ultrasound &, if necessary, assess GI motility. Assess for feeding difficulties. Community or Social work involvement for parental support; Home nursing referral. BWCFF = Baraitser-Winter cerebrofrontofacial; MOI = mode of inheritance Note that individuals diagnosed via molecular genetic testing with a pathogenic 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 brain MRI anomaly &/or seizures present. • Abdominal ultrasound &, if necessary, assess GI motility. • Assess for feeding difficulties. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations No specific treatment for BWCFF syndrome exists. Management recommendations are detailed in Treatment of Manifestations in Individuals with Baraitser-Winter Cerebrofrontofacial Syndrome Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers ASM = anti-seizure medication; GI = gastrointestinal; 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. Intensive and regular 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. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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. • Intensive and regular 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 Intensive and regular 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 • Intensive and regular 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 Baraitser-Winter Cerebrofrontofacial Syndrome Note: The risk of malignancies is not established for BWCFF syndrome, and thus no regular surveillance is recommended. However, screening for hematologic malignancies must be considered in case of physical deterioration or unexplained chronic fever. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is an autosomal dominant disorder. Most individuals with BWCFF syndrome reported to date have the disorder as the result of a In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic variant inherited from a parent with germline mosaicism [ 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 If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the proband has a known If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband 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 parents of affected individuals and to young adults who are affected. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals with BWCFF syndrome reported to date have the disorder as the result of a • In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic variant inherited from a parent with germline mosaicism [ • 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 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 has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the proband has a known • If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband 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 parents of affected individuals and to young adults who are affected. ## Mode of Inheritance Baraitser-Winter cerebrofrontofacial (BWCFF) syndrome is an autosomal dominant disorder. ## Risk to Family Members Most individuals with BWCFF syndrome reported to date have the disorder as the result of a In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic variant inherited from a parent with germline mosaicism [ 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 If a parent of the proband has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. If the proband has a known If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband is presumed to be low but greater than that of the general population because of the possibility of parental germline mosaicism. • Most individuals with BWCFF syndrome reported to date have the disorder as the result of a • In rare families, individuals diagnosed with BWCFF syndrome have the disorder as the result of a pathogenic variant inherited from a parent with germline mosaicism [ • 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 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 has the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. • If the proband has a known • If the parents have not been tested for the pathogenic variant identified in the proband but are clinically unaffected, the risk to the sibs of a proband 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 The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 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 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 Baraitser-Winter Cerebrofrontofacial Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Baraitser-Winter Cerebrofrontofacial Syndrome ( Baraitser-Winter Cerebrofrontofacial Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from Sporadic, isolated tumors (including hepatocellular carcinoma, melanoma, ovarian cancer, leukemia, and B-cell lymphoma) frequently harbor somatic pathogenic variants in A recent study using data available in the cBioPortal database have shown that somatic variants in ## Molecular Pathogenesis Baraitser-Winter Cerebrofrontofacial Syndrome: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from ## Cancer and Benign Tumors Sporadic, isolated tumors (including hepatocellular carcinoma, melanoma, ovarian cancer, leukemia, and B-cell lymphoma) frequently harbor somatic pathogenic variants in A recent study using data available in the cBioPortal database have shown that somatic variants in ## Chapter Notes 24 March 2022 (ha) Comprehensive update posted live 19 November 2015 (me) Review posted live 9 March 2015 (av) Original submission • 24 March 2022 (ha) Comprehensive update posted live • 19 November 2015 (me) Review posted live • 9 March 2015 (av) Original submission ## Revision History 24 March 2022 (ha) Comprehensive update posted live 19 November 2015 (me) Review posted live 9 March 2015 (av) Original submission • 24 March 2022 (ha) Comprehensive update posted live • 19 November 2015 (me) Review posted live • 9 March 2015 (av) Original submission ## References ## Literature Cited	[ "M Baumann, EM Beaver, M Palomares-Bralo, F Santos-Simarro, P Holzer, G Povysil, T Müller, T Valovka, AR Janecke. 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barth	barth	[ "Tafazzin", "TAFAZZIN", "Barth Syndrome" ]	Barth Syndrome	Carlos Ferreira, Germaine Pierre, Reid Thompson, Hilary Vernon	Abstract Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies. The diagnosis of Barth syndrome is established in a male proband with either an increased monolysocardiolipin:cardiolipin ratio (if available) or a hemizygous pathogenic variant in Barth syndrome is inherited in an X-linked manner. If a mother has a	## Diagnosis Formal clinical diagnostic criteria for Barth syndrome have not been established. Barth syndrome is an X-linked condition in which heterozygous females typically do not express clinical or biochemical features, although rare instances of affected females have been reported. Barth syndrome At least one of the following cardiac findings: Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness Skeletal myopathy or hypotonia Prepubertal growth delay Typical dysmorphic findings in infants and toddlers including round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes Lactic acidosis (normal: 0.5-2.2 mmol/L) Hypocholesterolemia (total cholesterol <110 mg/dL) Neutropenia (absolute neutrophil count <1,500 cells/µL) Elevated 3-methylglutaric acid, 3-methylglutaconic acid (3-MGC), and 2-ethylhydracrylic acid on 3-MGC is typically increased five- to 20-fold [ Note: Urinary 3-MGC levels can be normal on single sample testing [ Increased Increased monolysocardiolipins; Decreased cardiolipin (specifically tetralinoleylcardiolipin). Urine and Plasma Organic Acid Levels in Barth Syndrome Note: (1) Females with a heterozygous pathogenic variant in Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Barth syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Barth 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 cardiomyopathy and/or hypotonia, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Barth 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 Based on A synonymous variant in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • At least one of the following cardiac findings: • Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium • Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity • Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness • Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium • Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity • Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness • Skeletal myopathy or hypotonia • Prepubertal growth delay • Typical dysmorphic findings in infants and toddlers including round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes • Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium • Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity • Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness • Lactic acidosis (normal: 0.5-2.2 mmol/L) • Hypocholesterolemia (total cholesterol <110 mg/dL) • Neutropenia (absolute neutrophil count <1,500 cells/µL) • Elevated 3-methylglutaric acid, 3-methylglutaconic acid (3-MGC), and 2-ethylhydracrylic acid on • 3-MGC is typically increased five- to 20-fold [ • Note: Urinary 3-MGC levels can be normal on single sample testing [ • 3-MGC is typically increased five- to 20-fold [ • Note: Urinary 3-MGC levels can be normal on single sample testing [ • Increased • Increased monolysocardiolipins; • Decreased cardiolipin (specifically tetralinoleylcardiolipin). • Increased monolysocardiolipins; • Decreased cardiolipin (specifically tetralinoleylcardiolipin). • 3-MGC is typically increased five- to 20-fold [ • Note: Urinary 3-MGC levels can be normal on single sample testing [ • Increased monolysocardiolipins; • Decreased cardiolipin (specifically tetralinoleylcardiolipin). • For an introduction to multigene panels click ## Suggestive Findings Barth syndrome is an X-linked condition in which heterozygous females typically do not express clinical or biochemical features, although rare instances of affected females have been reported. Barth syndrome At least one of the following cardiac findings: Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness Skeletal myopathy or hypotonia Prepubertal growth delay Typical dysmorphic findings in infants and toddlers including round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes Lactic acidosis (normal: 0.5-2.2 mmol/L) Hypocholesterolemia (total cholesterol <110 mg/dL) Neutropenia (absolute neutrophil count <1,500 cells/µL) Elevated 3-methylglutaric acid, 3-methylglutaconic acid (3-MGC), and 2-ethylhydracrylic acid on 3-MGC is typically increased five- to 20-fold [ Note: Urinary 3-MGC levels can be normal on single sample testing [ Increased Increased monolysocardiolipins; Decreased cardiolipin (specifically tetralinoleylcardiolipin). Urine and Plasma Organic Acid Levels in Barth Syndrome • At least one of the following cardiac findings: • Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium • Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity • Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness • Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium • Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity • Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness • Skeletal myopathy or hypotonia • Prepubertal growth delay • Typical dysmorphic findings in infants and toddlers including round face, full cheeks, prominent pointed chin, large ears, and deep-set eyes • Dilated cardiomyopathy ± endocardial fibroelastosis. Ventricular chamber enlargement and contractile dysfunction in the setting of normal left ventricular wall thickness, with or without diffuse thickening of the ventricular endocardium • Left ventricular noncompaction. Noncompacted left ventricular myocardium with prominent trabeculations and deep intertrabecular recesses that communicate with the ventricular cavity • Hypertrophic cardiomyopathy (less common). Characterized by increased ventricular wall thickness • Lactic acidosis (normal: 0.5-2.2 mmol/L) • Hypocholesterolemia (total cholesterol <110 mg/dL) • Neutropenia (absolute neutrophil count <1,500 cells/µL) • Elevated 3-methylglutaric acid, 3-methylglutaconic acid (3-MGC), and 2-ethylhydracrylic acid on • 3-MGC is typically increased five- to 20-fold [ • Note: Urinary 3-MGC levels can be normal on single sample testing [ • 3-MGC is typically increased five- to 20-fold [ • Note: Urinary 3-MGC levels can be normal on single sample testing [ • Increased • Increased monolysocardiolipins; • Decreased cardiolipin (specifically tetralinoleylcardiolipin). • Increased monolysocardiolipins; • Decreased cardiolipin (specifically tetralinoleylcardiolipin). • 3-MGC is typically increased five- to 20-fold [ • Note: Urinary 3-MGC levels can be normal on single sample testing [ • Increased monolysocardiolipins; • Decreased cardiolipin (specifically tetralinoleylcardiolipin). ## Establishing the Diagnosis Note: (1) Females with a heterozygous pathogenic variant in Molecular genetic testing approaches can include a combination of Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Barth syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Barth 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 cardiomyopathy and/or hypotonia, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Barth 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 Based on A synonymous variant in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Barth 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 cardiomyopathy and/or hypotonia, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Barth 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 Based on A synonymous variant in Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. ## Clinical Characteristics To date, more than 200 individuals with Barth syndrome have been identified [ Select Features of Barth Syndrome 6MWT = distance walked on six-minute walk test The vast majority of affected individuals are male. At presentation Based on the study by Most affected individuals with Barth syndrome are male and present in infancy with cardiac issues, specifically dilated cardiomyopathy. In a French study of 22 males with Barth syndrome from 16 families, the median age at which medical care was first sought was 3.1 weeks (range: 0-1.4 years) [ In another study of 73 males enrolled in the Barth Syndrome Registry, the age of onset was 0.76±1.6 years and the mean age at diagnosis was 4.04±5.45 years [ The cardiomyopathy characteristically follows an undulating course in which the cardiac tissue can undergo remodeling, including a transition between hypertrophic and dilated appearances. Cardiomyopathy almost always presents before age five years [ In a study by In the study by The response to medical therapy for cardiac failure is generally good. All 20 affected males with EKGs in the French cohort had a normal sinus rhythm. Repolarization abnormalities (including ST flattening and T-wave inversion) were seen in 17. Five had QTc values within the normal range (QTc <420 ms), and five had QTc greater than 460 ms. The median QTc was 440 ms (range: 360-530 ms). In the study by In five instances of ventricular arrhythmia leading to cardiac arrest or placement of an internal defibrillator [ All five individuals had normal QTc intervals; All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability; Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest; Three showed inducible ventricular arrhythmias on electrophysiologic testing; Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no genotype-phenotype correlations predicted increased risk for arrhythmia; One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates; One had both ventricular and supraventricular tachycardia. In the study by In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [ These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [ In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [ * Defined as follows: Mild neutropenia: ANC between 1,000 and 1,500 cells/µL Moderate neutropenia: ANC between 500 and 1,000 cells/µL Severe neutropenia: ANC below 500 cells/µL In the original description of the syndrome by This relatively low incidence of bacterial infections despite an ANC persistently below 1,000 cells/µL could be due to the development of a chronic, substantial monocytosis [ In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL) In a report of 88 individuals with Barth syndrome [ Of note, hematologic parameters neither worsen nor improve with age [ In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives. In the French study the median age for walking was 19 months (range: 12-24 months). Some males with Barth syndrome were born with talipes equinovarus, indicating a possible prenatal onset of hypotonia [ Of note, the exercise intolerance seen in males with Barth syndrome is due to both cardiac impairment and decreased skeletal muscle oxygen utilization [ In a study of individuals with Barth syndrome, six-minute walk test (6MWT) distance was abnormal in 33/34 individuals compared to controls [ In males younger than age 18 years: Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile. Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%. In males older than age 18 years, mean weight was in the 13th percentile (range: <1-63) and mean height in the 50th percentile (range: 8-90). At this point and after the late pubertal period of "catch-up" growth the most striking feature is that of gynoid fat distribution [ In the Barth Syndrome Registry study, 30 of 60 males older than age three years reported delay either in first words or in putting words together; 31 of 67 participated in speech therapy. Twenty-two of 46 males older than age seven years reported some form of "learning disability." Delayed bone age (in 58%); Scoliosis (in 20%); Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals). In the Barth Syndrome Registry study, preterm birth from 29 to 36 weeks occurred in nine of 65 males; birth weight was below 2.5 kg in nine of 48 males. In the French study, median birth weight was 2.77 kg (range: 2.18-3.73 kg) and seven of 22 males had severe intrauterine growth restriction with birth weight below the third percentile. Males with an ANC 500 cells/µL. Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years. In the French study, the five-year survival rate was 51%, with no deaths reported in males age three years or older; thus, the risk for early mortality appears to peak in the first few years of life. Using a screening method in bloodspots, A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [ In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [ Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L). Plasma amino acids In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 affected individuals tested [ Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [ Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [ Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [ Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [ Liver. Lipid storage in the liver has also been described [ Bone marrow A maturation arrest at the myelocyte stage was noted in the original description of the disease [ More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ Heterozygous females typically do not manifest the disease. Biochemical abnormalities have not been found in eight heterozygous females [ It is proposed that heterozygous females are asymptomatic due to selection against cells with the mutated Two females with Barth syndrome have been reported: One had biallelic pathogenic variants in A second affected female with pathogenic In general, genotype-phenotype correlations have not been found [ As of 2020, an estimated 230-250 males have been identified with Barth syndrome worldwide [ • All five individuals had normal QTc intervals; • All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability; • Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest; • Three showed inducible ventricular arrhythmias on electrophysiologic testing; • Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no genotype-phenotype correlations predicted increased risk for arrhythmia; • One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates; • One had both ventricular and supraventricular tachycardia. • In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [ • These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [ • In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [ • Mild neutropenia: ANC between 1,000 and 1,500 cells/µL • Moderate neutropenia: ANC between 500 and 1,000 cells/µL • Severe neutropenia: ANC below 500 cells/µL • In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL) • In a report of 88 individuals with Barth syndrome [ • In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives. • In the French study the median age for walking was 19 months (range: 12-24 months). • Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile. • Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%. • Delayed bone age (in 58%); • Scoliosis (in 20%); • Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals). • Males with an ANC 500 cells/µL. • Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years. • A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [ • In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [ • Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L). • Plasma amino acids • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 affected individuals tested [ • Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [ • Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [ • Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [ • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [ • Liver. Lipid storage in the liver has also been described [ • Bone marrow • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • One had biallelic pathogenic variants in • A second affected female with pathogenic ## Clinical Description To date, more than 200 individuals with Barth syndrome have been identified [ Select Features of Barth Syndrome 6MWT = distance walked on six-minute walk test The vast majority of affected individuals are male. At presentation Based on the study by Most affected individuals with Barth syndrome are male and present in infancy with cardiac issues, specifically dilated cardiomyopathy. In a French study of 22 males with Barth syndrome from 16 families, the median age at which medical care was first sought was 3.1 weeks (range: 0-1.4 years) [ In another study of 73 males enrolled in the Barth Syndrome Registry, the age of onset was 0.76±1.6 years and the mean age at diagnosis was 4.04±5.45 years [ The cardiomyopathy characteristically follows an undulating course in which the cardiac tissue can undergo remodeling, including a transition between hypertrophic and dilated appearances. Cardiomyopathy almost always presents before age five years [ In a study by In the study by The response to medical therapy for cardiac failure is generally good. All 20 affected males with EKGs in the French cohort had a normal sinus rhythm. Repolarization abnormalities (including ST flattening and T-wave inversion) were seen in 17. Five had QTc values within the normal range (QTc <420 ms), and five had QTc greater than 460 ms. The median QTc was 440 ms (range: 360-530 ms). In the study by In five instances of ventricular arrhythmia leading to cardiac arrest or placement of an internal defibrillator [ All five individuals had normal QTc intervals; All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability; Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest; Three showed inducible ventricular arrhythmias on electrophysiologic testing; Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no genotype-phenotype correlations predicted increased risk for arrhythmia; One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates; One had both ventricular and supraventricular tachycardia. In the study by In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [ These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [ In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [ * Defined as follows: Mild neutropenia: ANC between 1,000 and 1,500 cells/µL Moderate neutropenia: ANC between 500 and 1,000 cells/µL Severe neutropenia: ANC below 500 cells/µL In the original description of the syndrome by This relatively low incidence of bacterial infections despite an ANC persistently below 1,000 cells/µL could be due to the development of a chronic, substantial monocytosis [ In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL) In a report of 88 individuals with Barth syndrome [ Of note, hematologic parameters neither worsen nor improve with age [ In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives. In the French study the median age for walking was 19 months (range: 12-24 months). Some males with Barth syndrome were born with talipes equinovarus, indicating a possible prenatal onset of hypotonia [ Of note, the exercise intolerance seen in males with Barth syndrome is due to both cardiac impairment and decreased skeletal muscle oxygen utilization [ In a study of individuals with Barth syndrome, six-minute walk test (6MWT) distance was abnormal in 33/34 individuals compared to controls [ In males younger than age 18 years: Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile. Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%. In males older than age 18 years, mean weight was in the 13th percentile (range: <1-63) and mean height in the 50th percentile (range: 8-90). At this point and after the late pubertal period of "catch-up" growth the most striking feature is that of gynoid fat distribution [ In the Barth Syndrome Registry study, 30 of 60 males older than age three years reported delay either in first words or in putting words together; 31 of 67 participated in speech therapy. Twenty-two of 46 males older than age seven years reported some form of "learning disability." Delayed bone age (in 58%); Scoliosis (in 20%); Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals). In the Barth Syndrome Registry study, preterm birth from 29 to 36 weeks occurred in nine of 65 males; birth weight was below 2.5 kg in nine of 48 males. In the French study, median birth weight was 2.77 kg (range: 2.18-3.73 kg) and seven of 22 males had severe intrauterine growth restriction with birth weight below the third percentile. Males with an ANC 500 cells/µL. Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years. In the French study, the five-year survival rate was 51%, with no deaths reported in males age three years or older; thus, the risk for early mortality appears to peak in the first few years of life. Using a screening method in bloodspots, A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [ In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [ Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L). Plasma amino acids In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 affected individuals tested [ Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [ Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [ Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [ Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [ Liver. Lipid storage in the liver has also been described [ Bone marrow A maturation arrest at the myelocyte stage was noted in the original description of the disease [ More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ Heterozygous females typically do not manifest the disease. Biochemical abnormalities have not been found in eight heterozygous females [ It is proposed that heterozygous females are asymptomatic due to selection against cells with the mutated Two females with Barth syndrome have been reported: One had biallelic pathogenic variants in A second affected female with pathogenic • All five individuals had normal QTc intervals; • All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability; • Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest; • Three showed inducible ventricular arrhythmias on electrophysiologic testing; • Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no genotype-phenotype correlations predicted increased risk for arrhythmia; • One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates; • One had both ventricular and supraventricular tachycardia. • In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [ • These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [ • In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [ • Mild neutropenia: ANC between 1,000 and 1,500 cells/µL • Moderate neutropenia: ANC between 500 and 1,000 cells/µL • Severe neutropenia: ANC below 500 cells/µL • In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL) • In a report of 88 individuals with Barth syndrome [ • In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives. • In the French study the median age for walking was 19 months (range: 12-24 months). • Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile. • Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%. • Delayed bone age (in 58%); • Scoliosis (in 20%); • Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals). • Males with an ANC 500 cells/µL. • Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years. • A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [ • In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [ • Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L). • Plasma amino acids • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 affected individuals tested [ • Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [ • Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [ • Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [ • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [ • Liver. Lipid storage in the liver has also been described [ • Bone marrow • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • One had biallelic pathogenic variants in • A second affected female with pathogenic ## Affected Males To date, more than 200 individuals with Barth syndrome have been identified [ Select Features of Barth Syndrome 6MWT = distance walked on six-minute walk test The vast majority of affected individuals are male. At presentation Based on the study by Most affected individuals with Barth syndrome are male and present in infancy with cardiac issues, specifically dilated cardiomyopathy. In a French study of 22 males with Barth syndrome from 16 families, the median age at which medical care was first sought was 3.1 weeks (range: 0-1.4 years) [ In another study of 73 males enrolled in the Barth Syndrome Registry, the age of onset was 0.76±1.6 years and the mean age at diagnosis was 4.04±5.45 years [ The cardiomyopathy characteristically follows an undulating course in which the cardiac tissue can undergo remodeling, including a transition between hypertrophic and dilated appearances. Cardiomyopathy almost always presents before age five years [ In a study by In the study by The response to medical therapy for cardiac failure is generally good. All 20 affected males with EKGs in the French cohort had a normal sinus rhythm. Repolarization abnormalities (including ST flattening and T-wave inversion) were seen in 17. Five had QTc values within the normal range (QTc <420 ms), and five had QTc greater than 460 ms. The median QTc was 440 ms (range: 360-530 ms). In the study by In five instances of ventricular arrhythmia leading to cardiac arrest or placement of an internal defibrillator [ All five individuals had normal QTc intervals; All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability; Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest; Three showed inducible ventricular arrhythmias on electrophysiologic testing; Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no genotype-phenotype correlations predicted increased risk for arrhythmia; One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates; One had both ventricular and supraventricular tachycardia. In the study by In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [ These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [ In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [ * Defined as follows: Mild neutropenia: ANC between 1,000 and 1,500 cells/µL Moderate neutropenia: ANC between 500 and 1,000 cells/µL Severe neutropenia: ANC below 500 cells/µL In the original description of the syndrome by This relatively low incidence of bacterial infections despite an ANC persistently below 1,000 cells/µL could be due to the development of a chronic, substantial monocytosis [ In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL) In a report of 88 individuals with Barth syndrome [ Of note, hematologic parameters neither worsen nor improve with age [ In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives. In the French study the median age for walking was 19 months (range: 12-24 months). Some males with Barth syndrome were born with talipes equinovarus, indicating a possible prenatal onset of hypotonia [ Of note, the exercise intolerance seen in males with Barth syndrome is due to both cardiac impairment and decreased skeletal muscle oxygen utilization [ In a study of individuals with Barth syndrome, six-minute walk test (6MWT) distance was abnormal in 33/34 individuals compared to controls [ In males younger than age 18 years: Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile. Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%. In males older than age 18 years, mean weight was in the 13th percentile (range: <1-63) and mean height in the 50th percentile (range: 8-90). At this point and after the late pubertal period of "catch-up" growth the most striking feature is that of gynoid fat distribution [ In the Barth Syndrome Registry study, 30 of 60 males older than age three years reported delay either in first words or in putting words together; 31 of 67 participated in speech therapy. Twenty-two of 46 males older than age seven years reported some form of "learning disability." Delayed bone age (in 58%); Scoliosis (in 20%); Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals). In the Barth Syndrome Registry study, preterm birth from 29 to 36 weeks occurred in nine of 65 males; birth weight was below 2.5 kg in nine of 48 males. In the French study, median birth weight was 2.77 kg (range: 2.18-3.73 kg) and seven of 22 males had severe intrauterine growth restriction with birth weight below the third percentile. Males with an ANC 500 cells/µL. Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years. In the French study, the five-year survival rate was 51%, with no deaths reported in males age three years or older; thus, the risk for early mortality appears to peak in the first few years of life. Using a screening method in bloodspots, A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [ In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [ Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L). Plasma amino acids In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 affected individuals tested [ Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [ Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [ Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [ Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [ Liver. Lipid storage in the liver has also been described [ Bone marrow A maturation arrest at the myelocyte stage was noted in the original description of the disease [ More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • All five individuals had normal QTc intervals; • All five had a history of recurrent vasovagal symptoms including postural dizziness, nausea, and pallor suggestive of autonomic instability; • Four had only mild LV dilatation and low normal to mildly depressed LV function; only one had poor but stable LV function prior to cardiac arrest; • Three showed inducible ventricular arrhythmias on electrophysiologic testing; • Two (and possibly 3) had a family history of sudden death in a brother suspected of having Barth syndrome; of note, no genotype-phenotype correlations predicted increased risk for arrhythmia; • One had a normal Holter monitor study; one had only repolarization abnormalities at higher heart rates; • One had both ventricular and supraventricular tachycardia. • In a study of 83 males with Barth syndrome, the median ANC was 1,100 cells/µL (range: 140-5,400 cells/µL) [ • These findings are similar to those of the French cohort, in which the median ANC was 1,300 cells/µL (range: 0-6,400 cells/µL) [ • In another report of 88 individuals with Barth syndrome, 84% had at least one ANC below 1,500 cells/µL [ • Mild neutropenia: ANC between 1,000 and 1,500 cells/µL • Moderate neutropenia: ANC between 500 and 1,000 cells/µL • Severe neutropenia: ANC below 500 cells/µL • In the French study the median absolute monocyte count (AMC) was 1,100 cells/µL (range: 500-4,300 cells/µL) • In a report of 88 individuals with Barth syndrome [ • In the Barth Syndrome Registry study it was observed that the myopathy led to developmental motor delay: 44 of 67 children showed a delay in sitting up, and 48 of 67 showed a delay in walking. Of note, 34% of affected males reported the use of foot and/or ankle orthoses, walkers, or wheelchairs at some point in their lives. • In the French study the median age for walking was 19 months (range: 12-24 months). • Mean weight is in the 15th percentile (range: <1-66), with 15 of 26 males below the fifth percentile. Mean height is in the eighth percentile (range: <1-38), with 15 of 26 males at or below the fifth percentile. • Body mass index is below the fifth percentile in 44% of males, normal in 48%, and above the 95th percentile in 7%. • Delayed bone age (in 58%); • Scoliosis (in 20%); • Supplemental feeds via either gastrostomy tube or nasogastric tube (in 23 of 70 individuals). • Males with an ANC 500 cells/µL. • Males born before 2000 had a five-year survival rate of 22% compared to 70% in those born in or after 2000. This finding is likely related to the better management of heart failure in more recent years. • A confirmatory method in cultured fibroblasts, lymphocytes, and skeletal muscle has also been validated [ • In the French study, all 16 affected males had an elevated MLCL:CL ratio: in fibroblasts (14 individuals); in lymphoblasts (1 individual); and in platelets (1 individual) [ • Lactic acidosis. Blood lactate ranges from normal to well above normal related to both cardiac and metabolic status (normal: 0.5-2.2 mmol/L). • Plasma amino acids • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • Hypocholesterolemia (total cholesterol <110 mg/dL). Described in six of 25 affected individuals tested [ • Hypoglycemia. Although not a common finding, hypoglycemia has been described occasionally [ • Creatine kinase. Mild elevations ranging from 192 to 397 mg/dL have been reported in three of 20 males tested [ • Prealbumin. Low prealbumin (<20 mg/dL) has been described in 15 of 19 males tested [ • In a French study in which plasma amino acid levels were available for eight affected males, all showed lower arginine levels than controls [ • This finding was reproduced in 28 males with Barth syndrome (mean arginine level: 43 μmol/L) vs controls (70 μmol/L) with a statistically significant p-value [ • Skeletal muscle. Accumulation of lipid droplets within type I muscle fibers and nonspecific mitochondrial abnormalities have been described [ • Liver. Lipid storage in the liver has also been described [ • Bone marrow • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ • A maturation arrest at the myelocyte stage was noted in the original description of the disease [ • More recently, in a French cohort in which five bone marrow smears were available, two showed promyelocyte-myelocyte maturation arrest, and the samples without a complete arrest showed an increased proportion of promyelocytes with a greatly decreased proportion of myelocytes, metamyelocytes, and neutrophils [ ## Female Heterozygotes Heterozygous females typically do not manifest the disease. Biochemical abnormalities have not been found in eight heterozygous females [ It is proposed that heterozygous females are asymptomatic due to selection against cells with the mutated Two females with Barth syndrome have been reported: One had biallelic pathogenic variants in A second affected female with pathogenic • One had biallelic pathogenic variants in • A second affected female with pathogenic ## Genotype-Phenotype Correlations In general, genotype-phenotype correlations have not been found [ ## Prevalence As of 2020, an estimated 230-250 males have been identified with Barth syndrome worldwide [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis A classification of inborn errors of metabolism with 3-methylglutaconic aciduria (3-MGCA) as the discriminative feature was published by Inborn Errors of Metabolism with 3-Methylglutaconic Aciduria as a Discriminative Feature Cataracts; cardiomyopathy DD Cataracts; central hypopnea; DD & ID; movement disorder; neutropenia Epilepsy DD & ID; deafness; movement disorder Epilepsy & optic atrophy Typically neonatal onset w/muscular hypotonia, hypertrophic cardiomyopathy, psychomotor disability, hyperammonemia, & lactic acidosis Children surviving neonatal period later show DD; phenotypic spectrum is variable. 3-MGCA = 3-methylglutaconic aciduria; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked Adapted from Seen in some individuals Other genes in which pathogenic variants can lead to isolated cardiomyopathy with left ventricular noncompaction include: LVNC and skeletal myopathy can be seen in Kostmann syndrome (OMIM Mutation of Benign familial neutropenia is an autosomal dominant form of congenital neutropenia with milder neutropenia and less severe symptoms. • Cataracts; cardiomyopathy • DD • Cataracts; central hypopnea; DD & ID; movement disorder; neutropenia • Epilepsy • DD & ID; deafness; movement disorder • Epilepsy & optic atrophy • Typically neonatal onset w/muscular hypotonia, hypertrophic cardiomyopathy, psychomotor disability, hyperammonemia, & lactic acidosis • Children surviving neonatal period later show DD; phenotypic spectrum is variable. • Kostmann syndrome (OMIM • Mutation of • Benign familial neutropenia is an autosomal dominant form of congenital neutropenia with milder neutropenia and less severe symptoms. ## Management Consensus clinical management recommendations for Barth syndrome have not been published. To establish the extent of disease and needs in a male diagnosed with Barth syndrome, the evaluations summarized in Note: In the very rare event that a heterozygous female has signs and/or symptoms of Barth syndrome, evaluation and treatment should follow what is recommended for affected males. Recommended Evaluations Following Initial Diagnosis in a Male with Barth Syndrome To incl eval of weight gain & nutritional status Consider eval for gastric tube placement in those w/poor weight gain. To incl motor, adaptive, & cognitive assessments Eval for early intervention/special education based on age Community or Social work involvement for parental support. MOI = mode of inheritance Derived from Medical geneticist, certified genetic counselor, or certified advanced genetics nurse Treatment of Manifestations in Individuals with Barth Syndrome ACE inhibitors & beta blockers for typical outpatient mgmt IV inotropes incl milrinone for in-patient mgmt of acute decompensation Consider regular administration of G-CSF (i.e., not only during times of high risk, e.g., surgery or infection). Consider prophylactic antibiotics (see Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. To avoid muscle protein loss overnight Specific dosing by age & weight can be obtained from the Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ACE = angiotensin-converting enzyme; DD = developmental delay; EF = ejection fraction; G-CSF = granulocyte colony-stimulating factor; HF = heart failure; ID = intellectual disability; IV = intravenous; PT = physical therapy See Although no studies are available to evaluate the effectiveness of medical therapy in males with Barth syndrome, when medications are stopped a decline in heart function is often observed. However, this can sometimes be difficult to distinguish from the natural fluctuations of the clinical phenotype ( Therapy received by 22 individuals in the French cohort [ In 83 affected males, 42 of whom had been treated with G-CSF, the median dose was 2.78±0.78 μg/kg/dose (range: 0.45-12.8 μg/kg/dose) [ Although neutropenia appears to improve with G-CSF treatment, in the French cohort in which six affected males were actively treated with G-CSF, two developed a severe infection, including one episode of septic shock [ The following information represents typical management recommendations for individuals with developmental delay / learning 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. The excessive fatigue that boys with Barth syndrome experience and the characteristic cognitive phenotype (see A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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 strength. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary. Prevention of Secondary Complications in Males with Barth Syndrome 5 mg/kg daily for children 81-325 mg daily for adults Males w/Barth syndrome have lower-than-normal caloric requirements. Attempts to induce growth by overfeeding can lead to chronic diarrhea. GI = gastrointestinal; IV = intravenous; LVNC = left ventricular noncompaction In the French study of 22 affected males, four received antibiotic prophylaxis [ Recommended Surveillance for Males with Barth Syndrome Consideration of Barth syndrome-specific growth patterns [ Avoid the following: Prolonged fasting because of a predisposition to hypoglycemia The use of rectal thermometers in those with neutropenia The use of succinylcholine, as nondepolarizing neuromuscular blockers could have a prolonged effect [ The use of human growth hormone is usually discouraged, as the majority of affected males will attain normal stature by adulthood. Although the use of sevoflurane has been reported without adverse effects, the muscular involvement in Barth syndrome may increase the risk for It is appropriate to evaluate the older and younger brothers of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. If the If the If MLCL:CL ratio is not available, a combination of urine organic acid analysis, complete blood count with differential, and echocardiogram may be able to clarify the genetic status of at-risk male sibs. However, such testing cannot exclude a diagnosis of Barth syndrome. See Given that Barth syndrome has been variably associated with different prenatal complications including intrauterine growth restriction, oligohydramnios, intrauterine ventricular dysfunction, and hydrops fetalis [ Search • To incl eval of weight gain & nutritional status • Consider eval for gastric tube placement in those w/poor weight gain. • To incl motor, adaptive, & cognitive assessments • Eval for early intervention/special education based on age • Community or • Social work involvement for parental support. • ACE inhibitors & beta blockers for typical outpatient mgmt • IV inotropes incl milrinone for in-patient mgmt of acute decompensation • Consider regular administration of G-CSF (i.e., not only during times of high risk, e.g., surgery or infection). • Consider prophylactic antibiotics (see • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • To avoid muscle protein loss overnight • Specific dosing by age & weight can be obtained from the • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • The excessive fatigue that boys with Barth syndrome experience and the characteristic cognitive phenotype (see • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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. • 5 mg/kg daily for children • 81-325 mg daily for adults • Males w/Barth syndrome have lower-than-normal caloric requirements. • Attempts to induce growth by overfeeding can lead to chronic diarrhea. • Prolonged fasting because of a predisposition to hypoglycemia • The use of rectal thermometers in those with neutropenia • The use of succinylcholine, as nondepolarizing neuromuscular blockers could have a prolonged effect [ • If the • If the • If MLCL:CL ratio is not available, a combination of urine organic acid analysis, complete blood count with differential, and echocardiogram may be able to clarify the genetic status of at-risk male sibs. However, such testing cannot exclude a diagnosis of Barth syndrome. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in a male diagnosed with Barth syndrome, the evaluations summarized in Note: In the very rare event that a heterozygous female has signs and/or symptoms of Barth syndrome, evaluation and treatment should follow what is recommended for affected males. Recommended Evaluations Following Initial Diagnosis in a Male with Barth Syndrome To incl eval of weight gain & nutritional status Consider eval for gastric tube placement in those w/poor weight gain. To incl motor, adaptive, & cognitive assessments Eval for early intervention/special education based on age Community or Social work involvement for parental support. MOI = mode of inheritance Derived from Medical geneticist, certified genetic counselor, or certified advanced genetics nurse • To incl eval of weight gain & nutritional status • Consider eval for gastric tube placement in those w/poor weight gain. • To incl motor, adaptive, & cognitive assessments • Eval for early intervention/special education based on age • Community or • Social work involvement for parental support. ## Treatment of Manifestations Treatment of Manifestations in Individuals with Barth Syndrome ACE inhibitors & beta blockers for typical outpatient mgmt IV inotropes incl milrinone for in-patient mgmt of acute decompensation Consider regular administration of G-CSF (i.e., not only during times of high risk, e.g., surgery or infection). Consider prophylactic antibiotics (see Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. To avoid muscle protein loss overnight Specific dosing by age & weight can be obtained from the Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ACE = angiotensin-converting enzyme; DD = developmental delay; EF = ejection fraction; G-CSF = granulocyte colony-stimulating factor; HF = heart failure; ID = intellectual disability; IV = intravenous; PT = physical therapy See Although no studies are available to evaluate the effectiveness of medical therapy in males with Barth syndrome, when medications are stopped a decline in heart function is often observed. However, this can sometimes be difficult to distinguish from the natural fluctuations of the clinical phenotype ( Therapy received by 22 individuals in the French cohort [ In 83 affected males, 42 of whom had been treated with G-CSF, the median dose was 2.78±0.78 μg/kg/dose (range: 0.45-12.8 μg/kg/dose) [ Although neutropenia appears to improve with G-CSF treatment, in the French cohort in which six affected males were actively treated with G-CSF, two developed a severe infection, including one episode of septic shock [ The following information represents typical management recommendations for individuals with developmental delay / learning 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. The excessive fatigue that boys with Barth syndrome experience and the characteristic cognitive phenotype (see A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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 strength. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary. • ACE inhibitors & beta blockers for typical outpatient mgmt • IV inotropes incl milrinone for in-patient mgmt of acute decompensation • Consider regular administration of G-CSF (i.e., not only during times of high risk, e.g., surgery or infection). • Consider prophylactic antibiotics (see • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • To avoid muscle protein loss overnight • Specific dosing by age & weight can be obtained from the • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • The excessive fatigue that boys with Barth syndrome experience and the characteristic cognitive phenotype (see • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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. ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / learning 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. The excessive fatigue that boys with Barth syndrome experience and the characteristic cognitive phenotype (see A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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. • The excessive fatigue that boys with Barth syndrome experience and the characteristic cognitive phenotype (see • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated 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. ## Gross Motor Dysfunction Physical therapy is recommended to maximize strength. ## Social/Behavioral Concerns Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, when necessary. ## Prevention of Secondary Complications Prevention of Secondary Complications in Males with Barth Syndrome 5 mg/kg daily for children 81-325 mg daily for adults Males w/Barth syndrome have lower-than-normal caloric requirements. Attempts to induce growth by overfeeding can lead to chronic diarrhea. GI = gastrointestinal; IV = intravenous; LVNC = left ventricular noncompaction In the French study of 22 affected males, four received antibiotic prophylaxis [ • 5 mg/kg daily for children • 81-325 mg daily for adults • Males w/Barth syndrome have lower-than-normal caloric requirements. • Attempts to induce growth by overfeeding can lead to chronic diarrhea. ## Surveillance Recommended Surveillance for Males with Barth Syndrome Consideration of Barth syndrome-specific growth patterns [ ## Agents/Circumstances to Avoid Avoid the following: Prolonged fasting because of a predisposition to hypoglycemia The use of rectal thermometers in those with neutropenia The use of succinylcholine, as nondepolarizing neuromuscular blockers could have a prolonged effect [ The use of human growth hormone is usually discouraged, as the majority of affected males will attain normal stature by adulthood. Although the use of sevoflurane has been reported without adverse effects, the muscular involvement in Barth syndrome may increase the risk for • Prolonged fasting because of a predisposition to hypoglycemia • The use of rectal thermometers in those with neutropenia • The use of succinylcholine, as nondepolarizing neuromuscular blockers could have a prolonged effect [ ## Evaluation of Relatives at Risk It is appropriate to evaluate the older and younger brothers of a proband in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures. If the If the If MLCL:CL ratio is not available, a combination of urine organic acid analysis, complete blood count with differential, and echocardiogram may be able to clarify the genetic status of at-risk male sibs. However, such testing cannot exclude a diagnosis of Barth syndrome. See • If the • If the • If MLCL:CL ratio is not available, a combination of urine organic acid analysis, complete blood count with differential, and echocardiogram may be able to clarify the genetic status of at-risk male sibs. However, such testing cannot exclude a diagnosis of Barth syndrome. ## Pregnancy Management Given that Barth syndrome has been variably associated with different prenatal complications including intrauterine growth restriction, oligohydramnios, intrauterine ventricular dysfunction, and hydrops fetalis [ ## Therapies Under Investigation Search ## Other ## Genetic Counseling Barth syndrome is inherited in an X-linked manner. The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a 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 or the affected male may have a If the mother of the proband has a If a male proband represents a simplex case (i.e., a single occurrence in a family) and if the All of their daughters, who will be heterozygotes and will typically not be affected; None of their sons. Note: Molecular genetic testing may be able to identify the family member in whom a Identification of female heterozygotes requires either (1) prior identification of the Heterozygous females typically do not manifest the disease. In Barth syndrome, heterozygous females often demonstrate skewed X-chromosome inactivation due to preferential inactivation of the X chromosome with the 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 heterozygous, or are at risk of being heterozygous. Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The father of an affected male will not have the disorder nor will he be hemizygous for the • In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the • If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a • If the mother of the proband has a • If a male proband represents a simplex case (i.e., a single occurrence in a family) and if the • All of their daughters, who will be heterozygotes and will typically not be affected; • None of their sons. • 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 heterozygous, or are at risk of being heterozygous. ## Mode of Inheritance Barth syndrome is inherited in an X-linked manner. ## Risk to Family Members The father of an affected male will not have the disorder nor will he be hemizygous for the In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a 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 or the affected male may have a If the mother of the proband has a If a male proband represents a simplex case (i.e., a single occurrence in a family) and if the All of their daughters, who will be heterozygotes and will typically not be affected; 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. 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 or the affected male may have a • If the mother of the proband has a • If a male proband represents a simplex case (i.e., a single occurrence in a family) and if the • All of their daughters, who will be heterozygotes and will typically not be affected; • None of their sons. ## Heterozygote Detection Identification of female heterozygotes requires either (1) prior identification of the Heterozygous females typically do not manifest the disease. In Barth syndrome, heterozygous females often demonstrate skewed X-chromosome inactivation due to preferential inactivation of the X chromosome with the ## 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 heterozygous, or are at risk of being heterozygous. • The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are 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 PO Box 618 Larchmont NY 10538 • • PO Box 618 • Larchmont NY 10538 • • • • • ## Molecular Genetics Barth Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Barth Syndrome ( Almost 45% of the genomic sequence of Notable Variants listed in the table have been provided by the authors. Denotes silent (no change) in the amino acid ## Molecular Pathogenesis Almost 45% of the genomic sequence of Notable Variants listed in the table have been provided by the authors. Denotes silent (no change) in the amino acid ## Chapter Notes We would like to acknowledge the Barth Syndrome Foundation for their support. 9 July 2020 (ma) Comprehensive update posted live 9 October 2014 (me) Review posted live 7 April 2014 (cf) Original submission • 9 July 2020 (ma) Comprehensive update posted live • 9 October 2014 (me) Review posted live • 7 April 2014 (cf) Original submission ## Acknowledgments We would like to acknowledge the Barth Syndrome Foundation for their support. ## Revision History 9 July 2020 (ma) Comprehensive update posted live 9 October 2014 (me) Review posted live 7 April 2014 (cf) Original submission • 9 July 2020 (ma) Comprehensive update posted live • 9 October 2014 (me) Review posted live • 7 April 2014 (cf) Original submission ## References ## Literature Cited	[ "LC Adès, AK Gedeon, MJ Wilson, M Latham, MW Partington, JC Mulley, J Nelson, K Lui, DO Sillence. Barth syndrome: clinical features and confirmation of gene localisation to distal Xq28.. 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Neurology. 2010;75:1079-83", "CW Yancy, M Jessup, B Bozkurt, J Butler, DE Casey, MM Colvin, MH Drazner, GS Filippatos, GC Fonarow, MM Givertz, SM Hollenberg, J Lindenfeld, FA Masoudi, PE McBride, PN Peterson, LW Stevenson, C Westlake. 2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America.. J Card Fail. 2017;23:628-51", "TY Yen, W-L Hwu, Y-H Chien, MH Wu, MT Lin, LY Tsao, WS Hsieh, NC Lee. Acute metabolic decompensation and sudden death in Barth syndrome: report of a family and a literature review.. Eur J Pediatr. 2008;167:941-4" ]	9/10/2014	9/7/2020		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bbs	bbs	[ "Biedl-Bardet Syndrome", "ADP-ribosylation factor-like protein 6", "BBSome complex assembly protein BBS10", "BBSome complex member BBS1", "BBSome complex member BBS2", "BBSome complex member BBS4", "BBSome complex member BBS5", "BBSome complex member BBS7", "BBSome-interacting protein 1", "Centrosomal protein of 164 kDa", "Centrosomal protein of 290 kDa", "Chaperonin-containing T-complex member BBS12", "Cilia- and flagella-associated protein 418", "E3 ubiquitin-protein ligase TRIM32", "Intraflagellar transport protein 172 homolog", "Intraflagellar transport protein 27 homolog", "Intraflagellar transport protein 74 homolog", "Leucine zipper transcription factor-like protein 1", "Molecular chaperone MKKS", "Protein PTHB1", "S phase cyclin A-associated protein in the endoplasmic reticulum", "Serologically defined colon cancer antigen 8", "Sodium channel and clathrin linker 1", "Tectonic-like complex member MKS1", "Tetratricopeptide repeat protein 8", "WD repeat-containing and planar cell polarity effector protein fritz homolog", "ARL6", "BBIP1", "BBS1", "BBS10", "BBS12", "BBS2", "BBS4", "BBS5", "BBS7", "BBS9", "CEP164", "CEP290", "CFAP418", "IFT172", "IFT27", "IFT74", "LZTFL1", "MKKS", "MKS1", "SCAPER", "SCLT1", "SDCCAG8", "TRIM32", "TTC8", "WDPCP", "Bardet-Biedl Syndrome", "Overview" ]	Bardet-Biedl Syndrome Overview	RaeLynn Forsyth, Meral Gunay-Aygun	Summary The purpose of this overview is to: Describe the Review the genetic Provide an Review Inform	## Clinical Characteristics of Bardet-Biedl Syndrome Bardet-Biedl syndrome (BBS) is a multisystem non-motile ciliopathy primarily characterized by retinal cone-rod dystrophy, obesity and related complications, postaxial polydactyly, cognitive impairment, hypogonadotropic hypogonadism and/or genitourinary malformations, and renal malformations and/or renal parenchymal disease. Individuals with BBS can also have other eye abnormalities (strabismus, astigmatism, cataracts), subtle craniofacial dysmorphisms, hearing loss, anosmia, oral/dental abnormalities (crowding, hypodontia, high-arched palate), gastrointestinal and liver disease, brachydactyly/syndactyly, musculoskeletal abnormalities, dermatologic abnormalities, and neurodevelopmental abnormalities including mild hypertonia, ataxia/poor coordination/imbalance, developmental delay(s), seizures, speech abnormalities, and behavioral/psychiatric abnormalities ( The motile ciliary structure and function is essentially normal in BBS, but affected individuals have an increased prevalence of manifestations associated with motile ciliopathies, such as neonatal respiratory distress, asthma, otitis media, and thoraco-abdominal laterality defects [ BBS exhibits variable expressivity and both inter- and intrafamilial variation. The usefulness of these clinical criteria is limited by: The fact that many of these clinical features emerge throughout infancy, childhood, and young adulthood; therefore, the sensitivity of the proposed clinical diagnostic criteria is likely low, especially in young children. It is important that findings as they pertain to these clinical criteria be reviewed periodically in individuals in whom the diagnosis of BBS has been considered. Variability in clinical features, which is increasingly realized as the underlying genetic cause is identified in a larger proportion of individuals with BBS. A recent meta-analysis [ Features of Bardet-Biedl Syndrome Retinal dystrophy symptoms often bring persons to medical attn, typically in 1st decade of life. Other eye abnormalities (e.g., strabismus, cataracts) can also be present & are considered minor features of BBS. Birth weight typically normal Features assoc w/obesity (incl endocrine/metabolic abnormalities & NAFLD) also common & considered minor features of BBS DD (81%) Epilepsy (9.6%) Behavior/psychiatric abnormalities (35%) Ataxia/poor coordination may contribute to gross motor & fine motor delays. Speech abnormalities are common. Hirschsprung disease (2.8%) Inflammatory bowel disease (1.1%) Celiac disease (1.5%) Liver disease (30%) ALT = alanine transaminase; DD = developmental delay; IDF = International Diabetes Federation; NAFLD = Nonalcoholic fatty liver disease; T2DM = type 2 diabetes mellitus Unless otherwise noted, incidence is based on data in meta-analysis of genotype-phenotype associations of 899 individuals with BBS by In addition to those listed under comments of major features Unpublished data from the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) International Diabetes Federation (IDF) criteria for metabolic syndrome:Central obesity (defined by waist circumference values that are sex and ethnicity specific) PLUS two or more of the following: • Elevated triglyceride level (>150 mg/dL) • Reduced high-density lipoprotein level (<40 mg/dL in males and <50 mg/dL in females) • Hypertension (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg) • Elevated fasting plasma glucose OR a diagnosis of T2DM Electroretinography (ERG) is more likely to show significant findings after age five years. Individuals often become legally blind by the second to third decade of life. Retinal disease is the most penetrant feature in BBS, affecting up to 100% of individuals in some studies [ Males can have micropenis and/or small-volume testes. Cryptorchidism is present in 9% of males with BBS. On endocrinologic assessment in one study, 19.5% of males were hypogonadal [ Females can have anatomic anomalies including hypoplastic or duplex uterus, hypoplastic fallopian tubes and/or ovaries, septate vagina, partial or complete vaginal atresia, absent vaginal and/or urethral orifice, hydrocolpos or hydrometrocolpos, persistent urogenital sinus, and vesico-vaginal fistula [ Infertility is common, but both sexes are known to have been able to have biological children. Structural kidney disease includes developmental anomalies such as horseshoe, ectopic, duplex, or absent kidneys; or dysplastic cystic disease ranging from single unilateral to multiple bilateral cysts. Urologic complications including neurogenic bladder and bladder outflow obstruction have been reported in 5%-10% of adults [ Chronic kidney disease (CKD) is a major contributor of morbidity and mortality in individuals with BBS. In a recent study, CKD was present in 31% of children and 42% of adults; 6% of children and 8% of adults developed end-stage kidney disease requiring dialysis and/or transplantation [ In the majority of children with BBS with advanced (Stage 4-5) chronic kidney disease, the initial diagnosis of kidney disease was made within the first year of life and almost all were diagnosed by age five years [ Comorbidities including hypertension (present in about one third of individuals with BBS) and type 2 diabetes mellitus (T2DM) may affect progression of CKD. Favorable long-term outcomes of kidney transplantation have been reported [ Seizures and/or epilepsy (as defined by the International League Against Epilepsy) were reported in individuals in the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) database, but the majority had resolution before adulthood [Unpublished data]. Speech abnormalities including receptive and expressive speech delay, articulation defects, and nasal and/or breathy speech quality are also observed, and likely multifactorial as a result of hearing issues, oral/dental abnormalities, and primary underlying neurologic issues. The behavioral and psychiatric abnormalities, including obsessive compulsive behavior, anxiety and mood disorder, that have been observed are also likely multifactorial. Because of the aforementioned, developmental delay in all domains (i.e., gross motor, fine motor, speech/language) is common in children with BBS; most children do eventually attain major developmental milestones (e.g., walking, talking). Potential secondary oral complications that can result from the other clinical manifestations of BBS (e.g., visual impairment, obesity, cognitive defects, kidney disease, mouth breathing, incompetent lips, anosmia) include poor oral hygiene, periodontal disease, dental caries, drug-induced gingival hyperplasia, xerostomia, altered taste, and speech disturbances [ Laterality defects can range from situs inversus totalis to various features of heterotaxy (i.e., midline abdominal organs, asplenia, or polysplenia). Congenital heart defects associated with laterality defects, including atrioventricular septal defects and vascular anomalies (i.e., bilateral persistent superior vena cava, interrupted inferior vena cava, and hemiazygos continuation) were also reported in the individuals with laterality defects in the CRIBBS database, but at a much lower rate than historically reported including in the meta-analysis by Dilated cardiomyopathy has been reported rarely in individuals with BBS, but exclusion of other genetic causes of these individuals' cardiomyopathy was not performed [ Inflammatory bowel disease and celiac disease were also more prevalent in individuals with BBS compared to the general population. Liver disease includes bile duct abnormalities with cystic dilatation, and periportal fibrosis and non-alcoholic fatty liver disease (NAFLD), thought to partially be a secondary effect of obesity [ T2DM may be controlled by diet but often requires medications including insulin. Subclinical hypothyroidism has also been reported; the clinical significance is unknown [ BBS is the second most common cause of syndromic retinal degeneration, after There is significant clinical and molecular overlap between Bardet-Biedl syndrome and other ciliopathies. Pathogenic variants in several genes that cause BBS can also lead to other distinct ciliopathy syndromes ( Disorders to Consider in the Differential Diagnosis of Bardet-Biedl Syndrome Cone-rod dystrophy (presents earlier in AS) Central obesity, insulin resistance / T2DM, & NAFLD Chronic progressive kidney disease Hypogonadism Preserved cognitive function; cardiomyopathy prevalent (in ~60%); symptomatic progressive SNHL; pulmonary fibrosis & pulmonary hypertension Absence of polydactyly Postaxial polydactyly Genitourinary malformations Congenital heart disease more prevalent (in ~14%); hydrometrocolpos a cardinal feature; renal cysts/dysplasia less common (in 4%-6%) Absence of retinal disease, obesity, & developmental disabilities Postaxial polydactyly Polycystic kidney disease Genitourinary malformations Hepatic fibrosis Occipital encephalocele & other CNS anomalies cardinal features; orofacial clefting common Perinatally lethal Retinal degeneration Polydactyly Kidney & liver disease Characteristic triad of molar tooth sign on brain MRI, hypotonia, & DD; breathing abnormalities that improve w/age common; eye mvmt abnormalities &/or ptosis common Central obesity, hypogonadism, & genitourinary malformations are atypical. Retinal degeneration Kidney disease AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; MOI = mode of inheritance; NAFLD = nonalcoholic fatty liver disease; SNHL = sensorineural hearing loss; T2DM = type 2 diabetes mellitus; XL = X-linked Pathogenic variants in See Digenic inheritance has been reported. • The fact that many of these clinical features emerge throughout infancy, childhood, and young adulthood; therefore, the sensitivity of the proposed clinical diagnostic criteria is likely low, especially in young children. It is important that findings as they pertain to these clinical criteria be reviewed periodically in individuals in whom the diagnosis of BBS has been considered. • Variability in clinical features, which is increasingly realized as the underlying genetic cause is identified in a larger proportion of individuals with BBS. A recent meta-analysis [ • Retinal dystrophy symptoms often bring persons to medical attn, typically in 1st decade of life. • Other eye abnormalities (e.g., strabismus, cataracts) can also be present & are considered minor features of BBS. • Birth weight typically normal • Features assoc w/obesity (incl endocrine/metabolic abnormalities & NAFLD) also common & considered minor features of BBS • DD (81%) • Epilepsy (9.6%) • Behavior/psychiatric abnormalities (35%) • Ataxia/poor coordination may contribute to gross motor & fine motor delays. • Speech abnormalities are common. • Hirschsprung disease (2.8%) • Inflammatory bowel disease (1.1%) • Celiac disease (1.5%) • Liver disease (30%) • Cone-rod dystrophy (presents earlier in AS) • Central obesity, insulin resistance / T2DM, & NAFLD • Chronic progressive kidney disease • Hypogonadism • Preserved cognitive function; cardiomyopathy prevalent (in ~60%); symptomatic progressive SNHL; pulmonary fibrosis & pulmonary hypertension • Absence of polydactyly • Postaxial polydactyly • Genitourinary malformations • Congenital heart disease more prevalent (in ~14%); hydrometrocolpos a cardinal feature; renal cysts/dysplasia less common (in 4%-6%) • Absence of retinal disease, obesity, & developmental disabilities • Postaxial polydactyly • Polycystic kidney disease • Genitourinary malformations • Hepatic fibrosis • Occipital encephalocele & other CNS anomalies cardinal features; orofacial clefting common • Perinatally lethal • Retinal degeneration • Polydactyly • Kidney & liver disease • Characteristic triad of molar tooth sign on brain MRI, hypotonia, & DD; breathing abnormalities that improve w/age common; eye mvmt abnormalities &/or ptosis common • Central obesity, hypogonadism, & genitourinary malformations are atypical. • Retinal degeneration • Kidney disease ## Establishing the Clinical Diagnosis of Bardet-Biedl Syndrome The usefulness of these clinical criteria is limited by: The fact that many of these clinical features emerge throughout infancy, childhood, and young adulthood; therefore, the sensitivity of the proposed clinical diagnostic criteria is likely low, especially in young children. It is important that findings as they pertain to these clinical criteria be reviewed periodically in individuals in whom the diagnosis of BBS has been considered. Variability in clinical features, which is increasingly realized as the underlying genetic cause is identified in a larger proportion of individuals with BBS. A recent meta-analysis [ Features of Bardet-Biedl Syndrome Retinal dystrophy symptoms often bring persons to medical attn, typically in 1st decade of life. Other eye abnormalities (e.g., strabismus, cataracts) can also be present & are considered minor features of BBS. Birth weight typically normal Features assoc w/obesity (incl endocrine/metabolic abnormalities & NAFLD) also common & considered minor features of BBS DD (81%) Epilepsy (9.6%) Behavior/psychiatric abnormalities (35%) Ataxia/poor coordination may contribute to gross motor & fine motor delays. Speech abnormalities are common. Hirschsprung disease (2.8%) Inflammatory bowel disease (1.1%) Celiac disease (1.5%) Liver disease (30%) ALT = alanine transaminase; DD = developmental delay; IDF = International Diabetes Federation; NAFLD = Nonalcoholic fatty liver disease; T2DM = type 2 diabetes mellitus Unless otherwise noted, incidence is based on data in meta-analysis of genotype-phenotype associations of 899 individuals with BBS by In addition to those listed under comments of major features Unpublished data from the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) International Diabetes Federation (IDF) criteria for metabolic syndrome:Central obesity (defined by waist circumference values that are sex and ethnicity specific) PLUS two or more of the following: • Elevated triglyceride level (>150 mg/dL) • Reduced high-density lipoprotein level (<40 mg/dL in males and <50 mg/dL in females) • Hypertension (systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85 mm Hg) • Elevated fasting plasma glucose OR a diagnosis of T2DM Electroretinography (ERG) is more likely to show significant findings after age five years. Individuals often become legally blind by the second to third decade of life. Retinal disease is the most penetrant feature in BBS, affecting up to 100% of individuals in some studies [ Males can have micropenis and/or small-volume testes. Cryptorchidism is present in 9% of males with BBS. On endocrinologic assessment in one study, 19.5% of males were hypogonadal [ Females can have anatomic anomalies including hypoplastic or duplex uterus, hypoplastic fallopian tubes and/or ovaries, septate vagina, partial or complete vaginal atresia, absent vaginal and/or urethral orifice, hydrocolpos or hydrometrocolpos, persistent urogenital sinus, and vesico-vaginal fistula [ Infertility is common, but both sexes are known to have been able to have biological children. Structural kidney disease includes developmental anomalies such as horseshoe, ectopic, duplex, or absent kidneys; or dysplastic cystic disease ranging from single unilateral to multiple bilateral cysts. Urologic complications including neurogenic bladder and bladder outflow obstruction have been reported in 5%-10% of adults [ Chronic kidney disease (CKD) is a major contributor of morbidity and mortality in individuals with BBS. In a recent study, CKD was present in 31% of children and 42% of adults; 6% of children and 8% of adults developed end-stage kidney disease requiring dialysis and/or transplantation [ In the majority of children with BBS with advanced (Stage 4-5) chronic kidney disease, the initial diagnosis of kidney disease was made within the first year of life and almost all were diagnosed by age five years [ Comorbidities including hypertension (present in about one third of individuals with BBS) and type 2 diabetes mellitus (T2DM) may affect progression of CKD. Favorable long-term outcomes of kidney transplantation have been reported [ Seizures and/or epilepsy (as defined by the International League Against Epilepsy) were reported in individuals in the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) database, but the majority had resolution before adulthood [Unpublished data]. Speech abnormalities including receptive and expressive speech delay, articulation defects, and nasal and/or breathy speech quality are also observed, and likely multifactorial as a result of hearing issues, oral/dental abnormalities, and primary underlying neurologic issues. The behavioral and psychiatric abnormalities, including obsessive compulsive behavior, anxiety and mood disorder, that have been observed are also likely multifactorial. Because of the aforementioned, developmental delay in all domains (i.e., gross motor, fine motor, speech/language) is common in children with BBS; most children do eventually attain major developmental milestones (e.g., walking, talking). Potential secondary oral complications that can result from the other clinical manifestations of BBS (e.g., visual impairment, obesity, cognitive defects, kidney disease, mouth breathing, incompetent lips, anosmia) include poor oral hygiene, periodontal disease, dental caries, drug-induced gingival hyperplasia, xerostomia, altered taste, and speech disturbances [ Laterality defects can range from situs inversus totalis to various features of heterotaxy (i.e., midline abdominal organs, asplenia, or polysplenia). Congenital heart defects associated with laterality defects, including atrioventricular septal defects and vascular anomalies (i.e., bilateral persistent superior vena cava, interrupted inferior vena cava, and hemiazygos continuation) were also reported in the individuals with laterality defects in the CRIBBS database, but at a much lower rate than historically reported including in the meta-analysis by Dilated cardiomyopathy has been reported rarely in individuals with BBS, but exclusion of other genetic causes of these individuals' cardiomyopathy was not performed [ Inflammatory bowel disease and celiac disease were also more prevalent in individuals with BBS compared to the general population. Liver disease includes bile duct abnormalities with cystic dilatation, and periportal fibrosis and non-alcoholic fatty liver disease (NAFLD), thought to partially be a secondary effect of obesity [ T2DM may be controlled by diet but often requires medications including insulin. Subclinical hypothyroidism has also been reported; the clinical significance is unknown [ • The fact that many of these clinical features emerge throughout infancy, childhood, and young adulthood; therefore, the sensitivity of the proposed clinical diagnostic criteria is likely low, especially in young children. It is important that findings as they pertain to these clinical criteria be reviewed periodically in individuals in whom the diagnosis of BBS has been considered. • Variability in clinical features, which is increasingly realized as the underlying genetic cause is identified in a larger proportion of individuals with BBS. A recent meta-analysis [ • Retinal dystrophy symptoms often bring persons to medical attn, typically in 1st decade of life. • Other eye abnormalities (e.g., strabismus, cataracts) can also be present & are considered minor features of BBS. • Birth weight typically normal • Features assoc w/obesity (incl endocrine/metabolic abnormalities & NAFLD) also common & considered minor features of BBS • DD (81%) • Epilepsy (9.6%) • Behavior/psychiatric abnormalities (35%) • Ataxia/poor coordination may contribute to gross motor & fine motor delays. • Speech abnormalities are common. • Hirschsprung disease (2.8%) • Inflammatory bowel disease (1.1%) • Celiac disease (1.5%) • Liver disease (30%) ## Major Features Electroretinography (ERG) is more likely to show significant findings after age five years. Individuals often become legally blind by the second to third decade of life. Retinal disease is the most penetrant feature in BBS, affecting up to 100% of individuals in some studies [ Males can have micropenis and/or small-volume testes. Cryptorchidism is present in 9% of males with BBS. On endocrinologic assessment in one study, 19.5% of males were hypogonadal [ Females can have anatomic anomalies including hypoplastic or duplex uterus, hypoplastic fallopian tubes and/or ovaries, septate vagina, partial or complete vaginal atresia, absent vaginal and/or urethral orifice, hydrocolpos or hydrometrocolpos, persistent urogenital sinus, and vesico-vaginal fistula [ Infertility is common, but both sexes are known to have been able to have biological children. Structural kidney disease includes developmental anomalies such as horseshoe, ectopic, duplex, or absent kidneys; or dysplastic cystic disease ranging from single unilateral to multiple bilateral cysts. Urologic complications including neurogenic bladder and bladder outflow obstruction have been reported in 5%-10% of adults [ Chronic kidney disease (CKD) is a major contributor of morbidity and mortality in individuals with BBS. In a recent study, CKD was present in 31% of children and 42% of adults; 6% of children and 8% of adults developed end-stage kidney disease requiring dialysis and/or transplantation [ In the majority of children with BBS with advanced (Stage 4-5) chronic kidney disease, the initial diagnosis of kidney disease was made within the first year of life and almost all were diagnosed by age five years [ Comorbidities including hypertension (present in about one third of individuals with BBS) and type 2 diabetes mellitus (T2DM) may affect progression of CKD. Favorable long-term outcomes of kidney transplantation have been reported [ ## Minor Features Seizures and/or epilepsy (as defined by the International League Against Epilepsy) were reported in individuals in the Clinical Registry Investigating Bardet-Biedl Syndrome (CRIBBS) database, but the majority had resolution before adulthood [Unpublished data]. Speech abnormalities including receptive and expressive speech delay, articulation defects, and nasal and/or breathy speech quality are also observed, and likely multifactorial as a result of hearing issues, oral/dental abnormalities, and primary underlying neurologic issues. The behavioral and psychiatric abnormalities, including obsessive compulsive behavior, anxiety and mood disorder, that have been observed are also likely multifactorial. Because of the aforementioned, developmental delay in all domains (i.e., gross motor, fine motor, speech/language) is common in children with BBS; most children do eventually attain major developmental milestones (e.g., walking, talking). Potential secondary oral complications that can result from the other clinical manifestations of BBS (e.g., visual impairment, obesity, cognitive defects, kidney disease, mouth breathing, incompetent lips, anosmia) include poor oral hygiene, periodontal disease, dental caries, drug-induced gingival hyperplasia, xerostomia, altered taste, and speech disturbances [ Laterality defects can range from situs inversus totalis to various features of heterotaxy (i.e., midline abdominal organs, asplenia, or polysplenia). Congenital heart defects associated with laterality defects, including atrioventricular septal defects and vascular anomalies (i.e., bilateral persistent superior vena cava, interrupted inferior vena cava, and hemiazygos continuation) were also reported in the individuals with laterality defects in the CRIBBS database, but at a much lower rate than historically reported including in the meta-analysis by Dilated cardiomyopathy has been reported rarely in individuals with BBS, but exclusion of other genetic causes of these individuals' cardiomyopathy was not performed [ Inflammatory bowel disease and celiac disease were also more prevalent in individuals with BBS compared to the general population. Liver disease includes bile duct abnormalities with cystic dilatation, and periportal fibrosis and non-alcoholic fatty liver disease (NAFLD), thought to partially be a secondary effect of obesity [ T2DM may be controlled by diet but often requires medications including insulin. Subclinical hypothyroidism has also been reported; the clinical significance is unknown [ ## Other Features (Not Part of the Clinical Diagnostic Criteria) ## Differential Diagnosis of Bardet-Biedl Syndrome BBS is the second most common cause of syndromic retinal degeneration, after There is significant clinical and molecular overlap between Bardet-Biedl syndrome and other ciliopathies. Pathogenic variants in several genes that cause BBS can also lead to other distinct ciliopathy syndromes ( Disorders to Consider in the Differential Diagnosis of Bardet-Biedl Syndrome Cone-rod dystrophy (presents earlier in AS) Central obesity, insulin resistance / T2DM, & NAFLD Chronic progressive kidney disease Hypogonadism Preserved cognitive function; cardiomyopathy prevalent (in ~60%); symptomatic progressive SNHL; pulmonary fibrosis & pulmonary hypertension Absence of polydactyly Postaxial polydactyly Genitourinary malformations Congenital heart disease more prevalent (in ~14%); hydrometrocolpos a cardinal feature; renal cysts/dysplasia less common (in 4%-6%) Absence of retinal disease, obesity, & developmental disabilities Postaxial polydactyly Polycystic kidney disease Genitourinary malformations Hepatic fibrosis Occipital encephalocele & other CNS anomalies cardinal features; orofacial clefting common Perinatally lethal Retinal degeneration Polydactyly Kidney & liver disease Characteristic triad of molar tooth sign on brain MRI, hypotonia, & DD; breathing abnormalities that improve w/age common; eye mvmt abnormalities &/or ptosis common Central obesity, hypogonadism, & genitourinary malformations are atypical. Retinal degeneration Kidney disease AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; MOI = mode of inheritance; NAFLD = nonalcoholic fatty liver disease; SNHL = sensorineural hearing loss; T2DM = type 2 diabetes mellitus; XL = X-linked Pathogenic variants in See Digenic inheritance has been reported. • Cone-rod dystrophy (presents earlier in AS) • Central obesity, insulin resistance / T2DM, & NAFLD • Chronic progressive kidney disease • Hypogonadism • Preserved cognitive function; cardiomyopathy prevalent (in ~60%); symptomatic progressive SNHL; pulmonary fibrosis & pulmonary hypertension • Absence of polydactyly • Postaxial polydactyly • Genitourinary malformations • Congenital heart disease more prevalent (in ~14%); hydrometrocolpos a cardinal feature; renal cysts/dysplasia less common (in 4%-6%) • Absence of retinal disease, obesity, & developmental disabilities • Postaxial polydactyly • Polycystic kidney disease • Genitourinary malformations • Hepatic fibrosis • Occipital encephalocele & other CNS anomalies cardinal features; orofacial clefting common • Perinatally lethal • Retinal degeneration • Polydactyly • Kidney & liver disease • Characteristic triad of molar tooth sign on brain MRI, hypotonia, & DD; breathing abnormalities that improve w/age common; eye mvmt abnormalities &/or ptosis common • Central obesity, hypogonadism, & genitourinary malformations are atypical. • Retinal degeneration • Kidney disease ## Causes of Bardet-Biedl Syndrome Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder caused by biallelic loss-of-function pathogenic variants in at least 26 genes; some genotype-phenotype correlations exist ( Bardet-Biedl Syndrome: Genes and Distinguishing Clinical Features Relatively less "syndromic" Founder variant in Newfoundland population Relatively more "syndromic" w/↑ penetrance of renal anomalies & polydactyly "Leanest" of obesity phenotype ↓ penetrance of renal anomalies Early-onset morbid obesity Least "syndromic" w/low penetrance of cognitive impairment & renal anomalies Polydactyly often affects all 4 limbs. Founder variant in population on La Réunion Island Most severe renal impairment Significant adiposity Founder variant in South African population Cone-rod dystrophy w/polydactyly (OMIM Meckel syndrome (OMIM Senior-Løken syndrome (OMIM Reported in 3 persons from 2 families, all w/major features of BBS 1 person w/AVCD Reported in 2 unrelated persons; both w/retinal disease, obesity, polydactyly, & no renal involvement 1 person w/ID Short-rib thoracic dysplasia w/ or w/o polydactyly (OMIM Reported in 3 persons from 2 families Mesoaxial-type polydactyly a unique feature Meckel syndrome (OMIM In 1 family, affected persons have pituitary hypoplasia & growth hormone deficiency + obesity, retinal disease, & polydactyly. In the other family, affected persons have major features of BBS. AVCD = atrioventricular canal defect; BBS = Bardet-Biedl syndrome; CHD = congenital heart defect; ID = intellectual disability; PCD = primary ciliary dyskinesia Genes are listed in alphabetic order. Included when BBS designation differs from gene Determined by data of 923 individuals with BBS (899 from a meta-analysis of genotype-phenotype associations by [ Link to OMIM gene description provided if no Use of the word "syndromic" refers to syndromic score used by These disorders have phenotypic overlap with BBS and should be considered in the differential diagnosis of BBS (see In the literature, both • Relatively less "syndromic" • Founder variant in Newfoundland population • Relatively more "syndromic" w/↑ penetrance of renal anomalies & polydactyly • "Leanest" of obesity phenotype • ↓ penetrance of renal anomalies • Early-onset morbid obesity • Least "syndromic" w/low penetrance of cognitive impairment & renal anomalies • Polydactyly often affects all 4 limbs. • Founder variant in population on La Réunion Island • Most severe renal impairment • Significant adiposity • Founder variant in South African population • Cone-rod dystrophy w/polydactyly (OMIM • Meckel syndrome (OMIM • Senior-Løken syndrome (OMIM • Reported in 3 persons from 2 families, all w/major features of BBS • 1 person w/AVCD • Reported in 2 unrelated persons; both w/retinal disease, obesity, polydactyly, & no renal involvement • 1 person w/ID • Short-rib thoracic dysplasia w/ or w/o polydactyly (OMIM • Reported in 3 persons from 2 families • Mesoaxial-type polydactyly a unique feature • Meckel syndrome (OMIM • In 1 family, affected persons have pituitary hypoplasia & growth hormone deficiency + obesity, retinal disease, & polydactyly. • In the other family, affected persons have major features of BBS. ## Evaluation Strategies to Identify the Genetic Cause of Bardet-Biedl Syndrome in a Proband Establishing a specific genetic cause of Bardet-Biedl syndrome (BBS) in a proband: Can aid in discussions of prognosis (which are beyond the scope of this Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. A diagnosis of BBS should be considered in any individual with any of the major features listed in BBS must be suspected in a fetus/infant with structural kidney disease, genitourinary malformations, and/or polydactyly as these may be the only features of BBS evident in this cohort. Central obesity, which often develops in the first year of life, is another prominent early feature of BBS that should raise suspicion of this diagnosis. Manifestations of cone-rod dystrophy (photophobia, decreased visual acuity, and loss of color discrimination) and chronic kidney disease (polyuria and polydipsia) may not be present until children are school-aged, while manifestations of hypogonadism (lack of pubertal development) are evident even later, in early adolescence. Other features in A three-generation family history should be obtained with attention to parental consanguinity and medical issues in sibs. Documentation of relevant findings in sibs can be accomplished either through direct examination of those individuals or review of their medical records. Because BBS is genetically heterogeneous with significant clinical overlap with other ciliopathies, recommended molecular genetic testing approaches include either gene-targeted testing ( Single-gene testing (sequence analysis of a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically not recommended. For an introduction to multigene panels click 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 • Can aid in discussions of prognosis (which are beyond the scope of this • Usually involves a medical history, physical examination, laboratory testing, family history, and genomic/genetic testing. • For an introduction to multigene panels click • 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 ## Medical History A diagnosis of BBS should be considered in any individual with any of the major features listed in BBS must be suspected in a fetus/infant with structural kidney disease, genitourinary malformations, and/or polydactyly as these may be the only features of BBS evident in this cohort. Central obesity, which often develops in the first year of life, is another prominent early feature of BBS that should raise suspicion of this diagnosis. Manifestations of cone-rod dystrophy (photophobia, decreased visual acuity, and loss of color discrimination) and chronic kidney disease (polyuria and polydipsia) may not be present until children are school-aged, while manifestations of hypogonadism (lack of pubertal development) are evident even later, in early adolescence. Other features in ## Family History A three-generation family history should be obtained with attention to parental consanguinity and medical issues in sibs. Documentation of relevant findings in sibs can be accomplished either through direct examination of those individuals or review of their medical records. ## Molecular Genetic Testing Because BBS is genetically heterogeneous with significant clinical overlap with other ciliopathies, recommended molecular genetic testing approaches include either gene-targeted testing ( Single-gene testing (sequence analysis of a given gene, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically not recommended. For an introduction to multigene panels click 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 • For an introduction to multigene panels click • 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 Bardet-Biedl Syndrome To establish the extent of disease and ongoing needs in an individual diagnosed with Bardet-Biedl syndrome (BBS), the evaluations summarized in Recommended Initial Evaluations and Surveillance in Individuals with Bardet-Biedl Syndrome Measure height, weight, head & waist circumference. Detailed dietary history: caloric intake & dietary components Assess daily physical activity level. Infants / young children: assess for strabismus, nystagmus, & impaired visual acuity. Older children / adults: assess for cataracts & impaired vision; perform visual field testing & electroretinography. Echocardiogram to assess for congenital heart defect &/or cardiomyopathy Complete abdominal US to assess for laterality defects If initial eval is normal, only if cardiac symptoms/signs develop If anatomic abnormality is present, more frequent monitoring as directed by cardiologist Symptoms of obstructive sleep apnea (e.g., snoring); Recurrent infection that could indicate ciliary dysfunction. Assess for anatomic abnormalities. Monitor for symptoms/signs of IBD & celiac disease. Liver US to evaluate for liver fibrosis & steatosis Lab assessments incl hepatic enzymes & tests of synthetic function (PT, PTT) Annually if normal Persons w/liver disease should be monitored as directed by hepatologist. Renal US to evaluate for congenital anomalies & assess for evidence of parenchymal disease Lab assessments incl CBC, serum electrolytes, creatine, BUN, cystatin C Measure blood pressure w/24-hr blood pressure monitoring as needed. Annually if normal Persons w/kidney disease should be monitored as directed by nephrologist. Lipid panel (triglycerides, HDL, LDL, total cholesterol) Fasting blood glucose & HgbA1c Annually starting at age 4 yrs if normal Those w/metabolic syndrome will require more frequent monitoring by experienced provider. Pelvic US in females to assess for malformations of uterus, fallopian tubes, ovaries, & vagina Check FSH, LH, estrogen, & testosterone levels if indicated due to delayed puberty. Developmental &/or neurocognitive assessment Consider brain MRI if neurologic abnormalities (i.e., ataxia, hypotonia, seizures). Routine developmental assessments during early childhood School-aged persons should have annual IEP/504 plans. Use of community or Need for social work involvement for parental support. BUN = blood urea nitrogen; CBC = complete blood cell count; FSH = follicle-stimulating hormone; HDL = high-density lipoproteins; HgbA1c = hemoglobin A1c; IBD = inflammatory bowel disease; IEP = individualized education program; LDL = low-density lipoproteins; LH = luteinizing hormone; MOI = mode of inheritance; PT = prothrombin time; PTT = partial thromboplastin time; SNHL = sensorineural hearing loss; US = ultrasound Recommended frequencies shown are for individuals who are stable and well-controlled. In many instances more frequent evaluations are needed. Individuals should be evaluated by a medical geneticist every one to two years, as they can help with coordination of care. Prenatal ultrasonography may detect renal cysts but can be normal in 39% of individuals with renal abnormalities detected postnatally [ MRI of the brain may show diffuse white matter loss predominantly in the occipital region, reduced grey matter in subcortical regions (caudate, putamen, thalamus), reduced hippocampal volume, and hippocampal dysgenesis [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) No therapy exists to prevent the multisystem and sometimes progressive organ involvement of BBS. Individuals with BBS require coordinated multidisciplinary care to formulate and coordinate management and therapeutic interventions. Metabolic syndrome and the other obesity-related complications of BBS should be treated as in the general population. All individuals will benefit from these lifestyle recommendations. Anatomic abnormalities, including The approach to 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 restricted environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. 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. Concerns about depression and anxiety are common in the late teens as young persons with BBS realize the severity of its effects. These issues can be addressed by a pediatric psychiatrist. • Measure height, weight, head & waist circumference. • Detailed dietary history: caloric intake & dietary components • Assess daily physical activity level. • Infants / young children: assess for strabismus, nystagmus, & impaired visual acuity. • Older children / adults: assess for cataracts & impaired vision; perform visual field testing & electroretinography. • Echocardiogram to assess for congenital heart defect &/or cardiomyopathy • Complete abdominal US to assess for laterality defects • If initial eval is normal, only if cardiac symptoms/signs develop • If anatomic abnormality is present, more frequent monitoring as directed by cardiologist • Symptoms of obstructive sleep apnea (e.g., snoring); • Recurrent infection that could indicate ciliary dysfunction. • Assess for anatomic abnormalities. • Monitor for symptoms/signs of IBD & celiac disease. • Liver US to evaluate for liver fibrosis & steatosis • Lab assessments incl hepatic enzymes & tests of synthetic function (PT, PTT) • Annually if normal • Persons w/liver disease should be monitored as directed by hepatologist. • Renal US to evaluate for congenital anomalies & assess for evidence of parenchymal disease • Lab assessments incl CBC, serum electrolytes, creatine, BUN, cystatin C • Measure blood pressure w/24-hr blood pressure monitoring as needed. • Annually if normal • Persons w/kidney disease should be monitored as directed by nephrologist. • Lipid panel (triglycerides, HDL, LDL, total cholesterol) • Fasting blood glucose & HgbA1c • Annually starting at age 4 yrs if normal • Those w/metabolic syndrome will require more frequent monitoring by experienced provider. • Pelvic US in females to assess for malformations of uterus, fallopian tubes, ovaries, & vagina • Check FSH, LH, estrogen, & testosterone levels if indicated due to delayed puberty. • Developmental &/or neurocognitive assessment • Consider brain MRI if neurologic abnormalities (i.e., ataxia, hypotonia, seizures). • Routine developmental assessments during early childhood • School-aged persons should have annual IEP/504 plans. • Use of community or • Need for social work involvement for parental support. • 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 restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into 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 ongoing needs in an individual diagnosed with Bardet-Biedl syndrome (BBS), the evaluations summarized in Recommended Initial Evaluations and Surveillance in Individuals with Bardet-Biedl Syndrome Measure height, weight, head & waist circumference. Detailed dietary history: caloric intake & dietary components Assess daily physical activity level. Infants / young children: assess for strabismus, nystagmus, & impaired visual acuity. Older children / adults: assess for cataracts & impaired vision; perform visual field testing & electroretinography. Echocardiogram to assess for congenital heart defect &/or cardiomyopathy Complete abdominal US to assess for laterality defects If initial eval is normal, only if cardiac symptoms/signs develop If anatomic abnormality is present, more frequent monitoring as directed by cardiologist Symptoms of obstructive sleep apnea (e.g., snoring); Recurrent infection that could indicate ciliary dysfunction. Assess for anatomic abnormalities. Monitor for symptoms/signs of IBD & celiac disease. Liver US to evaluate for liver fibrosis & steatosis Lab assessments incl hepatic enzymes & tests of synthetic function (PT, PTT) Annually if normal Persons w/liver disease should be monitored as directed by hepatologist. Renal US to evaluate for congenital anomalies & assess for evidence of parenchymal disease Lab assessments incl CBC, serum electrolytes, creatine, BUN, cystatin C Measure blood pressure w/24-hr blood pressure monitoring as needed. Annually if normal Persons w/kidney disease should be monitored as directed by nephrologist. Lipid panel (triglycerides, HDL, LDL, total cholesterol) Fasting blood glucose & HgbA1c Annually starting at age 4 yrs if normal Those w/metabolic syndrome will require more frequent monitoring by experienced provider. Pelvic US in females to assess for malformations of uterus, fallopian tubes, ovaries, & vagina Check FSH, LH, estrogen, & testosterone levels if indicated due to delayed puberty. Developmental &/or neurocognitive assessment Consider brain MRI if neurologic abnormalities (i.e., ataxia, hypotonia, seizures). Routine developmental assessments during early childhood School-aged persons should have annual IEP/504 plans. Use of community or Need for social work involvement for parental support. BUN = blood urea nitrogen; CBC = complete blood cell count; FSH = follicle-stimulating hormone; HDL = high-density lipoproteins; HgbA1c = hemoglobin A1c; IBD = inflammatory bowel disease; IEP = individualized education program; LDL = low-density lipoproteins; LH = luteinizing hormone; MOI = mode of inheritance; PT = prothrombin time; PTT = partial thromboplastin time; SNHL = sensorineural hearing loss; US = ultrasound Recommended frequencies shown are for individuals who are stable and well-controlled. In many instances more frequent evaluations are needed. Individuals should be evaluated by a medical geneticist every one to two years, as they can help with coordination of care. Prenatal ultrasonography may detect renal cysts but can be normal in 39% of individuals with renal abnormalities detected postnatally [ MRI of the brain may show diffuse white matter loss predominantly in the occipital region, reduced grey matter in subcortical regions (caudate, putamen, thalamus), reduced hippocampal volume, and hippocampal dysgenesis [ Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Measure height, weight, head & waist circumference. • Detailed dietary history: caloric intake & dietary components • Assess daily physical activity level. • Infants / young children: assess for strabismus, nystagmus, & impaired visual acuity. • Older children / adults: assess for cataracts & impaired vision; perform visual field testing & electroretinography. • Echocardiogram to assess for congenital heart defect &/or cardiomyopathy • Complete abdominal US to assess for laterality defects • If initial eval is normal, only if cardiac symptoms/signs develop • If anatomic abnormality is present, more frequent monitoring as directed by cardiologist • Symptoms of obstructive sleep apnea (e.g., snoring); • Recurrent infection that could indicate ciliary dysfunction. • Assess for anatomic abnormalities. • Monitor for symptoms/signs of IBD & celiac disease. • Liver US to evaluate for liver fibrosis & steatosis • Lab assessments incl hepatic enzymes & tests of synthetic function (PT, PTT) • Annually if normal • Persons w/liver disease should be monitored as directed by hepatologist. • Renal US to evaluate for congenital anomalies & assess for evidence of parenchymal disease • Lab assessments incl CBC, serum electrolytes, creatine, BUN, cystatin C • Measure blood pressure w/24-hr blood pressure monitoring as needed. • Annually if normal • Persons w/kidney disease should be monitored as directed by nephrologist. • Lipid panel (triglycerides, HDL, LDL, total cholesterol) • Fasting blood glucose & HgbA1c • Annually starting at age 4 yrs if normal • Those w/metabolic syndrome will require more frequent monitoring by experienced provider. • Pelvic US in females to assess for malformations of uterus, fallopian tubes, ovaries, & vagina • Check FSH, LH, estrogen, & testosterone levels if indicated due to delayed puberty. • Developmental &/or neurocognitive assessment • Consider brain MRI if neurologic abnormalities (i.e., ataxia, hypotonia, seizures). • Routine developmental assessments during early childhood • School-aged persons should have annual IEP/504 plans. • Use of community or • Need for social work involvement for parental support. ## Treatment of Manifestations No therapy exists to prevent the multisystem and sometimes progressive organ involvement of BBS. Individuals with BBS require coordinated multidisciplinary care to formulate and coordinate management and therapeutic interventions. Metabolic syndrome and the other obesity-related complications of BBS should be treated as in the general population. All individuals will benefit from these lifestyle recommendations. Anatomic abnormalities, including The approach to 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 restricted environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. 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. Concerns about depression and anxiety are common in the late teens as young persons with BBS realize the severity of its effects. These issues can be addressed by a pediatric psychiatrist. • 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 restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Medical Issues No therapy exists to prevent the multisystem and sometimes progressive organ involvement of BBS. Individuals with BBS require coordinated multidisciplinary care to formulate and coordinate management and therapeutic interventions. Metabolic syndrome and the other obesity-related complications of BBS should be treated as in the general population. All individuals will benefit from these lifestyle recommendations. Anatomic abnormalities, including ## Neurodevelopmental Issues The approach to 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 restricted environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine if any changes are needed. • Special education law requires that children participating in an IEP be in the least restricted environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the 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 into 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 is typically performed one on one with a board-certified behavior analyst. Concerns about depression and anxiety are common in the late teens as young persons with BBS realize the severity of its effects. These issues can be addressed by a pediatric psychiatrist. ## Genetic Counseling of Family Members of an Individual with Bardet-Biedl Syndrome Bardet-Biedl syndrome (BBS) is typically inherited in an autosomal recessive manner. Note: (1) Although oligogenic inheritance of BBS has been suggested in some families with individuals who are identified as having clinical features of BBS and variants in two or more different BBS-associated genes [ The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one BBS-related pathogenic variant based on family history). 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 BBS-related pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a BBS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. BBS is associated with intrafamilial variation; the clinical presentation of sibs who inherit biallelic pathogenic variants may differ from that the proband (see Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Carrier testing for at-risk relatives requires prior identification of the BBS-related pathogenic variants in the family. Once the BBS-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 and preimplantation genetic testing. While most health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one BBS-related pathogenic variant based on family history). • 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 BBS-related pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a BBS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • BBS is associated with intrafamilial variation; the clinical presentation of sibs who inherit biallelic pathogenic variants may differ from that the proband (see • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Mode of Inheritance Bardet-Biedl syndrome (BBS) is typically inherited in an autosomal recessive manner. Note: (1) Although oligogenic inheritance of BBS has been suggested in some families with individuals who are identified as having clinical features of BBS and variants in two or more different BBS-associated genes [ ## Risk to Family Members (Autosomal Recessive Inheritance) The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one BBS-related pathogenic variant based on family history). 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 BBS-related pathogenic variant and to allow reliable recurrence risk assessment. ( Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a BBS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. BBS is associated with intrafamilial variation; the clinical presentation of sibs who inherit biallelic pathogenic variants may differ from that the proband (see 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 BBS-related pathogenic variant based on family history). • 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 BBS-related pathogenic variant and to allow reliable recurrence risk assessment. ( • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • If both parents are known to be heterozygous for a BBS-related pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • BBS is associated with intrafamilial variation; the clinical presentation of sibs who inherit biallelic pathogenic variants may differ from that the proband (see • 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 BBS-related pathogenic variants in the family. ## Prenatal Testing and Preimplantation Genetic Testing Once the BBS-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 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 Ireland • • • • United Kingdom • • • • • Ireland • • • • • ## Chapter Notes Meral Gunay-Aygun, MD is the principal investigator of the National Institutes of Health research protocol "Clinical and Molecular Investigations into Ciliopathies" (www.ClinicalTrials.gov Philip L Beales, BSc, MD, FRCP, FMedSci; University College London (2003-2020)Elizabeth Forsythe, MBBS, BMedSci, MRCPCH; University College London (2014-2020)RaeLynn Forsyth, MD (2020-present)Meral Gunay-Aygun, MD (2020-present)Alison J Ross, PhD; University College London (2003-2009)Aoife M Waters, MB BAO, BCh, MRCPI, MSc; University College London (2009-2014) 23 March 2023 (aa/gm) Revision: 23 July 2020 (bp) Comprehensive update posted live; scope changed to overview 20 February 2014 (me) Comprehensive update posted live 13 October 2009 (me) Comprehensive update posted live 18 November 2005 (me) Comprehensive update posted live 14 July 2003 (me) Review posted live 22 January 2003 (pb) Original submission • 23 March 2023 (aa/gm) Revision: • 23 July 2020 (bp) Comprehensive update posted live; scope changed to overview • 20 February 2014 (me) Comprehensive update posted live • 13 October 2009 (me) Comprehensive update posted live • 18 November 2005 (me) Comprehensive update posted live • 14 July 2003 (me) Review posted live • 22 January 2003 (pb) Original submission ## Author Notes Meral Gunay-Aygun, MD is the principal investigator of the National Institutes of Health research protocol "Clinical and Molecular Investigations into Ciliopathies" (www.ClinicalTrials.gov ## Author History Philip L Beales, BSc, MD, FRCP, FMedSci; University College London (2003-2020)Elizabeth Forsythe, MBBS, BMedSci, MRCPCH; University College London (2014-2020)RaeLynn Forsyth, MD (2020-present)Meral Gunay-Aygun, MD (2020-present)Alison J Ross, PhD; University College London (2003-2009)Aoife M Waters, MB BAO, BCh, MRCPI, MSc; University College London (2009-2014) ## Revision History 23 March 2023 (aa/gm) Revision: 23 July 2020 (bp) Comprehensive update posted live; scope changed to overview 20 February 2014 (me) Comprehensive update posted live 13 October 2009 (me) Comprehensive update posted live 18 November 2005 (me) Comprehensive update posted live 14 July 2003 (me) Review posted live 22 January 2003 (pb) Original submission • 23 March 2023 (aa/gm) Revision: • 23 July 2020 (bp) Comprehensive update posted live; scope changed to overview • 20 February 2014 (me) Comprehensive update posted live • 13 October 2009 (me) Comprehensive update posted live • 18 November 2005 (me) Comprehensive update posted live • 14 July 2003 (me) Review posted live • 22 January 2003 (pb) Original submission ## References ## Literature Cited	[]	14/7/2003	23/7/2020	23/3/2023	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bcl11a-id	bcl11a-id	[ "Dias-Logan Syndrome", "Intellectual Developmental Disorder with Persistence of Fetal Hemoglobin", "Dias-Logan Syndrome", "Intellectual Developmental Disorder with Persistence of Fetal Hemoglobin", "BCL11 transcription factor A", "BCL11A", "BCL11A-Related Intellectual Disability" ]		Angela Peron, Kimberley Bradbury, David H Viskochil, Cristina Dias	Summary The diagnosis of	## Diagnosis Formal clinical diagnostic criteria for Mild-to-severe developmental delay or intellectual disability; AND Any of the following features presenting in infancy or childhood: Microcephaly Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ External ear anomalies Strabismus Blue sclerae in infancy Generalized hypotonia of infancy Infant feeding difficulties Language delay and/or dyspraxia Joint laxity Behavioral concerns (repetitive behavior, autism spectrum disorder) Sleep disturbance Seizures The diagnosis of Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, 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. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Includes partial or whole-gene deletions of • Mild-to-severe developmental delay or intellectual disability; AND • Any of the following features presenting in infancy or childhood: • Microcephaly • Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ • External ear anomalies • Strabismus • Blue sclerae in infancy • Generalized hypotonia of infancy • Infant feeding difficulties • Language delay and/or dyspraxia • Joint laxity • Behavioral concerns (repetitive behavior, autism spectrum disorder) • Sleep disturbance • Seizures • Microcephaly • Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ • External ear anomalies • Strabismus • Blue sclerae in infancy • Generalized hypotonia of infancy • Infant feeding difficulties • Language delay and/or dyspraxia • Joint laxity • Behavioral concerns (repetitive behavior, autism spectrum disorder) • Sleep disturbance • Seizures • Microcephaly • Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ • External ear anomalies • Strabismus • Blue sclerae in infancy • Generalized hypotonia of infancy • Infant feeding difficulties • Language delay and/or dyspraxia • Joint laxity • Behavioral concerns (repetitive behavior, autism spectrum disorder) • Sleep disturbance • Seizures ## Suggestive Findings Mild-to-severe developmental delay or intellectual disability; AND Any of the following features presenting in infancy or childhood: Microcephaly Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ External ear anomalies Strabismus Blue sclerae in infancy Generalized hypotonia of infancy Infant feeding difficulties Language delay and/or dyspraxia Joint laxity Behavioral concerns (repetitive behavior, autism spectrum disorder) Sleep disturbance Seizures • Mild-to-severe developmental delay or intellectual disability; AND • Any of the following features presenting in infancy or childhood: • Microcephaly • Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ • External ear anomalies • Strabismus • Blue sclerae in infancy • Generalized hypotonia of infancy • Infant feeding difficulties • Language delay and/or dyspraxia • Joint laxity • Behavioral concerns (repetitive behavior, autism spectrum disorder) • Sleep disturbance • Seizures • Microcephaly • Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ • External ear anomalies • Strabismus • Blue sclerae in infancy • Generalized hypotonia of infancy • Infant feeding difficulties • Language delay and/or dyspraxia • Joint laxity • Behavioral concerns (repetitive behavior, autism spectrum disorder) • Sleep disturbance • Seizures • Microcephaly • Craniofacial features including flat midface, small nares, thin vermilion of the upper lip and everted vermilion of the lower lip [ • External ear anomalies • Strabismus • Blue sclerae in infancy • Generalized hypotonia of infancy • Infant feeding difficulties • Language delay and/or dyspraxia • Joint laxity • Behavioral concerns (repetitive behavior, autism spectrum disorder) • Sleep disturbance • Seizures ## Establishing the Diagnosis The diagnosis of Note: Per ACMG variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. Note: Single-gene testing (sequence analysis of For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, 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. Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including Includes partial or whole-gene deletions of ## Clinical Characteristics To date, 27 individuals have been reported with a pathogenic (or likely pathogenic) variant in Other neurodevelopmental features: Neonatal hypotonia is seen in the majority of affected individuals, and may result in delayed acquisition of motor milestones (average age at walking: ~30 months). Hypotonia may resolve in childhood, though in some it persists into adolescence. Infant feeding difficulties are occasionally present and thought to be associated with central hypotonia as opposed to primary dysphagia. Ataxia and/or broad-based gait has been reported in three affected individuals. Various types of seizures have been described (including myoclonic, tonic, and atonic seizures; absence seizures; and spasms) without a common electroclinical pattern. Age at seizure onset among individuals reported in the literature varied from two months to three years. Seizures are usually controlled with single or combined (2) anti-seizure medication(s). Three reported individuals had seizures that were drug resistant [ Autism spectrum disorder has been described in a subset of affected individuals [ Others exhibit autistic-like traits, such as repetitive behaviors. Other behavior problems: Attention deficit and self-injurious behaviors have been reported in one person each. Sleep disturbances have been reported in three people. Elevated HbF (% of total hemoglobin) has been identified in all affected individuals who have been tested [ Persistence of HbF is not known to cause symptoms, and no affected individuals with hematologic problems have been reported thus far. Microcephaly (-2 to -3.5 SD) is seen in approximately half of affected individuals [ Structural anomalies of the central nervous system can be present, including hypoplasia of the corpus callosum and/or cerebellar vermis [ White matter abnormalities, including reduced white matter volume, have been reported [ Joint hypermobility is a common finding (>80%) in individuals with Scoliosis has occasionally been reported [ Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ With the limited number of affected individuals reported to date, no statistically significant genotype-phenotype correlations can be made. However, certain features described to date have been seen only in individuals with loss-of-function (nonsense and frameshift) variants [ Blue sclerae in infancy Epicanthal folds Micrognathia or retrognathia Short stature (mild) The prevalence of • Neonatal hypotonia is seen in the majority of affected individuals, and may result in delayed acquisition of motor milestones (average age at walking: ~30 months). Hypotonia may resolve in childhood, though in some it persists into adolescence. • Infant feeding difficulties are occasionally present and thought to be associated with central hypotonia as opposed to primary dysphagia. • Ataxia and/or broad-based gait has been reported in three affected individuals. • Various types of seizures have been described (including myoclonic, tonic, and atonic seizures; absence seizures; and spasms) without a common electroclinical pattern. • Age at seizure onset among individuals reported in the literature varied from two months to three years. • Seizures are usually controlled with single or combined (2) anti-seizure medication(s). Three reported individuals had seizures that were drug resistant [ • Autism spectrum disorder has been described in a subset of affected individuals [ • Others exhibit autistic-like traits, such as repetitive behaviors. • Other behavior problems: • Attention deficit and self-injurious behaviors have been reported in one person each. • Sleep disturbances have been reported in three people. • Attention deficit and self-injurious behaviors have been reported in one person each. • Sleep disturbances have been reported in three people. • Attention deficit and self-injurious behaviors have been reported in one person each. • Sleep disturbances have been reported in three people. • Elevated HbF (% of total hemoglobin) has been identified in all affected individuals who have been tested [ • Persistence of HbF is not known to cause symptoms, and no affected individuals with hematologic problems have been reported thus far. • Structural anomalies of the central nervous system can be present, including hypoplasia of the corpus callosum and/or cerebellar vermis [ • White matter abnormalities, including reduced white matter volume, have been reported [ • • Joint hypermobility is a common finding (>80%) in individuals with • Scoliosis has occasionally been reported [ • Joint hypermobility is a common finding (>80%) in individuals with • Scoliosis has occasionally been reported [ • Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ • A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ • Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ • A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ • Joint hypermobility is a common finding (>80%) in individuals with • Scoliosis has occasionally been reported [ • Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ • A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ • Blue sclerae in infancy • Epicanthal folds • Micrognathia or retrognathia • Short stature (mild) ## Clinical Description To date, 27 individuals have been reported with a pathogenic (or likely pathogenic) variant in Other neurodevelopmental features: Neonatal hypotonia is seen in the majority of affected individuals, and may result in delayed acquisition of motor milestones (average age at walking: ~30 months). Hypotonia may resolve in childhood, though in some it persists into adolescence. Infant feeding difficulties are occasionally present and thought to be associated with central hypotonia as opposed to primary dysphagia. Ataxia and/or broad-based gait has been reported in three affected individuals. Various types of seizures have been described (including myoclonic, tonic, and atonic seizures; absence seizures; and spasms) without a common electroclinical pattern. Age at seizure onset among individuals reported in the literature varied from two months to three years. Seizures are usually controlled with single or combined (2) anti-seizure medication(s). Three reported individuals had seizures that were drug resistant [ Autism spectrum disorder has been described in a subset of affected individuals [ Others exhibit autistic-like traits, such as repetitive behaviors. Other behavior problems: Attention deficit and self-injurious behaviors have been reported in one person each. Sleep disturbances have been reported in three people. Elevated HbF (% of total hemoglobin) has been identified in all affected individuals who have been tested [ Persistence of HbF is not known to cause symptoms, and no affected individuals with hematologic problems have been reported thus far. Microcephaly (-2 to -3.5 SD) is seen in approximately half of affected individuals [ Structural anomalies of the central nervous system can be present, including hypoplasia of the corpus callosum and/or cerebellar vermis [ White matter abnormalities, including reduced white matter volume, have been reported [ Joint hypermobility is a common finding (>80%) in individuals with Scoliosis has occasionally been reported [ Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ • Neonatal hypotonia is seen in the majority of affected individuals, and may result in delayed acquisition of motor milestones (average age at walking: ~30 months). Hypotonia may resolve in childhood, though in some it persists into adolescence. • Infant feeding difficulties are occasionally present and thought to be associated with central hypotonia as opposed to primary dysphagia. • Ataxia and/or broad-based gait has been reported in three affected individuals. • Various types of seizures have been described (including myoclonic, tonic, and atonic seizures; absence seizures; and spasms) without a common electroclinical pattern. • Age at seizure onset among individuals reported in the literature varied from two months to three years. • Seizures are usually controlled with single or combined (2) anti-seizure medication(s). Three reported individuals had seizures that were drug resistant [ • Autism spectrum disorder has been described in a subset of affected individuals [ • Others exhibit autistic-like traits, such as repetitive behaviors. • Other behavior problems: • Attention deficit and self-injurious behaviors have been reported in one person each. • Sleep disturbances have been reported in three people. • Attention deficit and self-injurious behaviors have been reported in one person each. • Sleep disturbances have been reported in three people. • Attention deficit and self-injurious behaviors have been reported in one person each. • Sleep disturbances have been reported in three people. • Elevated HbF (% of total hemoglobin) has been identified in all affected individuals who have been tested [ • Persistence of HbF is not known to cause symptoms, and no affected individuals with hematologic problems have been reported thus far. • Structural anomalies of the central nervous system can be present, including hypoplasia of the corpus callosum and/or cerebellar vermis [ • White matter abnormalities, including reduced white matter volume, have been reported [ • • Joint hypermobility is a common finding (>80%) in individuals with • Scoliosis has occasionally been reported [ • Joint hypermobility is a common finding (>80%) in individuals with • Scoliosis has occasionally been reported [ • Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ • A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ • Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ • A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ • Joint hypermobility is a common finding (>80%) in individuals with • Scoliosis has occasionally been reported [ • Affected individuals frequently have flat midface, full cheeks, small nares, thin vermilion of the upper lip, and full or everted vermilion of the lower lip [ • A subset of individuals have external ear anomalies, including overfolded helix, everted ears, and small earlobe [ ## Genotype-Phenotype Correlations With the limited number of affected individuals reported to date, no statistically significant genotype-phenotype correlations can be made. However, certain features described to date have been seen only in individuals with loss-of-function (nonsense and frameshift) variants [ Blue sclerae in infancy Epicanthal folds Micrognathia or retrognathia Short stature (mild) • Blue sclerae in infancy • Epicanthal folds • Micrognathia or retrognathia • Short stature (mild) ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No disease phenotypes other than those discussed in this Individuals with larger deletions of 2p15p16.1 encompassing Those with larger deletions typically have more severe structural brain defects, including cortical dysplasia and/or atrophy [ Congenital malformations (genitourinary anomalies and/or congenital heart defects) have only been identified in individuals with contiguous gene deletions involving One affected individual with a 2.5-Mb deletion of 2p15p16.1 encompassing multiple adjacent genes was reported to have intractable epilepsy [ • Those with larger deletions typically have more severe structural brain defects, including cortical dysplasia and/or atrophy [ • Congenital malformations (genitourinary anomalies and/or congenital heart defects) have only been identified in individuals with contiguous gene deletions involving • One affected individual with a 2.5-Mb deletion of 2p15p16.1 encompassing multiple adjacent genes was reported to have intractable epilepsy [ ## Differential Diagnosis Note: The phenotypic features associated with Selected Disorders to Consider in the Differential Diagnosis of Facial features incl blepharophimosis & bulbous or tubular nose More frequent congenital anomalies (renal & urogenital anomalies, heart defects) ID, hypotonia, small head circumference, everted lower lip, short nose, short stature Facial gestalt in a subset of those w/ Craniofacial features (telecanthus, tented vermilion of upper lip, progressive coarsening of facial features), genital abnormalities, & skeletal abnormalities ID is typically severe to profound in boys (heterozygous females w/craniofacial features, ID, & growth restriction have been described). Alpha-thalassemia (in ~85% of individuals) AD = autosomal dominant; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked • Facial features incl blepharophimosis & bulbous or tubular nose • More frequent congenital anomalies (renal & urogenital anomalies, heart defects) • ID, hypotonia, small head circumference, everted lower lip, short nose, short stature • Facial gestalt in a subset of those w/ • Craniofacial features (telecanthus, tented vermilion of upper lip, progressive coarsening of facial features), genital abnormalities, & skeletal abnormalities • ID is typically severe to profound in boys (heterozygous females w/craniofacial features, ID, & growth restriction have been described). • Alpha-thalassemia (in ~85% of individuals) ## Management To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with EEG if seizures suspected Consider brain MRI to detect brain abnormalities. Incl eval of motor, speech &language, general cognitive, & vocational skills Refer to speech & rehab therapy, PT, & OT as appropriate. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disorder; HbF = fetal hemoglobin; HPLC = high-performance liquid chromatography; OT = occupational therapist; PT = physical therapist Treatment of Manifestations in Individuals with ASM = anti-seizure medication; GERD = gastroesophageal reflux disorder; 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. 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, guardianship, 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 and/or a psychiatrist may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Recommended Surveillance for Individuals with GERD = gastroesophageal reflux disorder See Search • EEG if seizures suspected • Consider brain MRI to detect brain abnormalities. • Incl eval of motor, speech &language, general cognitive, & vocational skills • Refer to speech & rehab therapy, PT, & OT as appropriate. • 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, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with Recommended Evaluations Following Initial Diagnosis in Individuals with EEG if seizures suspected Consider brain MRI to detect brain abnormalities. Incl eval of motor, speech &language, general cognitive, & vocational skills Refer to speech & rehab therapy, PT, & OT as appropriate. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disorder; HbF = fetal hemoglobin; HPLC = high-performance liquid chromatography; OT = occupational therapist; PT = physical therapist • EEG if seizures suspected • Consider brain MRI to detect brain abnormalities. • Incl eval of motor, speech &language, general cognitive, & vocational skills • Refer to speech & rehab therapy, PT, & OT as appropriate. ## Treatment of Manifestations Treatment of Manifestations in Individuals with ASM = anti-seizure medication; GERD = gastroesophageal reflux disorder; 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. 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, guardianship, 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 and/or a psychiatrist may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a 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, guardianship, and medical arrangements should begin at age 12 years. Developmental pediatricians can provide assistance with transition to adulthood. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. In the US, an IEP based on the individual's level of function should be developed by the local public school district. Affected children are permitted to remain in the public school district until age 21. Discussion about transition plans including financial, vocation/employment, guardianship, 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, guardianship, 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 and/or a psychiatrist may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with GERD = gastroesophageal reflux disorder ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Almost all probands reported to date with One individual diagnosed with Molecular genetic testing is recommended for the parents of a proband with an apparent If the Theoretically, if the parent is the individual in whom the 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%. It is not possible to reliably predict clinical severity in sibs who inherit the pathogenic variant. 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. • Almost all probands reported to date with • One individual diagnosed with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • Theoretically, if the parent is the individual in whom the • 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%. It is not possible to reliably predict clinical severity in sibs who inherit the pathogenic variant. • 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 Almost all probands reported to date with One individual diagnosed with Molecular genetic testing is recommended for the parents of a proband with an apparent If the Theoretically, if the parent is the individual in whom the 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%. It is not possible to reliably predict clinical severity in sibs who inherit the pathogenic variant. If the • Almost all probands reported to date with • One individual diagnosed with • Molecular genetic testing is recommended for the parents of a proband with an apparent • If the • Theoretically, if the parent is the individual in whom the • 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%. It is not possible to reliably predict clinical severity in sibs who inherit the pathogenic variant. • 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 United Kingdom Speaking out for People with Intellectual and Developmental Disabilities • • • • • • Canada • • • United Kingdom • • • Speaking out for People with Intellectual and Developmental Disabilities • • • ## Molecular Genetics BCL11A-Related Intellectual Disability: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for BCL11A-Related Intellectual Disability ( BCL11A is a COUP-TF-interacting transcription factor that associates with the Multiple alternatively spliced transcript variants encoding different isoforms have been identified for Pathogenic missense variants cluster in the N-terminal region of BCL11A. This region is required for localization to the nucleus, via two C2H2 zinc finger domains. N-terminal missense variants affecting BCL11A localization, dimerization, and transcriptional activity, with putative hypomorphic function, also result in a loss-of-function phenotype. Heterozygous knockout mice have decreased brain size and aberrant brain transcriptional profiles; they present impaired social memory and decreased social interaction [ BCL11A interacts with calcium/calmodulin-dependent serine kinase ( ## Molecular Pathogenesis BCL11A is a COUP-TF-interacting transcription factor that associates with the Multiple alternatively spliced transcript variants encoding different isoforms have been identified for Pathogenic missense variants cluster in the N-terminal region of BCL11A. This region is required for localization to the nucleus, via two C2H2 zinc finger domains. N-terminal missense variants affecting BCL11A localization, dimerization, and transcriptional activity, with putative hypomorphic function, also result in a loss-of-function phenotype. Heterozygous knockout mice have decreased brain size and aberrant brain transcriptional profiles; they present impaired social memory and decreased social interaction [ BCL11A interacts with calcium/calmodulin-dependent serine kinase ( ## Chapter Notes The authors of this The authors would like to thank the patients and families. Cristina Dias's work is supported by the Wellcome Trust (209568/Z/17/Z). 26 September 2019 (ma) Review posted live 11 February 2019 (ap, cd) Original submission • 26 September 2019 (ma) Review posted live • 11 February 2019 (ap, cd) Original submission ## Author Notes The authors of this ## Acknowledgments The authors would like to thank the patients and families. Cristina Dias's work is supported by the Wellcome Trust (209568/Z/17/Z). ## Revision History 26 September 2019 (ma) Review posted live 11 February 2019 (ap, cd) Original submission • 26 September 2019 (ma) Review posted live • 11 February 2019 (ap, cd) Original submission ## References ## Literature Cited	[ "C Badens, N Martini, S Courrier, V DesPortes, R Touraine, N Levy, P. Edery. ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern.. Am J Med Genet A. 2006;140:2212-5", "H Bagheri, C Badduke, Y Qiao, R Colnaghi, I Abramowicz, D Alcantara, C Dunham, J Wen, RS Wildin, MJ Nowaczyk, J Eichmeyer, A Lehman, B Maranda, S Martell, X Shan, SM Lewis, M O'Driscoll, CY Gregory-Evans, E Rajcan-Separovic. Identifying candidate genes for 2p15p16.1 microdeletion syndrome using clinical, genomic, and functional analysis.. JCI insight. 2016;1", "TB Balci, SL Sawyer, J Davila, P Humphreys, DA Dyment. 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bcns	bcns	[ "Basal Cell Nevus Syndrome (BCNS)", "Gorlin Syndrome", "NBCCS", "Gorlin Syndrome", "Basal Cell Nevus Syndrome (BCNS)", "NBCCS", "Protein patched homolog 1", "Suppressor of fused homolog", "PTCH1", "SUFU", "Nevoid Basal Cell Carcinoma Syndrome" ]	Nevoid Basal Cell Carcinoma Syndrome	D Gareth Evans	Summary Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by the development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs), usually from the third decade onward. Many individuals have a recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia. Most individuals have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae). Ectopic calcification, particularly in the falx, is present in 90% of affected individuals by age 30 years. Cardiac and ovarian fibromas occur in approximately 2% and 20% of individuals, respectively. Approximately 5% of all children with NBCCS develop medulloblastoma (primitive neuroectodermal tumor), generally the desmoplastic subtype. The risk of developing medulloblastoma is substantially higher in individuals with an The diagnosis of NBCCS is established in a proband who fulfills proposed diagnostic clinical criteria. Identification of a heterozygous germline pathogenic variant in NBCCS is inherited in an autosomal dominant manner. Approximately 70%-80% of individuals with NBCCS have an affected parent and about 20%-30% have NBCCS as the result of a	## Diagnosis No consensus clinical diagnostic criteria for nevoid basal cell carcinoma syndrome (NBCCS) have been published. Diagnostic criteria for NBCCS have been proposed [ NBCCS Childhood medulloblastoma (also called primitive neuroectodermal tumor) Note: A consensus meeting consisting of US-based experts (with one French participant) has suggested changing medulloblastoma to a major criterion and allowing the diagnosis of NBCCS with only two minor criteria in addition to a major criterion [ Lymphomesenteric or pleural cysts Macrocephaly (OFC >97th centile) Cleft lip/palate Rib/vertebral anomalies observed on chest and/or spine radiograph: bifid/splayed/extra ribs, bifid vertebrae Note: (1) To verify a clinical diagnosis of NBCCS, AP and lateral radiographs of the skull, an orthopantogram, chest radiograph, and spine radiograph are usually necessary. (2) Radiographs should be avoided in children if they are not needed to confirm the diagnosis of NBCCS. (3) If radiographs have been taken previously (i.e., before the diagnosis of NBCCS is being considered), providers should obtain and review the original radiographs rather than repeat them because individuals with NBCCS are susceptible to x-irradiation. (4) Even when present, bifid ribs, bifid vertebrae, and falx calcification are often not mentioned in formal reports of radiographic findings, as these can also be normal variations in the general population. (5) Radiographic findings may be helpful in suggesting or confirming the diagnosis in young children with cardiac fibromas, cleft lip/palate, polydactyly, or macrocephaly. Preaxial or postaxial polydactyly Ovarian/cardiac fibromas Ocular anomalies (e.g., cataract, developmental defects, and pigmentary changes of the retinal epithelium) The clinical diagnosis of NBCCS can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ A clinical diagnosis of NBCCS Note: Some clinical features of NBCCS only become apparent with increasing age (e.g., BCCs, jaw keratocysts, ectopic calcifications, meningioma, and gonadal tumors). Clinical diagnostic criteria may be more informative in adults with NBCCS [ The molecular diagnosis of NBCCS Note: Identification of an identical Molecular testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of NBCCS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Nevoid Basal Cell Carcinoma Syndrome NA = not applicable; NBCCS = nevoid basal cell carcinoma 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. 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Heterozygous germline pathogenic variants in • • Childhood medulloblastoma (also called primitive neuroectodermal tumor) • Note: A consensus meeting consisting of US-based experts (with one French participant) has suggested changing medulloblastoma to a major criterion and allowing the diagnosis of NBCCS with only two minor criteria in addition to a major criterion [ • Lymphomesenteric or pleural cysts • Macrocephaly (OFC >97th centile) • Cleft lip/palate • Rib/vertebral anomalies observed on chest and/or spine radiograph: bifid/splayed/extra ribs, bifid vertebrae • Note: (1) To verify a clinical diagnosis of NBCCS, AP and lateral radiographs of the skull, an orthopantogram, chest radiograph, and spine radiograph are usually necessary. (2) Radiographs should be avoided in children if they are not needed to confirm the diagnosis of NBCCS. (3) If radiographs have been taken previously (i.e., before the diagnosis of NBCCS is being considered), providers should obtain and review the original radiographs rather than repeat them because individuals with NBCCS are susceptible to x-irradiation. (4) Even when present, bifid ribs, bifid vertebrae, and falx calcification are often not mentioned in formal reports of radiographic findings, as these can also be normal variations in the general population. (5) Radiographic findings may be helpful in suggesting or confirming the diagnosis in young children with cardiac fibromas, cleft lip/palate, polydactyly, or macrocephaly. • Preaxial or postaxial polydactyly • Ovarian/cardiac fibromas • Ocular anomalies (e.g., cataract, developmental defects, and pigmentary changes of the retinal epithelium) ## Suggestive Findings NBCCS Childhood medulloblastoma (also called primitive neuroectodermal tumor) Note: A consensus meeting consisting of US-based experts (with one French participant) has suggested changing medulloblastoma to a major criterion and allowing the diagnosis of NBCCS with only two minor criteria in addition to a major criterion [ Lymphomesenteric or pleural cysts Macrocephaly (OFC >97th centile) Cleft lip/palate Rib/vertebral anomalies observed on chest and/or spine radiograph: bifid/splayed/extra ribs, bifid vertebrae Note: (1) To verify a clinical diagnosis of NBCCS, AP and lateral radiographs of the skull, an orthopantogram, chest radiograph, and spine radiograph are usually necessary. (2) Radiographs should be avoided in children if they are not needed to confirm the diagnosis of NBCCS. (3) If radiographs have been taken previously (i.e., before the diagnosis of NBCCS is being considered), providers should obtain and review the original radiographs rather than repeat them because individuals with NBCCS are susceptible to x-irradiation. (4) Even when present, bifid ribs, bifid vertebrae, and falx calcification are often not mentioned in formal reports of radiographic findings, as these can also be normal variations in the general population. (5) Radiographic findings may be helpful in suggesting or confirming the diagnosis in young children with cardiac fibromas, cleft lip/palate, polydactyly, or macrocephaly. Preaxial or postaxial polydactyly Ovarian/cardiac fibromas Ocular anomalies (e.g., cataract, developmental defects, and pigmentary changes of the retinal epithelium) • • Childhood medulloblastoma (also called primitive neuroectodermal tumor) • Note: A consensus meeting consisting of US-based experts (with one French participant) has suggested changing medulloblastoma to a major criterion and allowing the diagnosis of NBCCS with only two minor criteria in addition to a major criterion [ • Lymphomesenteric or pleural cysts • Macrocephaly (OFC >97th centile) • Cleft lip/palate • Rib/vertebral anomalies observed on chest and/or spine radiograph: bifid/splayed/extra ribs, bifid vertebrae • Note: (1) To verify a clinical diagnosis of NBCCS, AP and lateral radiographs of the skull, an orthopantogram, chest radiograph, and spine radiograph are usually necessary. (2) Radiographs should be avoided in children if they are not needed to confirm the diagnosis of NBCCS. (3) If radiographs have been taken previously (i.e., before the diagnosis of NBCCS is being considered), providers should obtain and review the original radiographs rather than repeat them because individuals with NBCCS are susceptible to x-irradiation. (4) Even when present, bifid ribs, bifid vertebrae, and falx calcification are often not mentioned in formal reports of radiographic findings, as these can also be normal variations in the general population. (5) Radiographic findings may be helpful in suggesting or confirming the diagnosis in young children with cardiac fibromas, cleft lip/palate, polydactyly, or macrocephaly. • Preaxial or postaxial polydactyly • Ovarian/cardiac fibromas • Ocular anomalies (e.g., cataract, developmental defects, and pigmentary changes of the retinal epithelium) ## Establishing the Diagnosis The clinical diagnosis of NBCCS can be Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ A clinical diagnosis of NBCCS Note: Some clinical features of NBCCS only become apparent with increasing age (e.g., BCCs, jaw keratocysts, ectopic calcifications, meningioma, and gonadal tumors). Clinical diagnostic criteria may be more informative in adults with NBCCS [ The molecular diagnosis of NBCCS Note: Identification of an identical Molecular testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of NBCCS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Nevoid Basal Cell Carcinoma Syndrome NA = not applicable; NBCCS = nevoid basal cell carcinoma 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. 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Heterozygous germline pathogenic variants in ## Clinical Diagnosis A clinical diagnosis of NBCCS Note: Some clinical features of NBCCS only become apparent with increasing age (e.g., BCCs, jaw keratocysts, ectopic calcifications, meningioma, and gonadal tumors). Clinical diagnostic criteria may be more informative in adults with NBCCS [ ## Molecular Diagnosis The molecular diagnosis of NBCCS Note: Identification of an identical Molecular testing approaches can include a combination of For an introduction to multigene panels click When the diagnosis of NBCCS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Nevoid Basal Cell Carcinoma Syndrome NA = not applicable; NBCCS = nevoid basal cell carcinoma 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. 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Heterozygous germline pathogenic variants in ## For an introduction to multigene panels click ## When the diagnosis of NBCCS has not been considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Nevoid Basal Cell Carcinoma Syndrome NA = not applicable; NBCCS = nevoid basal cell carcinoma 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. 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. Data derived from the subscription-based professional view of Human Gene Mutation Database [ Heterozygous germline pathogenic variants in ## Clinical Characteristics Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by macrocephaly, characteristic facial features, congenital rib/vertebral anomalies, ectopic calcification of the falx, basal cell carcinoma, and an increased risk of medulloblastoma and other tumors. To date, more than 500 individuals have been identified with Nevoid Basal Cell Carcinoma Syndrome: Frequency of Select Features Based on NBCCS = nevoid basal cell carcinoma syndrome; NR = to date, this feature has not been reported in this group BCCs occur more frequently with age, although 10% of individuals with NBCCS never develop a BCC. Individuals with type 1 skin (white skin that burns but never tans) and individuals with excessive ultraviolet light exposure seem especially prone to developing large numbers of BCCs. Some affected individuals appear to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy. Jaw keratocysts have not been reported in individuals with Ameloblastoma, a rare malignant transformation of a jaw keratocyst, has been reported in individuals with NBCCS at least six times [ A review of 182 genotyped individuals with NBCCS found that individuals with Approximately 90% of individuals with Approximately 60% of individuals with a The risk for medulloblastoma in individuals with Facial features are likely more subtle in individuals with an Overall, clinical features are milder in individuals with Individuals with a heterozygous germline Although NBCCS shows intra- and interfamilial variation in expression, experience clinically and from molecular testing is compatible with complete penetrance for The prevalence of NBCCS is reported to be between 1:18,976 and 1:30,827 [ ## Clinical Description Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by macrocephaly, characteristic facial features, congenital rib/vertebral anomalies, ectopic calcification of the falx, basal cell carcinoma, and an increased risk of medulloblastoma and other tumors. To date, more than 500 individuals have been identified with Nevoid Basal Cell Carcinoma Syndrome: Frequency of Select Features Based on NBCCS = nevoid basal cell carcinoma syndrome; NR = to date, this feature has not been reported in this group BCCs occur more frequently with age, although 10% of individuals with NBCCS never develop a BCC. Individuals with type 1 skin (white skin that burns but never tans) and individuals with excessive ultraviolet light exposure seem especially prone to developing large numbers of BCCs. Some affected individuals appear to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy. Jaw keratocysts have not been reported in individuals with Ameloblastoma, a rare malignant transformation of a jaw keratocyst, has been reported in individuals with NBCCS at least six times [ ## Craniofacial Features ## Skeletal Features ## Tumors BCCs occur more frequently with age, although 10% of individuals with NBCCS never develop a BCC. Individuals with type 1 skin (white skin that burns but never tans) and individuals with excessive ultraviolet light exposure seem especially prone to developing large numbers of BCCs. Some affected individuals appear to be particularly radiosensitive, with new BCCs appearing in the field of radiation following radiotherapy. Jaw keratocysts have not been reported in individuals with Ameloblastoma, a rare malignant transformation of a jaw keratocyst, has been reported in individuals with NBCCS at least six times [ ## Other Reported Features ## Phenotype Correlations by Gene A review of 182 genotyped individuals with NBCCS found that individuals with Approximately 90% of individuals with Approximately 60% of individuals with a The risk for medulloblastoma in individuals with Facial features are likely more subtle in individuals with an Overall, clinical features are milder in individuals with Individuals with a heterozygous germline ## A review of 182 genotyped individuals with NBCCS found that individuals with Approximately 90% of individuals with Approximately 60% of individuals with a The risk for medulloblastoma in individuals with ## Facial features are likely more subtle in individuals with an Overall, clinical features are milder in individuals with Individuals with a heterozygous germline ## Genotype-Phenotype Correlations ## Penetrance Although NBCCS shows intra- and interfamilial variation in expression, experience clinically and from molecular testing is compatible with complete penetrance for ## Prevalence The prevalence of NBCCS is reported to be between 1:18,976 and 1:30,827 [ ## Genetically Related (Allelic) Disorders A non-recurrent contiguous gene deletion at chromosome 9q22.3 encompassing a 352-kb critical region including Note: Pathogenic variants in • A non-recurrent contiguous gene deletion at chromosome 9q22.3 encompassing a 352-kb critical region including ## Differential Diagnosis Genes of Interest in the Differential Diagnosis of Nevoid Basal Cell Carcinoma Syndrome Milia BCC Trichoepitheliomas & cylindromas Absence of macrocephaly & other congenital & skeletal features of NBCCS Multiple BCCs Medulloblastoma Meningioma Frontal bossing Multinodular thyroid goiter GI polyposis GI adenoma Macrocephaly DD Broad & prominent forehead, dolichocephaly, sparse frontotemporal hair, downslanting palpebral fissures, long & narrow face Mild-to-severe ID Risk of other types of tumors not reported in NBCCS Skin features such as trichilemmoma Lhermitte-Duclos disease Follicular atrophoderma on the dorsum of hands & feet, ↓ sweating, & hypotrichosis Pitting on backs of hands is reminiscent of orange peel & quite unlike palmar & plantar pits of NBCCS. Absence of macrocephaly & other congenital & skeletal features of NBCCS AD = autosomal dominant; BCC = basal cell carcinoma; DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; MOI = mode of inheritance; NBCCS = nevoid basal cell carcinoma syndrome; XL = X-linked Although increased risk of medulloblastoma is reported in individuals with a germline pathogenic variant in One individual with a Rombo syndrome, a dominantly inherited condition similar to Bazex-Dupre-Christol syndrome, has been reported in a single family (OMIM Acquired causes of multiple BCCs include arsenic exposure. • Milia • BCC • Trichoepitheliomas & cylindromas • Absence of macrocephaly & other congenital & skeletal features of NBCCS • Multiple BCCs • Medulloblastoma • Meningioma • Frontal bossing • Multinodular thyroid goiter • GI polyposis • GI adenoma • Macrocephaly • DD • Broad & prominent forehead, dolichocephaly, sparse frontotemporal hair, downslanting palpebral fissures, long & narrow face • Mild-to-severe ID • Risk of other types of tumors not reported in NBCCS • Skin features such as trichilemmoma • Lhermitte-Duclos disease • Follicular atrophoderma on the dorsum of hands & feet, ↓ sweating, & hypotrichosis • Pitting on backs of hands is reminiscent of orange peel & quite unlike palmar & plantar pits of NBCCS. • Absence of macrocephaly & other congenital & skeletal features of NBCCS ## Management To establish the extent of disease and needs in an individual diagnosed with nevoid basal cell carcinoma syndrome (NBCCS), the evaluations summarized in Nevoid Basal Cell Carcinoma Syndrome: Recommended Evaluations Following Initial Diagnosis Eval by dentist or orthodontist familiar w/NBCCS Jaw radiograph (orthopantogram) BCC = basal cell carcinoma; MOI = mode of inheritance; NBCCS = nevoid basal cell carcinoma syndrome Medical geneticist, certified genetic counselor, certified advanced genetic nurse Manifestations should be treated by specialists (e.g., ophthalmologist, orthopedist, dermatologist, plastic surgeon, oral surgeon, neurosurgeon, oncologist, gynecologist) experienced with the condition (see Nevoid Basal Cell Carcinoma Syndrome: Treatment of Manifestations Avoid direct sun exposure. Cover up exposed skin by wearing long sleeves, high collars, & hats. Complete sunblock should be used. Surgical treatment using Mohs microsurgery Photodynamic therapy is particularly suitable for thin lesions of <2 mm on ultrasound. Treatment of severe &/or advanced BCCs w/sonic hedgehog inhibitors (e.g., vismodegib) is particularly helpful w/lesions around the eyes, BCC = basal cell carcinoma; NICE = National Institute for Health and Care Excellence; UK = United Kingdom Systemic treatment of BCCs with retinoids (e.g., etretinate) is possible but often not well tolerated. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Nevoid Basal Cell Carcinoma Syndrome: Recommended Surveillance Assess head circumference using gender- & ethnicity-specific growth charts. Rapid enlargement of head circumference should prompt eval for possible hydrocephalus. In those w/ In those w/ In those w/clinical diagnosis of NBCCS & BCC = basal cell carcinoma; ENT = ears, nose, and throat specialist; NBCCS = nevoid basal cell carcinoma syndrome Avoid unnecessary radiation exposure from the environment, investigative radiology, or radiotherapy treatment. Use of radiotherapy can lead to the development of thousands of basal cell carcinomas (BCCs) in the radiation field [ Diagnostic radiographs should be used sparingly. Avoid direct sun exposure as much as possible. Excessive sun exposure increases the likelihood of developing BCCs. It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives (including children) of an affected individual in order to identify as early as possible those who would benefit from Molecular genetic testing if the Clinical examination and radiographs of the skull for calcification if the pathogenic variant in the family is not known; these may be less likely to clarify the genetic status in a very young child because of the age-related features of NBCCS. See Since individuals with NBCCS have a large head circumference, a woman who is carrying an affected fetus should be assessed for the need for either early induction of labor or cesarean section delivery due to cephalopelvic disproportion. Aminolevulinic acid has been investigated for treatment of BCCs [ Search • Eval by dentist or orthodontist familiar w/NBCCS • Jaw radiograph (orthopantogram) • Avoid direct sun exposure. • Cover up exposed skin by wearing long sleeves, high collars, & hats. • Complete sunblock should be used. • Surgical treatment using Mohs microsurgery • Photodynamic therapy is particularly suitable for thin lesions of <2 mm on ultrasound. • Treatment of severe &/or advanced BCCs w/sonic hedgehog inhibitors (e.g., vismodegib) is particularly helpful w/lesions around the eyes, • Assess head circumference using gender- & ethnicity-specific growth charts. • Rapid enlargement of head circumference should prompt eval for possible hydrocephalus. • In those w/ • In those w/ • In those w/clinical diagnosis of NBCCS & • Molecular genetic testing if the • Clinical examination and radiographs of the skull for calcification if the pathogenic variant in the family is not known; these may be less likely to clarify the genetic status in a very young child because of the age-related features of NBCCS. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with nevoid basal cell carcinoma syndrome (NBCCS), the evaluations summarized in Nevoid Basal Cell Carcinoma Syndrome: Recommended Evaluations Following Initial Diagnosis Eval by dentist or orthodontist familiar w/NBCCS Jaw radiograph (orthopantogram) BCC = basal cell carcinoma; MOI = mode of inheritance; NBCCS = nevoid basal cell carcinoma syndrome Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Eval by dentist or orthodontist familiar w/NBCCS • Jaw radiograph (orthopantogram) ## Treatment of Manifestations Manifestations should be treated by specialists (e.g., ophthalmologist, orthopedist, dermatologist, plastic surgeon, oral surgeon, neurosurgeon, oncologist, gynecologist) experienced with the condition (see Nevoid Basal Cell Carcinoma Syndrome: Treatment of Manifestations Avoid direct sun exposure. Cover up exposed skin by wearing long sleeves, high collars, & hats. Complete sunblock should be used. Surgical treatment using Mohs microsurgery Photodynamic therapy is particularly suitable for thin lesions of <2 mm on ultrasound. Treatment of severe &/or advanced BCCs w/sonic hedgehog inhibitors (e.g., vismodegib) is particularly helpful w/lesions around the eyes, BCC = basal cell carcinoma; NICE = National Institute for Health and Care Excellence; UK = United Kingdom Systemic treatment of BCCs with retinoids (e.g., etretinate) is possible but often not well tolerated. • Avoid direct sun exposure. • Cover up exposed skin by wearing long sleeves, high collars, & hats. • Complete sunblock should be used. • Surgical treatment using Mohs microsurgery • Photodynamic therapy is particularly suitable for thin lesions of <2 mm on ultrasound. • Treatment of severe &/or advanced BCCs w/sonic hedgehog inhibitors (e.g., vismodegib) is particularly helpful w/lesions around the eyes, ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Nevoid Basal Cell Carcinoma Syndrome: Recommended Surveillance Assess head circumference using gender- & ethnicity-specific growth charts. Rapid enlargement of head circumference should prompt eval for possible hydrocephalus. In those w/ In those w/ In those w/clinical diagnosis of NBCCS & BCC = basal cell carcinoma; ENT = ears, nose, and throat specialist; NBCCS = nevoid basal cell carcinoma syndrome • Assess head circumference using gender- & ethnicity-specific growth charts. • Rapid enlargement of head circumference should prompt eval for possible hydrocephalus. • In those w/ • In those w/ • In those w/clinical diagnosis of NBCCS & ## Agents/Circumstances to Avoid Avoid unnecessary radiation exposure from the environment, investigative radiology, or radiotherapy treatment. Use of radiotherapy can lead to the development of thousands of basal cell carcinomas (BCCs) in the radiation field [ Diagnostic radiographs should be used sparingly. Avoid direct sun exposure as much as possible. Excessive sun exposure increases the likelihood of developing BCCs. ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives (including children) of an affected individual in order to identify as early as possible those who would benefit from Molecular genetic testing if the Clinical examination and radiographs of the skull for calcification if the pathogenic variant in the family is not known; these may be less likely to clarify the genetic status in a very young child because of the age-related features of NBCCS. See • Molecular genetic testing if the • Clinical examination and radiographs of the skull for calcification if the pathogenic variant in the family is not known; these may be less likely to clarify the genetic status in a very young child because of the age-related features of NBCCS. ## Pregnancy Management Since individuals with NBCCS have a large head circumference, a woman who is carrying an affected fetus should be assessed for the need for either early induction of labor or cesarean section delivery due to cephalopelvic disproportion. ## Therapies Under Investigation Aminolevulinic acid has been investigated for treatment of BCCs [ Search ## Genetic Counseling Nevoid basal cell carcinoma syndrome (NBCCS) is inherited in an autosomal dominant manner. Approximately 70%-80% of individuals diagnosed with NBCCS have an affected parent. A proband with NBCCS may have the disorder as the result of a Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include a detailed skin examination, anterior to posterior (AP) and lateral radiographs of the skull, chest radiograph, and spine radiograph. Molecular genetic testing can be used to clarify the genetic status of a parent if a If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic and germline mosaicism for The family history of some individuals diagnosed with NBCCS may appear to be negative as a result of failure to recognize the disorder in a family member, early death of the parent before the onset of symptoms, late onset of the disorder in the affected parent, or reduced penetrance in a parent 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 a molecular diagnosis has been established in the proband and the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for NBCCS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. Each child of an individual with NBCCS has a 50% chance of inheriting the disorder. The offspring of an individual with mild NBCCS caused by somatic mosaicism may have a less than 50% chance of inheriting the pathogenic variant [ See Management, Predictive genetic testing for at-risk asymptomatic family members requires prior identification of the Clinical examination and radiographs frequently act as a "genetic test" in an apparently unaffected individual. (Clinical examination and radiographs of the skull for calcification may be less likely to clarify the genetic status in a very young child because of the age-related nature of features in NBCCS.) Individuals need to be aware of the predictive implications of these examinations as well as those of molecular genetic testing of Because of the need for surveillance for complications of NBCCS (most notably medulloblastoma) during childhood, clarification of the genetic status of at-risk individuals during childhood is appropriate. Parents often want to know the genetic status of their children prior to initiating screening 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. 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. If the NBCCS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for NBCCS are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Approximately 70%-80% of individuals diagnosed with NBCCS have an affected parent. • A proband with NBCCS may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include a detailed skin examination, anterior to posterior (AP) and lateral radiographs of the skull, chest radiograph, and spine radiograph. Molecular genetic testing can be used to clarify the genetic status of a parent if a • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and germline mosaicism for • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and germline mosaicism for • The family history of some individuals diagnosed with NBCCS may appear to be negative as a result of failure to recognize the disorder in a family member, early death of the parent before the onset of symptoms, late onset of the disorder in the affected parent, or reduced penetrance in a parent heterozygous for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and germline mosaicism for • 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 a molecular diagnosis has been established in the proband and the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for NBCCS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • Each child of an individual with NBCCS has a 50% chance of inheriting the disorder. • The offspring of an individual with mild NBCCS caused by somatic mosaicism may have a less than 50% chance of inheriting the pathogenic variant [ • Predictive genetic testing for at-risk asymptomatic family members requires prior identification of the • Clinical examination and radiographs frequently act as a "genetic test" in an apparently unaffected individual. (Clinical examination and radiographs of the skull for calcification may be less likely to clarify the genetic status in a very young child because of the age-related nature of features in NBCCS.) Individuals need to be aware of the predictive implications of these examinations as well as those of molecular genetic testing of • Because of the need for surveillance for complications of NBCCS (most notably medulloblastoma) during childhood, clarification of the genetic status of at-risk individuals during childhood is appropriate. Parents often want to know the genetic status of their children prior to initiating screening 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. • 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 Nevoid basal cell carcinoma syndrome (NBCCS) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 70%-80% of individuals diagnosed with NBCCS have an affected parent. A proband with NBCCS may have the disorder as the result of a Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include a detailed skin examination, anterior to posterior (AP) and lateral radiographs of the skull, chest radiograph, and spine radiograph. Molecular genetic testing can be used to clarify the genetic status of a parent if a If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. * A parent with somatic and germline mosaicism for The family history of some individuals diagnosed with NBCCS may appear to be negative as a result of failure to recognize the disorder in a family member, early death of the parent before the onset of symptoms, late onset of the disorder in the affected parent, or reduced penetrance in a parent 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 a molecular diagnosis has been established in the proband and the If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for NBCCS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. Each child of an individual with NBCCS has a 50% chance of inheriting the disorder. The offspring of an individual with mild NBCCS caused by somatic mosaicism may have a less than 50% chance of inheriting the pathogenic variant [ • Approximately 70%-80% of individuals diagnosed with NBCCS have an affected parent. • A proband with NBCCS may have the disorder as the result of a • Recommendations for the evaluation of parents of a proband who appears to be the only affected family member (i.e., a simplex case) include a detailed skin examination, anterior to posterior (AP) and lateral radiographs of the skull, chest radiograph, and spine radiograph. Molecular genetic testing can be used to clarify the genetic status of a parent if a • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and germline mosaicism for • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and germline mosaicism for • The family history of some individuals diagnosed with NBCCS may appear to be negative as a result of failure to recognize the disorder in a family member, early death of the parent before the onset of symptoms, late onset of the disorder in the affected parent, or reduced penetrance in a parent heterozygous for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ (gonadal) cells only. • * A parent with somatic and germline mosaicism for • 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 a molecular diagnosis has been established in the proband and the • If the parents are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low. However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for NBCCS because of the possibility of reduced penetrance in a heterozygous parent or parental germline mosaicism. • Each child of an individual with NBCCS has a 50% chance of inheriting the disorder. • The offspring of an individual with mild NBCCS caused by somatic mosaicism may have a less than 50% chance of inheriting the pathogenic variant [ ## Related Genetic Counseling Issues See Management, Predictive genetic testing for at-risk asymptomatic family members requires prior identification of the Clinical examination and radiographs frequently act as a "genetic test" in an apparently unaffected individual. (Clinical examination and radiographs of the skull for calcification may be less likely to clarify the genetic status in a very young child because of the age-related nature of features in NBCCS.) Individuals need to be aware of the predictive implications of these examinations as well as those of molecular genetic testing of Because of the need for surveillance for complications of NBCCS (most notably medulloblastoma) during childhood, clarification of the genetic status of at-risk individuals during childhood is appropriate. Parents often want to know the genetic status of their children prior to initiating screening 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. 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 genetic testing for at-risk asymptomatic family members requires prior identification of the • Clinical examination and radiographs frequently act as a "genetic test" in an apparently unaffected individual. (Clinical examination and radiographs of the skull for calcification may be less likely to clarify the genetic status in a very young child because of the age-related nature of features in NBCCS.) Individuals need to be aware of the predictive implications of these examinations as well as those of molecular genetic testing of • Because of the need for surveillance for complications of NBCCS (most notably medulloblastoma) during childhood, clarification of the genetic status of at-risk individuals during childhood is appropriate. Parents often want to know the genetic status of their children prior to initiating screening 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. • 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 If the NBCCS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for NBCCS are possible. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources • • • • ## Molecular Genetics Nevoid Basal Cell Carcinoma Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Nevoid Basal Cell Carcinoma Syndrome ( ## Molecular Pathogenesis ## Chapter Notes Dr Miriam Smith ( Dr Smith is also interested in hearing from clinicians treating families affected by NBCCS 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 Miriam Smith to inquire about review of The author acknowledges research support from the UK Gorlin Group. D Gareth Evans, MD, FRCP (2002-2024)Peter A Farndon, MD, FRCP; University of Birmingham (2002-2024) 22 February 2024 (sw) Comprehensive update posted live 29 March 2018 (sw) Comprehensive update posted live 1 October 2015 (me) Comprehensive update posted live 7 March 2013 (me) Comprehensive update posted live 22 July 2010 (me) Comprehensive update posted live 25 January 2008 (me) Comprehensive update posted live 6 October 2004 (me) Comprehensive update posted live 20 June 2002 (me) Review posted live 21 November 2001 (pf) Original submission • 22 February 2024 (sw) Comprehensive update posted live • 29 March 2018 (sw) Comprehensive update posted live • 1 October 2015 (me) Comprehensive update posted live • 7 March 2013 (me) Comprehensive update posted live • 22 July 2010 (me) Comprehensive update posted live • 25 January 2008 (me) Comprehensive update posted live • 6 October 2004 (me) Comprehensive update posted live • 20 June 2002 (me) Review posted live • 21 November 2001 (pf) Original submission ## Author Notes Dr Miriam Smith ( Dr Smith is also interested in hearing from clinicians treating families affected by NBCCS 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 Miriam Smith to inquire about review of ## Acknowledgments The author acknowledges research support from the UK Gorlin Group. ## Author History D Gareth Evans, MD, FRCP (2002-2024)Peter A Farndon, MD, FRCP; University of Birmingham (2002-2024) ## Revision History 22 February 2024 (sw) Comprehensive update posted live 29 March 2018 (sw) Comprehensive update posted live 1 October 2015 (me) Comprehensive update posted live 7 March 2013 (me) Comprehensive update posted live 22 July 2010 (me) Comprehensive update posted live 25 January 2008 (me) Comprehensive update posted live 6 October 2004 (me) Comprehensive update posted live 20 June 2002 (me) Review posted live 21 November 2001 (pf) Original submission • 22 February 2024 (sw) Comprehensive update posted live • 29 March 2018 (sw) Comprehensive update posted live • 1 October 2015 (me) Comprehensive update posted live • 7 March 2013 (me) Comprehensive update posted live • 22 July 2010 (me) Comprehensive update posted live • 25 January 2008 (me) Comprehensive update posted live • 6 October 2004 (me) Comprehensive update posted live • 20 June 2002 (me) Review posted live • 21 November 2001 (pf) Original submission ## References American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available ## Published Guidelines / Consensus Statements American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available ## Literature Cited	[]	20/6/2002	22/2/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
beck-fahrner	beck-fahrner	[ "TET3-BEFAHRS", "TET3 Deficiency", "TET3 Deficiency", "TET3-BEFAHRS", "Methylcytosine dioxygenase TET3", "TET3", "TET3-Related Beck-Fahrner Syndrome" ]		Jill A Fahrner	Summary The diagnosis of	## Diagnosis No consensus clinical diagnostic criteria for Mild-to-severe developmental delay or intellectual disability AND Any of the following features presenting in infancy or childhood: Generalized hypotonia of infancy Infant feeding difficulties Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis Nonspecific dysmorphic features (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 No data on detection rate of gene-targeted deletion/duplication analysis are available. • Mild-to-severe developmental delay or intellectual disability • Any of the following features presenting in infancy or childhood: • Generalized hypotonia of infancy • Infant feeding difficulties • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia • Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures • Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis • Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed • Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus • Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis • Nonspecific dysmorphic features (See • Generalized hypotonia of infancy • Infant feeding difficulties • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia • Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures • Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis • Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed • Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus • Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis • Nonspecific dysmorphic features (See • Generalized hypotonia of infancy • Infant feeding difficulties • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia • Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures • Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis • Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed • Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus • Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis • Nonspecific dysmorphic features (See ## Suggestive Findings Mild-to-severe developmental delay or intellectual disability AND Any of the following features presenting in infancy or childhood: Generalized hypotonia of infancy Infant feeding difficulties Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis Nonspecific dysmorphic features (See • Mild-to-severe developmental delay or intellectual disability • Any of the following features presenting in infancy or childhood: • Generalized hypotonia of infancy • Infant feeding difficulties • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia • Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures • Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis • Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed • Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus • Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis • Nonspecific dysmorphic features (See • Generalized hypotonia of infancy • Infant feeding difficulties • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia • Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures • Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis • Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed • Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus • Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis • Nonspecific dysmorphic features (See • Generalized hypotonia of infancy • Infant feeding difficulties • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and/or dystonia • Epilepsy, including generalized tonic-clonic, focal, and/or absence seizures • Neuropsychiatric issues, such as anxiety, attention-deficit/hyperactivity disorder, autism spectrum disorder, social interaction disorder, and occasionally depression or psychosis • Abnormalities in growth, most typically overgrowth, including macrocephaly and/or tall stature, although microcephaly and/or short stature have also been observed • Ophthalmologic involvement, such as strabismus, refractive errors, and nystagmus • Musculoskeletal findings, such as joint hypermobility, hip dysplasia, scoliosis, and kyphosis • Nonspecific dysmorphic features (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 No data on detection rate of gene-targeted deletion/duplication analysis are available. ## Clinical Characteristics To date, 28 individuals from 16 families have been identified with pathogenic variants in Defined as height and/or head circumference two standard deviations or more above or below the mean for age and sex Hypotonia is present in a subset of affected individuals and is most notable in infancy and childhood. Hypotonia can affect the acquisition of motor skills and expressive speech. Infant feeding difficulties occur in some affected individuals, which in some cases have required nasogastric or gastrostomy tube feeding (see Spasticity has been described in one individual. Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and dystonia have been observed. Generalized tonic-clonic seizures with occasional sharp- and slow-wave discharges in the right central area on EEG were observed in two brothers from a single family [ In another unrelated male, clinical presentation and EEG findings were consistent with electrical status epilepticus during slow-wave sleep, and the affected male experienced regression [ Absence seizures were observed in an affected female (whose EEG showed an abnormal focus on the right) and in an affected male. The male individual began having seizures around age 33 months, initially febrile partial seizures and then non-febrile absence seizures and myoclonic jerks of the limbs with preserved consciousness. Initial EEG showed bioccipital biphasic spikes, which progressed first to abundant bicentral spikes and waves with increased frequency during sleep and then to continuous spikes and waves of slow-wave sleep, similar to the male with electrical status epilepticus during slow-wave sleep. Seizures were refractory to therapy with sodium valproate, levetiracetam, lamotrigine, and clobazam; only a combination of sultiame and steroids was effective for this individual [ A female presented with complex partial seizures; her EEG showed an abnormal focus over the left temporal and occipital regions [ One affected individual presented with infantile spasms with an abnormal EEG at age six months [ Four affected individuals had conductive hearing loss and two experienced accompanying recurrent otitis media requiring tympanostomy tubes. Two affected sibs exhibited sensorineural hearing loss. Another affected individual had microtia and atresia of the left external ear canal. Joint hypermobility (4 affected individuals) Hip dysplasia in infancy (3 affected individuals) Kyphosis and/or scoliosis (2 affected individuals) Inguinal hernia (1 affected individual) Of those with overgrowth, four had macrocephaly, one had tall stature, and one had both macrocephaly and tall stature. The latter individual also had nephromegaly and cardiomegaly, suggestive of generalized somatic overgrowth. Of those with undergrowth, three had microcephaly, with two of these individuals also exhibiting short stature. All growth abnormalities were postnatal, except in one individual whose birth length was greater than two standard deviations above the mean for gestational age. Three individuals (including two sibs) had birth weights greater than two standard deviations below the mean for age. Increased extra-axial spaces in four unrelated affected individuals Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. Two related affected individuals – a mother and son – exhibited white matter changes, with the son's abnormality involving the periventricular white matter and the mother's not otherwise specified. Two individuals exhibited hypoplasia of the cerebellum and enlarged/mega cisterna magna; one individual exhibited hypoplasia of the tectum mesencephali. Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual Tetralogy of Fallot (1 affected individual) A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) No genotype-phenotype correlations have been confirmed. The BEFAHRS abbreviation can be used as a mnemonic for the most common features as follows: The prevalence of • Hypotonia is present in a subset of affected individuals and is most notable in infancy and childhood. Hypotonia can affect the acquisition of motor skills and expressive speech. • Infant feeding difficulties occur in some affected individuals, which in some cases have required nasogastric or gastrostomy tube feeding (see • Spasticity has been described in one individual. • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and dystonia have been observed. • Generalized tonic-clonic seizures with occasional sharp- and slow-wave discharges in the right central area on EEG were observed in two brothers from a single family [ • In another unrelated male, clinical presentation and EEG findings were consistent with electrical status epilepticus during slow-wave sleep, and the affected male experienced regression [ • Absence seizures were observed in an affected female (whose EEG showed an abnormal focus on the right) and in an affected male. The male individual began having seizures around age 33 months, initially febrile partial seizures and then non-febrile absence seizures and myoclonic jerks of the limbs with preserved consciousness. Initial EEG showed bioccipital biphasic spikes, which progressed first to abundant bicentral spikes and waves with increased frequency during sleep and then to continuous spikes and waves of slow-wave sleep, similar to the male with electrical status epilepticus during slow-wave sleep. Seizures were refractory to therapy with sodium valproate, levetiracetam, lamotrigine, and clobazam; only a combination of sultiame and steroids was effective for this individual [ • A female presented with complex partial seizures; her EEG showed an abnormal focus over the left temporal and occipital regions [ • One affected individual presented with infantile spasms with an abnormal EEG at age six months [ • Four affected individuals had conductive hearing loss and two experienced accompanying recurrent otitis media requiring tympanostomy tubes. • Two affected sibs exhibited sensorineural hearing loss. • Another affected individual had microtia and atresia of the left external ear canal. • Joint hypermobility (4 affected individuals) • Hip dysplasia in infancy (3 affected individuals) • Kyphosis and/or scoliosis (2 affected individuals) • Inguinal hernia (1 affected individual) • Of those with overgrowth, four had macrocephaly, one had tall stature, and one had both macrocephaly and tall stature. The latter individual also had nephromegaly and cardiomegaly, suggestive of generalized somatic overgrowth. • Of those with undergrowth, three had microcephaly, with two of these individuals also exhibiting short stature. • Increased extra-axial spaces in four unrelated affected individuals • Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. • The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. • Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. • The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. • Two related affected individuals – a mother and son – exhibited white matter changes, with the son's abnormality involving the periventricular white matter and the mother's not otherwise specified. • Two individuals exhibited hypoplasia of the cerebellum and enlarged/mega cisterna magna; one individual exhibited hypoplasia of the tectum mesencephali. • Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. • The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. • Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual • Tetralogy of Fallot (1 affected individual) • A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) • Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual • Tetralogy of Fallot (1 affected individual) • A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) • Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual • Tetralogy of Fallot (1 affected individual) • A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) ## Clinical Description To date, 28 individuals from 16 families have been identified with pathogenic variants in Defined as height and/or head circumference two standard deviations or more above or below the mean for age and sex Hypotonia is present in a subset of affected individuals and is most notable in infancy and childhood. Hypotonia can affect the acquisition of motor skills and expressive speech. Infant feeding difficulties occur in some affected individuals, which in some cases have required nasogastric or gastrostomy tube feeding (see Spasticity has been described in one individual. Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and dystonia have been observed. Generalized tonic-clonic seizures with occasional sharp- and slow-wave discharges in the right central area on EEG were observed in two brothers from a single family [ In another unrelated male, clinical presentation and EEG findings were consistent with electrical status epilepticus during slow-wave sleep, and the affected male experienced regression [ Absence seizures were observed in an affected female (whose EEG showed an abnormal focus on the right) and in an affected male. The male individual began having seizures around age 33 months, initially febrile partial seizures and then non-febrile absence seizures and myoclonic jerks of the limbs with preserved consciousness. Initial EEG showed bioccipital biphasic spikes, which progressed first to abundant bicentral spikes and waves with increased frequency during sleep and then to continuous spikes and waves of slow-wave sleep, similar to the male with electrical status epilepticus during slow-wave sleep. Seizures were refractory to therapy with sodium valproate, levetiracetam, lamotrigine, and clobazam; only a combination of sultiame and steroids was effective for this individual [ A female presented with complex partial seizures; her EEG showed an abnormal focus over the left temporal and occipital regions [ One affected individual presented with infantile spasms with an abnormal EEG at age six months [ Four affected individuals had conductive hearing loss and two experienced accompanying recurrent otitis media requiring tympanostomy tubes. Two affected sibs exhibited sensorineural hearing loss. Another affected individual had microtia and atresia of the left external ear canal. Joint hypermobility (4 affected individuals) Hip dysplasia in infancy (3 affected individuals) Kyphosis and/or scoliosis (2 affected individuals) Inguinal hernia (1 affected individual) Of those with overgrowth, four had macrocephaly, one had tall stature, and one had both macrocephaly and tall stature. The latter individual also had nephromegaly and cardiomegaly, suggestive of generalized somatic overgrowth. Of those with undergrowth, three had microcephaly, with two of these individuals also exhibiting short stature. All growth abnormalities were postnatal, except in one individual whose birth length was greater than two standard deviations above the mean for gestational age. Three individuals (including two sibs) had birth weights greater than two standard deviations below the mean for age. Increased extra-axial spaces in four unrelated affected individuals Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. Two related affected individuals – a mother and son – exhibited white matter changes, with the son's abnormality involving the periventricular white matter and the mother's not otherwise specified. Two individuals exhibited hypoplasia of the cerebellum and enlarged/mega cisterna magna; one individual exhibited hypoplasia of the tectum mesencephali. Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual Tetralogy of Fallot (1 affected individual) A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) • Hypotonia is present in a subset of affected individuals and is most notable in infancy and childhood. Hypotonia can affect the acquisition of motor skills and expressive speech. • Infant feeding difficulties occur in some affected individuals, which in some cases have required nasogastric or gastrostomy tube feeding (see • Spasticity has been described in one individual. • Movement disorders, including motor tics, myoclonic jerks, dysmetria, posturing, and dystonia have been observed. • Generalized tonic-clonic seizures with occasional sharp- and slow-wave discharges in the right central area on EEG were observed in two brothers from a single family [ • In another unrelated male, clinical presentation and EEG findings were consistent with electrical status epilepticus during slow-wave sleep, and the affected male experienced regression [ • Absence seizures were observed in an affected female (whose EEG showed an abnormal focus on the right) and in an affected male. The male individual began having seizures around age 33 months, initially febrile partial seizures and then non-febrile absence seizures and myoclonic jerks of the limbs with preserved consciousness. Initial EEG showed bioccipital biphasic spikes, which progressed first to abundant bicentral spikes and waves with increased frequency during sleep and then to continuous spikes and waves of slow-wave sleep, similar to the male with electrical status epilepticus during slow-wave sleep. Seizures were refractory to therapy with sodium valproate, levetiracetam, lamotrigine, and clobazam; only a combination of sultiame and steroids was effective for this individual [ • A female presented with complex partial seizures; her EEG showed an abnormal focus over the left temporal and occipital regions [ • One affected individual presented with infantile spasms with an abnormal EEG at age six months [ • Four affected individuals had conductive hearing loss and two experienced accompanying recurrent otitis media requiring tympanostomy tubes. • Two affected sibs exhibited sensorineural hearing loss. • Another affected individual had microtia and atresia of the left external ear canal. • Joint hypermobility (4 affected individuals) • Hip dysplasia in infancy (3 affected individuals) • Kyphosis and/or scoliosis (2 affected individuals) • Inguinal hernia (1 affected individual) • Of those with overgrowth, four had macrocephaly, one had tall stature, and one had both macrocephaly and tall stature. The latter individual also had nephromegaly and cardiomegaly, suggestive of generalized somatic overgrowth. • Of those with undergrowth, three had microcephaly, with two of these individuals also exhibiting short stature. • Increased extra-axial spaces in four unrelated affected individuals • Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. • The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. • Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. • The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. • Two related affected individuals – a mother and son – exhibited white matter changes, with the son's abnormality involving the periventricular white matter and the mother's not otherwise specified. • Two individuals exhibited hypoplasia of the cerebellum and enlarged/mega cisterna magna; one individual exhibited hypoplasia of the tectum mesencephali. • Two of these individuals exhibited mild ventriculomegaly and another had accompanying periventricular leukomalacia. • The fourth individual exhibited agenesis of the corpus callosum in addition to having an enlarged trigone and temporal horn. That individual's affected sib also had isolated agenesis of the corpus callosum. • Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual • Tetralogy of Fallot (1 affected individual) • A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) • Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual • Tetralogy of Fallot (1 affected individual) • A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) • Valve abnormalities (3 affected individuals): pulmonic stenosis in one individual, aortic insufficiency with a ventricular septal defect in another, and an unspecified type of valve abnormality with an unspecified abnormality on EKG in the third individual • Tetralogy of Fallot (1 affected individual) • A small, hemodynamically-insignificant arterial collateral from the descending aorta (1 affected individual) ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been confirmed. ## Nomenclature The BEFAHRS abbreviation can be used as a mnemonic for the most common features as follows: ## Prevalence The prevalence of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Although there is significant phenotypic overlap with other mendelian disorders of the epigenetic machinery (also called chromatin-modifying disorders or chromatinopathies; see Selected Chromatin-Modifying Disorders of Interest in the Differential Diagnosis of AD = autosomal dominant; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked In contrast to Tatton-Brown-Rahman syndrome, which is caused by loss-of-function pathogenic variants in ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with To assess for tone & any movement disorders To incl brain MRI, as clinically indicated Consider EEG if seizures are a concern. Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse There is no cure for 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. Standard ADHD or anxiety medications may be effective; none has been demonstrated effective specifically for this disorder. Standard autism therapies (e.g., ABA therapy) may be effective. Pressure equalizing tubes for those w/conductive hearing loss; Hearing aids for those w/sensorineural hearing loss. 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 ABA = applied behavior analysis; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; 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 Cochlear implants can also be considered, per ENT and audiologist recommendations. 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., scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Measurement of growth parameters, incl weight, length/height, & head circumference Eval of nutritional status & safety of oral intake 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 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 assess for tone & any movement disorders • To incl brain MRI, as clinically indicated • Consider EEG if seizures are a concern. • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • 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 • Gastrostomy tube placement may be required for persistent feeding issues. • Standard ADHD or anxiety medications may be effective; none has been demonstrated effective specifically for this disorder. • Standard autism therapies (e.g., ABA therapy) may be effective. • Pressure equalizing tubes for those w/conductive hearing loss; • Hearing aids for those w/sensorineural hearing loss. • 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., scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., orthotics, adaptive strollers). • Measurement of growth parameters, incl weight, length/height, & head circumference • 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 To assess for tone & any movement disorders To incl brain MRI, as clinically indicated Consider EEG if seizures are a concern. Gross motor & fine motor skills Mobility, activities of daily living, & need for adaptive devices Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) To incl motor, adaptive, cognitive, & speech-language eval Eval for early intervention / special education Community or Social work involvement for parental support. ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To assess for tone & any movement disorders • To incl brain MRI, as clinically indicated • Consider EEG if seizures are a concern. • Gross motor & fine motor skills • Mobility, activities of daily living, & need for adaptive devices • Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills) • To incl motor, adaptive, cognitive, & speech-language eval • Eval for early intervention / special education • Community or • Social work involvement for parental support. ## Treatment of Manifestations There is no cure for Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Standard ADHD or anxiety medications may be effective; none has been demonstrated effective specifically for this disorder. Standard autism therapies (e.g., ABA therapy) may be effective. Pressure equalizing tubes for those w/conductive hearing loss; Hearing aids for those w/sensorineural hearing loss. 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 ABA = applied behavior analysis; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; 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 Cochlear implants can also be considered, per ENT and audiologist recommendations. 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., scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., orthotics, adaptive strollers). Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Standard ADHD or anxiety medications may be effective; none has been demonstrated effective specifically for this disorder. • Standard autism therapies (e.g., ABA therapy) may be effective. • Pressure equalizing tubes for those w/conductive hearing loss; • Hearing aids for those w/sensorineural hearing loss. • 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., scoliosis, hip dislocation). • Consider use of durable medical equipment and positioning devices as needed (e.g., orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Motor Dysfunction Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation). Consider use of durable medical equipment and positioning devices as needed (e.g., orthotics, adaptive strollers). • 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 and positioning devices as needed (e.g., orthotics, adaptive strollers). ## Social/Behavioral Concerns Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst. Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Measurement of growth parameters, incl weight, length/height, & head circumference Eval of nutritional status & safety of oral intake OT = occupational therapy; PT = physical therapy • Measurement of growth parameters, incl weight, length/height, & head circumference • Eval of nutritional status & safety of oral intake ## 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 In some families reported to date, however, individuals with Of the 12 probands reported to date with a heterozygous Six probands from three families reported to date with biallelic One proband was initially reported to have biallelic variants inherited from both parents in The above observations suggest that If the proband appears to be the only affected family member (i.e., a simplex case), targeted molecular genetic testing for the pathogenic variant(s) identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has a heterozygous pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the proband has biallelic pathogenic variants and 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 If one parent of the proband has a If both parents of a proband have a If the If the parents have not been tested for the Unless a proband with a heterozygous Severely affected individuals with biallelic The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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 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. • Of the 12 probands reported to date with a heterozygous • Six probands from three families reported to date with biallelic • One proband was initially reported to have biallelic variants inherited from both parents in • The above observations suggest that • If the proband appears to be the only affected family member (i.e., a simplex case), targeted molecular genetic testing for the pathogenic variant(s) identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the proband has a heterozygous pathogenic variant that 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. • If the proband has biallelic pathogenic variants and 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 • 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 one parent of the proband has a • If both parents of a proband have a • If the • If the parents have not been tested for the • Unless a proband with a heterozygous • Severely affected individuals with biallelic • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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 a ## Mode of Inheritance In some families reported to date, however, individuals with ## Risk to Family Members (Autosomal Dominant Inheritance) Of the 12 probands reported to date with a heterozygous Six probands from three families reported to date with biallelic One proband was initially reported to have biallelic variants inherited from both parents in The above observations suggest that If the proband appears to be the only affected family member (i.e., a simplex case), targeted molecular genetic testing for the pathogenic variant(s) identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has a heterozygous pathogenic variant that is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. If the proband has biallelic pathogenic variants and 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 If one parent of the proband has a If both parents of a proband have a If the If the parents have not been tested for the Unless a proband with a heterozygous Severely affected individuals with biallelic • Of the 12 probands reported to date with a heterozygous • Six probands from three families reported to date with biallelic • One proband was initially reported to have biallelic variants inherited from both parents in • The above observations suggest that • If the proband appears to be the only affected family member (i.e., a simplex case), targeted molecular genetic testing for the pathogenic variant(s) identified in the proband is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the proband has a heterozygous pathogenic variant that 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. • If the proband has biallelic pathogenic variants and 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 • 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 one parent of the proband has a • If both parents of a proband have a • If the • If the parents have not been tested for the • Unless a proband with a heterozygous • Severely affected individuals with biallelic ## 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 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 have 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 • • ## Molecular Genetics TET3-Related Beck-Fahrner Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for TET3-Related Beck-Fahrner Syndrome ( Hypomorphic or loss-of-function pathogenic variants in ## Molecular Pathogenesis Hypomorphic or loss-of-function pathogenic variants in ## Chapter Notes A main focus of Dr Fahrner's research is Dr Fahrner's web page: Email Dr Fahrner ( Thank you to the patients and families and to the clinicians and researchers who have contributed to ongoing 18 May 2023 (ma) Review posted live 12 September 2022 (jf) Original submission • 18 May 2023 (ma) Review posted live • 12 September 2022 (jf) Original submission ## Author Notes A main focus of Dr Fahrner's research is Dr Fahrner's web page: Email Dr Fahrner ( ## Acknowledgments Thank you to the patients and families and to the clinicians and researchers who have contributed to ongoing ## Revision History 18 May 2023 (ma) Review posted live 12 September 2022 (jf) Original submission • 18 May 2023 (ma) Review posted live • 12 September 2022 (jf) Original submission ## References ## Literature Cited	[]	18/5/2023			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bethlem	bethlem	[ "COL6-Related Dystrophies (COL6-RDs)", "COL6-Related Dystrophies (COL6-RDs)", "Bethlem Muscular Dystrophy", "Intermediate COL6-RD", "Ullrich Congenital Muscular Dystrophy (UCMD)", "Collagen alpha-1(VI) chain", "Collagen alpha-2(VI) chain", "Collagen alpha-3(VI) chain", "COL6A1", "COL6A2", "COL6A3", "Collagen VI-Related Dystrophies" ]	Collagen VI-Related Dystrophies	A Reghan Foley, Payam Mohassel, Sandra Donkervoort, Véronique Bolduc, Carsten G Bönnemann	Summary Collagen VI-related dystrophies (COL6-RDs) represent a continuum of overlapping clinical phenotypes with Bethlem muscular dystrophy at the milder end, Ullrich congenital muscular dystrophy (UCMD) at the more severe end, and a phenotype in between UCMD and Bethlem muscular dystrophy, referred to as intermediate COL6-RD. Bethlem muscular dystrophy is characterized by a combination of proximal muscle weakness and joint contractures. Hypotonia and delayed motor milestones occur in early childhood; mild hypotonia and weakness may be present congenitally. By adulthood, there is evidence of proximal weakness and contractures of the elbows, Achilles tendons, and long finger flexors. The progression of weakness is slow, and more than two thirds of affected individuals older than age 50 years remain independently ambulatory indoors, while relying on supportive means for mobility outdoors. Respiratory involvement is not a consistent feature. UCMD is characterized by congenital weakness, hypotonia, proximal joint contractures, and striking hyperlaxity of distal joints. Decreased fetal movements are frequently reported. Some affected children acquire the ability to walk independently; however, progression of the disease results in a loss of ambulation by age ten to eleven years. Early and severe respiratory insufficiency occurs in all individuals, resulting in the need for nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) by age 11 years. Intermediate COL6-RD is characterized by independent ambulation past age 11 years and respiratory insufficiency that is later in onset than in UCMD and results in the need for NIV in the form of BiPAP by the late teens to early 20s. In contrast to individuals with Bethlem muscular dystrophy, those with intermediate COL6-RD typically do not achieve the ability to run, jump, or climb stairs without use of a railing. The diagnosis of a COL6-RD can be suspected in a proband with characteristic clinical features, muscle imaging features, and muscle immunohistochemical features. The diagnosis can be confirmed by identification of a heterozygous or biallelic pathogenic variant(s) in The COL6-RDs can be inherited in an autosomal dominant or an autosomal recessive manner. Bethlem muscular dystrophy is usually inherited in an autosomal dominant manner, although autosomal recessive inheritance has also been reported. UCMD and intermediate COL6-RD are typically caused by a Once the	Bethlem muscular dystrophy Ullrich congenital muscular dystrophy (UCMD) Intermediate COL6-RD For synonyms and outdated names see Disorders included in the • Bethlem muscular dystrophy • Ullrich congenital muscular dystrophy (UCMD) • Intermediate COL6-RD ## Diagnosis Formal diagnostic criteria for collagen VI-related dystrophies (COL6-RDs) have not been established. The COL6-RDs are caused by a pathogenic variant(s) in Note: Although these phenotypes are now recognized to comprise a continuum of overlapping phenotypes, the clinical designations are useful for providing a prognosis of future motor and pulmonary function and thus help to improve anticipatory clinical care. A COL6-RD Proximal muscle weakness Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders Congenital weakness and hypotonia Congenital torticollis Congenital hip dislocation Abnormal positioning of the hands and feet at birth (with the hands in a position of wrist flexion and the feet in a position of ankle dorsiflexion) Early kyphoscoliosis Proximal joint contractures (hips, knees, shoulders, and elbows) Striking hyperlaxity of distal joints Round face with mild facial erythema (over the cheeks) Weakness either preventing independent ambulation or resulting in loss of ambulation / full-time dependence on wheelchair-assisted mobility by approximately age ten to 11 years [ Progressive respiratory insufficiency uniformly necessitating the initiation of noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) while sleeping by approximately age 11 years [ Congenital weakness and hypotonia Congenital torticollis Congenital hip dislocation Proximal muscle weakness Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders At the same time, striking hyperlaxity of distal joints Weakness resulting in full-time dependence on wheelchair-assisted mobility by approximately age 19 years [ Progressive respiratory insufficiency resulting in nocturnal hypoventilation and need for NIV in the form of BiPAP while sleeping by approximately late teens / early 20s [ Intelligence is normal to high. Characteristic skin features include keratosis pilaris or follicular keratosis, keloid scars, and/or atrophic or "cigarette-paper" scars [ Serum creatine kinase concentration is normal or mildly elevated. Muscle MRI is an excellent diagnostic tool to identify suggestive findings of a COL6-RD and guide which individuals should undergo molecular analysis of In Bethlem muscular dystrophy the vastus lateralis muscle is typically strikingly affected, with a rim of abnormal signal along the periphery of the vastus lateralis and relative sparing of the central part, often referred to as an "outside-in" pattern. The rectus femoris muscle typically has evidence of abnormal signal within a central area of the muscle, surrounded by normal-appearing muscle, often referred to as a "central cloud" pattern [ In UCMD more diffuse involvement is typically observed with relative sparing of the sartorius, gracilis, and adductor longus. The "outside-in" pattern in the vastus lateralis and the "central cloud" pattern in the rectus femoris muscle may also been seen; however, as the disease progresses, these findings may be less obvious (see In intermediate COL6-RD the same muscle MRI findings described in Bethlem muscular dystrophy and UCMD can be seen. Muscle biopsy early in the disease may show nonspecific myopathic changes but subsequently will show more typical dystrophic changes (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Collagen VI immunolabeling of muscle tissue may show decreased collagen VI expression or mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin or collagen IV) ( Immunocytochemical analysis of collagen VI in dermal fibroblast cultures can demonstrate decreased and/or abnormal-appearing collagen VI extracellular matrix deposition with increased intracellular retention seen with cell permeabilization for dominant-acting pathogenic variants [ Muscle biopsy commonly shows dystrophic features (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Note: Muscle biopsies in children younger than age 30 months can have minimal findings (e.g., fiber atrophy, fiber type disproportion) with no evidence of dystrophic features [ Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin, or collagen IV) [ Immunocytochemical analysis of collagen VI in dermal fibroblast cultures may demonstrate loss of collagen VI matrix deposition or deposition of a dysmorphic matrix with strong intracellular immunoreactivity seen with permeabilization in those with dominant-acting pathogenic variants. It thus can be a useful adjunct to the diagnosis [ The diagnosis of a COL6-RD (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 comprehensive genomic testing does not. Because the phenotypes of COL6-RDs are broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of a COL6-RD, molecular genetic testing approaches can include Note: Sequence analysis should include the common For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by a myopathy / muscular dystrophy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Collagen VI-Related Dystrophies 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. Percentages reported from two different COL6-RD cohorts: one with 258 pathogenic variants identified [ Highly similar heterozygous genomic deletions were identified in a deletion-prone region of A large genomic deletion of A deletion in • Proximal muscle weakness • Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders • Congenital weakness and hypotonia • Congenital torticollis • Congenital hip dislocation • Abnormal positioning of the hands and feet at birth (with the hands in a position of wrist flexion and the feet in a position of ankle dorsiflexion) • Early kyphoscoliosis • Proximal joint contractures (hips, knees, shoulders, and elbows) • Striking hyperlaxity of distal joints • Round face with mild facial erythema (over the cheeks) • Weakness either preventing independent ambulation or resulting in loss of ambulation / full-time dependence on wheelchair-assisted mobility by approximately age ten to 11 years [ • Progressive respiratory insufficiency uniformly necessitating the initiation of noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) while sleeping by approximately age 11 years [ • Congenital weakness and hypotonia • Congenital torticollis • Congenital hip dislocation • Proximal muscle weakness • Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders • At the same time, striking hyperlaxity of distal joints • Weakness resulting in full-time dependence on wheelchair-assisted mobility by approximately age 19 years [ • Progressive respiratory insufficiency resulting in nocturnal hypoventilation and need for NIV in the form of BiPAP while sleeping by approximately late teens / early 20s [ • Intelligence is normal to high. • Characteristic skin features include keratosis pilaris or follicular keratosis, keloid scars, and/or atrophic or "cigarette-paper" scars [ • Serum creatine kinase concentration is normal or mildly elevated. • In Bethlem muscular dystrophy the vastus lateralis muscle is typically strikingly affected, with a rim of abnormal signal along the periphery of the vastus lateralis and relative sparing of the central part, often referred to as an "outside-in" pattern. The rectus femoris muscle typically has evidence of abnormal signal within a central area of the muscle, surrounded by normal-appearing muscle, often referred to as a "central cloud" pattern [ • In UCMD more diffuse involvement is typically observed with relative sparing of the sartorius, gracilis, and adductor longus. The "outside-in" pattern in the vastus lateralis and the "central cloud" pattern in the rectus femoris muscle may also been seen; however, as the disease progresses, these findings may be less obvious (see • In intermediate COL6-RD the same muscle MRI findings described in Bethlem muscular dystrophy and UCMD can be seen. • Muscle biopsy early in the disease may show nonspecific myopathic changes but subsequently will show more typical dystrophic changes (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). • Collagen VI immunolabeling of muscle tissue may show decreased collagen VI expression or mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin or collagen IV) ( • Immunocytochemical analysis of collagen VI in dermal fibroblast cultures can demonstrate decreased and/or abnormal-appearing collagen VI extracellular matrix deposition with increased intracellular retention seen with cell permeabilization for dominant-acting pathogenic variants [ • Muscle biopsy commonly shows dystrophic features (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Note: Muscle biopsies in children younger than age 30 months can have minimal findings (e.g., fiber atrophy, fiber type disproportion) with no evidence of dystrophic features [ • Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin, or collagen IV) [ • Immunocytochemical analysis of collagen VI in dermal fibroblast cultures may demonstrate loss of collagen VI matrix deposition or deposition of a dysmorphic matrix with strong intracellular immunoreactivity seen with permeabilization in those with dominant-acting pathogenic variants. It thus can be a useful adjunct to the diagnosis [ • Note: Sequence analysis should include the common • For an introduction to multigene panels click ## Suggestive Findings A COL6-RD Proximal muscle weakness Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders Congenital weakness and hypotonia Congenital torticollis Congenital hip dislocation Abnormal positioning of the hands and feet at birth (with the hands in a position of wrist flexion and the feet in a position of ankle dorsiflexion) Early kyphoscoliosis Proximal joint contractures (hips, knees, shoulders, and elbows) Striking hyperlaxity of distal joints Round face with mild facial erythema (over the cheeks) Weakness either preventing independent ambulation or resulting in loss of ambulation / full-time dependence on wheelchair-assisted mobility by approximately age ten to 11 years [ Progressive respiratory insufficiency uniformly necessitating the initiation of noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) while sleeping by approximately age 11 years [ Congenital weakness and hypotonia Congenital torticollis Congenital hip dislocation Proximal muscle weakness Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders At the same time, striking hyperlaxity of distal joints Weakness resulting in full-time dependence on wheelchair-assisted mobility by approximately age 19 years [ Progressive respiratory insufficiency resulting in nocturnal hypoventilation and need for NIV in the form of BiPAP while sleeping by approximately late teens / early 20s [ Intelligence is normal to high. Characteristic skin features include keratosis pilaris or follicular keratosis, keloid scars, and/or atrophic or "cigarette-paper" scars [ Serum creatine kinase concentration is normal or mildly elevated. Muscle MRI is an excellent diagnostic tool to identify suggestive findings of a COL6-RD and guide which individuals should undergo molecular analysis of In Bethlem muscular dystrophy the vastus lateralis muscle is typically strikingly affected, with a rim of abnormal signal along the periphery of the vastus lateralis and relative sparing of the central part, often referred to as an "outside-in" pattern. The rectus femoris muscle typically has evidence of abnormal signal within a central area of the muscle, surrounded by normal-appearing muscle, often referred to as a "central cloud" pattern [ In UCMD more diffuse involvement is typically observed with relative sparing of the sartorius, gracilis, and adductor longus. The "outside-in" pattern in the vastus lateralis and the "central cloud" pattern in the rectus femoris muscle may also been seen; however, as the disease progresses, these findings may be less obvious (see In intermediate COL6-RD the same muscle MRI findings described in Bethlem muscular dystrophy and UCMD can be seen. Muscle biopsy early in the disease may show nonspecific myopathic changes but subsequently will show more typical dystrophic changes (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Collagen VI immunolabeling of muscle tissue may show decreased collagen VI expression or mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin or collagen IV) ( Immunocytochemical analysis of collagen VI in dermal fibroblast cultures can demonstrate decreased and/or abnormal-appearing collagen VI extracellular matrix deposition with increased intracellular retention seen with cell permeabilization for dominant-acting pathogenic variants [ Muscle biopsy commonly shows dystrophic features (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Note: Muscle biopsies in children younger than age 30 months can have minimal findings (e.g., fiber atrophy, fiber type disproportion) with no evidence of dystrophic features [ Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin, or collagen IV) [ Immunocytochemical analysis of collagen VI in dermal fibroblast cultures may demonstrate loss of collagen VI matrix deposition or deposition of a dysmorphic matrix with strong intracellular immunoreactivity seen with permeabilization in those with dominant-acting pathogenic variants. It thus can be a useful adjunct to the diagnosis [ • Proximal muscle weakness • Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders • Congenital weakness and hypotonia • Congenital torticollis • Congenital hip dislocation • Abnormal positioning of the hands and feet at birth (with the hands in a position of wrist flexion and the feet in a position of ankle dorsiflexion) • Early kyphoscoliosis • Proximal joint contractures (hips, knees, shoulders, and elbows) • Striking hyperlaxity of distal joints • Round face with mild facial erythema (over the cheeks) • Weakness either preventing independent ambulation or resulting in loss of ambulation / full-time dependence on wheelchair-assisted mobility by approximately age ten to 11 years [ • Progressive respiratory insufficiency uniformly necessitating the initiation of noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) while sleeping by approximately age 11 years [ • Congenital weakness and hypotonia • Congenital torticollis • Congenital hip dislocation • Proximal muscle weakness • Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders • At the same time, striking hyperlaxity of distal joints • Weakness resulting in full-time dependence on wheelchair-assisted mobility by approximately age 19 years [ • Progressive respiratory insufficiency resulting in nocturnal hypoventilation and need for NIV in the form of BiPAP while sleeping by approximately late teens / early 20s [ • Intelligence is normal to high. • Characteristic skin features include keratosis pilaris or follicular keratosis, keloid scars, and/or atrophic or "cigarette-paper" scars [ • Serum creatine kinase concentration is normal or mildly elevated. • In Bethlem muscular dystrophy the vastus lateralis muscle is typically strikingly affected, with a rim of abnormal signal along the periphery of the vastus lateralis and relative sparing of the central part, often referred to as an "outside-in" pattern. The rectus femoris muscle typically has evidence of abnormal signal within a central area of the muscle, surrounded by normal-appearing muscle, often referred to as a "central cloud" pattern [ • In UCMD more diffuse involvement is typically observed with relative sparing of the sartorius, gracilis, and adductor longus. The "outside-in" pattern in the vastus lateralis and the "central cloud" pattern in the rectus femoris muscle may also been seen; however, as the disease progresses, these findings may be less obvious (see • In intermediate COL6-RD the same muscle MRI findings described in Bethlem muscular dystrophy and UCMD can be seen. • Muscle biopsy early in the disease may show nonspecific myopathic changes but subsequently will show more typical dystrophic changes (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). • Collagen VI immunolabeling of muscle tissue may show decreased collagen VI expression or mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin or collagen IV) ( • Immunocytochemical analysis of collagen VI in dermal fibroblast cultures can demonstrate decreased and/or abnormal-appearing collagen VI extracellular matrix deposition with increased intracellular retention seen with cell permeabilization for dominant-acting pathogenic variants [ • Muscle biopsy commonly shows dystrophic features (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Note: Muscle biopsies in children younger than age 30 months can have minimal findings (e.g., fiber atrophy, fiber type disproportion) with no evidence of dystrophic features [ • Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin, or collagen IV) [ • Immunocytochemical analysis of collagen VI in dermal fibroblast cultures may demonstrate loss of collagen VI matrix deposition or deposition of a dysmorphic matrix with strong intracellular immunoreactivity seen with permeabilization in those with dominant-acting pathogenic variants. It thus can be a useful adjunct to the diagnosis [ ## Clinical Findings Proximal muscle weakness Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders Congenital weakness and hypotonia Congenital torticollis Congenital hip dislocation Abnormal positioning of the hands and feet at birth (with the hands in a position of wrist flexion and the feet in a position of ankle dorsiflexion) Early kyphoscoliosis Proximal joint contractures (hips, knees, shoulders, and elbows) Striking hyperlaxity of distal joints Round face with mild facial erythema (over the cheeks) Weakness either preventing independent ambulation or resulting in loss of ambulation / full-time dependence on wheelchair-assisted mobility by approximately age ten to 11 years [ Progressive respiratory insufficiency uniformly necessitating the initiation of noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) while sleeping by approximately age 11 years [ Congenital weakness and hypotonia Congenital torticollis Congenital hip dislocation Proximal muscle weakness Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders At the same time, striking hyperlaxity of distal joints Weakness resulting in full-time dependence on wheelchair-assisted mobility by approximately age 19 years [ Progressive respiratory insufficiency resulting in nocturnal hypoventilation and need for NIV in the form of BiPAP while sleeping by approximately late teens / early 20s [ Intelligence is normal to high. Characteristic skin features include keratosis pilaris or follicular keratosis, keloid scars, and/or atrophic or "cigarette-paper" scars [ Serum creatine kinase concentration is normal or mildly elevated. • Proximal muscle weakness • Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders • Congenital weakness and hypotonia • Congenital torticollis • Congenital hip dislocation • Abnormal positioning of the hands and feet at birth (with the hands in a position of wrist flexion and the feet in a position of ankle dorsiflexion) • Early kyphoscoliosis • Proximal joint contractures (hips, knees, shoulders, and elbows) • Striking hyperlaxity of distal joints • Round face with mild facial erythema (over the cheeks) • Weakness either preventing independent ambulation or resulting in loss of ambulation / full-time dependence on wheelchair-assisted mobility by approximately age ten to 11 years [ • Progressive respiratory insufficiency uniformly necessitating the initiation of noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) while sleeping by approximately age 11 years [ • Congenital weakness and hypotonia • Congenital torticollis • Congenital hip dislocation • Proximal muscle weakness • Joint contractures, typically affecting the long finger flexors, elbows, ankles, and shoulders • At the same time, striking hyperlaxity of distal joints • Weakness resulting in full-time dependence on wheelchair-assisted mobility by approximately age 19 years [ • Progressive respiratory insufficiency resulting in nocturnal hypoventilation and need for NIV in the form of BiPAP while sleeping by approximately late teens / early 20s [ • Intelligence is normal to high. • Characteristic skin features include keratosis pilaris or follicular keratosis, keloid scars, and/or atrophic or "cigarette-paper" scars [ • Serum creatine kinase concentration is normal or mildly elevated. ## Imaging Findings Muscle MRI is an excellent diagnostic tool to identify suggestive findings of a COL6-RD and guide which individuals should undergo molecular analysis of In Bethlem muscular dystrophy the vastus lateralis muscle is typically strikingly affected, with a rim of abnormal signal along the periphery of the vastus lateralis and relative sparing of the central part, often referred to as an "outside-in" pattern. The rectus femoris muscle typically has evidence of abnormal signal within a central area of the muscle, surrounded by normal-appearing muscle, often referred to as a "central cloud" pattern [ In UCMD more diffuse involvement is typically observed with relative sparing of the sartorius, gracilis, and adductor longus. The "outside-in" pattern in the vastus lateralis and the "central cloud" pattern in the rectus femoris muscle may also been seen; however, as the disease progresses, these findings may be less obvious (see In intermediate COL6-RD the same muscle MRI findings described in Bethlem muscular dystrophy and UCMD can be seen. • In Bethlem muscular dystrophy the vastus lateralis muscle is typically strikingly affected, with a rim of abnormal signal along the periphery of the vastus lateralis and relative sparing of the central part, often referred to as an "outside-in" pattern. The rectus femoris muscle typically has evidence of abnormal signal within a central area of the muscle, surrounded by normal-appearing muscle, often referred to as a "central cloud" pattern [ • In UCMD more diffuse involvement is typically observed with relative sparing of the sartorius, gracilis, and adductor longus. The "outside-in" pattern in the vastus lateralis and the "central cloud" pattern in the rectus femoris muscle may also been seen; however, as the disease progresses, these findings may be less obvious (see • In intermediate COL6-RD the same muscle MRI findings described in Bethlem muscular dystrophy and UCMD can be seen. ## Tissue Studies Muscle biopsy early in the disease may show nonspecific myopathic changes but subsequently will show more typical dystrophic changes (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Collagen VI immunolabeling of muscle tissue may show decreased collagen VI expression or mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin or collagen IV) ( Immunocytochemical analysis of collagen VI in dermal fibroblast cultures can demonstrate decreased and/or abnormal-appearing collagen VI extracellular matrix deposition with increased intracellular retention seen with cell permeabilization for dominant-acting pathogenic variants [ Muscle biopsy commonly shows dystrophic features (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Note: Muscle biopsies in children younger than age 30 months can have minimal findings (e.g., fiber atrophy, fiber type disproportion) with no evidence of dystrophic features [ Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin, or collagen IV) [ Immunocytochemical analysis of collagen VI in dermal fibroblast cultures may demonstrate loss of collagen VI matrix deposition or deposition of a dysmorphic matrix with strong intracellular immunoreactivity seen with permeabilization in those with dominant-acting pathogenic variants. It thus can be a useful adjunct to the diagnosis [ • Muscle biopsy early in the disease may show nonspecific myopathic changes but subsequently will show more typical dystrophic changes (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). • Collagen VI immunolabeling of muscle tissue may show decreased collagen VI expression or mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin or collagen IV) ( • Immunocytochemical analysis of collagen VI in dermal fibroblast cultures can demonstrate decreased and/or abnormal-appearing collagen VI extracellular matrix deposition with increased intracellular retention seen with cell permeabilization for dominant-acting pathogenic variants [ • Muscle biopsy commonly shows dystrophic features (degeneration, regeneration, and replacement of muscle with fat and fibrous connective tissue). Note: Muscle biopsies in children younger than age 30 months can have minimal findings (e.g., fiber atrophy, fiber type disproportion) with no evidence of dystrophic features [ • Collagen VI immunolabeling of muscle ranges from absent collagen VI to mislocalized collagen VI (not colocalizing when double stained with other basement membrane markers such as perlecan, laminin, or collagen IV) [ • Immunocytochemical analysis of collagen VI in dermal fibroblast cultures may demonstrate loss of collagen VI matrix deposition or deposition of a dysmorphic matrix with strong intracellular immunoreactivity seen with permeabilization in those with dominant-acting pathogenic variants. It thus can be a useful adjunct to the diagnosis [ ## Establishing the Diagnosis The diagnosis of a COL6-RD (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 comprehensive genomic testing does not. Because the phenotypes of COL6-RDs are broad, individuals with the distinctive findings described in When the phenotypic findings suggest the diagnosis of a COL6-RD, molecular genetic testing approaches can include Note: Sequence analysis should include the common For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by a myopathy / muscular dystrophy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Collagen VI-Related Dystrophies 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. Percentages reported from two different COL6-RD cohorts: one with 258 pathogenic variants identified [ Highly similar heterozygous genomic deletions were identified in a deletion-prone region of A large genomic deletion of A deletion in • Note: Sequence analysis should include the common • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of a COL6-RD, molecular genetic testing approaches can include Note: Sequence analysis should include the common For an introduction to multigene panels click • Note: Sequence analysis should include the common • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by a myopathy / muscular dystrophy, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Collagen VI-Related Dystrophies 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. Percentages reported from two different COL6-RD cohorts: one with 258 pathogenic variants identified [ Highly similar heterozygous genomic deletions were identified in a deletion-prone region of A large genomic deletion of A deletion in ## Clinical Characteristics The phenotypes associated with collagen VI-related dystrophies (COL6-RDs), once thought to be distinct entities, were clinically defined long before their molecular basis was discovered. The COL6-RDs are now recognized to comprise a continuum of overlapping phenotypes with Bethlem muscular dystrophy at the mild end, Ullrich congenital muscular dystrophy (UCMD) at the severe end, and phenotypes in between that are now collectively categorized within a subgroup called intermediate COL6-RD. These clinical phenotypic designations play an important role in providing a prognosis for future motor and pulmonary function and thus help in improving anticipatory clinical care. The onset of symptoms of Bethlem muscular dystrophy can range from congenital to mid-adulthood. Obvious congenital manifestations are more rare but can include hypotonia and torticollis. Most individuals report a history of hypotonia, delayed motor milestones, and a tendency toward W-sitting, related to laxity of the hip joints [ As a result of slowly progressive proximal muscle weakness and progressive joint contractures, more than two thirds of affected individuals older than age 50 years rely on supportive means (e.g., canes, crutches, wheelchair) for outdoor mobility [ Respiratory muscle weakness, in particular of the diaphragm, can result in respiratory insufficiency resulting in nocturnal hypoventilation and necessitating nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP). In retrospective studies of Bethlem muscular dystrophy, the use of nocturnal NIV is less common and was required later in life [ Cardiac function is normal in individuals with Bethlem muscular dystrophy; any cardiac findings have been interpreted as unrelated to Bethlem muscular dystrophy [ Skin findings in Bethlem muscular dystrophy include keratosis pilaris or follicular keratosis, which is typically prominent along the extensor surfaces of the arms and legs and keloid scars [ The first signs of UCMD can be noted in utero, with decreased fetal movement frequently reported [ Independent walking is typically the most advanced motor milestone achieved in children with UCMD [ Progressive, severe respiratory insufficiency occurs in all individuals with UCMD, resulting in the need for nocturnal NIV on average by age 11 years [ Congenital kyphoscoliosis may occur. Typically, there is spinal rigidity with concomitant scoliosis, which in one cohort manifested by a mean age of seven years, with scoliosis surgical repair performed at a mean age of 11 years [ Transient feeding difficulties can occur, requiring nasogastric tube feeding during the newborn period [ There has been no evidence of primary cardiac involvement in UCMD. In those individuals with respiratory insufficiency in whom NIV in the form of BiPAP has not been initiated or the BiPAP pressures are insufficient, right-sided heart strain can be observed on echocardiography, and cor pulmonale can develop when left untreated. With the optimization of NIV support / BiPAP pressures, right-sided heart function typically normalizes. Skin findings in UCMD include keratosis pilaris or follicular keratosis (typically prominent along the extensor surfaces of the arms and legs), keloid scars, and atrophic or "cigarette-paper" scars [ The onset of intermediate COL6-RD is typically congenital with signs and symptoms including hypotonia, torticollis, hip dislocation, proximal joint contractures, and distal joint hyperlaxity. Infants typically demonstrate evidence of proximal muscle weakness; however, they usually attain the ability to rise from the floor without assistance (without holding onto furniture or another person) [ Progressive joint contractures affecting shoulders, elbows, long finger flexors, hips, knees, and ankles occur. The combination of progressive muscle weakness and joint contractures leads to loss of ambulation and need for full-time wheelchair-assisted mobility by an average age of 19 years [ Progressive respiratory insufficiency occurs in all individuals with intermediate COL6-RD. The onset of decline in pulmonary function occurs later than in individuals with UCMD. Nocturnal hypoventilation and the need for NIV in the form of BiPAP occurs by the late teens to early 20s [ There has been no evidence of primary cardiac involvement in intermediate COL6-RD. In those individuals with respiratory insufficiency in whom NIV in the form of BiPAP has not been initiated or the BiPAP pressures are insufficient, right-sided heart strain can be observed on echocardiography, and cor pulmonale can develop when left untreated. With the optimization of NIV support / BiPAP pressures, right-sided heart function typically normalizes. Skin findings in intermediate COL6-RD include keratosis pilaris or follicular keratosis (typically prominent along the extensor surfaces of the arms and legs), keloid scars, and atrophic or "cigarette-paper" scars [ COL6-RDs can be caused by either autosomal dominant or autosomal recessive pathogenic variants in In-frame skipping of exon 14, encoding the dimer-stabilizing cysteine residue of the α1(VI) chain, tends to result in a milder phenotype (Bethlem muscular dystrophy to intermediate COL6-RD) [ A deep intronic pathogenic variant in intron 11 ( Nonsense variant Nonsense variant Parents of individuals with recessively inherited COL6-RDs are usually heterozygous for a Individuals with dominantly inherited COL6-RDs are heterozygous for a Mild form of COL6-related myopathy Mild form of COL6-related dystrophy Mild collagen VI myopathy Severe form of COL6-related myopathy Severe form of COL6-related dystrophy Early-severe collagen VI myopathy Moderate-progressive collagen VI myopathy Mild UCMD Severe Bethlem myopathy Moderate-progressive collagen VI myopathy Mild early-onset collagen VI myopathy The exact prevalence of the COL6-RDs remains unknown. In northern England the prevalence of Bethlem muscular dystrophy is estimated at 0.77:100,000, and the prevalence of UCMD is estimated at 0.13:100,000 [ • In-frame skipping of exon 14, encoding the dimer-stabilizing cysteine residue of the α1(VI) chain, tends to result in a milder phenotype (Bethlem muscular dystrophy to intermediate COL6-RD) [ • A deep intronic pathogenic variant in intron 11 ( • Nonsense variant • Nonsense variant • Mild form of COL6-related myopathy • Mild form of COL6-related dystrophy • Mild collagen VI myopathy • Severe form of COL6-related myopathy • Severe form of COL6-related dystrophy • Early-severe collagen VI myopathy • Moderate-progressive collagen VI myopathy • Mild UCMD • Severe Bethlem myopathy • Moderate-progressive collagen VI myopathy • Mild early-onset collagen VI myopathy ## Clinical Description The phenotypes associated with collagen VI-related dystrophies (COL6-RDs), once thought to be distinct entities, were clinically defined long before their molecular basis was discovered. The COL6-RDs are now recognized to comprise a continuum of overlapping phenotypes with Bethlem muscular dystrophy at the mild end, Ullrich congenital muscular dystrophy (UCMD) at the severe end, and phenotypes in between that are now collectively categorized within a subgroup called intermediate COL6-RD. These clinical phenotypic designations play an important role in providing a prognosis for future motor and pulmonary function and thus help in improving anticipatory clinical care. The onset of symptoms of Bethlem muscular dystrophy can range from congenital to mid-adulthood. Obvious congenital manifestations are more rare but can include hypotonia and torticollis. Most individuals report a history of hypotonia, delayed motor milestones, and a tendency toward W-sitting, related to laxity of the hip joints [ As a result of slowly progressive proximal muscle weakness and progressive joint contractures, more than two thirds of affected individuals older than age 50 years rely on supportive means (e.g., canes, crutches, wheelchair) for outdoor mobility [ Respiratory muscle weakness, in particular of the diaphragm, can result in respiratory insufficiency resulting in nocturnal hypoventilation and necessitating nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP). In retrospective studies of Bethlem muscular dystrophy, the use of nocturnal NIV is less common and was required later in life [ Cardiac function is normal in individuals with Bethlem muscular dystrophy; any cardiac findings have been interpreted as unrelated to Bethlem muscular dystrophy [ Skin findings in Bethlem muscular dystrophy include keratosis pilaris or follicular keratosis, which is typically prominent along the extensor surfaces of the arms and legs and keloid scars [ The first signs of UCMD can be noted in utero, with decreased fetal movement frequently reported [ Independent walking is typically the most advanced motor milestone achieved in children with UCMD [ Progressive, severe respiratory insufficiency occurs in all individuals with UCMD, resulting in the need for nocturnal NIV on average by age 11 years [ Congenital kyphoscoliosis may occur. Typically, there is spinal rigidity with concomitant scoliosis, which in one cohort manifested by a mean age of seven years, with scoliosis surgical repair performed at a mean age of 11 years [ Transient feeding difficulties can occur, requiring nasogastric tube feeding during the newborn period [ There has been no evidence of primary cardiac involvement in UCMD. In those individuals with respiratory insufficiency in whom NIV in the form of BiPAP has not been initiated or the BiPAP pressures are insufficient, right-sided heart strain can be observed on echocardiography, and cor pulmonale can develop when left untreated. With the optimization of NIV support / BiPAP pressures, right-sided heart function typically normalizes. Skin findings in UCMD include keratosis pilaris or follicular keratosis (typically prominent along the extensor surfaces of the arms and legs), keloid scars, and atrophic or "cigarette-paper" scars [ The onset of intermediate COL6-RD is typically congenital with signs and symptoms including hypotonia, torticollis, hip dislocation, proximal joint contractures, and distal joint hyperlaxity. Infants typically demonstrate evidence of proximal muscle weakness; however, they usually attain the ability to rise from the floor without assistance (without holding onto furniture or another person) [ Progressive joint contractures affecting shoulders, elbows, long finger flexors, hips, knees, and ankles occur. The combination of progressive muscle weakness and joint contractures leads to loss of ambulation and need for full-time wheelchair-assisted mobility by an average age of 19 years [ Progressive respiratory insufficiency occurs in all individuals with intermediate COL6-RD. The onset of decline in pulmonary function occurs later than in individuals with UCMD. Nocturnal hypoventilation and the need for NIV in the form of BiPAP occurs by the late teens to early 20s [ There has been no evidence of primary cardiac involvement in intermediate COL6-RD. In those individuals with respiratory insufficiency in whom NIV in the form of BiPAP has not been initiated or the BiPAP pressures are insufficient, right-sided heart strain can be observed on echocardiography, and cor pulmonale can develop when left untreated. With the optimization of NIV support / BiPAP pressures, right-sided heart function typically normalizes. Skin findings in intermediate COL6-RD include keratosis pilaris or follicular keratosis (typically prominent along the extensor surfaces of the arms and legs), keloid scars, and atrophic or "cigarette-paper" scars [ ## Bethlem Muscular Dystrophy The onset of symptoms of Bethlem muscular dystrophy can range from congenital to mid-adulthood. Obvious congenital manifestations are more rare but can include hypotonia and torticollis. Most individuals report a history of hypotonia, delayed motor milestones, and a tendency toward W-sitting, related to laxity of the hip joints [ As a result of slowly progressive proximal muscle weakness and progressive joint contractures, more than two thirds of affected individuals older than age 50 years rely on supportive means (e.g., canes, crutches, wheelchair) for outdoor mobility [ Respiratory muscle weakness, in particular of the diaphragm, can result in respiratory insufficiency resulting in nocturnal hypoventilation and necessitating nocturnal noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP). In retrospective studies of Bethlem muscular dystrophy, the use of nocturnal NIV is less common and was required later in life [ Cardiac function is normal in individuals with Bethlem muscular dystrophy; any cardiac findings have been interpreted as unrelated to Bethlem muscular dystrophy [ Skin findings in Bethlem muscular dystrophy include keratosis pilaris or follicular keratosis, which is typically prominent along the extensor surfaces of the arms and legs and keloid scars [ ## Ullrich Congenital Muscular Dystrophy The first signs of UCMD can be noted in utero, with decreased fetal movement frequently reported [ Independent walking is typically the most advanced motor milestone achieved in children with UCMD [ Progressive, severe respiratory insufficiency occurs in all individuals with UCMD, resulting in the need for nocturnal NIV on average by age 11 years [ Congenital kyphoscoliosis may occur. Typically, there is spinal rigidity with concomitant scoliosis, which in one cohort manifested by a mean age of seven years, with scoliosis surgical repair performed at a mean age of 11 years [ Transient feeding difficulties can occur, requiring nasogastric tube feeding during the newborn period [ There has been no evidence of primary cardiac involvement in UCMD. In those individuals with respiratory insufficiency in whom NIV in the form of BiPAP has not been initiated or the BiPAP pressures are insufficient, right-sided heart strain can be observed on echocardiography, and cor pulmonale can develop when left untreated. With the optimization of NIV support / BiPAP pressures, right-sided heart function typically normalizes. Skin findings in UCMD include keratosis pilaris or follicular keratosis (typically prominent along the extensor surfaces of the arms and legs), keloid scars, and atrophic or "cigarette-paper" scars [ ## Intermediate COL6-RD The onset of intermediate COL6-RD is typically congenital with signs and symptoms including hypotonia, torticollis, hip dislocation, proximal joint contractures, and distal joint hyperlaxity. Infants typically demonstrate evidence of proximal muscle weakness; however, they usually attain the ability to rise from the floor without assistance (without holding onto furniture or another person) [ Progressive joint contractures affecting shoulders, elbows, long finger flexors, hips, knees, and ankles occur. The combination of progressive muscle weakness and joint contractures leads to loss of ambulation and need for full-time wheelchair-assisted mobility by an average age of 19 years [ Progressive respiratory insufficiency occurs in all individuals with intermediate COL6-RD. The onset of decline in pulmonary function occurs later than in individuals with UCMD. Nocturnal hypoventilation and the need for NIV in the form of BiPAP occurs by the late teens to early 20s [ There has been no evidence of primary cardiac involvement in intermediate COL6-RD. In those individuals with respiratory insufficiency in whom NIV in the form of BiPAP has not been initiated or the BiPAP pressures are insufficient, right-sided heart strain can be observed on echocardiography, and cor pulmonale can develop when left untreated. With the optimization of NIV support / BiPAP pressures, right-sided heart function typically normalizes. Skin findings in intermediate COL6-RD include keratosis pilaris or follicular keratosis (typically prominent along the extensor surfaces of the arms and legs), keloid scars, and atrophic or "cigarette-paper" scars [ ## Genotype-Phenotype Correlations COL6-RDs can be caused by either autosomal dominant or autosomal recessive pathogenic variants in In-frame skipping of exon 14, encoding the dimer-stabilizing cysteine residue of the α1(VI) chain, tends to result in a milder phenotype (Bethlem muscular dystrophy to intermediate COL6-RD) [ A deep intronic pathogenic variant in intron 11 ( Nonsense variant Nonsense variant • In-frame skipping of exon 14, encoding the dimer-stabilizing cysteine residue of the α1(VI) chain, tends to result in a milder phenotype (Bethlem muscular dystrophy to intermediate COL6-RD) [ • A deep intronic pathogenic variant in intron 11 ( • Nonsense variant • Nonsense variant ## Penetrance Parents of individuals with recessively inherited COL6-RDs are usually heterozygous for a Individuals with dominantly inherited COL6-RDs are heterozygous for a ## Nomenclature Mild form of COL6-related myopathy Mild form of COL6-related dystrophy Mild collagen VI myopathy Severe form of COL6-related myopathy Severe form of COL6-related dystrophy Early-severe collagen VI myopathy Moderate-progressive collagen VI myopathy Mild UCMD Severe Bethlem myopathy Moderate-progressive collagen VI myopathy Mild early-onset collagen VI myopathy • Mild form of COL6-related myopathy • Mild form of COL6-related dystrophy • Mild collagen VI myopathy • Severe form of COL6-related myopathy • Severe form of COL6-related dystrophy • Early-severe collagen VI myopathy • Moderate-progressive collagen VI myopathy • Mild UCMD • Severe Bethlem myopathy • Moderate-progressive collagen VI myopathy • Mild early-onset collagen VI myopathy ## Prevalence The exact prevalence of the COL6-RDs remains unknown. In northern England the prevalence of Bethlem muscular dystrophy is estimated at 0.77:100,000, and the prevalence of UCMD is estimated at 0.13:100,000 [ ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The differential diagnosis of the phenotypes observed in the collagen VI-related dystrophies (COL6-RDs) is discussed in this section. Of note, a normal-to-mildly elevated CK, suggestive findings on muscle MRI, lack of a cardiac phenotype, and normal-to-high intelligence are hallmarks of the COL6-RDs and help in distinguishing them from other disorders. When joint contractures are subtle or missed, the major differential diagnoses are the limb-girdle muscular dystrophies (LGMDs) (see When joint contractures are a prominent feature, the major differential diagnoses are those summarized in Disorders with Joint Contractures to Consider in the Differential Diagnosis of Bethlem Muscular Dystrophy AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; DiffDx = differential diagnosis; MOI = mode of inheritance; NCVs = nerve conduction studies; US = ultrasound; XL = X-linked More rarely, Emery-Dreifuss muscular dystrophy is caused by biallelic pathogenic variants in Note: Unlike Ullrich congenital muscular dystrophy (UCMD) and intermediate COL6-RD, the disorders in The presence at birth of torticollis, kyphoscoliosis, and abnormal positioning of the hands & feet; The combination of proximal joint contractures with distal joint hyperlaxity; Muscle imaging findings in the rectus femoris muscle (of a "central cloud" pattern) and vastus lateralis muscle (of an "outside-in" pattern). Disorders with Congenital Onset to Consider in the Differential Diagnosis of UCMD / Intermediate COL6-RD Generally have pronounced & widespread joint laxity May have joint dislocations Typically have elongated face Palate is often significantly high-arched. Respiratory insufficiency may present earlier (severe form). Weakness may be mostly distal (milder form). Muscle biopsy is typically myopathic. Hallmark findings of arachnodactyly & abnormal pinnae (crumpled superior helix) May have high-arched palate Neonatal hypotonia, weakness (esp axial & proximal), abnormal positioning of hands & feet Muscle biopsy may have histologic appearance of CFTD. At birth hands are typically in position of bilateral wrist extension w/ulnar deviation; feet are typically in position of foot eversion. May have cardiac involvement Muscle histology often has prominent central nuclei. Muscle imaging shows particular involvement of semitendinosus muscle. Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. Muscle biopsy may have prominent adipose tissue. In AR forms, extraocular movements are ↓ & muscle histology has central nuclei. Muscle imaging shows sparing of rectus femoris muscle. Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. May have eye abnormalities, abnormal findings on brain MRI, cognitive involvement, &/or cardiac involvement. Usually assoc w/serum CK concentrations higher than those observed in UCMD / intermediate COL6-RD Evidence of fasciculations on muscle ultrasound Features of denervation on muscle biopsy AD = autosomal dominant; AR = autosomal recessive; CFTD = congenital fiber type disproportion; CK = creatine kinase; CMD = congenital muscular dystrophy; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked Disorders are ordered by relevance, with diagnoses most similar to UCMD and intermediate COL6-RD listed first. Selected genes associated with the main CMD subtypes; see • The presence at birth of torticollis, kyphoscoliosis, and abnormal positioning of the hands & feet; • The combination of proximal joint contractures with distal joint hyperlaxity; • Muscle imaging findings in the rectus femoris muscle (of a "central cloud" pattern) and vastus lateralis muscle (of an "outside-in" pattern). • Generally have pronounced & widespread joint laxity • May have joint dislocations • Typically have elongated face • Palate is often significantly high-arched. • Respiratory insufficiency may present earlier (severe form). Weakness may be mostly distal (milder form). • Muscle biopsy is typically myopathic. • Hallmark findings of arachnodactyly & abnormal pinnae (crumpled superior helix) • May have high-arched palate • Neonatal hypotonia, weakness (esp axial & proximal), abnormal positioning of hands & feet • Muscle biopsy may have histologic appearance of CFTD. • At birth hands are typically in position of bilateral wrist extension w/ulnar deviation; feet are typically in position of foot eversion. • May have cardiac involvement • Muscle histology often has prominent central nuclei. • Muscle imaging shows particular involvement of semitendinosus muscle. • Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency • Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. • Muscle biopsy may have prominent adipose tissue. • In AR forms, extraocular movements are ↓ & muscle histology has central nuclei. • Muscle imaging shows sparing of rectus femoris muscle. • Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency • Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. • May have eye abnormalities, abnormal findings on brain MRI, cognitive involvement, &/or cardiac involvement. • Usually assoc w/serum CK concentrations higher than those observed in UCMD / intermediate COL6-RD • Evidence of fasciculations on muscle ultrasound • Features of denervation on muscle biopsy ## Bethlem Muscular Dystrophy When joint contractures are subtle or missed, the major differential diagnoses are the limb-girdle muscular dystrophies (LGMDs) (see When joint contractures are a prominent feature, the major differential diagnoses are those summarized in Disorders with Joint Contractures to Consider in the Differential Diagnosis of Bethlem Muscular Dystrophy AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; DiffDx = differential diagnosis; MOI = mode of inheritance; NCVs = nerve conduction studies; US = ultrasound; XL = X-linked More rarely, Emery-Dreifuss muscular dystrophy is caused by biallelic pathogenic variants in ## Ullrich Congenital Muscular Dystrophy and Intermediate COL6-RD Note: Unlike Ullrich congenital muscular dystrophy (UCMD) and intermediate COL6-RD, the disorders in The presence at birth of torticollis, kyphoscoliosis, and abnormal positioning of the hands & feet; The combination of proximal joint contractures with distal joint hyperlaxity; Muscle imaging findings in the rectus femoris muscle (of a "central cloud" pattern) and vastus lateralis muscle (of an "outside-in" pattern). Disorders with Congenital Onset to Consider in the Differential Diagnosis of UCMD / Intermediate COL6-RD Generally have pronounced & widespread joint laxity May have joint dislocations Typically have elongated face Palate is often significantly high-arched. Respiratory insufficiency may present earlier (severe form). Weakness may be mostly distal (milder form). Muscle biopsy is typically myopathic. Hallmark findings of arachnodactyly & abnormal pinnae (crumpled superior helix) May have high-arched palate Neonatal hypotonia, weakness (esp axial & proximal), abnormal positioning of hands & feet Muscle biopsy may have histologic appearance of CFTD. At birth hands are typically in position of bilateral wrist extension w/ulnar deviation; feet are typically in position of foot eversion. May have cardiac involvement Muscle histology often has prominent central nuclei. Muscle imaging shows particular involvement of semitendinosus muscle. Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. Muscle biopsy may have prominent adipose tissue. In AR forms, extraocular movements are ↓ & muscle histology has central nuclei. Muscle imaging shows sparing of rectus femoris muscle. Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. May have eye abnormalities, abnormal findings on brain MRI, cognitive involvement, &/or cardiac involvement. Usually assoc w/serum CK concentrations higher than those observed in UCMD / intermediate COL6-RD Evidence of fasciculations on muscle ultrasound Features of denervation on muscle biopsy AD = autosomal dominant; AR = autosomal recessive; CFTD = congenital fiber type disproportion; CK = creatine kinase; CMD = congenital muscular dystrophy; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked Disorders are ordered by relevance, with diagnoses most similar to UCMD and intermediate COL6-RD listed first. Selected genes associated with the main CMD subtypes; see • The presence at birth of torticollis, kyphoscoliosis, and abnormal positioning of the hands & feet; • The combination of proximal joint contractures with distal joint hyperlaxity; • Muscle imaging findings in the rectus femoris muscle (of a "central cloud" pattern) and vastus lateralis muscle (of an "outside-in" pattern). • Generally have pronounced & widespread joint laxity • May have joint dislocations • Typically have elongated face • Palate is often significantly high-arched. • Respiratory insufficiency may present earlier (severe form). Weakness may be mostly distal (milder form). • Muscle biopsy is typically myopathic. • Hallmark findings of arachnodactyly & abnormal pinnae (crumpled superior helix) • May have high-arched palate • Neonatal hypotonia, weakness (esp axial & proximal), abnormal positioning of hands & feet • Muscle biopsy may have histologic appearance of CFTD. • At birth hands are typically in position of bilateral wrist extension w/ulnar deviation; feet are typically in position of foot eversion. • May have cardiac involvement • Muscle histology often has prominent central nuclei. • Muscle imaging shows particular involvement of semitendinosus muscle. • Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency • Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. • Muscle biopsy may have prominent adipose tissue. • In AR forms, extraocular movements are ↓ & muscle histology has central nuclei. • Muscle imaging shows sparing of rectus femoris muscle. • Neonatal hypotonia, weakness (esp axial & proximal), poor weight gain, respiratory insufficiency • Muscle biopsy may have histologic findings of cores on oxidative stains & CFTD. • May have eye abnormalities, abnormal findings on brain MRI, cognitive involvement, &/or cardiac involvement. • Usually assoc w/serum CK concentrations higher than those observed in UCMD / intermediate COL6-RD • Evidence of fasciculations on muscle ultrasound • Features of denervation on muscle biopsy ## Management Recommended Evaluations Following Initial Diagnosis in Individuals with Bethlem Muscular Dystrophy Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility Exam of joint contractures, esp assessing for asymmetry of Achilles tendon contractures PT & OT assessment BiPAP = bilevel positive airway pressure; NIV = noninvasive ventilation; OT = occupational therapy; PT = physical therapy Recommended Evaluations Following Initial Diagnosis in Individuals with UCMD / Intermediate COL6-RD Feeding difficulties may manifest as FTT during 1st 1-2 yrs of life. FTT at age 10-12 yrs may reflect inadequately supported ventilation. Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility Exam of joint contractures & joint hyperlaxity Exam of back for evidence of stiffness &/or scoliosis PT & OT assessment BiPAP = bilevel positive airway pressure; FTT = failure to thrive; NIV = noninvasive ventilation; OT = occupational therapy; PT = physical therapy Disproportionate weakness of the diaphragm can cause nocturnal hypoventilation, even in individuals who remain independently ambulant. For forced vital capacity (FVC) measurements of 60% predicted or lower, noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) should be initiated during a polysomnogram – with pressures adjusted to ensure adequate ventilation – and then consistently used while sleeping. If nocturnal BiPAP is started, BiPAP pressures should be carefully monitored and adjusted during repeat polysomnogram monitoring in order to provide adequate pressures as the body grows / pressure requirements increase related to progressive respiratory insufficiency. If BiPAP is not initiated when needed or inadequate BiPAP pressures are used, right-sided heart strain can be seen on echocardiogram monitoring. Optimization of BiPAP pressures can help to prevent the development of cor pulmonale. Surgical repair of scoliosis is rarely needed in individuals with Bethlem muscular dystrophy. If scoliosis surgery is considered, carefully planning for supporting respiratory needs preoperatively, intraoperatively, and postoperatively should be coordinated with orthopedic surgery, anesthesia, intensive care, and pulmonary teams. Physical therapy and occupational therapy assessments can provide recommendations for joint stretching and swimming/aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. Strategies to avoid excessive joint strain should be discussed with a physical therapist and occupational therapist, given that joint pain has been reported by some individuals with Bethlem muscular dystrophy. If Achilles tendon contractures are severe or asymmetric, thus adversely affecting gait, Achilles tendon release surgery can provide increased range of motion, especially if the Achilles tendon release is followed by casting. A noninvasive approach that can help promote improved range of motion of the Achilles tendons is serial casting. Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion in individuals with Bethlem muscular dystrophy who have undergone joint surgery. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. NIV in the form of BiPAP is needed in all individuals with UCMD by approximately age 11 years and all individuals with intermediate COL6-RD by the teenage years. Use of an insufflator/exsufflator such as with a cough assist machine is essential for promoting coughing and expectoration of phlegm and airway clearance during respiratory infections and should be used as frequently as possible in order to help prevent the progression of upper respiratory infections to lower respiratory tract infections (pneumonias). Right-sided heart strain can be evident on echocardiogram in individuals with respiratory insufficiency who are not using NIV in the form of BiPAP when needed or who are using BiPAP at pressures that are inadequate for supporting ventilation. If left unadjusted, cor pulmonale can develop. Right-sided heart function typically normalizes once BiPAP pressures are adequate for supporting nocturnal ventilation. Bracing for scoliosis should be carefully approached, given how important movement of the chest wall is for respiration/ventilation in individuals with COL6-RDs. If spinal bracing is considered, a brace that does not cover the lower thorax and is less restrictive of chest wall movement should be considered (e.g., Garchois plexidur brace). Surgical repair of scoliosis using various forms of fixed instrumentation and dynamic instrumentation (in young and still growing children) is commonly indicated for individuals with UCMD and intermediate COL6-RD, the timing of which is based on the degree of spine curvature and the rate of progression. In preparation for scoliosis surgery, careful coordination between orthopedic, anesthesia, intensive care, and pulmonary teams is essential for planning the preoperative, intraoperative, and postoperative respiratory needs. In particular, NIV in the form of BiPAP should be initiated prior to scoliosis surgery. Most individuals with UCMD or intermediate COL6-RD will need to be extubated directly to BiPAP following scoliosis surgery, and thus BiPAP initiation prior to surgery is essential both for optimizing lung function preoperatively and for assuring familiarity and comfort with BiPAP postoperatively. Physical therapists and occupational therapists can provide recommendations for stretching of the joints as well as for swimming and aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. If Achilles tendon contractures are severe or are asymmetric, thus adversely affecting gait, Achilles tendon release surgery by an orthopedic surgeon can provide increased range of motion, especially if Achilles tendon release is followed by casting. Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion / no movement at the joint in individuals with UCMD or intermediate COL6-RD who have undergone surgeries that disrupt the joint capsule. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. Feeding via a gastrostomy tube may be indicated for maintaining adequate nutrition and weight. The recurrence of failure to thrive at age ten to 12 years should prompt an evaluation for nocturnal hypoventilation via polysomnogram with continuous CO Respiratory function surveillance is of utmost importance, since unrecognized respiratory insufficiency is a leading cause of morbidity and mortality. Pulmonary function tests (PFTs) should be performed in both the upright (seated) and supine (lying down) positions at least annually to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO Annual clinical and radiographic assessment of scoliosis Annual cardiac evaluation with echocardiogram and EKG to evaluate for evidence of right-sided heart strain Annual neuromuscular assessment by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. Respiratory function surveillance is of utmost importance in UCMD and intermediate COL6-RD, since unrecognized or underrecognized respiratory insufficiency is the leading cause of morbidity and mortality. PFTs should be performed in both the upright (seated) and supine (lying down) positions every six months to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO Annual clinical and radiographic spine assessment for scoliosis and kyphoscoliosis Annual cardiac evaluation with echocardiogram and EKG to screen for evidence of right-sided heart strain Annual neuromuscular evaluation by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. Annual nutrition assessment See For a pregnant woman with COL6-RD, careful pulmonary surveillance during pregnancy for potential increased needs for ventilatory support is recommended, particularly given the disproportionate weakness of the diaphragm in the COL6-RDs. A prenatal physiotherapy assessment for hip dislocation and/or hip contractures may be recommended, given that the presence and degree of decreased range of motion at the hips could affect considerations for delivery. An assessment of the overall level of muscle weakness is also recommended, which may help in predicting the degree of weakness of abdominal muscles and thus the potential for a difficult birthing process, which could also affect considerations for delivery. Search • Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility • Exam of joint contractures, esp assessing for asymmetry of Achilles tendon contractures • PT & OT assessment • Feeding difficulties may manifest as FTT during 1st 1-2 yrs of life. • FTT at age 10-12 yrs may reflect inadequately supported ventilation. • Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility • Exam of joint contractures & joint hyperlaxity • Exam of back for evidence of stiffness &/or scoliosis • PT & OT assessment • Disproportionate weakness of the diaphragm can cause nocturnal hypoventilation, even in individuals who remain independently ambulant. For forced vital capacity (FVC) measurements of 60% predicted or lower, noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) should be initiated during a polysomnogram – with pressures adjusted to ensure adequate ventilation – and then consistently used while sleeping. If nocturnal BiPAP is started, BiPAP pressures should be carefully monitored and adjusted during repeat polysomnogram monitoring in order to provide adequate pressures as the body grows / pressure requirements increase related to progressive respiratory insufficiency. • If BiPAP is not initiated when needed or inadequate BiPAP pressures are used, right-sided heart strain can be seen on echocardiogram monitoring. Optimization of BiPAP pressures can help to prevent the development of cor pulmonale. • Surgical repair of scoliosis is rarely needed in individuals with Bethlem muscular dystrophy. If scoliosis surgery is considered, carefully planning for supporting respiratory needs preoperatively, intraoperatively, and postoperatively should be coordinated with orthopedic surgery, anesthesia, intensive care, and pulmonary teams. • Physical therapy and occupational therapy assessments can provide recommendations for joint stretching and swimming/aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. Strategies to avoid excessive joint strain should be discussed with a physical therapist and occupational therapist, given that joint pain has been reported by some individuals with Bethlem muscular dystrophy. • If Achilles tendon contractures are severe or asymmetric, thus adversely affecting gait, Achilles tendon release surgery can provide increased range of motion, especially if the Achilles tendon release is followed by casting. A noninvasive approach that can help promote improved range of motion of the Achilles tendons is serial casting. • Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion in individuals with Bethlem muscular dystrophy who have undergone joint surgery. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. • NIV in the form of BiPAP is needed in all individuals with UCMD by approximately age 11 years and all individuals with intermediate COL6-RD by the teenage years. • Use of an insufflator/exsufflator such as with a cough assist machine is essential for promoting coughing and expectoration of phlegm and airway clearance during respiratory infections and should be used as frequently as possible in order to help prevent the progression of upper respiratory infections to lower respiratory tract infections (pneumonias). • Right-sided heart strain can be evident on echocardiogram in individuals with respiratory insufficiency who are not using NIV in the form of BiPAP when needed or who are using BiPAP at pressures that are inadequate for supporting ventilation. If left unadjusted, cor pulmonale can develop. Right-sided heart function typically normalizes once BiPAP pressures are adequate for supporting nocturnal ventilation. • Bracing for scoliosis should be carefully approached, given how important movement of the chest wall is for respiration/ventilation in individuals with COL6-RDs. If spinal bracing is considered, a brace that does not cover the lower thorax and is less restrictive of chest wall movement should be considered (e.g., Garchois plexidur brace). Surgical repair of scoliosis using various forms of fixed instrumentation and dynamic instrumentation (in young and still growing children) is commonly indicated for individuals with UCMD and intermediate COL6-RD, the timing of which is based on the degree of spine curvature and the rate of progression. In preparation for scoliosis surgery, careful coordination between orthopedic, anesthesia, intensive care, and pulmonary teams is essential for planning the preoperative, intraoperative, and postoperative respiratory needs. In particular, NIV in the form of BiPAP should be initiated prior to scoliosis surgery. Most individuals with UCMD or intermediate COL6-RD will need to be extubated directly to BiPAP following scoliosis surgery, and thus BiPAP initiation prior to surgery is essential both for optimizing lung function preoperatively and for assuring familiarity and comfort with BiPAP postoperatively. • Physical therapists and occupational therapists can provide recommendations for stretching of the joints as well as for swimming and aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. • If Achilles tendon contractures are severe or are asymmetric, thus adversely affecting gait, Achilles tendon release surgery by an orthopedic surgeon can provide increased range of motion, especially if Achilles tendon release is followed by casting. Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion / no movement at the joint in individuals with UCMD or intermediate COL6-RD who have undergone surgeries that disrupt the joint capsule. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. • Feeding via a gastrostomy tube may be indicated for maintaining adequate nutrition and weight. The recurrence of failure to thrive at age ten to 12 years should prompt an evaluation for nocturnal hypoventilation via polysomnogram with continuous CO • Respiratory function surveillance is of utmost importance, since unrecognized respiratory insufficiency is a leading cause of morbidity and mortality. Pulmonary function tests (PFTs) should be performed in both the upright (seated) and supine (lying down) positions at least annually to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO • Annual clinical and radiographic assessment of scoliosis • Annual cardiac evaluation with echocardiogram and EKG to evaluate for evidence of right-sided heart strain • Annual neuromuscular assessment by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. • Respiratory function surveillance is of utmost importance in UCMD and intermediate COL6-RD, since unrecognized or underrecognized respiratory insufficiency is the leading cause of morbidity and mortality. PFTs should be performed in both the upright (seated) and supine (lying down) positions every six months to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO • Annual clinical and radiographic spine assessment for scoliosis and kyphoscoliosis • Annual cardiac evaluation with echocardiogram and EKG to screen for evidence of right-sided heart strain • Annual neuromuscular evaluation by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. • Annual nutrition assessment ## Evaluations Following Initial Diagnosis Recommended Evaluations Following Initial Diagnosis in Individuals with Bethlem Muscular Dystrophy Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility Exam of joint contractures, esp assessing for asymmetry of Achilles tendon contractures PT & OT assessment BiPAP = bilevel positive airway pressure; NIV = noninvasive ventilation; OT = occupational therapy; PT = physical therapy Recommended Evaluations Following Initial Diagnosis in Individuals with UCMD / Intermediate COL6-RD Feeding difficulties may manifest as FTT during 1st 1-2 yrs of life. FTT at age 10-12 yrs may reflect inadequately supported ventilation. Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility Exam of joint contractures & joint hyperlaxity Exam of back for evidence of stiffness &/or scoliosis PT & OT assessment BiPAP = bilevel positive airway pressure; FTT = failure to thrive; NIV = noninvasive ventilation; OT = occupational therapy; PT = physical therapy • Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility • Exam of joint contractures, esp assessing for asymmetry of Achilles tendon contractures • PT & OT assessment • Feeding difficulties may manifest as FTT during 1st 1-2 yrs of life. • FTT at age 10-12 yrs may reflect inadequately supported ventilation. • Neuromuscular exam to evaluate degree & distribution of muscle weakness & its effects on mobility • Exam of joint contractures & joint hyperlaxity • Exam of back for evidence of stiffness &/or scoliosis • PT & OT assessment ## Treatment of Manifestations Disproportionate weakness of the diaphragm can cause nocturnal hypoventilation, even in individuals who remain independently ambulant. For forced vital capacity (FVC) measurements of 60% predicted or lower, noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) should be initiated during a polysomnogram – with pressures adjusted to ensure adequate ventilation – and then consistently used while sleeping. If nocturnal BiPAP is started, BiPAP pressures should be carefully monitored and adjusted during repeat polysomnogram monitoring in order to provide adequate pressures as the body grows / pressure requirements increase related to progressive respiratory insufficiency. If BiPAP is not initiated when needed or inadequate BiPAP pressures are used, right-sided heart strain can be seen on echocardiogram monitoring. Optimization of BiPAP pressures can help to prevent the development of cor pulmonale. Surgical repair of scoliosis is rarely needed in individuals with Bethlem muscular dystrophy. If scoliosis surgery is considered, carefully planning for supporting respiratory needs preoperatively, intraoperatively, and postoperatively should be coordinated with orthopedic surgery, anesthesia, intensive care, and pulmonary teams. Physical therapy and occupational therapy assessments can provide recommendations for joint stretching and swimming/aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. Strategies to avoid excessive joint strain should be discussed with a physical therapist and occupational therapist, given that joint pain has been reported by some individuals with Bethlem muscular dystrophy. If Achilles tendon contractures are severe or asymmetric, thus adversely affecting gait, Achilles tendon release surgery can provide increased range of motion, especially if the Achilles tendon release is followed by casting. A noninvasive approach that can help promote improved range of motion of the Achilles tendons is serial casting. Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion in individuals with Bethlem muscular dystrophy who have undergone joint surgery. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. NIV in the form of BiPAP is needed in all individuals with UCMD by approximately age 11 years and all individuals with intermediate COL6-RD by the teenage years. Use of an insufflator/exsufflator such as with a cough assist machine is essential for promoting coughing and expectoration of phlegm and airway clearance during respiratory infections and should be used as frequently as possible in order to help prevent the progression of upper respiratory infections to lower respiratory tract infections (pneumonias). Right-sided heart strain can be evident on echocardiogram in individuals with respiratory insufficiency who are not using NIV in the form of BiPAP when needed or who are using BiPAP at pressures that are inadequate for supporting ventilation. If left unadjusted, cor pulmonale can develop. Right-sided heart function typically normalizes once BiPAP pressures are adequate for supporting nocturnal ventilation. Bracing for scoliosis should be carefully approached, given how important movement of the chest wall is for respiration/ventilation in individuals with COL6-RDs. If spinal bracing is considered, a brace that does not cover the lower thorax and is less restrictive of chest wall movement should be considered (e.g., Garchois plexidur brace). Surgical repair of scoliosis using various forms of fixed instrumentation and dynamic instrumentation (in young and still growing children) is commonly indicated for individuals with UCMD and intermediate COL6-RD, the timing of which is based on the degree of spine curvature and the rate of progression. In preparation for scoliosis surgery, careful coordination between orthopedic, anesthesia, intensive care, and pulmonary teams is essential for planning the preoperative, intraoperative, and postoperative respiratory needs. In particular, NIV in the form of BiPAP should be initiated prior to scoliosis surgery. Most individuals with UCMD or intermediate COL6-RD will need to be extubated directly to BiPAP following scoliosis surgery, and thus BiPAP initiation prior to surgery is essential both for optimizing lung function preoperatively and for assuring familiarity and comfort with BiPAP postoperatively. Physical therapists and occupational therapists can provide recommendations for stretching of the joints as well as for swimming and aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. If Achilles tendon contractures are severe or are asymmetric, thus adversely affecting gait, Achilles tendon release surgery by an orthopedic surgeon can provide increased range of motion, especially if Achilles tendon release is followed by casting. Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion / no movement at the joint in individuals with UCMD or intermediate COL6-RD who have undergone surgeries that disrupt the joint capsule. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. Feeding via a gastrostomy tube may be indicated for maintaining adequate nutrition and weight. The recurrence of failure to thrive at age ten to 12 years should prompt an evaluation for nocturnal hypoventilation via polysomnogram with continuous CO • Disproportionate weakness of the diaphragm can cause nocturnal hypoventilation, even in individuals who remain independently ambulant. For forced vital capacity (FVC) measurements of 60% predicted or lower, noninvasive ventilation (NIV) in the form of bilevel positive airway pressure (BiPAP) should be initiated during a polysomnogram – with pressures adjusted to ensure adequate ventilation – and then consistently used while sleeping. If nocturnal BiPAP is started, BiPAP pressures should be carefully monitored and adjusted during repeat polysomnogram monitoring in order to provide adequate pressures as the body grows / pressure requirements increase related to progressive respiratory insufficiency. • If BiPAP is not initiated when needed or inadequate BiPAP pressures are used, right-sided heart strain can be seen on echocardiogram monitoring. Optimization of BiPAP pressures can help to prevent the development of cor pulmonale. • Surgical repair of scoliosis is rarely needed in individuals with Bethlem muscular dystrophy. If scoliosis surgery is considered, carefully planning for supporting respiratory needs preoperatively, intraoperatively, and postoperatively should be coordinated with orthopedic surgery, anesthesia, intensive care, and pulmonary teams. • Physical therapy and occupational therapy assessments can provide recommendations for joint stretching and swimming/aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. Strategies to avoid excessive joint strain should be discussed with a physical therapist and occupational therapist, given that joint pain has been reported by some individuals with Bethlem muscular dystrophy. • If Achilles tendon contractures are severe or asymmetric, thus adversely affecting gait, Achilles tendon release surgery can provide increased range of motion, especially if the Achilles tendon release is followed by casting. A noninvasive approach that can help promote improved range of motion of the Achilles tendons is serial casting. • Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion in individuals with Bethlem muscular dystrophy who have undergone joint surgery. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. • NIV in the form of BiPAP is needed in all individuals with UCMD by approximately age 11 years and all individuals with intermediate COL6-RD by the teenage years. • Use of an insufflator/exsufflator such as with a cough assist machine is essential for promoting coughing and expectoration of phlegm and airway clearance during respiratory infections and should be used as frequently as possible in order to help prevent the progression of upper respiratory infections to lower respiratory tract infections (pneumonias). • Right-sided heart strain can be evident on echocardiogram in individuals with respiratory insufficiency who are not using NIV in the form of BiPAP when needed or who are using BiPAP at pressures that are inadequate for supporting ventilation. If left unadjusted, cor pulmonale can develop. Right-sided heart function typically normalizes once BiPAP pressures are adequate for supporting nocturnal ventilation. • Bracing for scoliosis should be carefully approached, given how important movement of the chest wall is for respiration/ventilation in individuals with COL6-RDs. If spinal bracing is considered, a brace that does not cover the lower thorax and is less restrictive of chest wall movement should be considered (e.g., Garchois plexidur brace). Surgical repair of scoliosis using various forms of fixed instrumentation and dynamic instrumentation (in young and still growing children) is commonly indicated for individuals with UCMD and intermediate COL6-RD, the timing of which is based on the degree of spine curvature and the rate of progression. In preparation for scoliosis surgery, careful coordination between orthopedic, anesthesia, intensive care, and pulmonary teams is essential for planning the preoperative, intraoperative, and postoperative respiratory needs. In particular, NIV in the form of BiPAP should be initiated prior to scoliosis surgery. Most individuals with UCMD or intermediate COL6-RD will need to be extubated directly to BiPAP following scoliosis surgery, and thus BiPAP initiation prior to surgery is essential both for optimizing lung function preoperatively and for assuring familiarity and comfort with BiPAP postoperatively. • Physical therapists and occupational therapists can provide recommendations for stretching of the joints as well as for swimming and aquatherapy exercises, which promote stretching of the joints and conditioning of the muscles. • If Achilles tendon contractures are severe or are asymmetric, thus adversely affecting gait, Achilles tendon release surgery by an orthopedic surgeon can provide increased range of motion, especially if Achilles tendon release is followed by casting. Surgical intervention on any joint contractures (beyond Achilles tendon release surgery) is not recommended, given the high postoperative risk of fixed contractures with complete loss of range of motion / no movement at the joint in individuals with UCMD or intermediate COL6-RD who have undergone surgeries that disrupt the joint capsule. New surgical approaches with the potential of avoiding the postoperative risk of fixed contractures should be carefully considered in consultation with neuromuscular specialists, physical therapists, and occupational therapists. • Feeding via a gastrostomy tube may be indicated for maintaining adequate nutrition and weight. The recurrence of failure to thrive at age ten to 12 years should prompt an evaluation for nocturnal hypoventilation via polysomnogram with continuous CO ## Surveillance Respiratory function surveillance is of utmost importance, since unrecognized respiratory insufficiency is a leading cause of morbidity and mortality. Pulmonary function tests (PFTs) should be performed in both the upright (seated) and supine (lying down) positions at least annually to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO Annual clinical and radiographic assessment of scoliosis Annual cardiac evaluation with echocardiogram and EKG to evaluate for evidence of right-sided heart strain Annual neuromuscular assessment by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. Respiratory function surveillance is of utmost importance in UCMD and intermediate COL6-RD, since unrecognized or underrecognized respiratory insufficiency is the leading cause of morbidity and mortality. PFTs should be performed in both the upright (seated) and supine (lying down) positions every six months to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO Annual clinical and radiographic spine assessment for scoliosis and kyphoscoliosis Annual cardiac evaluation with echocardiogram and EKG to screen for evidence of right-sided heart strain Annual neuromuscular evaluation by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. Annual nutrition assessment • Respiratory function surveillance is of utmost importance, since unrecognized respiratory insufficiency is a leading cause of morbidity and mortality. Pulmonary function tests (PFTs) should be performed in both the upright (seated) and supine (lying down) positions at least annually to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO • Annual clinical and radiographic assessment of scoliosis • Annual cardiac evaluation with echocardiogram and EKG to evaluate for evidence of right-sided heart strain • Annual neuromuscular assessment by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. • Respiratory function surveillance is of utmost importance in UCMD and intermediate COL6-RD, since unrecognized or underrecognized respiratory insufficiency is the leading cause of morbidity and mortality. PFTs should be performed in both the upright (seated) and supine (lying down) positions every six months to monitor the FVC. For FVC measurements of 60% predicted or lower, NIV in the form of BiPAP should be planned for and initiated during a polysomnogram – with pressures adjusted while CO • Annual clinical and radiographic spine assessment for scoliosis and kyphoscoliosis • Annual cardiac evaluation with echocardiogram and EKG to screen for evidence of right-sided heart strain • Annual neuromuscular evaluation by physical therapy and occupational therapy including an evaluation of the distribution of muscle weakness and joint contractures to inform recommendations for stretching regimens and mobility devices. Potential asymmetries of joint contractures are important to assess, given their effect on gait, sitting posture, and overall function. • Annual nutrition assessment ## Evaluation of Relatives at Risk See ## Pregnancy Management For a pregnant woman with COL6-RD, careful pulmonary surveillance during pregnancy for potential increased needs for ventilatory support is recommended, particularly given the disproportionate weakness of the diaphragm in the COL6-RDs. A prenatal physiotherapy assessment for hip dislocation and/or hip contractures may be recommended, given that the presence and degree of decreased range of motion at the hips could affect considerations for delivery. An assessment of the overall level of muscle weakness is also recommended, which may help in predicting the degree of weakness of abdominal muscles and thus the potential for a difficult birthing process, which could also affect considerations for delivery. ## Therapies Under Investigation Search ## Genetic Counseling The collagen VI-related dystrophies (a continuum of overlapping phenotypes encompassing Bethlem muscular dystrophy, Ullrich congenital muscular dystrophy [UCMD], and intermediate collagen VI-related dystrophy [COL6-RD]) are associated with both autosomal dominant and autosomal recessive inheritance. Bethlem muscular dystrophy is usually inherited in an autosomal dominant manner, although autosomal recessive inheritance has also been reported [ UCMD and intermediate COL6-RD are typically caused by a Some individuals diagnosed with autosomal dominant COL6-RD have an affected parent. Approximately 50%-75% of individuals diagnosed with COL6-RD have the disorder as the result of a Molecular genetic testing is recommended for the apparently asymptomatic parents of a proband with a presumed If the pathogenic variant found 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 [ It should be noted that parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the COL6-RDs [ The family history of some individuals diagnosed with autosomal dominant COL6-RD may appear to be negative due to failure to recognize the disorder in a mildly symptomatic family member, early death of the parent before the onset of symptoms, or late onset in an affected parent. Therefore, an apparently negative family history cannot be confirmed unless detailed neuromuscular clinical examination of the parents has been performed and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the risk to the sibs of inheriting the variant is 50%. The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant. The most significant intrafamilial clinical variability is observed in families segregating If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the significant possibility of parental mosaicism. Parental somatic mosaicism (and concomitant germline mosaicism) with full penetrance of the pathogenic variant in heterozygous offspring is not uncommon in the COL6-RDs [ If the parents have not been tested for the pathogenic variant but are clinically unaffected, the recurrence risk to the sibs of a proband is presumed to be greater than that of the general population because of possibility of reduced penetrance in a heterozygous parent or parental somatic and germline mosaicism. The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of the disorder. If both parents are known to be heterozygous for a Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of 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. 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 autosomal dominant COL6-RD have an affected parent. • Approximately 50%-75% of individuals diagnosed with COL6-RD have the disorder as the result of a • Molecular genetic testing is recommended for the apparently asymptomatic parents of a proband with a presumed • If the pathogenic variant found 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 [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline – or somatic and germline – mosaicism [ • It should be noted that parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the COL6-RDs [ • The family history of some individuals diagnosed with autosomal dominant COL6-RD may appear to be negative due to failure to recognize the disorder in a mildly symptomatic family member, early death of the parent before the onset of symptoms, or late onset in an affected parent. Therefore, an apparently negative family history cannot be confirmed unless detailed neuromuscular clinical examination of the parents has been performed and 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 [ • If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the risk to the sibs of inheriting the variant is 50%. • The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant. The most significant intrafamilial clinical variability is observed in families segregating • If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the significant possibility of parental mosaicism. Parental somatic mosaicism (and concomitant germline mosaicism) with full penetrance of the pathogenic variant in heterozygous offspring is not uncommon in the COL6-RDs [ • If the parents have not been tested for the pathogenic variant but are clinically unaffected, the recurrence risk to the sibs of a proband is presumed to be greater than that of the general population because of possibility of reduced penetrance in a heterozygous parent or parental somatic and germline mosaicism. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of 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 • Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of 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 The collagen VI-related dystrophies (a continuum of overlapping phenotypes encompassing Bethlem muscular dystrophy, Ullrich congenital muscular dystrophy [UCMD], and intermediate collagen VI-related dystrophy [COL6-RD]) are associated with both autosomal dominant and autosomal recessive inheritance. Bethlem muscular dystrophy is usually inherited in an autosomal dominant manner, although autosomal recessive inheritance has also been reported [ UCMD and intermediate COL6-RD are typically caused by a ## Autosomal Dominant Inheritance – Risk to Family Members Some individuals diagnosed with autosomal dominant COL6-RD have an affected parent. Approximately 50%-75% of individuals diagnosed with COL6-RD have the disorder as the result of a Molecular genetic testing is recommended for the apparently asymptomatic parents of a proband with a presumed If the pathogenic variant found 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 [ It should be noted that parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the COL6-RDs [ The family history of some individuals diagnosed with autosomal dominant COL6-RD may appear to be negative due to failure to recognize the disorder in a mildly symptomatic family member, early death of the parent before the onset of symptoms, or late onset in an affected parent. Therefore, an apparently negative family history cannot be confirmed unless detailed neuromuscular clinical examination of the parents has been performed and molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband. If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the risk to the sibs of inheriting the variant is 50%. The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant. The most significant intrafamilial clinical variability is observed in families segregating If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the significant possibility of parental mosaicism. Parental somatic mosaicism (and concomitant germline mosaicism) with full penetrance of the pathogenic variant in heterozygous offspring is not uncommon in the COL6-RDs [ If the parents have not been tested for the pathogenic variant but are clinically unaffected, the recurrence risk to the sibs of a proband is presumed to be greater than that of the general population because of possibility of reduced penetrance in a heterozygous parent or parental somatic and germline mosaicism. • Some individuals diagnosed with autosomal dominant COL6-RD have an affected parent. • Approximately 50%-75% of individuals diagnosed with COL6-RD have the disorder as the result of a • Molecular genetic testing is recommended for the apparently asymptomatic parents of a proband with a presumed • If the pathogenic variant found 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 [ • The proband has a • The proband inherited a pathogenic variant from a parent with germline – or somatic and germline – mosaicism [ • It should be noted that parental somatic mosaicism (and concomitant germline mosaicism) is not uncommon in the COL6-RDs [ • The family history of some individuals diagnosed with autosomal dominant COL6-RD may appear to be negative due to failure to recognize the disorder in a mildly symptomatic family member, early death of the parent before the onset of symptoms, or late onset in an affected parent. Therefore, an apparently negative family history cannot be confirmed unless detailed neuromuscular clinical examination of the parents has been performed and 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 [ • If a parent of the proband has the pathogenic variant identified in the proband and/or is affected, the risk to the sibs of inheriting the variant is 50%. • The severity of COL6-RD manifestations may vary among family members who are heterozygous for the same pathogenic variant. The most significant intrafamilial clinical variability is observed in families segregating • If the proband has a known pathogenic variant that cannot be detected in the leukocyte DNA of either parent, the recurrence risk to sibs is presumed to be greater than that of the general population because of the significant possibility of parental mosaicism. Parental somatic mosaicism (and concomitant germline mosaicism) with full penetrance of the pathogenic variant in heterozygous offspring is not uncommon in the COL6-RDs [ • If the parents have not been tested for the pathogenic variant but are clinically unaffected, the recurrence risk to the sibs of a proband is presumed to be greater than that of the general population because of possibility of reduced penetrance in a heterozygous parent or parental somatic and germline mosaicism. ## 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 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. Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of the disorder. If both parents are known to be heterozygous for a Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of the disorder. • The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one • Molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of 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 • Individuals who are heterozygotes (carriers) for a pathogenic variant associated with autosomal recessive COL6-RD do not appear to develop manifestations of the disorder. ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Prenatal Testing and Preimplantation Genetic Testing Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. ## Resources United Kingdom CMDIR/Cure CMD • • • • • • United Kingdom • • • • CMDIR/Cure CMD • ## Molecular Genetics Collagen VI-Related Dystrophies: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Collagen VI-Related Dystrophies ( Collagen VI is expressed in the extracellular matrices of several tissues and tissue components including muscle, blood vessels, nerves, skin, tendons, cartilage, intervertebral discs, lenses, and internal organs [ The assembly of collagen VI is a complex multistep process. Association of the three genetically distinct subunits α1(VI), α2(VI), and α3(VI) to form a triple helical monomer is followed by staggered assembly into disulfide-bonded antiparallel dimers [ Other dominant-negative variants that commonly occur in the COL6-RDs are heterozygous single-amino-acid substitutions disrupting the Gly-Xaa-Yaa motifs of the highly conserved N-terminal triple helical domains of any of the three COL6 genes, so-called glycine variants [ An additional recurrent dominant-negative pathogenic variant consists of a deep-intronic change in intron 11 of Intragenic deletions and splice site variants can also result in a transcript which is out of frame [ Of note, missense variants in compound heterozygosity with other missense variants may be pathogenic – the pathogenicity of which depends on the location and effects of the particular variants. Homozygous missense variants are a less common cause of COL6-RD but can result in a phenotype of UCMD if affecting crucial functions or interactions of the collagen VI protein [ Given the highly polymorphic nature of A recurrent deep-intronic Collagen VI-Related Dystrophies: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from • Other dominant-negative variants that commonly occur in the COL6-RDs are heterozygous single-amino-acid substitutions disrupting the Gly-Xaa-Yaa motifs of the highly conserved N-terminal triple helical domains of any of the three COL6 genes, so-called glycine variants [ • An additional recurrent dominant-negative pathogenic variant consists of a deep-intronic change in intron 11 of • Intragenic deletions and splice site variants can also result in a transcript which is out of frame [ • Of note, missense variants in compound heterozygosity with other missense variants may be pathogenic – the pathogenicity of which depends on the location and effects of the particular variants. Homozygous missense variants are a less common cause of COL6-RD but can result in a phenotype of UCMD if affecting crucial functions or interactions of the collagen VI protein [ • Given the highly polymorphic nature of • A recurrent deep-intronic ## Molecular Pathogenesis Collagen VI is expressed in the extracellular matrices of several tissues and tissue components including muscle, blood vessels, nerves, skin, tendons, cartilage, intervertebral discs, lenses, and internal organs [ The assembly of collagen VI is a complex multistep process. Association of the three genetically distinct subunits α1(VI), α2(VI), and α3(VI) to form a triple helical monomer is followed by staggered assembly into disulfide-bonded antiparallel dimers [ Other dominant-negative variants that commonly occur in the COL6-RDs are heterozygous single-amino-acid substitutions disrupting the Gly-Xaa-Yaa motifs of the highly conserved N-terminal triple helical domains of any of the three COL6 genes, so-called glycine variants [ An additional recurrent dominant-negative pathogenic variant consists of a deep-intronic change in intron 11 of Intragenic deletions and splice site variants can also result in a transcript which is out of frame [ Of note, missense variants in compound heterozygosity with other missense variants may be pathogenic – the pathogenicity of which depends on the location and effects of the particular variants. Homozygous missense variants are a less common cause of COL6-RD but can result in a phenotype of UCMD if affecting crucial functions or interactions of the collagen VI protein [ Given the highly polymorphic nature of A recurrent deep-intronic Collagen VI-Related Dystrophies: Notable Pathogenic Variants by Gene Variants listed in the table have been provided by the authors. Genes from • Other dominant-negative variants that commonly occur in the COL6-RDs are heterozygous single-amino-acid substitutions disrupting the Gly-Xaa-Yaa motifs of the highly conserved N-terminal triple helical domains of any of the three COL6 genes, so-called glycine variants [ • An additional recurrent dominant-negative pathogenic variant consists of a deep-intronic change in intron 11 of • Intragenic deletions and splice site variants can also result in a transcript which is out of frame [ • Of note, missense variants in compound heterozygosity with other missense variants may be pathogenic – the pathogenicity of which depends on the location and effects of the particular variants. Homozygous missense variants are a less common cause of COL6-RD but can result in a phenotype of UCMD if affecting crucial functions or interactions of the collagen VI protein [ • Given the highly polymorphic nature of • A recurrent deep-intronic ## Chapter Notes Véronique Bolduc, PhD (2021-present)Carsten G Bönnemann, MD, habil (2021-present)Katharine Mary Bushby, MD, MBCHB FRCP; University of Newcastle upon Tyne (2004-2021)Sandra Donkervoort, MS, CGC (2021-present)Kevin M Flanigan, MD; Nationwide Children's Hospital (2004-2021)A Reghan Foley, MD, MD(Res) (2021-present)Debbie Hicks, PhD; University of Newcastle upon Tyne (2012-2021)Anne Katrin Lampe, MD; Western General Hospital (2004-2021)Payam Mohassel, MD (2021-present) 11 March 2021 (sw) Comprehensive update posted live 9 August 2012 (me) Comprehensive update posted live 6 April 2007 (me) Comprehensive update posted to live Web site 25 June 2004 (me) Review posted to live Web site 18 February 2004 (kf) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 11 March 2021 (sw) Comprehensive update posted live • 9 August 2012 (me) Comprehensive update posted live • 6 April 2007 (me) Comprehensive update posted to live Web site • 25 June 2004 (me) Review posted to live Web site • 18 February 2004 (kf) Original submission ## Author History Véronique Bolduc, PhD (2021-present)Carsten G Bönnemann, MD, habil (2021-present)Katharine Mary Bushby, MD, MBCHB FRCP; University of Newcastle upon Tyne (2004-2021)Sandra Donkervoort, MS, CGC (2021-present)Kevin M Flanigan, MD; Nationwide Children's Hospital (2004-2021)A Reghan Foley, MD, MD(Res) (2021-present)Debbie Hicks, PhD; University of Newcastle upon Tyne (2012-2021)Anne Katrin Lampe, MD; Western General Hospital (2004-2021)Payam Mohassel, MD (2021-present) ## Revision History 11 March 2021 (sw) Comprehensive update posted live 9 August 2012 (me) Comprehensive update posted live 6 April 2007 (me) Comprehensive update posted to live Web site 25 June 2004 (me) Review posted to live Web site 18 February 2004 (kf) Original submission Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the • 11 March 2021 (sw) Comprehensive update posted live • 9 August 2012 (me) Comprehensive update posted live • 6 April 2007 (me) Comprehensive update posted to live Web site • 25 June 2004 (me) Review posted to live Web site • 18 February 2004 (kf) Original submission ## References ## Literature Cited Muscle MRI findings in Bethlem muscular dystrophy Axial T Reproduced from Muscle MRI findings in Ullrich congenital muscular dystrophy (UCMD) Axial T Reproduced from Collagen VI immunohistochemical labeling in muscle in COL6-RD a. Collagen VI (red) and laminin γ-1 (green) colocalize in the basement membrane (resulting in a yellow color) in muscle from an individual without neuromuscular disease. b. Collagen VI staining (red) does not colocalize with laminin subunit γ-1 (green) in the basement membrane in muscle from an individual with COL6-RD due to a dominant pathogenic variant in a COL6 gene, which affects the function of the collagen VI protein via a dominant-negative mutational mechanism. Reproduced from Collagen VI immunocytochemical studies in dermal fibroblasts in COL6-RD A. The normal control with collagen VI labeling with antibody demonstrates an abundance of well-organized collagen VI microfibrils in a linear, unidirectional trend. B. The negative control (with no antibody) does not label collagen VI. C-F. 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Congenital titinopathy: comprehensive characterization and pathogenic insights.. Ann Neurol 2018;83:1105-24", "M Okada, G Kawahara, S Noguchi, K Sugie, K Murayama, I Nonaka, YK Hayashi, I Nishino. Primary collagen VI deficiency is the second most common congenital muscular dystrophy in Japan.. Neurology 2007;69:1035-42", "RA Pace, RA Peat, NL Baker, L Zamurs, M Mörgelin, M Irving, NE Adams, JF Bateman, D Mowat, NJ Smith, PJ Lamont, SA Moore, KD Mathews, KN North, SR Lamandé. Collagen VI glycine mutations: perturbed assembly and a spectrum of clinical severity.. Ann Neurol 2008;64:294-303", "TC Pan, RZ Zhang, DG Sudano, SK Marie, CG Bönnemann, ML Chu. New molecular mechanism for Ullrich congenital muscular dystrophy: a heterozygous in-frame deletion in the COL6A1 gene causes a severe phenotype.. Am J Hum Genet 2003;73:355-69", "RA Peat, NL Baker, KJ Jones, KN North, SR Lamandé. Variable penetrance of COL6A1 null mutations: implications for prenatal diagnosis and genetic counselling in Ullrich congenital muscular dystrophy families.. Neuromuscul Disord. 2007;17:547-57", "RA Peat, JM Smith, AG Compton, NL Baker, RA Pace, DJ Burkin, SJ Kaufman, SR Lamandé, KN North. Diagnosis and etiology of congenital muscular dystrophy.. Neurology 2008;71:312-21", "G Pepe, E Bertini, P Bonaldo, K Bushby, B Giusti, M de Visser, P Guicheney, G Lattanzi, L Merlini, F Muntoni, I Nishino, I Nonaka, RB Yaou, P Sabatelli, C Sewry, H Topaloglu, A van der Kooi. Bethlem myopathy (BETHLEM) and Ullrich scleroatonic muscular dystrophy: 100th ENMC international workshop, 23-24 November 2001, Naarden, the Netherlands.. Neuromuscul Disord 2002;12:984-93", "G Pepe, L Lucarini, RZ Zhang, TC Pan, B Giusti, S Quijano-Roy, C Gartioux, KM Bushby, P Guicheney, ML Chu. COL6A1 genomic deletions in Bethlem myopathy and Ullrich muscular dystrophy.. Ann Neurol. 2006;59:190-5", "S Petrini, A Tessa, WB Stallcup, P Sabatelli, M Pescatori, B Giusti, R Carrozzo, M Verardo, N Bergamin, M Columbaro, C Bernardini, L Merlini, G Pepe, P Bonaldo, E Bertini. Altered expression of the MCSP/NG2 chondroitin sulfate proteoglycan in collagen VI deficiency.. Mol Cell Neurosci 2005;30:408-17", "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 Schessl, NM Goemans, AI Magold, Y Zou, Y Hu, J Kirschner, R Scot, CG Bönnemann. Predominant fiber atrophy and fiber type disproportion in early ullrich disease.. Muscle Nerve 2008;38:1184-91", "O Ullrich. Kongenitale, atonisch-sklerotische Muskeldystrophie, ein weiterer Typus der heredodegenerativen Erkrankungen des neuromuskulaeren Systems.. Z Ges Neurol Psychiatr 1930a;126:171-201", "O Ullrich. Kongenitale atonisch-sklerotische Muskeldystrophie.. Monatsschr Kinderheilkd 1930b;47:502-10", "CA Valencia, A Ankala, D Rhodenizer, S Bhide, MR Littlejohn, LM Keong, A Rutkowski, S Sparks, C Bönnemann, M Hegde. Comprehensive mutation analysis for congenital muscular dystrophy: a clinical PCR-based enrichment and next-generation sequencing panel.. PLoS One 2013;8", "AJ van der Kooi, WG de Voogt, E Bertini, L Merlini, FB Talim, R Ben Yaou, A Urtziberea, M de Visser. Cardiac and pulmonary investigations in Bethlem myopathy.. Arch Neurol 2006;63:1617-21", "T Yonekawa, H Komaki, M Okada, YK Hayashi, I Nonaka, K Sugai, M Sasaki, I Nishino. Rapidly progressive scoliosis and respiratory deterioration in Ullrich congenital muscular dystrophy.. J Neurol Neurosurg Psychiatry 2013;84:982-8", "RZ Zhang, P Sabatelli, TC Pan, S Squarzoni, E Mattioli, E Bertini, G Pepe, ML Chu. Effects on collagen VI mRNA stability and microfibrillar assembly of three COL6A2 mutations in two families with Ullrich congenital muscular dystrophy.. J Biol Chem 2002;277:43557-64", "RZ Zhang, Y Zou, TC Pan, D Markova, A Fertala, Y Hu, S Squarzoni, UC Reed, SK Marie, CG Bönnemann, ML Chu. Recessive COL6A2 C-globular missense mutations in Ullrich congenital muscular dystrophy: role of the C2a splice variant.. J Biol Chem 2010;285:10005-15" ]	25/6/2004	11/3/2021		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bfns	bfns	[ "KCNQ2-Related Self-Limited Familial Neonatal Epilepsy (SLFNE)", "KCNQ2-Related Neonatal-Onset Developmental and Epileptic Encephalopathy (NEO-DEE)", "KCNQ2-Related Neonatal Encephalopathy with Non-Epileptic Myoclonus", "KCNQ2-Related Non-Neonatal-Onset Developmental and Epileptic Encephalopathy", "KCNQ2-Related Isolated Intellectual Disability", "Potassium voltage-gated channel subfamily KQT member 2", "KCNQ2", "KCNQ2-Related Disorders" ]		Francesco Miceli, Maria Virginia Soldovieri, Sarah Weckhuysen, Edward Cooper, Maurizio Taglialatela	Summary The diagnosis of a	Self-limited familial neonatal epilepsy (SLFNE) Neonatal-onset developmental and epileptic encephalopathy (NEO-DEE) Neonatal encephalopathy with non-epileptic myoclonus Non-neonatal-onset developmental and epileptic encephalopathy Isolated intellectual disability For synonyms and outdated names see For other genetic causes of these phenotypes see • Self-limited familial neonatal epilepsy (SLFNE) • Neonatal-onset developmental and epileptic encephalopathy (NEO-DEE) • Neonatal encephalopathy with non-epileptic myoclonus • Non-neonatal-onset developmental and epileptic encephalopathy • Isolated intellectual disability ## Diagnosis A Seizures in an otherwise healthy infant with onset between two and eight days after term birth and spontaneously disappearing between the first and the sixth to the 12th month of life The neonatal seizures may appear "convulsive" to some observers, as they share several features with generalized convulsions occurring in older children: sudden onset with prominent motor involvement, often accompanied by apnea and cyanosis. However, more careful electroclinical review using video EEG identifies the seizures as focal onset with tonic stiffening of limb(s) and some migration during each seizure's evolution. Normal physical examination and laboratory tests prior to onset of seizures, between seizure episodes, and following cessation of seizures No specific EEG criteria; EEG background is normal, or may show focal epileptiform discharges at neonatal onset but rapidly normalizes during early infancy. Normal brain imaging Family history of neonatal seizures is usually present; full family history may require interviewing older relatives (parent may be unaware). Seizure onset in the first week of life with EEGs showing a burst-suppression pattern or multifocal epileptiform activity Seizures are mostly tonic, with associated focal motor and autonomic features (similar to SLFNE). Multiple daily seizures occur at onset, with frequent seizures in the first few months to the first year of life, although this natural history is frequently ameliorated by treatment using appropriate anti-seizure medication. Cessation of seizures generally between age nine months and four years. Recurrence of (generally less frequent) seizures may occur later in life. Encephalopathy is present from birth and persists even after seizures are controlled. Subsequent developmental impairment ranges from moderate to profound. Neonatal brain MRI may be normal or may show transient hyperdensities in the basal ganglia, and later MRIs may show white matter or general volume loss. The following additional phenotypes appear more rarely in hospital-based, multicenter, and registry-based series, but have become established as Profound encephalopathy at birth with hypotonia and poor respiratory effort Spontaneous episodes of jerking movements (myoclonus); may also be provoked by touch and/or attempted arousal Defining neonatal video EEG findings: invariant burst-suppression EEG background; body and limb jerks (myoclonus) without cortical accompaniment Epileptic spasms and other seizure types and profound encephalopathy emerging in early infancy Progressive volume loss and hypomyelination on brain MRI Infantile- or childhood-onset epilepsy, including West syndrome Neurodevelopment is usually impaired from birth, although normal early development with stagnation at onset of seizures has been described. Subsequent developmental impairment is moderate to severe, even if seizures are controlled. Brain MRI may show mild volume loss. ID without epilepsy Motor and speech delay may be present. Brain MRI is normal or shows mild myelinization delay. The diagnosis of a 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 No specific study has been carried out on the cost-effectiveness or diagnostic yield of specific genetic tests in individuals with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Thirteen additional individuals with large contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes (e.g., those described by • Seizures in an otherwise healthy infant with onset between two and eight days after term birth and spontaneously disappearing between the first and the sixth to the 12th month of life • The neonatal seizures may appear "convulsive" to some observers, as they share several features with generalized convulsions occurring in older children: sudden onset with prominent motor involvement, often accompanied by apnea and cyanosis. However, more careful electroclinical review using video EEG identifies the seizures as focal onset with tonic stiffening of limb(s) and some migration during each seizure's evolution. • Normal physical examination and laboratory tests prior to onset of seizures, between seizure episodes, and following cessation of seizures • No specific EEG criteria; EEG background is normal, or may show focal epileptiform discharges at neonatal onset but rapidly normalizes during early infancy. • Normal brain imaging • Family history of neonatal seizures is usually present; full family history may require interviewing older relatives (parent may be unaware). • Seizure onset in the first week of life with EEGs showing a burst-suppression pattern or multifocal epileptiform activity • Seizures are mostly tonic, with associated focal motor and autonomic features (similar to SLFNE). • Multiple daily seizures occur at onset, with frequent seizures in the first few months to the first year of life, although this natural history is frequently ameliorated by treatment using appropriate anti-seizure medication. • Cessation of seizures generally between age nine months and four years. Recurrence of (generally less frequent) seizures may occur later in life. • Encephalopathy is present from birth and persists even after seizures are controlled. Subsequent developmental impairment ranges from moderate to profound. • Neonatal brain MRI may be normal or may show transient hyperdensities in the basal ganglia, and later MRIs may show white matter or general volume loss. • Profound encephalopathy at birth with hypotonia and poor respiratory effort • Spontaneous episodes of jerking movements (myoclonus); may also be provoked by touch and/or attempted arousal • Defining neonatal video EEG findings: invariant burst-suppression EEG background; body and limb jerks (myoclonus) without cortical accompaniment • Epileptic spasms and other seizure types and profound encephalopathy emerging in early infancy • Progressive volume loss and hypomyelination on brain MRI • Infantile- or childhood-onset epilepsy, including West syndrome • Neurodevelopment is usually impaired from birth, although normal early development with stagnation at onset of seizures has been described. • Subsequent developmental impairment is moderate to severe, even if seizures are controlled. • Brain MRI may show mild volume loss. • ID without epilepsy • Motor and speech delay may be present. • Brain MRI is normal or shows mild myelinization delay. • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings A Seizures in an otherwise healthy infant with onset between two and eight days after term birth and spontaneously disappearing between the first and the sixth to the 12th month of life The neonatal seizures may appear "convulsive" to some observers, as they share several features with generalized convulsions occurring in older children: sudden onset with prominent motor involvement, often accompanied by apnea and cyanosis. However, more careful electroclinical review using video EEG identifies the seizures as focal onset with tonic stiffening of limb(s) and some migration during each seizure's evolution. Normal physical examination and laboratory tests prior to onset of seizures, between seizure episodes, and following cessation of seizures No specific EEG criteria; EEG background is normal, or may show focal epileptiform discharges at neonatal onset but rapidly normalizes during early infancy. Normal brain imaging Family history of neonatal seizures is usually present; full family history may require interviewing older relatives (parent may be unaware). Seizure onset in the first week of life with EEGs showing a burst-suppression pattern or multifocal epileptiform activity Seizures are mostly tonic, with associated focal motor and autonomic features (similar to SLFNE). Multiple daily seizures occur at onset, with frequent seizures in the first few months to the first year of life, although this natural history is frequently ameliorated by treatment using appropriate anti-seizure medication. Cessation of seizures generally between age nine months and four years. Recurrence of (generally less frequent) seizures may occur later in life. Encephalopathy is present from birth and persists even after seizures are controlled. Subsequent developmental impairment ranges from moderate to profound. Neonatal brain MRI may be normal or may show transient hyperdensities in the basal ganglia, and later MRIs may show white matter or general volume loss. The following additional phenotypes appear more rarely in hospital-based, multicenter, and registry-based series, but have become established as Profound encephalopathy at birth with hypotonia and poor respiratory effort Spontaneous episodes of jerking movements (myoclonus); may also be provoked by touch and/or attempted arousal Defining neonatal video EEG findings: invariant burst-suppression EEG background; body and limb jerks (myoclonus) without cortical accompaniment Epileptic spasms and other seizure types and profound encephalopathy emerging in early infancy Progressive volume loss and hypomyelination on brain MRI Infantile- or childhood-onset epilepsy, including West syndrome Neurodevelopment is usually impaired from birth, although normal early development with stagnation at onset of seizures has been described. Subsequent developmental impairment is moderate to severe, even if seizures are controlled. Brain MRI may show mild volume loss. ID without epilepsy Motor and speech delay may be present. Brain MRI is normal or shows mild myelinization delay. • Seizures in an otherwise healthy infant with onset between two and eight days after term birth and spontaneously disappearing between the first and the sixth to the 12th month of life • The neonatal seizures may appear "convulsive" to some observers, as they share several features with generalized convulsions occurring in older children: sudden onset with prominent motor involvement, often accompanied by apnea and cyanosis. However, more careful electroclinical review using video EEG identifies the seizures as focal onset with tonic stiffening of limb(s) and some migration during each seizure's evolution. • Normal physical examination and laboratory tests prior to onset of seizures, between seizure episodes, and following cessation of seizures • No specific EEG criteria; EEG background is normal, or may show focal epileptiform discharges at neonatal onset but rapidly normalizes during early infancy. • Normal brain imaging • Family history of neonatal seizures is usually present; full family history may require interviewing older relatives (parent may be unaware). • Seizure onset in the first week of life with EEGs showing a burst-suppression pattern or multifocal epileptiform activity • Seizures are mostly tonic, with associated focal motor and autonomic features (similar to SLFNE). • Multiple daily seizures occur at onset, with frequent seizures in the first few months to the first year of life, although this natural history is frequently ameliorated by treatment using appropriate anti-seizure medication. • Cessation of seizures generally between age nine months and four years. Recurrence of (generally less frequent) seizures may occur later in life. • Encephalopathy is present from birth and persists even after seizures are controlled. Subsequent developmental impairment ranges from moderate to profound. • Neonatal brain MRI may be normal or may show transient hyperdensities in the basal ganglia, and later MRIs may show white matter or general volume loss. • Profound encephalopathy at birth with hypotonia and poor respiratory effort • Spontaneous episodes of jerking movements (myoclonus); may also be provoked by touch and/or attempted arousal • Defining neonatal video EEG findings: invariant burst-suppression EEG background; body and limb jerks (myoclonus) without cortical accompaniment • Epileptic spasms and other seizure types and profound encephalopathy emerging in early infancy • Progressive volume loss and hypomyelination on brain MRI • Infantile- or childhood-onset epilepsy, including West syndrome • Neurodevelopment is usually impaired from birth, although normal early development with stagnation at onset of seizures has been described. • Subsequent developmental impairment is moderate to severe, even if seizures are controlled. • Brain MRI may show mild volume loss. • ID without epilepsy • Motor and speech delay may be present. • Brain MRI is normal or shows mild myelinization delay. ## Establishing the Diagnosis The diagnosis of a 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 No specific study has been carried out on the cost-effectiveness or diagnostic yield of specific genetic tests in individuals with For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in See See Thirteen additional individuals with large contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click 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. 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 • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Seizures in neonates with Approximately 30% of children with In most affected individuals, developmental delay is associated with axial hypotonia and/or spastic quadriplegia. Most individuals are severely delayed in reaching developmental milestones and are nonverbal or only use a few words or short sentences. Some are unable to sit independently, have poor eye contact, and show little interest in their surroundings. Seizures as well as early MRI brain abnormalities (mainly occurring in the basal ganglia and thalamus) are generally resolved by age three years. Seizures may, however, recur later in life. At the most severe end of the spectrum, some affected individuals have findings that fall within the clinical description of Ohtahara syndrome [ Pathogenic changes associated with Pathogenic changes identified in More rarely, specific variants cause gain-of-function effects, with the M-current density being increased to >100% when mutated subunits are coexpressed with wild type subunits. Gain-of-function variants are typically associated with neurodevelopmental phenotypes Individuals harboring identical recurring pathogenic variants so far appear to have broadly similar seizure and developmental outcomes. However, there are a few reports in which the same A few children with Penetrance is incomplete in Penetrance is complete for germline variants leading to No age- or sex-related differences have been reported. The familial occurrence of neonatal seizures was first reported by Subsequently it was noted that in rare instances, More recent reports of certain A recent prospective national epidemiologic cohort study from Scotland determined the incidence of the more common single-gene epilepsies of early childhood, and estimated that in infants under age six months ## Clinical Description Seizures in neonates with Approximately 30% of children with In most affected individuals, developmental delay is associated with axial hypotonia and/or spastic quadriplegia. Most individuals are severely delayed in reaching developmental milestones and are nonverbal or only use a few words or short sentences. Some are unable to sit independently, have poor eye contact, and show little interest in their surroundings. Seizures as well as early MRI brain abnormalities (mainly occurring in the basal ganglia and thalamus) are generally resolved by age three years. Seizures may, however, recur later in life. At the most severe end of the spectrum, some affected individuals have findings that fall within the clinical description of Ohtahara syndrome [ Seizures in neonates with Approximately 30% of children with In most affected individuals, developmental delay is associated with axial hypotonia and/or spastic quadriplegia. Most individuals are severely delayed in reaching developmental milestones and are nonverbal or only use a few words or short sentences. Some are unable to sit independently, have poor eye contact, and show little interest in their surroundings. Seizures as well as early MRI brain abnormalities (mainly occurring in the basal ganglia and thalamus) are generally resolved by age three years. Seizures may, however, recur later in life. At the most severe end of the spectrum, some affected individuals have findings that fall within the clinical description of Ohtahara syndrome [ ## Other Rarer Phenotypes ## Genotype-Phenotype Correlations Pathogenic changes associated with Pathogenic changes identified in More rarely, specific variants cause gain-of-function effects, with the M-current density being increased to >100% when mutated subunits are coexpressed with wild type subunits. Gain-of-function variants are typically associated with neurodevelopmental phenotypes Individuals harboring identical recurring pathogenic variants so far appear to have broadly similar seizure and developmental outcomes. However, there are a few reports in which the same A few children with ## Penetrance Penetrance is incomplete in Penetrance is complete for germline variants leading to No age- or sex-related differences have been reported. ## Nomenclature The familial occurrence of neonatal seizures was first reported by Subsequently it was noted that in rare instances, More recent reports of certain ## Prevalence A recent prospective national epidemiologic cohort study from Scotland determined the incidence of the more common single-gene epilepsies of early childhood, and estimated that in infants under age six months ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Self-limited familial neonatal epilepsy (SLFNE); Self-limited familial infantile epilepsy (SLFIE); Self-limited familial neonatal-infantile epilepsy (SLFNIE); and Developmental and epileptic encephalopathy (DEE). Selected Genes To Consider in the Differential Diagnosis of AD = autosomal dominant; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked • Self-limited familial neonatal epilepsy (SLFNE); • Self-limited familial infantile epilepsy (SLFIE); • Self-limited familial neonatal-infantile epilepsy (SLFNIE); and • Developmental and epileptic encephalopathy (DEE). ## Management No clinical practice guidelines for To establish the extent of disease and needs in an individual diagnosed with a Recommended Evaluations Following Initial Diagnosis in Individuals with a To incl brain MRI & EEG Video EEG monitoring incl sleep phase to obtain information on presence of seizures. A burst-suppression EEG pattern might only be seen during sleep. 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 persons w/dysphagia &/or aspiration risk. To assess for ↓ vision, abnormal ocular movement, best corrected visual acuity, refractive errors, strabismus More complex findings may require subspecialty referral. 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 Treatment of Manifestations in Individuals with a Education of parents/caregivers Seizures in persons w/SLFNE are generally controlled w/conventional ASM treatment, while seizures in persons w/NEO-DEE may be resistant to multiple ASMs alone or in combination. Per a recent systematic review on ASM treatment in In persons w/ Orthopedics / physical medicine & rehab / PT & OT Incl stretching to help avoid contractures & falls Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; CBZ = carbamazepine; DD/ID = developmental delay / intellectual disability; LTG = lamotrigine; NEO-DEE = neonatal-onset developmental and epileptic encephalopathy; OT = occupational therapy; OXC = oxacarbazepine; PHT = phenytoin; PT = physical therapy; SLFNE = self-limited familial neonatal epilepsy 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. Recommended Surveillance for Individuals with a At age 3, 12, & 24 mos EEG at 24 mos should be normal. Measurement of growth parameters Eval of nutritional status & safety of oral intake NEO-DEE = neonatal-onset developmental and epileptic encephalopathy; OT = occupational therapy; PT = physical therapy; SLFNE = self-limited familial neonatal epilepsy In individuals with known gain-of-function pathogenic variants in See The pregnancy management of a woman with a See Ezogabine (US approved name; also known as retigabine [trade name Trobalt in Europe or Potiga in US]) is a KCNQ activator that was approved in 2011 for clinical use as an adjunctive treatment of focal-onset seizures in individuals who respond inadequately to alternative treatments. Commercialization of retigabine was discontinued after June 2017, mainly due to its tendency to cause retinal and muco-cutaneous blue-gray discoloration after prolonged (>5 years) treatment. Treatment with ezogabine has been suggested as a form of targeted therapy in severe forms of Search • To incl brain MRI & EEG • Video EEG monitoring incl sleep phase to obtain information on presence of seizures. A burst-suppression EEG pattern might only be seen during sleep. • 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 persons w/dysphagia &/or aspiration risk. • To assess for ↓ vision, abnormal ocular movement, best corrected visual acuity, refractive errors, strabismus • More complex findings may require subspecialty referral. • Community or • Social work involvement for parental support; • Home nursing referral. • Education of parents/caregivers • Seizures in persons w/SLFNE are generally controlled w/conventional ASM treatment, while seizures in persons w/NEO-DEE may be resistant to multiple ASMs alone or in combination. • Per a recent systematic review on ASM treatment in • In persons w/ • Orthopedics / physical medicine & rehab / PT & OT • Incl stretching to help avoid contractures & falls • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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 • At age 3, 12, & 24 mos • EEG at 24 mos should be normal. • 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 a Recommended Evaluations Following Initial Diagnosis in Individuals with a To incl brain MRI & EEG Video EEG monitoring incl sleep phase to obtain information on presence of seizures. A burst-suppression EEG pattern might only be seen during sleep. 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 persons w/dysphagia &/or aspiration risk. To assess for ↓ vision, abnormal ocular movement, best corrected visual acuity, refractive errors, strabismus More complex findings may require subspecialty referral. 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 • To incl brain MRI & EEG • Video EEG monitoring incl sleep phase to obtain information on presence of seizures. A burst-suppression EEG pattern might only be seen during sleep. • 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 persons w/dysphagia &/or aspiration risk. • To assess for ↓ vision, abnormal ocular movement, best corrected visual acuity, refractive errors, strabismus • More complex findings may require subspecialty referral. • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Treatment of Manifestations in Individuals with a Education of parents/caregivers Seizures in persons w/SLFNE are generally controlled w/conventional ASM treatment, while seizures in persons w/NEO-DEE may be resistant to multiple ASMs alone or in combination. Per a recent systematic review on ASM treatment in In persons w/ Orthopedics / physical medicine & rehab / PT & OT Incl stretching to help avoid contractures & falls Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or Special Olympics. ASM = anti-seizure medication; CBZ = carbamazepine; DD/ID = developmental delay / intellectual disability; LTG = lamotrigine; NEO-DEE = neonatal-onset developmental and epileptic encephalopathy; OT = occupational therapy; OXC = oxacarbazepine; PHT = phenytoin; PT = physical therapy; SLFNE = self-limited familial neonatal epilepsy 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. • Education of parents/caregivers • Seizures in persons w/SLFNE are generally controlled w/conventional ASM treatment, while seizures in persons w/NEO-DEE may be resistant to multiple ASMs alone or in combination. • Per a recent systematic review on ASM treatment in • In persons w/ • Orthopedics / physical medicine & rehab / PT & OT • Incl stretching to help avoid contractures & falls • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or Special Olympics. • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision and hearing consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should 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, when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Surveillance Recommended Surveillance for Individuals with a At age 3, 12, & 24 mos EEG at 24 mos should be normal. Measurement of growth parameters Eval of nutritional status & safety of oral intake NEO-DEE = neonatal-onset developmental and epileptic encephalopathy; OT = occupational therapy; PT = physical therapy; SLFNE = self-limited familial neonatal epilepsy • At age 3, 12, & 24 mos • EEG at 24 mos should be normal. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake ## Agents/Circumstances to Avoid In individuals with known gain-of-function pathogenic variants in ## Evaluation of Relatives at Risk See ## Pregnancy Management The pregnancy management of a woman with a See ## Therapies Under Investigation Ezogabine (US approved name; also known as retigabine [trade name Trobalt in Europe or Potiga in US]) is a KCNQ activator that was approved in 2011 for clinical use as an adjunctive treatment of focal-onset seizures in individuals who respond inadequately to alternative treatments. Commercialization of retigabine was discontinued after June 2017, mainly due to its tendency to cause retinal and muco-cutaneous blue-gray discoloration after prolonged (>5 years) treatment. Treatment with ezogabine has been suggested as a form of targeted therapy in severe forms of Search ## Genetic Counseling Most individuals diagnosed with Most individuals diagnosed with Molecular genetic testing is recommended for the parents of a proband with a 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 mosaicism [ * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with If a parent of the proband is heterozygous for a If the If the parents have not been tested for the Each child of a heterozygous individual with Note: The possibility of somatic mosaicism should be evaluated in probands with The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. Given the severity of the disease course, individuals with The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals and young adults who are affected. Once a Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • Most individuals diagnosed with • Most individuals diagnosed with • Molecular genetic testing is recommended for the parents of a proband with a • 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 mosaicism [ • * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with • The proband has a • The proband inherited a pathogenic variant from a parent with germline mosaicism [ • * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with • The proband has a • The proband inherited a pathogenic variant from a parent with germline mosaicism [ • * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with • If a parent of the proband is heterozygous for a • If the • If the parents have not been tested for the • Each child of a heterozygous individual with • Note: The possibility of somatic mosaicism should be evaluated in probands with • The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. • Note: The possibility of somatic mosaicism should be evaluated in probands with • The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. • Given the severity of the disease course, individuals with • Note: The possibility of somatic mosaicism should be evaluated in probands with • The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/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 Most individuals diagnosed with Most individuals diagnosed with Molecular genetic testing is recommended for the parents of a proband with a 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 mosaicism [ * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with If a parent of the proband is heterozygous for a If the If the parents have not been tested for the Each child of a heterozygous individual with Note: The possibility of somatic mosaicism should be evaluated in probands with The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. Given the severity of the disease course, individuals with • Most individuals diagnosed with • Most individuals diagnosed with • Molecular genetic testing is recommended for the parents of a proband with a • 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 mosaicism [ • * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with • The proband has a • The proband inherited a pathogenic variant from a parent with germline mosaicism [ • * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with • The proband has a • The proband inherited a pathogenic variant from a parent with germline mosaicism [ • * Because parental mosaicism (with leukocyte DNA allele frequencies ranging from 1% to 30%) has been reported in the parents of several individuals with • If a parent of the proband is heterozygous for a • If the • If the parents have not been tested for the • Each child of a heterozygous individual with • Note: The possibility of somatic mosaicism should be evaluated in probands with • The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. • Note: The possibility of somatic mosaicism should be evaluated in probands with • The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. • Given the severity of the disease course, individuals with • Note: The possibility of somatic mosaicism should be evaluated in probands with • The level of mosaicism in blood or other tissues may not reflect the level of mosaicism in the germline. ## 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 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 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 60187 Canada • • • • • • 60187 • • • • • Canada • • • • • ## Molecular Genetics KCNQ2-Related Disorders: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for KCNQ2-Related Disorders ( In vitro studies revealed a correlation between changes in KCNQ2 molecular properties and the associated phenotypes. Variants predicted to cause Various molecular mechanisms appear responsible for the pathogenic variant-induced current decrease, including a reduced number of functional channels in the plasma membrane, changes in the subcellular targeting of the channels [ By contrast, Many questions remain as to how the functional changes observed at the molecular level result in changes at the neuronal, circuit, and behavioral level during development. Efforts to standardize variant characterization and thereby improve comparability among studies are currently under way. The molecular mechanisms responsible for the decrease in channel function caused by these variants appear heterogeneous, and include: (1) reduced K Notable DD = developmental delay; ID = intellectual disability; NEO-DEE = neonatal-onset developmental and epileptic encephalopathy; SLFNE = self-limited familial neonatal epilepsy Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis In vitro studies revealed a correlation between changes in KCNQ2 molecular properties and the associated phenotypes. Variants predicted to cause Various molecular mechanisms appear responsible for the pathogenic variant-induced current decrease, including a reduced number of functional channels in the plasma membrane, changes in the subcellular targeting of the channels [ By contrast, Many questions remain as to how the functional changes observed at the molecular level result in changes at the neuronal, circuit, and behavioral level during development. Efforts to standardize variant characterization and thereby improve comparability among studies are currently under way. The molecular mechanisms responsible for the decrease in channel function caused by these variants appear heterogeneous, and include: (1) reduced K Notable DD = developmental delay; ID = intellectual disability; NEO-DEE = neonatal-onset developmental and epileptic encephalopathy; SLFNE = self-limited familial neonatal epilepsy Variants listed in the table have been provided by the authors. ## Chapter Notes MT acknowledges the Italian Ministry for University and Research (MIUR) (PRIN 2017ALCR7C), the Italian Ministry of Health (Project RF-2019-12370491), the European Commission H2020 (UNICOM – 875299), and the European Joint Programme on Rare Diseases JTC 2020 (TreatKCNQ). FM received funding from the Italian Ministry for University and Research (MIUR) (PRIN 2017YH3SXK). MVS received funding from the Italian Ministry of Health (Project GR-2016-02363337) and the Italian Ministry for University and Research (MIUR) (PRIN 2017ALCR7C). ECC is supported by NIH NS49119, CURE, and the Jack Pribaz Foundation. SW is supported by FWO (1861419N and G041821N), the European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ), KCNQ2-Cure, Jack Pribaz Foundation, and KCNQ2e.v. The collaboration of patients and their families is highly appreciated. Giulia Bellini, PhD; Second University of Naples (2009-2016)Edward Cooper, MD, PhD (2016-present)Giangennaro Coppola, MD; University of Salerno (2013-2016)Nishtha Joshi, BDS, MPH; Baylor College of Medicine (2016-2022)Francesco Miceli, PhD (2009-present)Emanuele Miraglia del Giudice, MD; Second University of Naples (2009-2016)Antonio Pascotto, MD; Second University of Naples (2009-2013)Maria Virginia Soldovieri, PhD (2009-present)Maurizio Taglialatela, MD, PhD (2005-present)Sarah Weckhuysen, MD, PhD (2016-present) 19 May 2022 (ha) Comprehensive update posted live 27 September 2018 (aa) Revision: removed linkaway Table 4 31 March 2016 (ha) Comprehensive update posted live 11 April 2013 (me) Comprehensive update posted live 4 August 2011 (cd) Revision: deletion/duplication analysis available clinically for 27 April 2010 (me) Review posted live 4 December 2009 (mt) Initial submission • 19 May 2022 (ha) Comprehensive update posted live • 27 September 2018 (aa) Revision: removed linkaway Table 4 • 31 March 2016 (ha) Comprehensive update posted live • 11 April 2013 (me) Comprehensive update posted live • 4 August 2011 (cd) Revision: deletion/duplication analysis available clinically for • 27 April 2010 (me) Review posted live • 4 December 2009 (mt) Initial submission ## Acknowledgments MT acknowledges the Italian Ministry for University and Research (MIUR) (PRIN 2017ALCR7C), the Italian Ministry of Health (Project RF-2019-12370491), the European Commission H2020 (UNICOM – 875299), and the European Joint Programme on Rare Diseases JTC 2020 (TreatKCNQ). FM received funding from the Italian Ministry for University and Research (MIUR) (PRIN 2017YH3SXK). MVS received funding from the Italian Ministry of Health (Project GR-2016-02363337) and the Italian Ministry for University and Research (MIUR) (PRIN 2017ALCR7C). ECC is supported by NIH NS49119, CURE, and the Jack Pribaz Foundation. SW is supported by FWO (1861419N and G041821N), the European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ), KCNQ2-Cure, Jack Pribaz Foundation, and KCNQ2e.v. The collaboration of patients and their families is highly appreciated. ## Author History Giulia Bellini, PhD; Second University of Naples (2009-2016)Edward Cooper, MD, PhD (2016-present)Giangennaro Coppola, MD; University of Salerno (2013-2016)Nishtha Joshi, BDS, MPH; Baylor College of Medicine (2016-2022)Francesco Miceli, PhD (2009-present)Emanuele Miraglia del Giudice, MD; Second University of Naples (2009-2016)Antonio Pascotto, MD; Second University of Naples (2009-2013)Maria Virginia Soldovieri, PhD (2009-present)Maurizio Taglialatela, MD, PhD (2005-present)Sarah Weckhuysen, MD, PhD (2016-present) ## Revision History 19 May 2022 (ha) Comprehensive update posted live 27 September 2018 (aa) Revision: removed linkaway Table 4 31 March 2016 (ha) Comprehensive update posted live 11 April 2013 (me) Comprehensive update posted live 4 August 2011 (cd) Revision: deletion/duplication analysis available clinically for 27 April 2010 (me) Review posted live 4 December 2009 (mt) Initial submission • 19 May 2022 (ha) Comprehensive update posted live • 27 September 2018 (aa) Revision: removed linkaway Table 4 • 31 March 2016 (ha) Comprehensive update posted live • 11 April 2013 (me) Comprehensive update posted live • 4 August 2011 (cd) Revision: deletion/duplication analysis available clinically for • 27 April 2010 (me) Review posted live • 4 December 2009 (mt) Initial submission ## References ## Literature Cited	[ "A Abidi, JJ Devaux, F Molinari, G Alcaraz, FX Michon, J Sutera-Sardo, H Becq, C Lacoste, C Altuzarra, A Afenjar, C Mignot, D Doummar, B Isidor, SN Guyen, E Colin, S De La Vaissière, D Haye, A Trauffler, C Badens, F Prieur, G Lesca, L Villard, M Milh, L Aniksztejn. 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Gene mutation analysis of 175 Chinese patients with early-onset epileptic encephalopathy.. Clin Genet 2017;91:717-24", "X Zhou, A Ma, X Liu, C Huang, Y Zhang, R Shi, S Mao, T Geng, S Li. Infantile seizures and other epileptic phenotypes in a Chinese family with a missense mutation of KCNQ2.. Eur J Pediatr 2006;165:691-5" ]	27/4/2010	19/5/2022	27/9/2018	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bgc	bgc	[ "Platelet-derived growth factor receptor beta", "Platelet-derived growth factor subunit B", "Sodium-dependent phosphate transporter 2", "Solute carrier family 53 member 1", "PDGFB", "PDGFRB", "SLC20A2", "XPR1", "Primary Familial Brain Calcification (PFBC)" ]	Primary Familial Brain Calcification	Eliana Marisa Ramos, Joao Oliveira, Maria J Sobrido, Giovanni Coppola	Summary Primary familial brain calcification (PFBC) is a neurodegenerative disorder with characteristic calcium deposits in the basal ganglia and other brain areas visualized on neuroimaging. Most affected individuals are in good health during childhood and young adulthood and typically present in the fourth to fifth decade with a gradually progressive movement disorder and neuropsychiatric symptoms. The movement disorder first manifests as clumsiness, fatigability, unsteady gait, slow or slurred speech, dysphagia, involuntary movements, or muscle cramping. Neuropsychiatric symptoms, often the first or most prominent manifestations, range from mild difficulty with concentration and memory to changes in personality and/or behavior, to psychosis and dementia. Seizures of various types occur frequently, some individuals experience chronic headache and vertigo; urinary urgency or incontinence may be present. The diagnosis of PFBC relies on: visualization of bilateral calcification of the basal ganglia on neuroimaging; presence of progressive neurologic dysfunction; and absence of metabolic, infectious, toxic, or traumatic cause. A family history consistent with autosomal dominant inheritance is often found as well. Thus, the diagnosis of PFBC should be left for those cases where other neurologic or systemic disorders potentially associated with ectopic calcium deposits have not been identified after appropriate examinations. A heterozygous pathogenic variant in PFBC is inherited in an autosomal dominant manner. Most individuals diagnosed with PFBC have an affected parent identified either clinically or by brain CT scan. However, the transmitting parent may be clinically asymptomatic throughout life or may develop disease manifestations that are later in onset or less severe than those in the proband. If a parent of the proband is affected and/or is known to be heterozygous for a PFBC-related pathogenic variant, sibs of a proband are at a 50% risk of inheriting the pathogenic variant; however, the risk to sibs of being clinically affected may be slightly lower due to reduced penetrance. Offspring of an affected individual have a 50% chance of inheriting the pathogenic variant. Prenatal testing for pregnancies at increased risk is possible if the pathogenic variant has been identified in an affected family member.	## Diagnosis Primary familial brain calcification (PFBC) Cerebellum, the brain stem, centrum semiovale, and subcortical white matter may also be affected [ MRI provides better anatomic detail than CT but is less sensitive in detecting calcification. Calcified lesions on MRI produce various levels of signal intensities that may be misinterpreted as not representing brain calcification. Serum concentration of calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin, and parathyroid hormone (PTH) Routine hematologic and biochemical investigations Workup for metabolic, inflammatory, and infectious conditions Blood and urine heavy metal concentrations Ellsworth Howard test (i.e., a 10- to 20-fold increase of urinary cAMP excretion following stimulation with 200 U of PTH) Cerebrospinal fluid evaluation for bacteria, viruses, and parasites. However, a slight increase in protein has been described [ Gross pathologic examination shows accumulation of a granular material and solid nodules in the striatum, internal capsule, white matter, and cerebellum. Circumscribed calcium deposits may also be seen in the thalamus and cerebral cortex. Mild lobar atrophy is common [ Histologic examination of affected areas shows concentric calcium deposits within the walls of small and medium-sized arteries and, less frequently, veins [ On The diagnosis of PFBC Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Primary Familial Brain Calcification Genes are listed alphabetically. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include 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 del/dup variants were found in a total of 52 cases screened for CNVs in No data on detection rate of gene-targeted deletion/duplication analysis are available. Author, personal laboratory data • Cerebellum, the brain stem, centrum semiovale, and subcortical white matter may also be affected [ • MRI provides better anatomic detail than CT but is less sensitive in detecting calcification. Calcified lesions on MRI produce various levels of signal intensities that may be misinterpreted as not representing brain calcification. • Serum concentration of calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin, and parathyroid hormone (PTH) • Routine hematologic and biochemical investigations • Workup for metabolic, inflammatory, and infectious conditions • Blood and urine heavy metal concentrations • Ellsworth Howard test (i.e., a 10- to 20-fold increase of urinary cAMP excretion following stimulation with 200 U of PTH) • Cerebrospinal fluid evaluation for bacteria, viruses, and parasites. However, a slight increase in protein has been described [ • Gross pathologic examination shows accumulation of a granular material and solid nodules in the striatum, internal capsule, white matter, and cerebellum. Circumscribed calcium deposits may also be seen in the thalamus and cerebral cortex. Mild lobar atrophy is common [ • Histologic examination of affected areas shows concentric calcium deposits within the walls of small and medium-sized arteries and, less frequently, veins [ • On • For an introduction to multigene panels click ## Suggestive Findings Primary familial brain calcification (PFBC) Cerebellum, the brain stem, centrum semiovale, and subcortical white matter may also be affected [ MRI provides better anatomic detail than CT but is less sensitive in detecting calcification. Calcified lesions on MRI produce various levels of signal intensities that may be misinterpreted as not representing brain calcification. • Cerebellum, the brain stem, centrum semiovale, and subcortical white matter may also be affected [ • MRI provides better anatomic detail than CT but is less sensitive in detecting calcification. Calcified lesions on MRI produce various levels of signal intensities that may be misinterpreted as not representing brain calcification. ## Testing Serum concentration of calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin, and parathyroid hormone (PTH) Routine hematologic and biochemical investigations Workup for metabolic, inflammatory, and infectious conditions Blood and urine heavy metal concentrations Ellsworth Howard test (i.e., a 10- to 20-fold increase of urinary cAMP excretion following stimulation with 200 U of PTH) Cerebrospinal fluid evaluation for bacteria, viruses, and parasites. However, a slight increase in protein has been described [ Gross pathologic examination shows accumulation of a granular material and solid nodules in the striatum, internal capsule, white matter, and cerebellum. Circumscribed calcium deposits may also be seen in the thalamus and cerebral cortex. Mild lobar atrophy is common [ Histologic examination of affected areas shows concentric calcium deposits within the walls of small and medium-sized arteries and, less frequently, veins [ On • Serum concentration of calcium, phosphorus, magnesium, alkaline phosphatase, calcitonin, and parathyroid hormone (PTH) • Routine hematologic and biochemical investigations • Workup for metabolic, inflammatory, and infectious conditions • Blood and urine heavy metal concentrations • Ellsworth Howard test (i.e., a 10- to 20-fold increase of urinary cAMP excretion following stimulation with 200 U of PTH) • Cerebrospinal fluid evaluation for bacteria, viruses, and parasites. However, a slight increase in protein has been described [ • Gross pathologic examination shows accumulation of a granular material and solid nodules in the striatum, internal capsule, white matter, and cerebellum. Circumscribed calcium deposits may also be seen in the thalamus and cerebral cortex. Mild lobar atrophy is common [ • Histologic examination of affected areas shows concentric calcium deposits within the walls of small and medium-sized arteries and, less frequently, veins [ • On ## Establishing the Diagnosis The diagnosis of PFBC Molecular testing approaches can include For an introduction to multigene panels click Molecular Genetic Testing Used in Primary Familial Brain Calcification Genes are listed alphabetically. See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include 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 del/dup variants were found in a total of 52 cases screened for CNVs in No data on detection rate of gene-targeted deletion/duplication analysis are available. Author, personal laboratory data • For an introduction to multigene panels click ## Clinical Characteristics Since the first description of primary familial brain calcification (PFBC) [ The clinical manifestations of PFBC are limited to the nervous system. Most individuals with PFBC are in good health during childhood and young adulthood. Pyramidal or cerebellar signs may also be present; in some cases the cerebellar picture predominates. Dystonia is prominent in a few families [ The pattern of dementia includes frequent frontal-executive dysfunction and resembles that occurring in other disorders affecting subcortical structures, including Although premorbid psychomotor development is generally normal, low IQ and mild delay in motor or intellectual milestones during school age are described. Seizures of various types occur frequently. Some individuals experience chronic headache and vertigo [ Urinary urgency or incontinence and impotence may be present [ Severe hypertension has been reported in two sisters with basal ganglia calcification with no other neurologic or systemic abnormalities [ General medical examination, growth, and facial appearance are normal. Strength and sensation are generally intact. Specifically, no abnormalities are detected in the skull, hands, teeth, nails, or skin, and there is no evidence of a parathyroid disorder. Neurophysiologic studies are generally normal. In addition, the limited number of affected individuals with Incomplete and age-related penetrance is reported in PFBC, but the factors that influence clinical manifestations are unknown. The degree of penetrance may depend on whether diagnosis is considered at an anatomic level (presence of calcifications in the brain) or at a clinical level (presence of clinical symptoms). With respect to calcium deposits, analysis of reported pedigrees indicates about 95% penetrance by age 50 years or older. If clinical manifestations are considered, the penetrance is incomplete and may vary between and within families. The precise clinical penetrance has not been fully established for the different PFBC-related genes and pathogenic variants, but it may be around 70% or even lower [ No reliable correlations exist between age of onset, extent of calcium deposits, and neurologic deficit. Although most individuals with calcifications eventually develop neurologic dysfunction, the type or severity of clinical symptoms cannot be predicted from the pattern of calcification. Anticipation has occasionally been observed in kindreds with PFBC [ Traditionally described as "Fahr's disease," this disorder has been referred to in the literature by about 35 different names [ With the identification of the first associated genes, following an autosomal dominant trait, the term "idiopathic" (i.e., calcifications of unknown cause) ceased to be appropriate and was replaced by "primary" (as opposed to calcifications secondary to infectious, inflammatory, toxic, or other causes). Therefore, and because calcium deposits are not limited to the basal ganglia but can also be seen in other brain areas (as described in Although the term Fahr's disease is still often used to designate either familial or sporadic basal ganglia calcification, it is unknown whether the nonfamilial cases represent the same disease. The term Fahr's disease is ambiguous and therefore should be avoided. The prevalence of PFBC is unknown; more than 100 kindreds and sporadic cases have been reported. However, the disorder is probably under-recognized because of insufficient investigation of other family members of individuals presenting with brain calcification. • Seizures of various types occur frequently. • Some individuals experience chronic headache and vertigo [ • Urinary urgency or incontinence and impotence may be present [ • Severe hypertension has been reported in two sisters with basal ganglia calcification with no other neurologic or systemic abnormalities [ • General medical examination, growth, and facial appearance are normal. Strength and sensation are generally intact. Specifically, no abnormalities are detected in the skull, hands, teeth, nails, or skin, and there is no evidence of a parathyroid disorder. • Neurophysiologic studies are generally normal. ## Clinical Description Since the first description of primary familial brain calcification (PFBC) [ The clinical manifestations of PFBC are limited to the nervous system. Most individuals with PFBC are in good health during childhood and young adulthood. Pyramidal or cerebellar signs may also be present; in some cases the cerebellar picture predominates. Dystonia is prominent in a few families [ The pattern of dementia includes frequent frontal-executive dysfunction and resembles that occurring in other disorders affecting subcortical structures, including Although premorbid psychomotor development is generally normal, low IQ and mild delay in motor or intellectual milestones during school age are described. Seizures of various types occur frequently. Some individuals experience chronic headache and vertigo [ Urinary urgency or incontinence and impotence may be present [ Severe hypertension has been reported in two sisters with basal ganglia calcification with no other neurologic or systemic abnormalities [ General medical examination, growth, and facial appearance are normal. Strength and sensation are generally intact. Specifically, no abnormalities are detected in the skull, hands, teeth, nails, or skin, and there is no evidence of a parathyroid disorder. Neurophysiologic studies are generally normal. • Seizures of various types occur frequently. • Some individuals experience chronic headache and vertigo [ • Urinary urgency or incontinence and impotence may be present [ • Severe hypertension has been reported in two sisters with basal ganglia calcification with no other neurologic or systemic abnormalities [ • General medical examination, growth, and facial appearance are normal. Strength and sensation are generally intact. Specifically, no abnormalities are detected in the skull, hands, teeth, nails, or skin, and there is no evidence of a parathyroid disorder. • Neurophysiologic studies are generally normal. ## Genotype-Phenotype Correlations In addition, the limited number of affected individuals with ## Penetrance Incomplete and age-related penetrance is reported in PFBC, but the factors that influence clinical manifestations are unknown. The degree of penetrance may depend on whether diagnosis is considered at an anatomic level (presence of calcifications in the brain) or at a clinical level (presence of clinical symptoms). With respect to calcium deposits, analysis of reported pedigrees indicates about 95% penetrance by age 50 years or older. If clinical manifestations are considered, the penetrance is incomplete and may vary between and within families. The precise clinical penetrance has not been fully established for the different PFBC-related genes and pathogenic variants, but it may be around 70% or even lower [ No reliable correlations exist between age of onset, extent of calcium deposits, and neurologic deficit. Although most individuals with calcifications eventually develop neurologic dysfunction, the type or severity of clinical symptoms cannot be predicted from the pattern of calcification. ## Anticipation Anticipation has occasionally been observed in kindreds with PFBC [ ## Nomenclature Traditionally described as "Fahr's disease," this disorder has been referred to in the literature by about 35 different names [ With the identification of the first associated genes, following an autosomal dominant trait, the term "idiopathic" (i.e., calcifications of unknown cause) ceased to be appropriate and was replaced by "primary" (as opposed to calcifications secondary to infectious, inflammatory, toxic, or other causes). Therefore, and because calcium deposits are not limited to the basal ganglia but can also be seen in other brain areas (as described in Although the term Fahr's disease is still often used to designate either familial or sporadic basal ganglia calcification, it is unknown whether the nonfamilial cases represent the same disease. The term Fahr's disease is ambiguous and therefore should be avoided. ## Prevalence The prevalence of PFBC is unknown; more than 100 kindreds and sporadic cases have been reported. However, the disorder is probably under-recognized because of insufficient investigation of other family members of individuals presenting with brain calcification. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic tumors (including dermatofibrosarcoma protruberans) and some hematologic malignancies in the absence of other findings of PFBC frequently harbor somatic translocations involving ## Differential Diagnosis PHP results from end-organ unresponsiveness to PTH. The biochemical hallmarks are hypocalcemia and hyperphosphatemia with an elevated serum concentration of PTH. The average age of onset of PHP is age eight to ten years. Most clinical manifestations are related to hypocalcemia, and thus similar to those in hypoparathyroidism, with intellectual disability being somewhat more common in PHP. Affected individuals may have other manifestations of Albright hereditary osteodystrophy, including short stature, round facies, obesity, soft tissue calcification, short metacarpals or metatarsals, and other hormone resistance, resulting in hypothyroidism and/or hypogonadism. PPHP is characterized by the physical findings of Albright hereditary osteodystrophy with normal serum concentration of calcium and phosphorus and normal response to PTH stimulation. Mineral deposits in the basal ganglia and other brain structures are observed in mitochondrial diseases (see Calcifications in the basal ganglia and other brain structures are observed in several congenital or early-onset syndromes with normal calcium-phosphorus metabolism and are frequently associated with intellectual disability. Calcifications of the basal ganglia may result from the following: ## Parathyroid Disorders PHP results from end-organ unresponsiveness to PTH. The biochemical hallmarks are hypocalcemia and hyperphosphatemia with an elevated serum concentration of PTH. The average age of onset of PHP is age eight to ten years. Most clinical manifestations are related to hypocalcemia, and thus similar to those in hypoparathyroidism, with intellectual disability being somewhat more common in PHP. Affected individuals may have other manifestations of Albright hereditary osteodystrophy, including short stature, round facies, obesity, soft tissue calcification, short metacarpals or metatarsals, and other hormone resistance, resulting in hypothyroidism and/or hypogonadism. PPHP is characterized by the physical findings of Albright hereditary osteodystrophy with normal serum concentration of calcium and phosphorus and normal response to PTH stimulation. ## Infectious Diseases ## Mitochondrial Disorders Mineral deposits in the basal ganglia and other brain structures are observed in mitochondrial diseases (see ## Inherited Congenital or Early-Onset Syndromes Calcifications in the basal ganglia and other brain structures are observed in several congenital or early-onset syndromes with normal calcium-phosphorus metabolism and are frequently associated with intellectual disability. ## Adult-Onset Neurodegenerative Conditions ## Other Calcifications of the basal ganglia may result from the following: ## Management To establish the extent of disease and needs in an individual diagnosed with primary familial brain calcification (PFBC), the following evaluations are recommended: Thorough neurologic and neuropsychiatric assessment Consultation with a clinical geneticist and/or genetic counselor The following are appropriate: Pharmacologic treatment to improve anxiety, depression, and obsessive-compulsive behaviors To alleviate dystonia and other associated involuntary movements, pharmacologic therapies as typically used in neurologic practice for the treatment of movement disorders For urinary urgency or incontinence, oxybutynin or other anticholinergic medications Anti-seizure medication for seizures Symptomatic treatment for headaches Thorough neurologic and neuropsychiatric assessment is indicated annually. Neuroleptic medications should be used cautiously, since they may exacerbate extrapyramidal symptoms [ See Search The response of parkinsonian features to levodopa therapy is generally poor. • Thorough neurologic and neuropsychiatric assessment • Consultation with a clinical geneticist and/or genetic counselor • Pharmacologic treatment to improve anxiety, depression, and obsessive-compulsive behaviors • To alleviate dystonia and other associated involuntary movements, pharmacologic therapies as typically used in neurologic practice for the treatment of movement disorders • For urinary urgency or incontinence, oxybutynin or other anticholinergic medications • Anti-seizure medication for seizures • Symptomatic treatment for headaches ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with primary familial brain calcification (PFBC), the following evaluations are recommended: Thorough neurologic and neuropsychiatric assessment Consultation with a clinical geneticist and/or genetic counselor • Thorough neurologic and neuropsychiatric assessment • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations The following are appropriate: Pharmacologic treatment to improve anxiety, depression, and obsessive-compulsive behaviors To alleviate dystonia and other associated involuntary movements, pharmacologic therapies as typically used in neurologic practice for the treatment of movement disorders For urinary urgency or incontinence, oxybutynin or other anticholinergic medications Anti-seizure medication for seizures Symptomatic treatment for headaches • Pharmacologic treatment to improve anxiety, depression, and obsessive-compulsive behaviors • To alleviate dystonia and other associated involuntary movements, pharmacologic therapies as typically used in neurologic practice for the treatment of movement disorders • For urinary urgency or incontinence, oxybutynin or other anticholinergic medications • Anti-seizure medication for seizures • Symptomatic treatment for headaches ## Surveillance Thorough neurologic and neuropsychiatric assessment is indicated annually. ## Agents/Circumstances to Avoid Neuroleptic medications should be used cautiously, since they may exacerbate extrapyramidal symptoms [ ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Other The response of parkinsonian features to levodopa therapy is generally poor. ## Genetic Counseling Primary familial brain calcification (PFBC) is inherited in an autosomal dominant manner. Most individuals diagnosed with PFBC have an affected parent identified either clinically or by brain CT scan. However, the transmitting parent may be clinically asymptomatic throughout life or may develop disease manifestations that are later in onset or less severe than those in the proband. Some individuals diagnosed with PFBC have the disorder as the result of a The proportion of cases caused by a Molecular genetic testing, physical and neurologic examination, and CT scan are 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, possible explanations include a The family history of some individuals diagnosed with PFBC 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 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. The risk to the sibs of a proband depends on the genetic status of the proband's parents. If a parent of the proband is affected and/or is known to be heterozygous for a PFBC-related pathogenic variant, sibs of a proband are at a 50% of inheriting the pathogenic variant; however, the risk to sibs of being clinically affected may be slightly lower because of reduced penetrance (see If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism. 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 or the theoretic possibility of parental germline mosaicism. A thorough discussion of the implications and limitations of clinical genetic testing, particularly in presymptomatic at-risk individuals, is advisable. Molecular genetic testing and brain CT scan are not useful in predicting age of onset, severity or type of symptoms, or rate of progression in asymptomatic individuals. Molecular genetic testing and testing for calcium deposits using brain CT scan in the absence of definite clinical symptoms of the disease is predictive testing. For more information, see also the National Society of Genetic Counselors It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of PFBC. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. 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 PFBC have an affected parent identified either clinically or by brain CT scan. However, the transmitting parent may be clinically asymptomatic throughout life or may develop disease manifestations that are later in onset or less severe than those in the proband. • Some individuals diagnosed with PFBC have the disorder as the result of a • The proportion of cases caused by a • Molecular genetic testing, physical and neurologic examination, and CT scan are 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, possible explanations include a • The family history of some individuals diagnosed with PFBC 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 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. • The risk to the sibs of a proband depends on the genetic status of the proband's parents. • If a parent of the proband is affected and/or is known to be heterozygous for a PFBC-related pathogenic variant, sibs of a proband are at a 50% of inheriting the pathogenic variant; however, the risk to sibs of being clinically affected may be slightly lower because of reduced penetrance (see • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism. • 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 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 Primary familial brain calcification (PFBC) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with PFBC have an affected parent identified either clinically or by brain CT scan. However, the transmitting parent may be clinically asymptomatic throughout life or may develop disease manifestations that are later in onset or less severe than those in the proband. Some individuals diagnosed with PFBC have the disorder as the result of a The proportion of cases caused by a Molecular genetic testing, physical and neurologic examination, and CT scan are 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, possible explanations include a The family history of some individuals diagnosed with PFBC 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 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. The risk to the sibs of a proband depends on the genetic status of the proband's parents. If a parent of the proband is affected and/or is known to be heterozygous for a PFBC-related pathogenic variant, sibs of a proband are at a 50% of inheriting the pathogenic variant; however, the risk to sibs of being clinically affected may be slightly lower because of reduced penetrance (see If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism. 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 or the theoretic possibility of parental germline mosaicism. • Most individuals diagnosed with PFBC have an affected parent identified either clinically or by brain CT scan. However, the transmitting parent may be clinically asymptomatic throughout life or may develop disease manifestations that are later in onset or less severe than those in the proband. • Some individuals diagnosed with PFBC have the disorder as the result of a • The proportion of cases caused by a • Molecular genetic testing, physical and neurologic examination, and CT scan are 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, possible explanations include a • The family history of some individuals diagnosed with PFBC 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 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. • The risk to the sibs of a proband depends on the genetic status of the proband's parents. • If a parent of the proband is affected and/or is known to be heterozygous for a PFBC-related pathogenic variant, sibs of a proband are at a 50% of inheriting the pathogenic variant; however, the risk to sibs of being clinically affected may be slightly lower because of reduced penetrance (see • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the empiric recurrence risk to sibs is approximately 1% because of the theoretic possibility of parental germline mosaicism. • 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 or the theoretic possibility of parental germline mosaicism. ## Related Genetic Counseling Issues A thorough discussion of the implications and limitations of clinical genetic testing, particularly in presymptomatic at-risk individuals, is advisable. Molecular genetic testing and brain CT scan are not useful in predicting age of onset, severity or type of symptoms, or rate of progression in asymptomatic individuals. Molecular genetic testing and testing for calcium deposits using brain CT scan in the absence of definite clinical symptoms of the disease is predictive testing. For more information, see also the National Society of Genetic Counselors It is appropriate to consider testing symptomatic individuals regardless of age in a family with an established diagnosis of PFBC. The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. 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 Primary Familial Brain Calcification: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Primary Familial Brain Calcification ( To date, four genes have been associated with primary familial brain calcification: The relationship between these two conditions and PFBC-associated genes, and therefore PFBC, is currently unclear. ## Molecular Pathogenesis To date, four genes have been associated with primary familial brain calcification: ## ## ## ## ## Cancer and Benign Tumors The relationship between these two conditions and PFBC-associated genes, and therefore PFBC, is currently unclear. ## Chapter Notes Giovanni Coppola, MD (2013-present)Daniel H Geschwind, MD, PhD; University of California Los Angeles (2002-2017)Suellen Hopfer, MD, PhD; Pennsylvania State University (2002-2017)Joao Oliveira, MD, PhD (2013-present)Eliana Marisa Ramos, PhD (2017-present)Maria J Sobrido, MD, PhD (2002-present) 24 August 2017 (ha) Comprehensive update posted live 16 October 2014 (aa) Revision: mutation of 27 June 2013 (me) Comprehensive update posted live 20 September 2007 (me) Comprehensive update posted live 9 June 2004 (me) Comprehensive update posted live 18 April 2002 (me) Review posted live 28 September 2001 (ms) Original submission • 24 August 2017 (ha) Comprehensive update posted live • 16 October 2014 (aa) Revision: mutation of • 27 June 2013 (me) Comprehensive update posted live • 20 September 2007 (me) Comprehensive update posted live • 9 June 2004 (me) Comprehensive update posted live • 18 April 2002 (me) Review posted live • 28 September 2001 (ms) Original submission ## Author History Giovanni Coppola, MD (2013-present)Daniel H Geschwind, MD, PhD; University of California Los Angeles (2002-2017)Suellen Hopfer, MD, PhD; Pennsylvania State University (2002-2017)Joao Oliveira, MD, PhD (2013-present)Eliana Marisa Ramos, PhD (2017-present)Maria J Sobrido, MD, PhD (2002-present) ## Revision History 24 August 2017 (ha) Comprehensive update posted live 16 October 2014 (aa) Revision: mutation of 27 June 2013 (me) Comprehensive update posted live 20 September 2007 (me) Comprehensive update posted live 9 June 2004 (me) Comprehensive update posted live 18 April 2002 (me) Review posted live 28 September 2001 (ms) Original submission • 24 August 2017 (ha) Comprehensive update posted live • 16 October 2014 (aa) Revision: mutation of • 27 June 2013 (me) Comprehensive update posted live • 20 September 2007 (me) Comprehensive update posted live • 9 June 2004 (me) Comprehensive update posted live • 18 April 2002 (me) Review posted live • 28 September 2001 (ms) Original submission ## References ## Published Guidelines / Consensus Statements ## Literature Cited	[]	18/4/2004	24/8/2017	16/10/2014	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bgd-biotin	bgd-biotin	[ "Biotin-Responsive Basal Ganglia Disease (BBGD)", "BTBGD", "BTRBGD", "Thiamine Metabolism Dysfunction Syndrome 2", "Thiamine Transporter-2 Deficiency", "Biotin-Responsive Basal Ganglia Disease (BBGD)", "BTBGD", "BTRBGD", "Thiamine Metabolism Dysfunction Syndrome 2", "Thiamine Transporter-2 Deficiency", "Early-Infantile Biotin-Thiamine-Responsive Basal Ganglia Disease (BTBGD)", "Classic (Childhood) Biotin-Thiamine-Responsive Basal Ganglia Disease (BTBGD)", "Adult Wernicke-Like Encephalopathy Biotin-Thiamine-Responsive Basal Ganglia Disease (BTBGD)", "Thiamine transporter 2", "SLC19A3", "Biotin-Thiamine-Responsive Basal Ganglia Disease" ]	Biotin-Thiamine-Responsive Basal Ganglia Disease	Brahim Tabarki, Amal Al-Hashem, Juan Darío Ortigoza-Escobar, Hind Alsharhan, Majid Alfadhel	Summary Biotin-thiamine-responsive basal ganglia disease (BTBGD) may present in early infancy, childhood, or adulthood. Early-infantile BTBGD presents before age three months with vomiting, feeding difficulties, encephalopathy, hypotonia, seizures, and respiratory failure. Classic BTBGD presents between ages three and ten years with recurrent subacute encephalopathy manifesting as confusion, seizures, ataxia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia that, if left untreated, can eventually lead to coma and even death. Dystonia and cogwheel rigidity are nearly always present; hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Episodes are often triggered by febrile illness or mild trauma or stress. Simple partial or generalized seizures are easily controlled with anti-seizure medication. Adult Wernicke-like encephalopathy BTBGD, described in three individuals to date, presents after age ten years with acute onset of status epilepticus, ataxia, nystagmus, diplopia, and ophthalmoplegia. Prompt administration of biotin and thiamine early in the disease course results in partial or complete improvement within days in classic and adult BTBGD; however, most infants with early-infantile BTBGD have a poor outcome. The diagnosis of BTBGD is established in a proband with biallelic pathogenic variants in BTBGD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an	Early-infantile BTBGD Classic (childhood) BTBGD Adult Wernicke-like encephalopathy BTBGD • Early-infantile BTBGD • Classic (childhood) BTBGD • Adult Wernicke-like encephalopathy BTBGD ## Diagnosis No consensus clinical diagnostic criteria for biotin-thiamine-responsive basal ganglia disease (BTBGD) have been published; however, suggested criteria for the diagnosis of inherited thiamine defects with prominent neurologic involvement have been proposed [ BTBGD Vomiting Feeding difficulties Irritability Encephalopathy Hypotonia Seizures, infantile spasms Respiratory failure Elevated lactate concentrations in blood and cerebrospinal fluid (CSF) Elevated blood alanine, leucine, and isoleucine concentrations Increased alpha-ketoglutarate in urinary organic acid analysis Low free thiamine in CSF and/or fibroblasts [ Note: Oxidative phosphorylation (OXPHOS) abnormalities, found exclusively in early-infantile BTBGD, are associated with poor outcomes, including high mortality rates [ Note: It is recommended that treatment start with high-dose thiamine and biotin in encephalopathic infants with symmetric basal ganglia involvement on imaging (Leigh-like syndrome), even before genetic confirmation of BTBGD, as prompt treatment may improve outcomes [ Subsequent MRIs reveal cystic degeneration of the white matter that progresses to cerebral, cerebellar, and brain stem atrophy. Thalamic lesions are more common in early-infantile BTBGD. Neonates and young toddlers may present with extensive areas of restricted diffusion affecting the perirolandic white matter and thalami, with or without involvement of the basal ganglia [ Seizures Extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia) Pyramidal tract signs (quadriparesis, hyperreflexia) Variable presence of cerebellar signs (supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia) BTBGD can present with mild neurologic symptoms without encephalopathy at onset, as seen in older children with progressive cognitive deficits [ Tandem mass spectrometry of blood Urine gas chromatography-mass spectrometry (GC-MS), urine amino acids Serum concentrations of lactic acid, ammonia, and thiamine Plasma amino acids, liver enzymes, coagulation profile, lipid profile CSF cell count, protein, glucose, and cultures In the acute phase of decompensation, some individuals show increased lactate concentration in blood and CSF. Additionally, in some specialized laboratories, low free thiamine concentration may be observed in CSF and/or fibroblasts [ Swelling and bilateral and symmetric increased T Vasogenic edema during acute crises as demonstrated by diffusion-weighted imaging / apparent diffusion coefficient MRI. Chronic changes including atrophy and necrosis of the caudate nuclei and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [ Brain stem involvement on MRI can be observed [ Less common findings include the following: Spinal cord involvement (1 individual) [ Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ Two Japanese males who presented in the second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia; An Indian woman who presented initially at age 49 years with rapidly progressive dementia. Family history for all phenotypes is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Note: (1) Presumably affected (but undiagnosed) sibs may have had unexplained coma or encephalopathy. (2) Consanguinity has been reported in many families [ The diagnosis of BTBGD Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis for the For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Biotin-Thiamine-Responsive Basal Ganglia 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. A 45-kb deletion including the promoter region but no coding exons of • Vomiting • Feeding difficulties • Irritability • Encephalopathy • Hypotonia • Seizures, infantile spasms • Respiratory failure • Elevated lactate concentrations in blood and cerebrospinal fluid (CSF) • Elevated blood alanine, leucine, and isoleucine concentrations • Increased alpha-ketoglutarate in urinary organic acid analysis • Low free thiamine in CSF and/or fibroblasts [ • Seizures • Extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia) • Pyramidal tract signs (quadriparesis, hyperreflexia) • Variable presence of cerebellar signs (supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia) • Tandem mass spectrometry of blood • Urine gas chromatography-mass spectrometry (GC-MS), urine amino acids • Serum concentrations of lactic acid, ammonia, and thiamine • Plasma amino acids, liver enzymes, coagulation profile, lipid profile • CSF cell count, protein, glucose, and cultures • Swelling and bilateral and symmetric increased T • Vasogenic edema during acute crises as demonstrated by diffusion-weighted imaging / apparent diffusion coefficient MRI. • Chronic changes including atrophy and necrosis of the caudate nuclei and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [ • Brain stem involvement on MRI can be observed [ • Less common findings include the following: • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Two Japanese males who presented in the second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia; • An Indian woman who presented initially at age 49 years with rapidly progressive dementia. ## Suggestive Findings BTBGD Vomiting Feeding difficulties Irritability Encephalopathy Hypotonia Seizures, infantile spasms Respiratory failure Elevated lactate concentrations in blood and cerebrospinal fluid (CSF) Elevated blood alanine, leucine, and isoleucine concentrations Increased alpha-ketoglutarate in urinary organic acid analysis Low free thiamine in CSF and/or fibroblasts [ Note: Oxidative phosphorylation (OXPHOS) abnormalities, found exclusively in early-infantile BTBGD, are associated with poor outcomes, including high mortality rates [ Note: It is recommended that treatment start with high-dose thiamine and biotin in encephalopathic infants with symmetric basal ganglia involvement on imaging (Leigh-like syndrome), even before genetic confirmation of BTBGD, as prompt treatment may improve outcomes [ Subsequent MRIs reveal cystic degeneration of the white matter that progresses to cerebral, cerebellar, and brain stem atrophy. Thalamic lesions are more common in early-infantile BTBGD. Neonates and young toddlers may present with extensive areas of restricted diffusion affecting the perirolandic white matter and thalami, with or without involvement of the basal ganglia [ Seizures Extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia) Pyramidal tract signs (quadriparesis, hyperreflexia) Variable presence of cerebellar signs (supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia) BTBGD can present with mild neurologic symptoms without encephalopathy at onset, as seen in older children with progressive cognitive deficits [ Tandem mass spectrometry of blood Urine gas chromatography-mass spectrometry (GC-MS), urine amino acids Serum concentrations of lactic acid, ammonia, and thiamine Plasma amino acids, liver enzymes, coagulation profile, lipid profile CSF cell count, protein, glucose, and cultures In the acute phase of decompensation, some individuals show increased lactate concentration in blood and CSF. Additionally, in some specialized laboratories, low free thiamine concentration may be observed in CSF and/or fibroblasts [ Swelling and bilateral and symmetric increased T Vasogenic edema during acute crises as demonstrated by diffusion-weighted imaging / apparent diffusion coefficient MRI. Chronic changes including atrophy and necrosis of the caudate nuclei and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [ Brain stem involvement on MRI can be observed [ Less common findings include the following: Spinal cord involvement (1 individual) [ Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ Two Japanese males who presented in the second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia; An Indian woman who presented initially at age 49 years with rapidly progressive dementia. Family history for all phenotypes is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Note: (1) Presumably affected (but undiagnosed) sibs may have had unexplained coma or encephalopathy. (2) Consanguinity has been reported in many families [ • Vomiting • Feeding difficulties • Irritability • Encephalopathy • Hypotonia • Seizures, infantile spasms • Respiratory failure • Elevated lactate concentrations in blood and cerebrospinal fluid (CSF) • Elevated blood alanine, leucine, and isoleucine concentrations • Increased alpha-ketoglutarate in urinary organic acid analysis • Low free thiamine in CSF and/or fibroblasts [ • Seizures • Extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia) • Pyramidal tract signs (quadriparesis, hyperreflexia) • Variable presence of cerebellar signs (supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia) • Tandem mass spectrometry of blood • Urine gas chromatography-mass spectrometry (GC-MS), urine amino acids • Serum concentrations of lactic acid, ammonia, and thiamine • Plasma amino acids, liver enzymes, coagulation profile, lipid profile • CSF cell count, protein, glucose, and cultures • Swelling and bilateral and symmetric increased T • Vasogenic edema during acute crises as demonstrated by diffusion-weighted imaging / apparent diffusion coefficient MRI. • Chronic changes including atrophy and necrosis of the caudate nuclei and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [ • Brain stem involvement on MRI can be observed [ • Less common findings include the following: • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Two Japanese males who presented in the second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia; • An Indian woman who presented initially at age 49 years with rapidly progressive dementia. ## Early-Infantile (Leigh-Like) BTBGD (age <3 months) Vomiting Feeding difficulties Irritability Encephalopathy Hypotonia Seizures, infantile spasms Respiratory failure Elevated lactate concentrations in blood and cerebrospinal fluid (CSF) Elevated blood alanine, leucine, and isoleucine concentrations Increased alpha-ketoglutarate in urinary organic acid analysis Low free thiamine in CSF and/or fibroblasts [ Note: Oxidative phosphorylation (OXPHOS) abnormalities, found exclusively in early-infantile BTBGD, are associated with poor outcomes, including high mortality rates [ Note: It is recommended that treatment start with high-dose thiamine and biotin in encephalopathic infants with symmetric basal ganglia involvement on imaging (Leigh-like syndrome), even before genetic confirmation of BTBGD, as prompt treatment may improve outcomes [ Subsequent MRIs reveal cystic degeneration of the white matter that progresses to cerebral, cerebellar, and brain stem atrophy. Thalamic lesions are more common in early-infantile BTBGD. Neonates and young toddlers may present with extensive areas of restricted diffusion affecting the perirolandic white matter and thalami, with or without involvement of the basal ganglia [ • Vomiting • Feeding difficulties • Irritability • Encephalopathy • Hypotonia • Seizures, infantile spasms • Respiratory failure • Elevated lactate concentrations in blood and cerebrospinal fluid (CSF) • Elevated blood alanine, leucine, and isoleucine concentrations • Increased alpha-ketoglutarate in urinary organic acid analysis • Low free thiamine in CSF and/or fibroblasts [ ## Classic BTBGD (typically ages 3-10 years) Seizures Extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia) Pyramidal tract signs (quadriparesis, hyperreflexia) Variable presence of cerebellar signs (supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia) BTBGD can present with mild neurologic symptoms without encephalopathy at onset, as seen in older children with progressive cognitive deficits [ Tandem mass spectrometry of blood Urine gas chromatography-mass spectrometry (GC-MS), urine amino acids Serum concentrations of lactic acid, ammonia, and thiamine Plasma amino acids, liver enzymes, coagulation profile, lipid profile CSF cell count, protein, glucose, and cultures In the acute phase of decompensation, some individuals show increased lactate concentration in blood and CSF. Additionally, in some specialized laboratories, low free thiamine concentration may be observed in CSF and/or fibroblasts [ Swelling and bilateral and symmetric increased T Vasogenic edema during acute crises as demonstrated by diffusion-weighted imaging / apparent diffusion coefficient MRI. Chronic changes including atrophy and necrosis of the caudate nuclei and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [ Brain stem involvement on MRI can be observed [ Less common findings include the following: Spinal cord involvement (1 individual) [ Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Seizures • Extrapyramidal manifestations (dystonia, cogwheel rigidity, dysarthria, dysphagia) • Pyramidal tract signs (quadriparesis, hyperreflexia) • Variable presence of cerebellar signs (supranuclear facial nerve palsy, external ophthalmoplegia, and ataxia) • Tandem mass spectrometry of blood • Urine gas chromatography-mass spectrometry (GC-MS), urine amino acids • Serum concentrations of lactic acid, ammonia, and thiamine • Plasma amino acids, liver enzymes, coagulation profile, lipid profile • CSF cell count, protein, glucose, and cultures • Swelling and bilateral and symmetric increased T • Vasogenic edema during acute crises as demonstrated by diffusion-weighted imaging / apparent diffusion coefficient MRI. • Chronic changes including atrophy and necrosis of the caudate nuclei and putamen with diffuse cerebral cortical and (to a lesser extent) cerebellar atrophy [ • Brain stem involvement on MRI can be observed [ • Less common findings include the following: • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ • Spinal cord involvement (1 individual) [ • Severe subdural hematoma, along with basal ganglia lesions, brain stem abnormalities, and cerebral atrophy [ ## Adult Wernicke-Like Encephalopathy BTBGD (age >10 years) Two Japanese males who presented in the second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia; An Indian woman who presented initially at age 49 years with rapidly progressive dementia. • Two Japanese males who presented in the second decade of life with status epilepticus, diplopia, nystagmus, ptosis, ophthalmoplegia, and ataxia; • An Indian woman who presented initially at age 49 years with rapidly progressive dementia. ## Family History Family history for all phenotypes is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Note: (1) Presumably affected (but undiagnosed) sibs may have had unexplained coma or encephalopathy. (2) Consanguinity has been reported in many families [ ## Establishing the Diagnosis The diagnosis of BTBGD Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of Note: Targeted analysis for the For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Biotin-Thiamine-Responsive Basal Ganglia 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. A 45-kb deletion including the promoter region but no coding exons of ## Option 1 Note: Targeted analysis for the For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Biotin-Thiamine-Responsive Basal Ganglia 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. A 45-kb deletion including the promoter region but no coding exons of ## Clinical Characteristics Biotin-thiamine-responsive basal ganglia disease (BTBGD), resulting from the inability of thiamine to cross the blood-brain barrier, comprises three age-related phenotypes: early-infantile BTBGD (presenting by age 3 months), classic (childhood) BTBGD (ages 3-10 years), and adult Wernicke-like encephalopathy BTBGD (age >10 years). To date, more than 169 individuals have been identified with biallelic pathogenic variants in Most commonly, classic BTBGD is characterized by recurrent acute/subacute onset of encephalopathy, often triggered by febrile illness, mild trauma, or stress, manifesting as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia. The encephalopathy may be associated with raised intracranial pressure. Dystonia and cogwheel rigidity are nearly always present. Hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Seizures are mainly simple partial or generalized and are easily controlled with anti-seizure medication. Infantile spasms also occur [ Administration of biotin and thiamine early in the disease course results in complete clinical improvement within days (see Management, Affected individuals show dramatic response to high doses of thiamine (see Management, Biotin-thiamine-responsive basal ganglia disease (BTBGD) is pan ethnic. Of note, homozygosity for the Saudi Arabian founder variant The carrier frequency of the Although genotype-phenotype correlations remain unclear, the following have been observed: Biallelic Compound heterozygosity for one Homozygosity for the founder Saudi Arabian pathogenic variant • Biallelic • Compound heterozygosity for one • Homozygosity for the founder Saudi Arabian pathogenic variant ## Clinical Description Biotin-thiamine-responsive basal ganglia disease (BTBGD), resulting from the inability of thiamine to cross the blood-brain barrier, comprises three age-related phenotypes: early-infantile BTBGD (presenting by age 3 months), classic (childhood) BTBGD (ages 3-10 years), and adult Wernicke-like encephalopathy BTBGD (age >10 years). To date, more than 169 individuals have been identified with biallelic pathogenic variants in Most commonly, classic BTBGD is characterized by recurrent acute/subacute onset of encephalopathy, often triggered by febrile illness, mild trauma, or stress, manifesting as confusion, seizures, ataxia, dystonia, supranuclear facial palsy, external ophthalmoplegia, and/or dysphagia. The encephalopathy may be associated with raised intracranial pressure. Dystonia and cogwheel rigidity are nearly always present. Hyperreflexia, ankle clonus, and Babinski responses are common. Hemiparesis or quadriparesis may be seen. Seizures are mainly simple partial or generalized and are easily controlled with anti-seizure medication. Infantile spasms also occur [ Administration of biotin and thiamine early in the disease course results in complete clinical improvement within days (see Management, Affected individuals show dramatic response to high doses of thiamine (see Management, ## Prevalence Biotin-thiamine-responsive basal ganglia disease (BTBGD) is pan ethnic. Of note, homozygosity for the Saudi Arabian founder variant The carrier frequency of the ## Genotype-Phenotype Correlations Although genotype-phenotype correlations remain unclear, the following have been observed: Biallelic Compound heterozygosity for one Homozygosity for the founder Saudi Arabian pathogenic variant • Biallelic • Compound heterozygosity for one • Homozygosity for the founder Saudi Arabian pathogenic variant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genetic disorders of interest in the differential diagnosis of infants, children, and adults presenting with Genes of Interest in the Differential Diagnosis of Acute Biotin-Thiamine-Responsive Basal Ganglia Disease AD = autosomal dominant; AR = autosomal recessive; IVA = isovaleric acidemia; Mat = maternal; MMA = methylmalonic acidemia; MOI = mode of inheritance; MSUD = maple syrup urine disease; PA = propionic acidemia Major clinical features are developmental delay, seizures, lethargy, coma, hypotonia, vomiting, failure to thrive, hepatomegaly, respiratory distress, cardiac dysfunction, hypoglycemia, and acidosis. More than 65 organic acids are known [ Note: Dopa-responsive dystonia and Wilson disease are important to consider because they are treatable. Wernicke encephalopathy Toxic encephalopathy Infectious encephalopathy Inflammatory disease (including central nervous system vasculitis) Acute disseminated encephalomyelitis (ADEM) In its • Wernicke encephalopathy • Toxic encephalopathy • Infectious encephalopathy • Inflammatory disease (including central nervous system vasculitis) • Acute disseminated encephalomyelitis (ADEM) ## Management No clinical practice guidelines for biotin-thiamine-responsive basal ganglia disease (BTBGD) 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 BTBGD, the evaluations summarized in Biotin-Thiamine-Responsive Basal Ganglia Disease: Recommended Evaluations Following Initial Diagnosis Baseline exam for tone & movement disorders incl dystonia, spasticity, & ataxia Eval for seizures 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, 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; BTBGD = biotin-thiamine-responsive basal ganglia disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment with oral biotin (5-10 mg/kg/day) and thiamine (≤40 mg/kg/day; maximum of 1,500 mg/day) is critical from the time of diagnosis. Treatment with thiamine alone or in combination with biotin typically shows better outcomes than biotin alone [ Lifelong treatment with biotin and thiamine is required. Adults with BTBGD are typically maintained on oral biotin at 600 mg daily along with oral thiamine at 1,500 mg daily. For individuals with BTBGD who have an insufficient response to standard doses of thiamine, increasing the dose up to 75 mg/kg/day during the acute phase may significantly improve outcomes. Subsequent dose reduction to maintenance levels (e.g., 30 mg/kg/day) has been effective in preventing relapses [ During acute decompensation, thiamine may be increased to two times the regular dose and given intravenously. Although most individuals with the early-infantile form do not respond to thiamine treatment and eventually succumb to the disease, it is always worth trying [ 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 Biotin-Thiamine-Responsive Basal Ganglia Disease: Treatment of Manifestations Thiamine may be ↑ to 2x regular dose & given intravenously. Empiric treatment w/antimicrobial/antiviral agents recommended until infectious causes of acute/subacute encephalopathy are ruled out. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Avoid valproate. Use ACTH w/caution due to risk of status dystonicus. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Biotin-Thiamine-Responsive Basal Ganglia Disease: Recommended Surveillance Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & movement disorders. OT = occupational therapy; PT = physical therapy Use of sodium valproate for treatment of epilepsy should be avoided. Use of adrenocorticotropic hormone (ACTH) for epileptic spasms in individuals with BTBGD can induce status dystonicus [ It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk sibs of an affected individual to identify as early as possible those who would benefit from prompt initiation of treatment with biotin and thiamine and avoidance of use of sodium valproate (for treatment of epilepsy) or ACTH (for treatment of infantile spasms). See Affected women should continue biotin and thiamine therapy during pregnancy. No information regarding risk to the fetus of an affected mother is available. Search • Baseline exam for tone & movement disorders incl dystonia, spasticity, & ataxia • Eval for seizures • 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, 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 • Thiamine may be ↑ to 2x regular dose & given intravenously. • Empiric treatment w/antimicrobial/antiviral agents recommended until infectious causes of acute/subacute encephalopathy are ruled out. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Avoid valproate. • Use ACTH w/caution due to risk of status dystonicus. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with BTBGD, the evaluations summarized in Biotin-Thiamine-Responsive Basal Ganglia Disease: Recommended Evaluations Following Initial Diagnosis Baseline exam for tone & movement disorders incl dystonia, spasticity, & ataxia Eval for seizures 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, 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; BTBGD = biotin-thiamine-responsive basal ganglia disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy Medical geneticist, certified genetic counselor, certified advanced genetic nurse • Baseline exam for tone & movement disorders incl dystonia, spasticity, & ataxia • Eval for seizures • 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, 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 with oral biotin (5-10 mg/kg/day) and thiamine (≤40 mg/kg/day; maximum of 1,500 mg/day) is critical from the time of diagnosis. Treatment with thiamine alone or in combination with biotin typically shows better outcomes than biotin alone [ Lifelong treatment with biotin and thiamine is required. Adults with BTBGD are typically maintained on oral biotin at 600 mg daily along with oral thiamine at 1,500 mg daily. For individuals with BTBGD who have an insufficient response to standard doses of thiamine, increasing the dose up to 75 mg/kg/day during the acute phase may significantly improve outcomes. Subsequent dose reduction to maintenance levels (e.g., 30 mg/kg/day) has been effective in preventing relapses [ During acute decompensation, thiamine may be increased to two times the regular dose and given intravenously. Although most individuals with the early-infantile form do not respond to thiamine treatment and eventually succumb to the disease, it is always worth trying [ 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 Biotin-Thiamine-Responsive Basal Ganglia Disease: Treatment of Manifestations Thiamine may be ↑ to 2x regular dose & given intravenously. Empiric treatment w/antimicrobial/antiviral agents recommended until infectious causes of acute/subacute encephalopathy are ruled out. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Avoid valproate. Use ACTH w/caution due to risk of status dystonicus. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Thiamine may be ↑ to 2x regular dose & given intravenously. • Empiric treatment w/antimicrobial/antiviral agents recommended until infectious causes of acute/subacute encephalopathy are ruled out. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Avoid valproate. • Use ACTH w/caution due to risk of status dystonicus. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## Targeted Therapies Treatment with oral biotin (5-10 mg/kg/day) and thiamine (≤40 mg/kg/day; maximum of 1,500 mg/day) is critical from the time of diagnosis. Treatment with thiamine alone or in combination with biotin typically shows better outcomes than biotin alone [ Lifelong treatment with biotin and thiamine is required. Adults with BTBGD are typically maintained on oral biotin at 600 mg daily along with oral thiamine at 1,500 mg daily. For individuals with BTBGD who have an insufficient response to standard doses of thiamine, increasing the dose up to 75 mg/kg/day during the acute phase may significantly improve outcomes. Subsequent dose reduction to maintenance levels (e.g., 30 mg/kg/day) has been effective in preventing relapses [ During acute decompensation, thiamine may be increased to two times the regular dose and given intravenously. Although most individuals with the early-infantile form do not respond to thiamine treatment and eventually succumb to the disease, it is always worth trying [ ## 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 Biotin-Thiamine-Responsive Basal Ganglia Disease: Treatment of Manifestations Thiamine may be ↑ to 2x regular dose & given intravenously. Empiric treatment w/antimicrobial/antiviral agents recommended until infectious causes of acute/subacute encephalopathy are ruled out. Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. Avoid valproate. Use ACTH w/caution due to risk of status dystonicus. Education of parents/caregivers Feeding therapy Gastrostomy tube placement may be required for persistent feeding issues. Ensure appropriate social work involvement to connect families w/local resources, respite, & support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. Ongoing assessment of need for palliative care involvement &/or home nursing Consider involvement in adaptive sports or ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy Education of parents/caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for children diagnosed with epilepsy, see The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. IEP services: An IEP provides specially designed instruction and related services to children who qualify. IEP services will be reviewed annually to determine whether any changes are needed. Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. Vision consultants should be a part of the child's IEP team to support access to academic material. PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Thiamine may be ↑ to 2x regular dose & given intravenously. • Empiric treatment w/antimicrobial/antiviral agents recommended until infectious causes of acute/subacute encephalopathy are ruled out. • Many ASMs may be effective; none has been demonstrated effective specifically for this disorder. • Avoid valproate. • Use ACTH w/caution due to risk of status dystonicus. • Education of parents/caregivers • Feeding therapy • Gastrostomy tube placement may be required for persistent feeding issues. • Ensure appropriate social work involvement to connect families w/local resources, respite, & support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Ongoing assessment of need for palliative care involvement &/or home nursing • Consider involvement in adaptive sports or • IEP services: • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. • A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • An IEP provides specially designed instruction and related services to children who qualify. • IEP services will be reviewed annually to determine whether any changes are needed. • Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate. • Vision consultants should be a part of the child's IEP team to support access to academic material. • PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. • As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21. ## 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 To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Biotin-Thiamine-Responsive Basal Ganglia Disease: Recommended Surveillance Measurement of growth parameters Eval of nutritional status & safety of oral intake Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & movement disorders. OT = occupational therapy; PT = physical therapy • Measurement of growth parameters • Eval of nutritional status & safety of oral intake • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. ## Agents/Circumstances to Avoid Use of sodium valproate for treatment of epilepsy should be avoided. Use of adrenocorticotropic hormone (ACTH) for epileptic spasms in individuals with BTBGD can induce status dystonicus [ ## 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 to identify as early as possible those who would benefit from prompt initiation of treatment with biotin and thiamine and avoidance of use of sodium valproate (for treatment of epilepsy) or ACTH (for treatment of infantile spasms). See ## Pregnancy Management Affected women should continue biotin and thiamine therapy during pregnancy. No information regarding risk to the fetus of an affected mother is available. ## Therapies Under Investigation Search ## Genetic Counseling Biotin-thiamine-responsive basal ganglia disease (BTBGD) is inherited in an autosomal recessive manner. The parents of an affected individual 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. Carrier testing should be considered for the reproductive partners of individuals affected with BTBGD and individuals known to be carriers of BTBGD, particularly if consanguinity is likely and/or if both partners are of the same ancestry. An Once the Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While use of prenatal and preimplantation genetic testing is a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for an • Molecular genetic testing 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. • Carrier testing should be considered for the reproductive partners of individuals affected with BTBGD and individuals known to be carriers of BTBGD, particularly if consanguinity is likely and/or if both partners are of the same ancestry. An ## Mode of Inheritance Biotin-thiamine-responsive basal ganglia disease (BTBGD) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for an Molecular genetic testing 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 individual 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. Carrier testing should be considered for the reproductive partners of individuals affected with BTBGD and individuals known to be carriers of BTBGD, particularly if consanguinity is likely and/or if both partners are of the same ancestry. An • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing should be considered for the reproductive partners of individuals affected with BTBGD and individuals known to be carriers of BTBGD, particularly if consanguinity is likely and/or if both partners are of the same ancestry. 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 use of prenatal and preimplantation genetic testing is a personal decision, discussion of these issues may be helpful. ## Resources • • ## Molecular Genetics Biotin-Thiamine-Responsive Basal Ganglia Disease : Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Biotin-Thiamine-Responsive Basal Ganglia Disease ( Thiamine pyrophosphate is: An essential cofactor for transketolase in the cytoplasm; Transported into mitochondria, where it binds to pyruvate dehydrogenase and stimulates conversion of pyruvate to acetyl-coenzyme A; A cofactor for alpha-ketoglutarate and branched-chain alpha-ketoacid dehydrogenase, entering the tricarboxylic acid cycle for energy production and biosynthesis. Founder variant in Saudi population [ See also Variants listed in the table have been provided by the authors. • An essential cofactor for transketolase in the cytoplasm; • Transported into mitochondria, where it binds to pyruvate dehydrogenase and stimulates conversion of pyruvate to acetyl-coenzyme A; • A cofactor for alpha-ketoglutarate and branched-chain alpha-ketoacid dehydrogenase, entering the tricarboxylic acid cycle for energy production and biosynthesis. • Founder variant in Saudi population [ • See also ## Molecular Pathogenesis Thiamine pyrophosphate is: An essential cofactor for transketolase in the cytoplasm; Transported into mitochondria, where it binds to pyruvate dehydrogenase and stimulates conversion of pyruvate to acetyl-coenzyme A; A cofactor for alpha-ketoglutarate and branched-chain alpha-ketoacid dehydrogenase, entering the tricarboxylic acid cycle for energy production and biosynthesis. Founder variant in Saudi population [ See also Variants listed in the table have been provided by the authors. • An essential cofactor for transketolase in the cytoplasm; • Transported into mitochondria, where it binds to pyruvate dehydrogenase and stimulates conversion of pyruvate to acetyl-coenzyme A; • A cofactor for alpha-ketoglutarate and branched-chain alpha-ketoacid dehydrogenase, entering the tricarboxylic acid cycle for energy production and biosynthesis. • Founder variant in Saudi population [ • See also ## Chapter Notes 9 January 2025 (bp) Comprehensive update posted live 16 April 2020 (ha) Comprehensive update posted live 21 November 2013 (me) Review posted live 28 May 2013 (aah) Original submission • 9 January 2025 (bp) Comprehensive update posted live • 16 April 2020 (ha) Comprehensive update posted live • 21 November 2013 (me) Review posted live • 28 May 2013 (aah) Original submission ## Revision History 9 January 2025 (bp) Comprehensive update posted live 16 April 2020 (ha) Comprehensive update posted live 21 November 2013 (me) Review posted live 28 May 2013 (aah) Original submission • 9 January 2025 (bp) Comprehensive update posted live • 16 April 2020 (ha) Comprehensive update posted live • 21 November 2013 (me) Review posted live • 28 May 2013 (aah) Original submission ## Key Sections in This ## References ## Literature Cited	[]	21/11/2013	9/1/2025	20/8/2020	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bgs	bgs	[ "ATP-dependent DNA helicase Q4", "RECQL4", "Baller-Gerold Syndrome" ]	Baller-Gerold Syndrome	Lionel Van Maldergem, Juliette Piard, Lidia Larizza, Lisa L Wang	Summary Baller-Gerold syndrome (BGS) can be suspected at birth in an infant with craniosynostosis and upper limb abnormality. The coronal suture is most commonly affected; the metopic, lambdoid, and sagittal sutures may also be involved alone or in combination. Upper limb abnormality can include a combination of thumb hypo- or aplasia and radial hypo- or aplasia and may be asymmetric. Malformation or absence of carpal or metacarpal bones has also been described. Skin lesions may appear anytime within the first few years after birth, typically beginning with erythema of the face and extremities and evolving into poikiloderma. Slow growth is apparent in infancy with eventual height and length typically at 4 SD below the mean. The diagnosis of BGS is established in a proband with typical clinical findings and/or the identification of biallelic pathogenic variants in Baller-Gerold syndrome is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes and therefore carry one pathogenic variant. Heterozygotes (carriers) are asymptomatic. 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 family members, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible if both pathogenic variants in the family have been identified.	## Diagnosis Baller-Gerold syndrome When the coronal sutures are fused, the orbit is pulled forward. The coronal sutures cannot be discerned on the frontal view, and the same holds true for the lambdoidal sutures. Note: Radiographs may be necessary for confirmation of minor radial ray malformations. The diagnosis of Baller-Gerold 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 [ 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 Baller-Gerold syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Baller-Gerold syndrome, molecular genetic testing approaches can include Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. A multigene panel that also includes deletion/duplication analysis should be considered if only one or no pathogenic variant is found on the multigene panel sequence analysis (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by craniosynostosis or when the diagnosis of Baller-Gerold syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Baller-Gerold 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. A large homozygous intragenic deletion was reported in a single individual of Japanese heritage with Baller-Gerold syndrome [ • When the coronal sutures are fused, the orbit is pulled forward. The coronal sutures cannot be discerned on the frontal view, and the same holds true for the lambdoidal sutures. • Note: Radiographs may be necessary for confirmation of minor radial ray malformations. • • Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • A multigene panel that also includes deletion/duplication analysis should be considered if only one or no pathogenic variant is found on the multigene panel sequence analysis (see • For an introduction to multigene panels click ## Suggestive Findings Baller-Gerold syndrome When the coronal sutures are fused, the orbit is pulled forward. The coronal sutures cannot be discerned on the frontal view, and the same holds true for the lambdoidal sutures. Note: Radiographs may be necessary for confirmation of minor radial ray malformations. • When the coronal sutures are fused, the orbit is pulled forward. The coronal sutures cannot be discerned on the frontal view, and the same holds true for the lambdoidal sutures. • Note: Radiographs may be necessary for confirmation of minor radial ray malformations. • ## Establishing the Diagnosis The diagnosis of Baller-Gerold 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 [ 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 Baller-Gerold syndrome is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Baller-Gerold syndrome, molecular genetic testing approaches can include Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. A multigene panel that also includes deletion/duplication analysis should be considered if only one or no pathogenic variant is found on the multigene panel sequence analysis (see For an introduction to multigene panels click When the phenotype is indistinguishable from many other inherited disorders characterized by craniosynostosis or when the diagnosis of Baller-Gerold syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Baller-Gerold 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. A large homozygous intragenic deletion was reported in a single individual of Japanese heritage with Baller-Gerold syndrome [ • Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • A multigene panel that also includes deletion/duplication analysis should be considered if only one or no pathogenic variant is found on the multigene panel sequence analysis (see • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Baller-Gerold syndrome, molecular genetic testing approaches can include Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. A multigene panel that also includes deletion/duplication analysis should be considered if only one or no pathogenic variant is found on the multigene panel sequence analysis (see For an introduction to multigene panels click • Perform sequence analysis first. If only one or no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. • A multigene panel that also includes deletion/duplication analysis should be considered if only one or no pathogenic variant is found on the multigene panel sequence analysis (see • For an introduction to multigene panels click ## Option 2 When the phenotype is indistinguishable from many other inherited disorders characterized by craniosynostosis or when the diagnosis of Baller-Gerold syndrome is not considered because an individual has atypical phenotypic features, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Baller-Gerold 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. No data on detection rate of gene-targeted deletion/duplication analysis are available. A large homozygous intragenic deletion was reported in a single individual of Japanese heritage with Baller-Gerold syndrome [ ## Clinical Characteristics Since the original description of Baller-Gerold syndrome (BGS) by Brachycephaly Proptosis Prominent forehead Large fontanelles Concave nasal ridge Short nose Narrow mouth with thin vermilion of the lips High arched palate Late ossification of the patella may be misinterpreted as absence of the patella in infants. Absence of patella may result in genu recurvatum and knee instability. Lesions typically begin with erythema of the face and extremities. Findings later evolve into poikiloderma (mottled hypo-and hyper-pigmentation, atrophy, and telangiectasias). Imperforate or anterior displacement of the anus has been reported in several individuals. Cardiovascular defects such as ventricular septal defects, tetralogy of Fallot, and congenital portal venous malformations have been occasionally described. No formal genotype-phenotype correlations have been made owing to the small number of affected individuals reported to date. The name Baller-Gerold syndrome was coined by Since 1975 the designation Baller-Gerold syndrome has been used to refer to any type of craniosynostosis associated with any type of radial ray defect; this is likely an incorrect use of the term, and has led some authors to consider metopic ridging and radial ray defects observed in valproate embryopathy sufficient for a diagnosis of BGS [ The prevalence of Baller-Gerold syndrome is unknown; it is probably less than 1:1,000,000 [ • Brachycephaly • Proptosis • Prominent forehead • Large fontanelles • Concave nasal ridge • Short nose • Narrow mouth with thin vermilion of the lips • High arched palate • Late ossification of the patella may be misinterpreted as absence of the patella in infants. • Absence of patella may result in genu recurvatum and knee instability. • Late ossification of the patella may be misinterpreted as absence of the patella in infants. • Absence of patella may result in genu recurvatum and knee instability. • Late ossification of the patella may be misinterpreted as absence of the patella in infants. • Absence of patella may result in genu recurvatum and knee instability. • Lesions typically begin with erythema of the face and extremities. • Findings later evolve into poikiloderma (mottled hypo-and hyper-pigmentation, atrophy, and telangiectasias). • Imperforate or anterior displacement of the anus has been reported in several individuals. • Cardiovascular defects such as ventricular septal defects, tetralogy of Fallot, and congenital portal venous malformations have been occasionally described. ## Clinical Description Since the original description of Baller-Gerold syndrome (BGS) by Brachycephaly Proptosis Prominent forehead Large fontanelles Concave nasal ridge Short nose Narrow mouth with thin vermilion of the lips High arched palate Late ossification of the patella may be misinterpreted as absence of the patella in infants. Absence of patella may result in genu recurvatum and knee instability. Lesions typically begin with erythema of the face and extremities. Findings later evolve into poikiloderma (mottled hypo-and hyper-pigmentation, atrophy, and telangiectasias). Imperforate or anterior displacement of the anus has been reported in several individuals. Cardiovascular defects such as ventricular septal defects, tetralogy of Fallot, and congenital portal venous malformations have been occasionally described. • Brachycephaly • Proptosis • Prominent forehead • Large fontanelles • Concave nasal ridge • Short nose • Narrow mouth with thin vermilion of the lips • High arched palate • Late ossification of the patella may be misinterpreted as absence of the patella in infants. • Absence of patella may result in genu recurvatum and knee instability. • Late ossification of the patella may be misinterpreted as absence of the patella in infants. • Absence of patella may result in genu recurvatum and knee instability. • Late ossification of the patella may be misinterpreted as absence of the patella in infants. • Absence of patella may result in genu recurvatum and knee instability. • Lesions typically begin with erythema of the face and extremities. • Findings later evolve into poikiloderma (mottled hypo-and hyper-pigmentation, atrophy, and telangiectasias). • Imperforate or anterior displacement of the anus has been reported in several individuals. • Cardiovascular defects such as ventricular septal defects, tetralogy of Fallot, and congenital portal venous malformations have been occasionally described. ## Genotype-Phenotype Correlations No formal genotype-phenotype correlations have been made owing to the small number of affected individuals reported to date. ## Nomenclature The name Baller-Gerold syndrome was coined by Since 1975 the designation Baller-Gerold syndrome has been used to refer to any type of craniosynostosis associated with any type of radial ray defect; this is likely an incorrect use of the term, and has led some authors to consider metopic ridging and radial ray defects observed in valproate embryopathy sufficient for a diagnosis of BGS [ ## Prevalence The prevalence of Baller-Gerold syndrome is unknown; it is probably less than 1:1,000,000 [ ## Genetically Related (Allelic) Disorders Pathogenic variants in The diagnosis of RTS is established by clinical findings. Molecular testing is confirmatory and may be useful in situations in which clinical findings are atypical. Identification of biallelic pathogenic variants in The Finn-specific RTS, RAPADILINO syndrome, and BGS share the clinical features of pre- and postnatal growth retardation, chronic diarrhea, and patellar hypo- or aplasia. Radial hypo- or aplasia is almost always present in individuals with RAPADILINO syndrome and BGS and less frequently seen in those with RTS. Poikiloderma, a characteristic of RTS and also described in BGS, is not seen in RAPADILINO syndrome. However, the absence of poikiloderma cannot be confirmed before age one year because of its late onset. Craniosynostosis, particularly affecting the coronal suture, is a diagnostic feature of BGS, and is rarely seen in RTS. Alopecia and absence of eyelashes and brows, characteristics of RTS, have not been observed in individuals with BGS or RAPADILINO. • The diagnosis of RTS is established by clinical findings. Molecular testing is confirmatory and may be useful in situations in which clinical findings are atypical. Identification of biallelic pathogenic variants in • The Finn-specific ## Differential Diagnosis The major differential diagnosis for Baller-Gerold syndrome (BGS) comprises the allelic disorders Additional conditions to consider are included in Disorders to Consider in the Differential Diagnosis of BGS Radial ray defects Craniosynostosis in some Cardiac malformation & hematologic anomalies often present Chromosome breakage after incubation w/clastogens Radial hypo-or aplasia Craniosynostosis (metopic) History of maternal use of valproate during pregnancy Facial dysmorphia Cleft palate Neural tube defect Cranial nerves palsies Cardiac malformation Choanal atresia Coloboma Outer &/or inner ear abnormality Orofacial cleft Shape of pinnae Anorectal anomalies Cardiac malformation &/or conduction defect present No craniosynostosis No craniosynostosis Thumbs present in TAR Craniosynostosis Occasional radial defects (radioulnar synostosis or hypoplastic radius) Facial asymmetry Small ears w/prominent crus Brachydactyly Partial 2-3 syndactyly of hand Radial aplasia/hypoplasia Occasional craniosynostosis Shortening of 4 limbs Intellectual disability Craniosynostosis Porokeratosis resembling poikiloderma Clavicular hypoplasia Hearing loss AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked CDAGS = The diagnosis of FA rests on the detection of chromosomal aberrations (breaks, rearrangements, radials, exchanges) in cells after culture with a DNA interstrand cross-linking agent such as diepoxybutane (DEB) or mitomycin C (MMC). Approximately 20 genes have been associated with FA. Previously thought to be autosomal recessive, the mode of inheritance of TAR syndrome is complex, with a microdeletion in 1q21.1 being necessary but not sufficient to determine the phenotype [ • Radial ray defects • Craniosynostosis in some • Cardiac malformation & hematologic anomalies often present • Chromosome breakage after incubation w/clastogens • Radial hypo-or aplasia • Craniosynostosis (metopic) • History of maternal use of valproate during pregnancy • Facial dysmorphia • Cleft palate • Neural tube defect • Cranial nerves palsies • Cardiac malformation • Choanal atresia • Coloboma • Outer &/or inner ear abnormality • Orofacial cleft • Shape of pinnae • Anorectal anomalies • Cardiac malformation &/or conduction defect present • No craniosynostosis • No craniosynostosis • Thumbs present in TAR • Craniosynostosis • Occasional radial defects (radioulnar synostosis or hypoplastic radius) • Facial asymmetry • Small ears w/prominent crus • Brachydactyly • Partial 2-3 syndactyly of hand • Radial aplasia/hypoplasia • Occasional craniosynostosis • Shortening of 4 limbs • Intellectual disability • Craniosynostosis • Porokeratosis resembling poikiloderma • Clavicular hypoplasia • Hearing loss ## Management To establish the extent of disease in an individual diagnosed with Baller-Gerold syndrome (BGS), the following are recommended if they have not already been completed: Consultation with a clinical geneticist and/or genetic counselor Neurosurgery or craniofacial specialist consultation for evaluation of craniosynostosis Orthopedic surgery and occupational therapy assessment to evaluate hand and arm function and need for surgery Dermatology evaluation if poikiloderma develops Craniosynostosis should be managed by neurosurgical/craniofacial specialists. When craniosynostosis is bilateral, surgery is usually performed before age six months. Pollicization of the index finger to restore a functional grasp has had satisfactory results in a number of persons with absence of the thumb [ If poikiloderma is present, sensible use of sunscreens may protect against potential risk for skin cancer due to UV exposure. If cancer arises, medical care should be sought from an oncologist familiar with the type of cancer. Although lymphoma has only been described in one individual with BGS to date [ Excessive sun exposure should be avoided because of the theoretic increased risk for skin cancer. See Search • Consultation with a clinical geneticist and/or genetic counselor • Neurosurgery or craniofacial specialist consultation for evaluation of craniosynostosis • Orthopedic surgery and occupational therapy assessment to evaluate hand and arm function and need for surgery • Dermatology evaluation if poikiloderma develops ## Evaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with Baller-Gerold syndrome (BGS), the following are recommended if they have not already been completed: Consultation with a clinical geneticist and/or genetic counselor Neurosurgery or craniofacial specialist consultation for evaluation of craniosynostosis Orthopedic surgery and occupational therapy assessment to evaluate hand and arm function and need for surgery Dermatology evaluation if poikiloderma develops • Consultation with a clinical geneticist and/or genetic counselor • Neurosurgery or craniofacial specialist consultation for evaluation of craniosynostosis • Orthopedic surgery and occupational therapy assessment to evaluate hand and arm function and need for surgery • Dermatology evaluation if poikiloderma develops ## Treatment of Manifestations Craniosynostosis should be managed by neurosurgical/craniofacial specialists. When craniosynostosis is bilateral, surgery is usually performed before age six months. Pollicization of the index finger to restore a functional grasp has had satisfactory results in a number of persons with absence of the thumb [ If poikiloderma is present, sensible use of sunscreens may protect against potential risk for skin cancer due to UV exposure. If cancer arises, medical care should be sought from an oncologist familiar with the type of cancer. ## Surveillance Although lymphoma has only been described in one individual with BGS to date [ ## Agents/Circumstances to Avoid Excessive sun exposure should be avoided because of the theoretic increased risk for skin cancer. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Baller-Gerold syndrome (BGS) is inherited in an autosomal recessive manner. The parents of an affected child are obligate heterozygotes (i.e., carriers of one pathogenic variant). 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 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 pathogenic variant). • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring, and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. ## Mode of Inheritance Baller-Gerold syndrome (BGS) 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 pathogenic variant). 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 pathogenic variant). • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring, and reproductive options) to 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 • • • • • • • United Kingdom • ## Molecular Genetics Baller-Gerold Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Baller-Gerold Syndrome ( RecQ helicases have essential functions not only at various stages of DNA processing (replication, recombination, repair, telomere maintenance) but also in translation, RNA processing, mtDNA maintenance, and chromosome segregation [ c.3056-2A>C (homozygous) [ c.3061C>T (p.Arg1021Trp) and c.1573del – compound heterozygous in two families [ c.2335_2356del (homozygous) [ c.496C>T (p.Gln166Ter) and c.3151A>G (p.Ile1051Val) – compound heterozygous in two terminated pregnancies [ c.2492_2493del and c.2506_2518del – compound heterozygous in a child with a severe BGS phenotype who developed a midline NK/T lymphoma at age 2.5 years [ c.2059-1G>C and c.2141_2142del – compound heterozygous in a fetus with (prenatally diagnosed) severe BGS [ An intron 12 through exon 18 deletion (1,614-bp deletion and 1-bp G insertion; g.145737562_145739175delinsC) – homozygous in a Japanese boy age four years with café au lait-like spots but no poikiloderma [ Interestingly both missense variants p.Arg1021Trp and p.Ile1051Val are located in the RecQ C-terminal region (RQC), which is essential for proper function not only of RECQL4 but also of its paralogs [ Of the 11 Seven have been detected only in BGS. The p.Arg1021Trp and c.2492_2493del variants were observed in BGS and RTS. The recurrent c.1573del has been observed in BGS, RTS, and RAPADILINO. The c.2059-1G>C variant was detected in a fetus with BGS and was reported in one individual with RTS [ Notwithstanding the small number of unrelated cases confirmed by molecular diagnosis, compound heterozygosity is observed in more than half of the cases (4 vs 3 homozygotes), in line with the trend of RTS, where about two thirds of affected individuals reported are compound heterozygotes [ Variants listed in the table have been provided by the authors. RECQL4 is a highly multifunctional protein whose biologic role is partially interconnected with the other RecQ family proteins. Its helicase activity, questioned for some time, has been fully demonstrated and assigned to RECQL4 conserved helicase motif and N-terminal domain between amino acids 240 and 400, each independently promoting ATP-dependent DNA unwinding [ Absolutely unique to RECQL4 is regulation of maintenance of mitochondrial DNA copy number and transport of p53 (pathogenic variants in which cause • c.3056-2A>C (homozygous) [ • c.3061C>T (p.Arg1021Trp) and c.1573del – compound heterozygous in two families [ • c.2335_2356del (homozygous) [ • c.496C>T (p.Gln166Ter) and c.3151A>G (p.Ile1051Val) – compound heterozygous in two terminated pregnancies [ • c.2492_2493del and c.2506_2518del – compound heterozygous in a child with a severe BGS phenotype who developed a midline NK/T lymphoma at age 2.5 years [ • c.2059-1G>C and c.2141_2142del – compound heterozygous in a fetus with (prenatally diagnosed) severe BGS [ • An intron 12 through exon 18 deletion (1,614-bp deletion and 1-bp G insertion; g.145737562_145739175delinsC) – homozygous in a Japanese boy age four years with café au lait-like spots but no poikiloderma [ • Seven have been detected only in BGS. • The p.Arg1021Trp and c.2492_2493del variants were observed in BGS and RTS. • The recurrent c.1573del has been observed in BGS, RTS, and RAPADILINO. • The c.2059-1G>C variant was detected in a fetus with BGS and was reported in one individual with RTS [ ## Molecular Pathogenesis RecQ helicases have essential functions not only at various stages of DNA processing (replication, recombination, repair, telomere maintenance) but also in translation, RNA processing, mtDNA maintenance, and chromosome segregation [ c.3056-2A>C (homozygous) [ c.3061C>T (p.Arg1021Trp) and c.1573del – compound heterozygous in two families [ c.2335_2356del (homozygous) [ c.496C>T (p.Gln166Ter) and c.3151A>G (p.Ile1051Val) – compound heterozygous in two terminated pregnancies [ c.2492_2493del and c.2506_2518del – compound heterozygous in a child with a severe BGS phenotype who developed a midline NK/T lymphoma at age 2.5 years [ c.2059-1G>C and c.2141_2142del – compound heterozygous in a fetus with (prenatally diagnosed) severe BGS [ An intron 12 through exon 18 deletion (1,614-bp deletion and 1-bp G insertion; g.145737562_145739175delinsC) – homozygous in a Japanese boy age four years with café au lait-like spots but no poikiloderma [ Interestingly both missense variants p.Arg1021Trp and p.Ile1051Val are located in the RecQ C-terminal region (RQC), which is essential for proper function not only of RECQL4 but also of its paralogs [ Of the 11 Seven have been detected only in BGS. The p.Arg1021Trp and c.2492_2493del variants were observed in BGS and RTS. The recurrent c.1573del has been observed in BGS, RTS, and RAPADILINO. The c.2059-1G>C variant was detected in a fetus with BGS and was reported in one individual with RTS [ Notwithstanding the small number of unrelated cases confirmed by molecular diagnosis, compound heterozygosity is observed in more than half of the cases (4 vs 3 homozygotes), in line with the trend of RTS, where about two thirds of affected individuals reported are compound heterozygotes [ Variants listed in the table have been provided by the authors. RECQL4 is a highly multifunctional protein whose biologic role is partially interconnected with the other RecQ family proteins. Its helicase activity, questioned for some time, has been fully demonstrated and assigned to RECQL4 conserved helicase motif and N-terminal domain between amino acids 240 and 400, each independently promoting ATP-dependent DNA unwinding [ Absolutely unique to RECQL4 is regulation of maintenance of mitochondrial DNA copy number and transport of p53 (pathogenic variants in which cause • c.3056-2A>C (homozygous) [ • c.3061C>T (p.Arg1021Trp) and c.1573del – compound heterozygous in two families [ • c.2335_2356del (homozygous) [ • c.496C>T (p.Gln166Ter) and c.3151A>G (p.Ile1051Val) – compound heterozygous in two terminated pregnancies [ • c.2492_2493del and c.2506_2518del – compound heterozygous in a child with a severe BGS phenotype who developed a midline NK/T lymphoma at age 2.5 years [ • c.2059-1G>C and c.2141_2142del – compound heterozygous in a fetus with (prenatally diagnosed) severe BGS [ • An intron 12 through exon 18 deletion (1,614-bp deletion and 1-bp G insertion; g.145737562_145739175delinsC) – homozygous in a Japanese boy age four years with café au lait-like spots but no poikiloderma [ • Seven have been detected only in BGS. • The p.Arg1021Trp and c.2492_2493del variants were observed in BGS and RTS. • The recurrent c.1573del has been observed in BGS, RTS, and RAPADILINO. • The c.2059-1G>C variant was detected in a fetus with BGS and was reported in one individual with RTS [ ## Chapter Notes 19 April 2018 (ha) Comprehensive update posted live 7 June 2011 (me) Comprehensive update posted live 13 August 2007 (me) Review posted live 23 April 2007 (lvm) Original submission • 19 April 2018 (ha) Comprehensive update posted live • 7 June 2011 (me) Comprehensive update posted live • 13 August 2007 (me) Review posted live • 23 April 2007 (lvm) Original submission ## Revision History 19 April 2018 (ha) Comprehensive update posted live 7 June 2011 (me) Comprehensive update posted live 13 August 2007 (me) Review posted live 23 April 2007 (lvm) Original submission • 19 April 2018 (ha) Comprehensive update posted live • 7 June 2011 (me) Comprehensive update posted live • 13 August 2007 (me) Review posted live • 23 April 2007 (lvm) Original submission ## References ## Literature Cited Diagram showing overlapping and unique clinical features of the From	[ "F Baller. 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bhd	bhd	[ "Hornstein-Knickenberg Syndrome", "Hornstein-Knickenberg Syndrome", "Folliculin", "FLCN", "Birt-Hogg-Dube Syndrome" ]	Birt-Hogg-Dubé Syndrome	Elke C Sattler, Ortrud K Steinlein	Summary The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include cutaneous manifestations (fibrofolliculomas, acrochordons, angiofibromas, oral papules, cutaneous collagenomas, and epidermal cysts), pulmonary cysts / history of pneumothorax, renal cysts, and various types of renal tumors. Disease severity can vary significantly even within the same family. Skin lesions typically appear between the second and fourth decades of life and typically increase in size and number with age. Lung cysts are mainly in the basal lung regions; most individuals are asymptomatic but at high risk for spontaneous pneumothorax. Renal tumors can be bilateral and multifocal. The most common renal tumors are a hybrid of oncocytoma and chromophobe histologic cell types (oncocytic hybrid tumor); clear cell carcinoma and oncocytoma are also common. The clinical diagnosis of BHDS is established in a proband with either one major criteria (>5 fibrofolliculomas/trichodiscomas; one histologically confirmed) or two minor criteria (bilateral basally located lung cysts without other cause, early-onset renal cell cancer [age <50 years], multifocal/bilateral renal cell cancer, renal cell cancer with mixed chromophobe/oncocytic histology, and/or a first-degree relative with BHDS). The molecular diagnosis is established in a proband with any suggestive findings and a germline heterozygous pathogenic variant in BHDS is inherited in an autosomal dominant manner. Most individuals diagnosed with BHDS have an affected parent; some individuals have a	## Diagnosis Clinical diagnostic criteria for the diagnosis of Birt-Hogg-Dubé syndrome (BHDS) have been published [ BHDS Primary spontaneous pneumothorax Multiple lung cysts (particular in the lower lung zone) without known cause Early-onset renal cell cancer (age <50 years) Multifocal or bilateral renal cell cancer or oncocytoma ≥2 family members with renal cancer The clinical diagnosis of BHDS Bilateral basally located lung cysts without other cause Early-onset renal cell cancer (at age <50 years) Multifocal or bilateral renal cell cancer Chromophobe/oncocytic mixed renal cell cancer First-degree relative with BHDS The molecular diagnosis of BHDS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic findings suggest the diagnosis of BHDS, 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 facial papules and renal tumors, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Birt-Hogg-Dubé Syndrome BHDS = Birt-Hogg-Dubé syndrome; NA = not applicable 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 20%-24% of families with BHDS were found to have deletion (c.1285delC) or duplication (c.1285dupC) of a C nucleotide in the polycytosine tract in exon 11, which is a mutational hot spot (see Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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. • • Primary spontaneous pneumothorax • Multiple lung cysts (particular in the lower lung zone) without known cause • Primary spontaneous pneumothorax • Multiple lung cysts (particular in the lower lung zone) without known cause • • Early-onset renal cell cancer (age <50 years) • Multifocal or bilateral renal cell cancer or oncocytoma • ≥2 family members with renal cancer • Early-onset renal cell cancer (age <50 years) • Multifocal or bilateral renal cell cancer or oncocytoma • ≥2 family members with renal cancer • Primary spontaneous pneumothorax • Multiple lung cysts (particular in the lower lung zone) without known cause • Early-onset renal cell cancer (age <50 years) • Multifocal or bilateral renal cell cancer or oncocytoma • ≥2 family members with renal cancer • Bilateral basally located lung cysts without other cause • Early-onset renal cell cancer (at age <50 years) • Multifocal or bilateral renal cell cancer • Chromophobe/oncocytic mixed renal cell cancer • First-degree relative with BHDS • For an introduction to multigene panels click ## Suggestive Findings BHDS Primary spontaneous pneumothorax Multiple lung cysts (particular in the lower lung zone) without known cause Early-onset renal cell cancer (age <50 years) Multifocal or bilateral renal cell cancer or oncocytoma ≥2 family members with renal cancer • • Primary spontaneous pneumothorax • Multiple lung cysts (particular in the lower lung zone) without known cause • Primary spontaneous pneumothorax • Multiple lung cysts (particular in the lower lung zone) without known cause • • Early-onset renal cell cancer (age <50 years) • Multifocal or bilateral renal cell cancer or oncocytoma • ≥2 family members with renal cancer • Early-onset renal cell cancer (age <50 years) • Multifocal or bilateral renal cell cancer or oncocytoma • ≥2 family members with renal cancer • Primary spontaneous pneumothorax • Multiple lung cysts (particular in the lower lung zone) without known cause • Early-onset renal cell cancer (age <50 years) • Multifocal or bilateral renal cell cancer or oncocytoma • ≥2 family members with renal cancer ## Establishing the Diagnosis The clinical diagnosis of BHDS Bilateral basally located lung cysts without other cause Early-onset renal cell cancer (at age <50 years) Multifocal or bilateral renal cell cancer Chromophobe/oncocytic mixed renal cell cancer First-degree relative with BHDS The molecular diagnosis of BHDS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic findings suggest the diagnosis of BHDS, 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 facial papules and renal tumors, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Birt-Hogg-Dubé Syndrome BHDS = Birt-Hogg-Dubé syndrome; NA = not applicable 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 20%-24% of families with BHDS were found to have deletion (c.1285delC) or duplication (c.1285dupC) of a C nucleotide in the polycytosine tract in exon 11, which is a mutational hot spot (see Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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. • Bilateral basally located lung cysts without other cause • Early-onset renal cell cancer (at age <50 years) • Multifocal or bilateral renal cell cancer • Chromophobe/oncocytic mixed renal cell cancer • First-degree relative with BHDS • For an introduction to multigene panels click ## Clinical Diagnosis The clinical diagnosis of BHDS Bilateral basally located lung cysts without other cause Early-onset renal cell cancer (at age <50 years) Multifocal or bilateral renal cell cancer Chromophobe/oncocytic mixed renal cell cancer First-degree relative with BHDS • Bilateral basally located lung cysts without other cause • Early-onset renal cell cancer (at age <50 years) • Multifocal or bilateral renal cell cancer • Chromophobe/oncocytic mixed renal cell cancer • First-degree relative with BHDS ## Molecular Diagnosis The molecular diagnosis of BHDS Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic findings suggest the diagnosis of BHDS, 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 facial papules and renal tumors, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Birt-Hogg-Dubé Syndrome BHDS = Birt-Hogg-Dubé syndrome; NA = not applicable 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 20%-24% of families with BHDS were found to have deletion (c.1285delC) or duplication (c.1285dupC) of a C nucleotide in the polycytosine tract in exon 11, which is a mutational hot spot (see Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 ## When the phenotypic findings suggest the diagnosis of BHDS, 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 facial papules and renal tumors, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Birt-Hogg-Dubé Syndrome BHDS = Birt-Hogg-Dubé syndrome; NA = not applicable 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 20%-24% of families with BHDS were found to have deletion (c.1285delC) or duplication (c.1285dupC) of a C nucleotide in the polycytosine tract in exon 11, which is a mutational hot spot (see Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. 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 characteristics of Birt-Hogg-Dubé syndrome (BHDS) include fibrofolliculomas (specific cutaneous lesions), pulmonary cysts / history of pneumothorax, and various types of renal tumors. Intra- as well as interfamilial variation in disease severity can be significant. To date, more than 1,000 individuals have been identified with a pathogenic variant in Birt-Hogg-Dubé Syndrome: Frequency of Select Features Individuals with BHDS usually present with multiple small skin-colored, opaque, whitish or yellowish dome-shaped papules known as fibrofolliculomas. These noncancerous skin lesions start to appear between the second and fourth decade of life. They are the most common cutaneous manifestation in individuals with BHDS by age 70 years. In early stages they are typically found centrofacially (nasal and paranasal) and in a retroauricular location. They often increase in size, number, and distribution with age, eventually involving the face, neck, and upper trunk. Later onset of cutaneous lesions tends to correlate with a milder skin phenotype. Women tend to have smaller and fewer lesions than men. The large variability in age of onset and expression often limits their usefulness for clinical diagnosis, especially in younger individuals. If present, however, they are a helpful indicator of BHDS. Histopathologically circumscribed fibrosis is seen, which, depending on the location, is described as: perifollicular fibroma, often replacing the entire hair follicle in the corium; as fibrofolliculoma, with elongated fingerlike extensions; or as trichodiscoma, located subepidermally, mostly parallel to the skin surface. Note: Trichodiscomas, formerly described as tumors of the hair disc, are now considered to be scarred remnants of fibrofolliculomas [ Additional benign adnexal tumors have been described as achrocordons (skin tags) [ BHDS has been reported to be associated with cutaneous melanoma, including multiple desmoplastic melanomas [ Lung cysts, located mainly in the basal lung regions (subpleural and intrapulmonary areas), are common in adults with BHDS. The total number of lung cysts per individual ranges from zero to 166 (mean: 16). They are of irregular shape and variable size (1.0-30 mm). The cysts are usually embedded in normal parenchyma that does not exhibit signs of proliferation (as seen in tuberous sclerosis), inflammation (as seen in With an average age of onset of 30.2 years in females and 38.4 years in males, spontaneous pneumothorax is often the first manifestation in individuals with BHDS (onset range: age 13-69 years). In most individuals the risk of pneumothorax decreases in later adulthood. This could indicate that the formation of lung cysts is a process mainly restricted to younger individuals. Chest CT examination to screen for lung cysts is not feasible in healthy children from families with BHDS; thus, the age at which the lung cysts start to develop is unknown. Renal tumors associated with BHDS tend to be bilateral and multifocal, but isolated tumors are also common. The reported overall prevalence of renal tumors among individuals with a germline The most typical renal tumor in BHDS is a hybrid of oncocytoma and chromophobe histologic cell types, the so-called oncocytic hybrid tumor or hybrid oncocytoma/chromophobe tumor. It has been previously described as the most common tumor type in BHDS, but this could be an ascertainment artifact. Other common renal tumor types are clear cell carcinoma and oncocytoma; papillary carcinoma is less common. Discordance of histologic subtypes in bilateral and multifocal tumors is common. Multifocal renal oncocytosis, a rare pathologic condition characterized by numerous oncocytic nodules, is found in the renal parenchyma surrounding tumors in 50%-58% of individuals with BHDS [ No genotype-phenotype correlations for Based on the three major clinical manifestations, penetrance of BHDS is considered to be very high. Up to 97% of individuals with a heterozygous germline Hornstein-Knickenberg syndrome, which describes familial multiple perifollicular fibromas and fibromata pendulantia [ More than 1,000 affected families from various populations have been described. ## Clinical Description The clinical characteristics of Birt-Hogg-Dubé syndrome (BHDS) include fibrofolliculomas (specific cutaneous lesions), pulmonary cysts / history of pneumothorax, and various types of renal tumors. Intra- as well as interfamilial variation in disease severity can be significant. To date, more than 1,000 individuals have been identified with a pathogenic variant in Birt-Hogg-Dubé Syndrome: Frequency of Select Features Individuals with BHDS usually present with multiple small skin-colored, opaque, whitish or yellowish dome-shaped papules known as fibrofolliculomas. These noncancerous skin lesions start to appear between the second and fourth decade of life. They are the most common cutaneous manifestation in individuals with BHDS by age 70 years. In early stages they are typically found centrofacially (nasal and paranasal) and in a retroauricular location. They often increase in size, number, and distribution with age, eventually involving the face, neck, and upper trunk. Later onset of cutaneous lesions tends to correlate with a milder skin phenotype. Women tend to have smaller and fewer lesions than men. The large variability in age of onset and expression often limits their usefulness for clinical diagnosis, especially in younger individuals. If present, however, they are a helpful indicator of BHDS. Histopathologically circumscribed fibrosis is seen, which, depending on the location, is described as: perifollicular fibroma, often replacing the entire hair follicle in the corium; as fibrofolliculoma, with elongated fingerlike extensions; or as trichodiscoma, located subepidermally, mostly parallel to the skin surface. Note: Trichodiscomas, formerly described as tumors of the hair disc, are now considered to be scarred remnants of fibrofolliculomas [ Additional benign adnexal tumors have been described as achrocordons (skin tags) [ BHDS has been reported to be associated with cutaneous melanoma, including multiple desmoplastic melanomas [ Lung cysts, located mainly in the basal lung regions (subpleural and intrapulmonary areas), are common in adults with BHDS. The total number of lung cysts per individual ranges from zero to 166 (mean: 16). They are of irregular shape and variable size (1.0-30 mm). The cysts are usually embedded in normal parenchyma that does not exhibit signs of proliferation (as seen in tuberous sclerosis), inflammation (as seen in With an average age of onset of 30.2 years in females and 38.4 years in males, spontaneous pneumothorax is often the first manifestation in individuals with BHDS (onset range: age 13-69 years). In most individuals the risk of pneumothorax decreases in later adulthood. This could indicate that the formation of lung cysts is a process mainly restricted to younger individuals. Chest CT examination to screen for lung cysts is not feasible in healthy children from families with BHDS; thus, the age at which the lung cysts start to develop is unknown. Renal tumors associated with BHDS tend to be bilateral and multifocal, but isolated tumors are also common. The reported overall prevalence of renal tumors among individuals with a germline The most typical renal tumor in BHDS is a hybrid of oncocytoma and chromophobe histologic cell types, the so-called oncocytic hybrid tumor or hybrid oncocytoma/chromophobe tumor. It has been previously described as the most common tumor type in BHDS, but this could be an ascertainment artifact. Other common renal tumor types are clear cell carcinoma and oncocytoma; papillary carcinoma is less common. Discordance of histologic subtypes in bilateral and multifocal tumors is common. Multifocal renal oncocytosis, a rare pathologic condition characterized by numerous oncocytic nodules, is found in the renal parenchyma surrounding tumors in 50%-58% of individuals with BHDS [ ## Cutaneous Manifestations Individuals with BHDS usually present with multiple small skin-colored, opaque, whitish or yellowish dome-shaped papules known as fibrofolliculomas. These noncancerous skin lesions start to appear between the second and fourth decade of life. They are the most common cutaneous manifestation in individuals with BHDS by age 70 years. In early stages they are typically found centrofacially (nasal and paranasal) and in a retroauricular location. They often increase in size, number, and distribution with age, eventually involving the face, neck, and upper trunk. Later onset of cutaneous lesions tends to correlate with a milder skin phenotype. Women tend to have smaller and fewer lesions than men. The large variability in age of onset and expression often limits their usefulness for clinical diagnosis, especially in younger individuals. If present, however, they are a helpful indicator of BHDS. Histopathologically circumscribed fibrosis is seen, which, depending on the location, is described as: perifollicular fibroma, often replacing the entire hair follicle in the corium; as fibrofolliculoma, with elongated fingerlike extensions; or as trichodiscoma, located subepidermally, mostly parallel to the skin surface. Note: Trichodiscomas, formerly described as tumors of the hair disc, are now considered to be scarred remnants of fibrofolliculomas [ Additional benign adnexal tumors have been described as achrocordons (skin tags) [ BHDS has been reported to be associated with cutaneous melanoma, including multiple desmoplastic melanomas [ ## Pulmonary Cysts and Spontaneous Pneumothorax Lung cysts, located mainly in the basal lung regions (subpleural and intrapulmonary areas), are common in adults with BHDS. The total number of lung cysts per individual ranges from zero to 166 (mean: 16). They are of irregular shape and variable size (1.0-30 mm). The cysts are usually embedded in normal parenchyma that does not exhibit signs of proliferation (as seen in tuberous sclerosis), inflammation (as seen in With an average age of onset of 30.2 years in females and 38.4 years in males, spontaneous pneumothorax is often the first manifestation in individuals with BHDS (onset range: age 13-69 years). In most individuals the risk of pneumothorax decreases in later adulthood. This could indicate that the formation of lung cysts is a process mainly restricted to younger individuals. Chest CT examination to screen for lung cysts is not feasible in healthy children from families with BHDS; thus, the age at which the lung cysts start to develop is unknown. ## Renal Cysts and Tumors Renal tumors associated with BHDS tend to be bilateral and multifocal, but isolated tumors are also common. The reported overall prevalence of renal tumors among individuals with a germline The most typical renal tumor in BHDS is a hybrid of oncocytoma and chromophobe histologic cell types, the so-called oncocytic hybrid tumor or hybrid oncocytoma/chromophobe tumor. It has been previously described as the most common tumor type in BHDS, but this could be an ascertainment artifact. Other common renal tumor types are clear cell carcinoma and oncocytoma; papillary carcinoma is less common. Discordance of histologic subtypes in bilateral and multifocal tumors is common. Multifocal renal oncocytosis, a rare pathologic condition characterized by numerous oncocytic nodules, is found in the renal parenchyma surrounding tumors in 50%-58% of individuals with BHDS [ ## Other Findings ## Genotype-Phenotype Correlations No genotype-phenotype correlations for ## Penetrance Based on the three major clinical manifestations, penetrance of BHDS is considered to be very high. Up to 97% of individuals with a heterozygous germline ## Nomenclature Hornstein-Knickenberg syndrome, which describes familial multiple perifollicular fibromas and fibromata pendulantia [ ## Prevalence More than 1,000 affected families from various populations have been described. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genes of interest in the differential diagnosis of Birt-Hogg-Dubé syndrome (BHDS) are listed in Genes of Interest in the Differential Diagnosis of Birt-Hogg-Dubé Syndrome AD = autosomal dominant; AR = autosomal recessive; BHDS = Birt-Hogg-Dubé syndrome; CNS = central nervous system; MOI = mode of inheritance; RCC = renal cell carcinoma Fibrofolliculomas are rare and specific for BHDS. Because fibrofolliculomas are clinically similar to various cutaneous lesions, histologic diagnosis is required. Acrochordons, or skin tags, are nonspecific and are found in the general population. Multiple familial trichoepithelioma 1 is caused by pathogenic variants in Alpha-1 antitrypsin deficiency is inherited in an autosomal codominant manner. Most syndromes with an increased risk of renal cancer are associated with renal pathology that is distinct from that seen in individuals with BHDS-related renal tumors [ ## Management The following recommendations are based on published practice guidelines [ To establish the extent of disease and needs in an individual diagnosed with BHDS, the evaluations summarized in Birt-Hogg-Dubé Syndrome: Recommended Evaluations Following Initial Diagnosis In adults at diagnosis Note: Persons w/manifestations of pneumothorax should immediately undergo chest radiograph & chest CT. BHDS = Birt-Hogg-Dubé syndrome; HRCT = high-resolution computed tomography; MOI = mode of inheritance 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 Birt-Hogg-Dubé Syndrome: Treatment of Manifestations Fibrofolliculomas are benign lesions for which no treatment is required; however, affected persons may seek treatment for cosmetic purposes, particularly for facial lesions. Surgical & laser treatment can provide temporary improvement, but lesions often recur. Often no treatment is needed. Some persons develop mild signs of airway obstruction, which are treated conservatively. It is crucial to detect renal tumors before they exceed 3.0 cm in diameter because nephron-sparing surgery is the treatment of choice whenever possible, depending on size & location of tumors. It has been previously reported that renal tumors in BHDS tend to be slow growing & metastasize late. This is most likely not accurate for all tumor subtypes, & metastatic disease has been reported in several persons. BHDS = Birt-Hogg-Dubé syndrome The recommendations summarized in Birt-Hogg-Dubé Syndrome: Recommended Surveillance Assess for pulmonary signs/symptoms of lung cysts / pneumothorax. Discuss avoidance of activities that might ↑ pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving) Only as needed No routine screening in those w/o signs/symptoms to avoid cumulative radiation exposure Abdominal/pelvic MRI is optimal. Abdominal/pelvic CT w/contrast (if MRI is not an option) Annually starting at age 20 yrs Continue annually in those w/suspicious lesion(s) (<1.0 cm in diameter, indeterminate lesion, or complex cysts) In those w/o family history of renal tumors, after 2-3 consecutive normal MRIs, continue screening every 2 yrs The use of renal ultrasound examination is helpful in further characterization of kidney lesions but should not be used as a primary screening modality due to its unreliability in detecting tumors <3 cm in diameter [ The long-term effect of cumulative radiation exposure in individuals with BHDS is unknown and has not been studied. Surveillance can start earlier in those with a family history of renal tumors before age 30 years. According to the 3 cm rule used by surgeons in treating renal tumors [ Avoid the following: Cigarette smoking High ambient pressures, which may precipitate spontaneous pneumothorax. Air travel increases pneumothorax risk [ Radiation exposure It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with BHDS in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: Molecular genetic testing if the familial Screening for lung cysts, fibrofolliculomas, and trichodiscomas if the pathogenic variant in the family is not known. Genetic testing should be considered in family members of a proband with BHDS starting at age 18 years [ See Search • In adults at diagnosis • Note: Persons w/manifestations of pneumothorax should immediately undergo chest radiograph & chest CT. • Fibrofolliculomas are benign lesions for which no treatment is required; however, affected persons may seek treatment for cosmetic purposes, particularly for facial lesions. • Surgical & laser treatment can provide temporary improvement, but lesions often recur. • Often no treatment is needed. • Some persons develop mild signs of airway obstruction, which are treated conservatively. • It is crucial to detect renal tumors before they exceed 3.0 cm in diameter because nephron-sparing surgery is the treatment of choice whenever possible, depending on size & location of tumors. • It has been previously reported that renal tumors in BHDS tend to be slow growing & metastasize late. This is most likely not accurate for all tumor subtypes, & metastatic disease has been reported in several persons. • Assess for pulmonary signs/symptoms of lung cysts / pneumothorax. • Discuss avoidance of activities that might ↑ pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving) • Only as needed • No routine screening in those w/o signs/symptoms to avoid cumulative radiation exposure • Abdominal/pelvic MRI is optimal. • Abdominal/pelvic CT w/contrast (if MRI is not an option) • Annually starting at age 20 yrs • Continue annually in those w/suspicious lesion(s) (<1.0 cm in diameter, indeterminate lesion, or complex cysts) • In those w/o family history of renal tumors, after 2-3 consecutive normal MRIs, continue screening every 2 yrs • Cigarette smoking • High ambient pressures, which may precipitate spontaneous pneumothorax. Air travel increases pneumothorax risk [ • Radiation exposure • Molecular genetic testing if the familial • Screening for lung cysts, fibrofolliculomas, and trichodiscomas if the pathogenic variant in the family is not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with BHDS, the evaluations summarized in Birt-Hogg-Dubé Syndrome: Recommended Evaluations Following Initial Diagnosis In adults at diagnosis Note: Persons w/manifestations of pneumothorax should immediately undergo chest radiograph & chest CT. BHDS = Birt-Hogg-Dubé syndrome; HRCT = high-resolution computed tomography; MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • In adults at diagnosis • Note: Persons w/manifestations of pneumothorax should immediately undergo chest radiograph & chest CT. ## 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 Birt-Hogg-Dubé Syndrome: Treatment of Manifestations Fibrofolliculomas are benign lesions for which no treatment is required; however, affected persons may seek treatment for cosmetic purposes, particularly for facial lesions. Surgical & laser treatment can provide temporary improvement, but lesions often recur. Often no treatment is needed. Some persons develop mild signs of airway obstruction, which are treated conservatively. It is crucial to detect renal tumors before they exceed 3.0 cm in diameter because nephron-sparing surgery is the treatment of choice whenever possible, depending on size & location of tumors. It has been previously reported that renal tumors in BHDS tend to be slow growing & metastasize late. This is most likely not accurate for all tumor subtypes, & metastatic disease has been reported in several persons. BHDS = Birt-Hogg-Dubé syndrome • Fibrofolliculomas are benign lesions for which no treatment is required; however, affected persons may seek treatment for cosmetic purposes, particularly for facial lesions. • Surgical & laser treatment can provide temporary improvement, but lesions often recur. • Often no treatment is needed. • Some persons develop mild signs of airway obstruction, which are treated conservatively. • It is crucial to detect renal tumors before they exceed 3.0 cm in diameter because nephron-sparing surgery is the treatment of choice whenever possible, depending on size & location of tumors. • It has been previously reported that renal tumors in BHDS tend to be slow growing & metastasize late. This is most likely not accurate for all tumor subtypes, & metastatic disease has been reported in several persons. ## Surveillance The recommendations summarized in Birt-Hogg-Dubé Syndrome: Recommended Surveillance Assess for pulmonary signs/symptoms of lung cysts / pneumothorax. Discuss avoidance of activities that might ↑ pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving) Only as needed No routine screening in those w/o signs/symptoms to avoid cumulative radiation exposure Abdominal/pelvic MRI is optimal. Abdominal/pelvic CT w/contrast (if MRI is not an option) Annually starting at age 20 yrs Continue annually in those w/suspicious lesion(s) (<1.0 cm in diameter, indeterminate lesion, or complex cysts) In those w/o family history of renal tumors, after 2-3 consecutive normal MRIs, continue screening every 2 yrs The use of renal ultrasound examination is helpful in further characterization of kidney lesions but should not be used as a primary screening modality due to its unreliability in detecting tumors <3 cm in diameter [ The long-term effect of cumulative radiation exposure in individuals with BHDS is unknown and has not been studied. Surveillance can start earlier in those with a family history of renal tumors before age 30 years. According to the 3 cm rule used by surgeons in treating renal tumors [ • Assess for pulmonary signs/symptoms of lung cysts / pneumothorax. • Discuss avoidance of activities that might ↑ pneumothorax risk (e.g., working as a pilot, flying in unpressurized aircraft, diving) • Only as needed • No routine screening in those w/o signs/symptoms to avoid cumulative radiation exposure • Abdominal/pelvic MRI is optimal. • Abdominal/pelvic CT w/contrast (if MRI is not an option) • Annually starting at age 20 yrs • Continue annually in those w/suspicious lesion(s) (<1.0 cm in diameter, indeterminate lesion, or complex cysts) • In those w/o family history of renal tumors, after 2-3 consecutive normal MRIs, continue screening every 2 yrs ## Agents/Circumstances to Avoid Avoid the following: Cigarette smoking High ambient pressures, which may precipitate spontaneous pneumothorax. Air travel increases pneumothorax risk [ Radiation exposure • Cigarette smoking • High ambient pressures, which may precipitate spontaneous pneumothorax. Air travel increases pneumothorax risk [ • Radiation exposure ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic at-risk sibs, parents, and relatives of individuals with BHDS in order to identify as early as possible those who would benefit from prompt initiation of treatment and preventive measures. Evaluations can include: Molecular genetic testing if the familial Screening for lung cysts, fibrofolliculomas, and trichodiscomas if the pathogenic variant in the family is not known. Genetic testing should be considered in family members of a proband with BHDS starting at age 18 years [ See • Molecular genetic testing if the familial • Screening for lung cysts, fibrofolliculomas, and trichodiscomas if the pathogenic variant in the family is not known. ## Therapies Under Investigation Search ## Genetic Counseling Birt-Hogg-Dubé syndrome (BHDS) is inherited in an autosomal dominant manner. Most individuals diagnosed with BHDS have an affected parent. Some individuals diagnosed with BHDS have the disorder as a result of a If 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 gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) If a molecular diagnosis has not been established in the proband, the parents should be offered screening for common BHDS manifestations (i.e., lung cysts, fibrofolliculomas, and trichodiscomas). If a parent of a proband is clinically affected and/or is known to have the The degree of clinical severity in sibs who inherit an If the proband has a known If the parents are clinically unaffected but their genetic status is known, sibs are still presumed to be at increased risk for BHDS because of the possibility of reduced penetrance in a parent and the possibility of parental gonadal mosaicism. See Management, Predictive testing for at-risk family members is possible once an Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Individuals who have the In a family with an established diagnosis of BHDS, 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 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 BHDS have an affected parent. • Some individuals diagnosed with BHDS have the disorder as a result of a • If 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 gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) • If a molecular diagnosis has not been established in the proband, the parents should be offered screening for common BHDS manifestations (i.e., lung cysts, fibrofolliculomas, and trichodiscomas). • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) • If a parent of a proband is clinically affected and/or is known to have the • The degree of clinical severity in sibs who inherit an • If the proband has a known • If the parents are clinically unaffected but their genetic status is known, sibs are still presumed to be at increased risk for BHDS because of the possibility of reduced penetrance in a parent and the possibility of parental gonadal mosaicism. • Predictive testing for at-risk family members is possible once an • Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Individuals who 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 young adults who are affected or at risk. ## Mode of Inheritance Birt-Hogg-Dubé syndrome (BHDS) is inherited in an autosomal dominant manner. ## Risk to Family Members Most individuals diagnosed with BHDS have an affected parent. Some individuals diagnosed with BHDS have the disorder as a result of a If 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 gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) If a molecular diagnosis has not been established in the proband, the parents should be offered screening for common BHDS manifestations (i.e., lung cysts, fibrofolliculomas, and trichodiscomas). If a parent of a proband is clinically affected and/or is known to have the The degree of clinical severity in sibs who inherit an If the proband has a known If the parents are clinically unaffected but their genetic status is known, sibs are still presumed to be at increased risk for BHDS because of the possibility of reduced penetrance in a parent and the possibility of parental gonadal mosaicism. • Most individuals diagnosed with BHDS have an affected parent. • Some individuals diagnosed with BHDS have the disorder as a result of a • If 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 gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) • If a molecular diagnosis has not been established in the proband, the parents should be offered screening for common BHDS manifestations (i.e., lung cysts, fibrofolliculomas, and trichodiscomas). • The proband has a • The proband inherited a pathogenic variant from a parent with gonadal (or somatic and gonadal) mosaicism. (Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ [gonadal] cells only.) • If a parent of a proband is clinically affected and/or is known to have the • The degree of clinical severity in sibs who inherit an • If the proband has a known • If the parents are clinically unaffected but their genetic status is known, sibs are still presumed to be at increased risk for BHDS because of the possibility of reduced penetrance in a parent and the possibility of parental gonadal mosaicism. ## Related Genetic Counseling Issues See Management, Predictive testing for at-risk family members is possible once an Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Individuals who have the In a family with an established diagnosis of BHDS, 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 family members is possible once an • Molecular genetic testing of at-risk family members is appropriate in order to identify the need for continued lifelong clinical surveillance. Individuals who 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 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 London United Kingdom • • London • United Kingdom • • • • • ## Molecular Genetics Birt-Hogg-Dube Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Birt-Hogg-Dube Syndrome ( The tumor suppressor gene responsible for Birt-Hogg-Dubé syndrome (BHDS), Variants listed in the table have been provided by the authors. ## Molecular Pathogenesis The tumor suppressor gene responsible for Birt-Hogg-Dubé syndrome (BHDS), Variants listed in the table have been provided by the authors. ## Chapter Notes Manop Pithukpakorn, MD; Mahidol University (2006-2008)Elke C Sattler, MD (2020-present)Ortrud K Steinlein, MD (2020-present)Jorge R Toro, MD; National Cancer Institute, NIH (2006-2020) 5 December 2024 (sw) Comprehensive update posted live 30 January 2020 (sw) Comprehensive update posted live 7 August 2014 (me) Comprehensive update posted live 9 September 2008 (me) Comprehensive update posted live 27 February 2006 (me) Review posted live 30 November 2005 (jt) Original submission • 5 December 2024 (sw) Comprehensive update posted live • 30 January 2020 (sw) Comprehensive update posted live • 7 August 2014 (me) Comprehensive update posted live • 9 September 2008 (me) Comprehensive update posted live • 27 February 2006 (me) Review posted live • 30 November 2005 (jt) Original submission ## Author History Manop Pithukpakorn, MD; Mahidol University (2006-2008)Elke C Sattler, MD (2020-present)Ortrud K Steinlein, MD (2020-present)Jorge R Toro, MD; National Cancer Institute, NIH (2006-2020) ## Revision History 5 December 2024 (sw) Comprehensive update posted live 30 January 2020 (sw) Comprehensive update posted live 7 August 2014 (me) Comprehensive update posted live 9 September 2008 (me) Comprehensive update posted live 27 February 2006 (me) Review posted live 30 November 2005 (jt) Original submission • 5 December 2024 (sw) Comprehensive update posted live • 30 January 2020 (sw) Comprehensive update posted live • 7 August 2014 (me) Comprehensive update posted live • 9 September 2008 (me) Comprehensive update posted live • 27 February 2006 (me) Review posted live • 30 November 2005 (jt) Original submission ## References American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003. • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available ## Published Guidelines / Consensus Statements American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003. American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. 2003. • American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available ## Literature Cited	[]	27/2/2006	5/12/2024		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bietti-cd	bietti-cd	[ "Bietti Crystalline Corneoretinal Dystrophy", "Bietti Crystalline Retinopathy", "Bietti Crystalline Retinopathy", "Bietti Crystalline Corneoretinal Dystrophy", "Cytochrome P450 4V2", "CYP4V2", "Bietti Crystalline Dystrophy" ]	Bietti Crystalline Dystrophy	Mauricio Vargas, Amanda Mitchell, Paul Yang, Richard Weleber	Summary Bietti crystalline dystrophy (BCD) is a chorioretinal degeneration characterized by the presence of yellow-white crystals and/or complex lipid deposits in the retina and (to a variable degree) the cornea. Progressive atrophy and degeneration of the retinal pigment epithelium (RPE) / choroid lead to symptoms similar to those of other forms of retinal degeneration that fall under the category of retinitis pigmentosa and allied disorders, namely: reduced visual acuity, poor night vision, abnormal retinal electrophysiology, visual field loss, and often impaired color vision. Marked asymmetry between eyes is not uncommon. Onset is typically during the second to third decade of life, but ranges from the early teenage years to beyond the third decade. With time, loss of peripheral visual field, central acuity, or both result in legal blindness in most if not all affected individuals. The diagnosis of BCD is based on the finding of numerous small, glistening yellow-white retinal crystals associated with atrophy of the RPE, pigment clumps, and sclerosis of the choroidal vessels; variable crystalline deposits in the corneal limbus; varying degrees of rod and cone dysfunction on electroretinography; visual field defects; and reflective dots visualized by spectral domain optical coherence tomography. Identification of biallelic pathogenic variants in BCD 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.	## Diagnosis The diagnosis of BCD, a chorioretinal degeneration, is based on the clinical findings of the typical crystalline deposits in the cornea and retina. BCD is one of few ocular diseases for which the diagnosis can be made with a high degree of confidence by careful examination alone. Bietti crystalline dystrophy Visual field loss. Visual field defects are variable and correlate with atrophic lesions that can encroach on the central vision. Nyctalopia (i.e., night blindness) Reduction in visual acuity Numerous small, glistening yellow-white crystals scattered throughout the posterior pole may extend to the midperiphery; crystalline deposits may tend to diminish with advanced disease. Atrophy of the retinal pigment epithelium (RPE) and choriocapillaris Pigment clumping Sclerosis of the choroidal vessels Patchy hypofluorescent areas of RPE, choriocapillaris atrophy, and a generalized disturbance of the RPE seen on fluorescein angiography Spectral microscopy may be appropriate if corneal crystalline deposits are too subtle to detect on slit lamp examination. Crystalline deposits can be seen as hyper-reflective dots in the choriocapillaris on spectral domain OCT. Other reflective spots of various shapes (called retinal tubulation by The degeneration in BCD seen by OCT is most prominent in the outer retina, including the photoreceptor layer, but the degeneration is not uniformly distributed. The diagnosis of Bietti crystalline dystrophy 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 Bietti crystalline dystrophy is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Bietti crystalline dystrophy, 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 chorioretinal degeneration, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Bietti Crystalline Dystrophy 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 Pathogenic variants were identified in 95.4% (N=109) families or 93.6% of alleles [ In a study from Japan, eight probands were found to have mutation of 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 large deletion encompassing exon 8 was reported by A ~4-Mb deletion encompassing • Visual field loss. Visual field defects are variable and correlate with atrophic lesions that can encroach on the central vision. • Nyctalopia (i.e., night blindness) • Reduction in visual acuity • Numerous small, glistening yellow-white crystals scattered throughout the posterior pole may extend to the midperiphery; crystalline deposits may tend to diminish with advanced disease. • Atrophy of the retinal pigment epithelium (RPE) and choriocapillaris • Pigment clumping • Sclerosis of the choroidal vessels • Patchy hypofluorescent areas of RPE, choriocapillaris atrophy, and a generalized disturbance of the RPE seen on fluorescein angiography • For an introduction to multigene panels click ## Suggestive Findings Bietti crystalline dystrophy Visual field loss. Visual field defects are variable and correlate with atrophic lesions that can encroach on the central vision. Nyctalopia (i.e., night blindness) Reduction in visual acuity Numerous small, glistening yellow-white crystals scattered throughout the posterior pole may extend to the midperiphery; crystalline deposits may tend to diminish with advanced disease. Atrophy of the retinal pigment epithelium (RPE) and choriocapillaris Pigment clumping Sclerosis of the choroidal vessels Patchy hypofluorescent areas of RPE, choriocapillaris atrophy, and a generalized disturbance of the RPE seen on fluorescein angiography Spectral microscopy may be appropriate if corneal crystalline deposits are too subtle to detect on slit lamp examination. Crystalline deposits can be seen as hyper-reflective dots in the choriocapillaris on spectral domain OCT. Other reflective spots of various shapes (called retinal tubulation by The degeneration in BCD seen by OCT is most prominent in the outer retina, including the photoreceptor layer, but the degeneration is not uniformly distributed. • Visual field loss. Visual field defects are variable and correlate with atrophic lesions that can encroach on the central vision. • Nyctalopia (i.e., night blindness) • Reduction in visual acuity • Numerous small, glistening yellow-white crystals scattered throughout the posterior pole may extend to the midperiphery; crystalline deposits may tend to diminish with advanced disease. • Atrophy of the retinal pigment epithelium (RPE) and choriocapillaris • Pigment clumping • Sclerosis of the choroidal vessels • Patchy hypofluorescent areas of RPE, choriocapillaris atrophy, and a generalized disturbance of the RPE seen on fluorescein angiography ## Clinical Findings Visual field loss. Visual field defects are variable and correlate with atrophic lesions that can encroach on the central vision. Nyctalopia (i.e., night blindness) Reduction in visual acuity Numerous small, glistening yellow-white crystals scattered throughout the posterior pole may extend to the midperiphery; crystalline deposits may tend to diminish with advanced disease. Atrophy of the retinal pigment epithelium (RPE) and choriocapillaris Pigment clumping Sclerosis of the choroidal vessels Patchy hypofluorescent areas of RPE, choriocapillaris atrophy, and a generalized disturbance of the RPE seen on fluorescein angiography Spectral microscopy may be appropriate if corneal crystalline deposits are too subtle to detect on slit lamp examination. • Visual field loss. Visual field defects are variable and correlate with atrophic lesions that can encroach on the central vision. • Nyctalopia (i.e., night blindness) • Reduction in visual acuity • Numerous small, glistening yellow-white crystals scattered throughout the posterior pole may extend to the midperiphery; crystalline deposits may tend to diminish with advanced disease. • Atrophy of the retinal pigment epithelium (RPE) and choriocapillaris • Pigment clumping • Sclerosis of the choroidal vessels • Patchy hypofluorescent areas of RPE, choriocapillaris atrophy, and a generalized disturbance of the RPE seen on fluorescein angiography ## Electrophysiology ## Optical Coherence Tomography (OCT) Crystalline deposits can be seen as hyper-reflective dots in the choriocapillaris on spectral domain OCT. Other reflective spots of various shapes (called retinal tubulation by The degeneration in BCD seen by OCT is most prominent in the outer retina, including the photoreceptor layer, but the degeneration is not uniformly distributed. ## Establishing the Diagnosis The diagnosis of Bietti crystalline dystrophy 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 Bietti crystalline dystrophy is broad, individuals with the distinctive findings described in When the phenotypic and laboratory findings suggest the diagnosis of Bietti crystalline dystrophy, 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 chorioretinal degeneration, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Bietti Crystalline Dystrophy 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 Pathogenic variants were identified in 95.4% (N=109) families or 93.6% of alleles [ In a study from Japan, eight probands were found to have mutation of 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 large deletion encompassing exon 8 was reported by A ~4-Mb deletion encompassing • For an introduction to multigene panels click ## Option 1 When the phenotypic and laboratory findings suggest the diagnosis of Bietti crystalline dystrophy, 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 chorioretinal degeneration, If exome sequencing is not diagnostic, For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Bietti Crystalline Dystrophy 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 Pathogenic variants were identified in 95.4% (N=109) families or 93.6% of alleles [ In a study from Japan, eight probands were found to have mutation of 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 large deletion encompassing exon 8 was reported by A ~4-Mb deletion encompassing ## Clinical Characteristics Bietti crystalline dystrophy (BCD) is characerized by progressive chorioretinal degeneration with onset typically during the second to third decade of life (range: early teens to >3 The presenting symptom, rate of disease progression, and disease severity are also highly variable in BCD, even among those of the same age, within the same family, and with the same Persons with BCD may also have impaired color vision, particularly if the atrophic lesion encroaches on the fovea or cystoid macular edema is present. In early or milder stages of disease, affected individuals can drive a car; with time, however, loss of peripheral visual field and/or central acuity results in legal blindness in most if not all affected individuals. Whereas affected individuals typically have profound vision loss by the fifth or sixth decade of life, central acuity can be spared through late stages of the disease in some [ The crystalline deposits have been observed to diminish or even disappear in areas of severe chorioretinal atrophy as the disease progresses to later stages [ Fluorescein angiography reveals patchy hypofluorescent areas of RPE and choriocapillaris atrophy and a generalized disturbance of the RPE. Additional potential retinal complications of BCD include choroidal neovascularization [ If present, the deposits can usually be seen on slit lamp examination. However, some crystals may be so fine as to go undetected unless specifically and carefully sought; Although studies have shown that the ffERG responses appear to correlate well with stages of disease severity [ The ffERG can remain normal or near normal even in later stages of the disease. Normal ffERG responses can occur in individuals with BCD with severe atrophy of the RPE and choroid, suggesting that the neural retina may remain viable despite disruption of retinal lamination [ Regional forms of BCD that may have normal ffERGs have also been described [ This degree of variation of electrophysiology may be the result of testing at different stages of disease progression. This variability may also reflect variation in loss of function in the gene product, with alleles with residual function associated with greater retention of ffERG amplitudes. Using OCT, the integrity of the outer retinal structure can be visualized in individuals with BCD, including the hyper-reflective dots thought to represent the crystalline deposits. The majority of OCT studies report that the crystalline deposits appear to reside in the RPE-choriocapillaris complex [ In addition to the crystalline deposits, other reflective spots of various shapes (called retinal tubulation by The degeneration in BCD seen by OCT is most prominent in the outer retina, including the photoreceptor layer, but typically the degeneration is not uniformly distributed. A study of 125 individuals of Chinese ancestry with BCD showed that individuals who were compound heterozygous for the most common pathogenic variant Another study of 18 individuals of Chinese descent with BCD showed that those who were homozygous for The variant Of note, individuals without two identified pathogenic The high degree of clinical variability in BCD suggests the influence of factors other than the primary While BCD is generally considered to be a rare disease, it may be underdiagnosed. For example, in a study done by BCD appears to be more common in people of East Asian descent, particularly the Chinese and Japanese [ • Persons with BCD may also have impaired color vision, particularly if the atrophic lesion encroaches on the fovea or cystoid macular edema is present. • The ffERG can remain normal or near normal even in later stages of the disease. Normal ffERG responses can occur in individuals with BCD with severe atrophy of the RPE and choroid, suggesting that the neural retina may remain viable despite disruption of retinal lamination [ • Regional forms of BCD that may have normal ffERGs have also been described [ ## Clinical Description Bietti crystalline dystrophy (BCD) is characerized by progressive chorioretinal degeneration with onset typically during the second to third decade of life (range: early teens to >3 The presenting symptom, rate of disease progression, and disease severity are also highly variable in BCD, even among those of the same age, within the same family, and with the same Persons with BCD may also have impaired color vision, particularly if the atrophic lesion encroaches on the fovea or cystoid macular edema is present. In early or milder stages of disease, affected individuals can drive a car; with time, however, loss of peripheral visual field and/or central acuity results in legal blindness in most if not all affected individuals. Whereas affected individuals typically have profound vision loss by the fifth or sixth decade of life, central acuity can be spared through late stages of the disease in some [ The crystalline deposits have been observed to diminish or even disappear in areas of severe chorioretinal atrophy as the disease progresses to later stages [ Fluorescein angiography reveals patchy hypofluorescent areas of RPE and choriocapillaris atrophy and a generalized disturbance of the RPE. Additional potential retinal complications of BCD include choroidal neovascularization [ If present, the deposits can usually be seen on slit lamp examination. However, some crystals may be so fine as to go undetected unless specifically and carefully sought; Although studies have shown that the ffERG responses appear to correlate well with stages of disease severity [ The ffERG can remain normal or near normal even in later stages of the disease. Normal ffERG responses can occur in individuals with BCD with severe atrophy of the RPE and choroid, suggesting that the neural retina may remain viable despite disruption of retinal lamination [ Regional forms of BCD that may have normal ffERGs have also been described [ This degree of variation of electrophysiology may be the result of testing at different stages of disease progression. This variability may also reflect variation in loss of function in the gene product, with alleles with residual function associated with greater retention of ffERG amplitudes. Using OCT, the integrity of the outer retinal structure can be visualized in individuals with BCD, including the hyper-reflective dots thought to represent the crystalline deposits. The majority of OCT studies report that the crystalline deposits appear to reside in the RPE-choriocapillaris complex [ In addition to the crystalline deposits, other reflective spots of various shapes (called retinal tubulation by The degeneration in BCD seen by OCT is most prominent in the outer retina, including the photoreceptor layer, but typically the degeneration is not uniformly distributed. • Persons with BCD may also have impaired color vision, particularly if the atrophic lesion encroaches on the fovea or cystoid macular edema is present. • The ffERG can remain normal or near normal even in later stages of the disease. Normal ffERG responses can occur in individuals with BCD with severe atrophy of the RPE and choroid, suggesting that the neural retina may remain viable despite disruption of retinal lamination [ • Regional forms of BCD that may have normal ffERGs have also been described [ ## Genotype-Phenotype Correlations A study of 125 individuals of Chinese ancestry with BCD showed that individuals who were compound heterozygous for the most common pathogenic variant Another study of 18 individuals of Chinese descent with BCD showed that those who were homozygous for The variant Of note, individuals without two identified pathogenic The high degree of clinical variability in BCD suggests the influence of factors other than the primary ## Prevalence While BCD is generally considered to be a rare disease, it may be underdiagnosed. For example, in a study done by BCD appears to be more common in people of East Asian descent, particularly the Chinese and Japanese [ ## Genetically Related (Allelic) Disorders A single report identified pathogenic variants in A novel homozygous A common single-nucleotide variant (SNV) of ## Differential Diagnosis Crystalline deposits in the retina may be associated with the following: Sjögren-Larsson syndrome (OMIM Drug toxicity (e.g., tamoxifen, the anesthetic methoxyflurane, the oral tanning agent canthaxanthine) Drug abuse (talc retinopathy) • Sjögren-Larsson syndrome (OMIM • Drug toxicity (e.g., tamoxifen, the anesthetic methoxyflurane, the oral tanning agent canthaxanthine) • Drug abuse (talc retinopathy) ## Management To establish the extent of disease and needs of an individual diagnosed with Bietti crystalline dystrophy (BCD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Fundoscopic examination Full-field electroretinogram (ffERG) to establish a baseline Visual field testing (perimetry) to evaluate the degree of visual field constriction or presence of scotomas and to establish a baseline Optical coherence tomography to evaluate for complications such as choroidal neovascularization (CNV) or macular hole formation Consultation with a clinical geneticist and/or genetic counselor No specific treatment for BCD currently exists; however, affected individuals should be referred to services specific to those with vision impairment: Low-vision specialists can prescribe low-vision aids/devices to optimize remaining vision. State services for the blind or organizations/professionals trained to work with the visually impaired provide access to services related to employment, education, and counseling regarding the psychosocial adaptation to visual loss. Note: CNV is uncommon in BCD. Laser photocoagulation is not usually considered for CNV in inherited forms of retinal degeneration and has recently been superseded by the use of antivascular endothelial growth factor (anti-VEGF) therapy in a fashion similar to its use in age-related macular dystrophy. Ophthalmologic examination is recommended every one to two years to monitor disease progression. Examination should include visual field testing particularly as it relates to determination of driving eligibility and eligibility for government programs and/or disability. Affected individuals should be aware of the possibility of CNV and the option of self-monitoring using an Amsler grid under direction of their primary care ophthalmologist. See Search • Fundoscopic examination • Full-field electroretinogram (ffERG) to establish a baseline • Visual field testing (perimetry) to evaluate the degree of visual field constriction or presence of scotomas and to establish a baseline • Optical coherence tomography to evaluate for complications such as choroidal neovascularization (CNV) or macular hole formation • Consultation with a clinical geneticist and/or genetic counselor • Low-vision specialists can prescribe low-vision aids/devices to optimize remaining vision. • State services for the blind or organizations/professionals trained to work with the visually impaired provide access to services related to employment, education, and counseling regarding the psychosocial adaptation to visual loss. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs of an individual diagnosed with Bietti crystalline dystrophy (BCD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended: Fundoscopic examination Full-field electroretinogram (ffERG) to establish a baseline Visual field testing (perimetry) to evaluate the degree of visual field constriction or presence of scotomas and to establish a baseline Optical coherence tomography to evaluate for complications such as choroidal neovascularization (CNV) or macular hole formation Consultation with a clinical geneticist and/or genetic counselor • Fundoscopic examination • Full-field electroretinogram (ffERG) to establish a baseline • Visual field testing (perimetry) to evaluate the degree of visual field constriction or presence of scotomas and to establish a baseline • Optical coherence tomography to evaluate for complications such as choroidal neovascularization (CNV) or macular hole formation • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations No specific treatment for BCD currently exists; however, affected individuals should be referred to services specific to those with vision impairment: Low-vision specialists can prescribe low-vision aids/devices to optimize remaining vision. State services for the blind or organizations/professionals trained to work with the visually impaired provide access to services related to employment, education, and counseling regarding the psychosocial adaptation to visual loss. Note: CNV is uncommon in BCD. Laser photocoagulation is not usually considered for CNV in inherited forms of retinal degeneration and has recently been superseded by the use of antivascular endothelial growth factor (anti-VEGF) therapy in a fashion similar to its use in age-related macular dystrophy. • Low-vision specialists can prescribe low-vision aids/devices to optimize remaining vision. • State services for the blind or organizations/professionals trained to work with the visually impaired provide access to services related to employment, education, and counseling regarding the psychosocial adaptation to visual loss. ## Surveillance Ophthalmologic examination is recommended every one to two years to monitor disease progression. Examination should include visual field testing particularly as it relates to determination of driving eligibility and eligibility for government programs and/or disability. Affected individuals should be aware of the possibility of CNV and the option of self-monitoring using an Amsler grid under direction of their primary care ophthalmologist. ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Bietti crystalline dystrophy (BCD) 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 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 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 Bietti crystalline dystrophy (BCD) 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 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 31 Center Drive MSC 2510 Bethesda MD 20892-2510 211 West Wacker Drive Suite 1700 Chicago IL 60606 Ireland • • 31 Center Drive • MSC 2510 • Bethesda MD 20892-2510 • • • • • • • • • 211 West Wacker Drive • Suite 1700 • Chicago IL 60606 • • • Ireland • ## Molecular Genetics Bietti Crystalline Dystrophy: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Bietti Crystalline Dystrophy ( Though the biochemical basis of BCD remains unknown, findings suggest that BCD may result from a systemic abnormality in lipid metabolism. There also have been reports of a missing 32-kd fatty-acid binding protein with a high affinity for fatty acids: docosahexaenoic acid (DHA; 22:6n-3), α-linolenic acid (18:3n-3), and palmitic acid (16:0) in the lymphocytes of persons with BCD compared to controls [ Free fatty acid profiling revealed significantly altered fatty acid concentrations in the serum of persons with BCD: stearic acid (18:0) was elevated and oleic acid (18:1n-9) was lowered in persons with BCD compared to controls [ In addition to ocular tissues, transmission electron microscopy showed crystalline material of unknown lipid composition in lymphoblasts and fibroblasts of persons with BCD [ Several common variants are specific to geographic or ethnic backgrounds, such as c.802-8_810delinsGC in East Asian individuals, p.Met66Arg in individuals of South Asian ancestry, and p.Ile111Thr in European individuals [ The most frequent Two other disease-associated variants, c.1091-2A>G and c.1226-6_1235del16 (a deletion spanning the splice acceptor site for exon 9), result in skipping of exons 9 and 10, respectively [ Numerous disease-associated variants have been described. The majority of described variants are missense variants, while the remaining variants include nonsense variants, small insertions or deletions, and splicing defects. One large deletion encompassing exon 8 and an additional deletion including all of Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Skipping of exon 2, resulting in a frameshift in which the exon 1 sequence is followed by four novel amino acids and a premature terminating [ Skipping of exon 7, which encodes 62 amino acids [ Skipping of exon 9, which encodes 62 amino acids Skipping of exon 10, which encodes 60 amino acids [ Recent studies support a role for CYP4V2 function in controlling intracellular lipid metabolisms [ Exon-skipping pathogenic variants, namely c.802-8_810delinsGC, are associated with more severe forms of the disease than are pathogenic missense variants [ Defects in the catalytic function of this enzyme lead to altered fatty acid metabolism; the endogenous substrate(s) have yet to be identified. ## Molecular Pathogenesis Though the biochemical basis of BCD remains unknown, findings suggest that BCD may result from a systemic abnormality in lipid metabolism. There also have been reports of a missing 32-kd fatty-acid binding protein with a high affinity for fatty acids: docosahexaenoic acid (DHA; 22:6n-3), α-linolenic acid (18:3n-3), and palmitic acid (16:0) in the lymphocytes of persons with BCD compared to controls [ Free fatty acid profiling revealed significantly altered fatty acid concentrations in the serum of persons with BCD: stearic acid (18:0) was elevated and oleic acid (18:1n-9) was lowered in persons with BCD compared to controls [ In addition to ocular tissues, transmission electron microscopy showed crystalline material of unknown lipid composition in lymphoblasts and fibroblasts of persons with BCD [ Several common variants are specific to geographic or ethnic backgrounds, such as c.802-8_810delinsGC in East Asian individuals, p.Met66Arg in individuals of South Asian ancestry, and p.Ile111Thr in European individuals [ The most frequent Two other disease-associated variants, c.1091-2A>G and c.1226-6_1235del16 (a deletion spanning the splice acceptor site for exon 9), result in skipping of exons 9 and 10, respectively [ Numerous disease-associated variants have been described. The majority of described variants are missense variants, while the remaining variants include nonsense variants, small insertions or deletions, and splicing defects. One large deletion encompassing exon 8 and an additional deletion including all of Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Skipping of exon 2, resulting in a frameshift in which the exon 1 sequence is followed by four novel amino acids and a premature terminating [ Skipping of exon 7, which encodes 62 amino acids [ Skipping of exon 9, which encodes 62 amino acids Skipping of exon 10, which encodes 60 amino acids [ Recent studies support a role for CYP4V2 function in controlling intracellular lipid metabolisms [ Exon-skipping pathogenic variants, namely c.802-8_810delinsGC, are associated with more severe forms of the disease than are pathogenic missense variants [ Defects in the catalytic function of this enzyme lead to altered fatty acid metabolism; the endogenous substrate(s) have yet to be identified. ## References ## Literature Cited ## Chapter Notes Supported in part by a Center Grant from Foundation Fighting Blindness, Columbia, MD, and an unrestricted grant from Research to Prevent Blindness (New York, NY) Edward J Kelly, PhD; University of Washington School of Pharmacy (2012-2019)Amanda Mitchell, MS, CGC (2019-present)Krystle A Okialda, BS; University of Washington Department of Pharmaceutics (2012-2019)Niamh B Stover, MS, CGC; Banner Health (2012-2019)Mauricio Vargas, MD, PhD (2019-present)Richard Weleber, MD, DABMG, FACMG (2012-present)Paul Yang, MD, PhD (2019-present) 7 February 2019 (sw) Comprehensive update posted live 14 June 2012 (cd) Revision: prenatal testing available 12 April 2012 (me) Review posted live 31 October 2011 (ek) Original submission • 7 February 2019 (sw) Comprehensive update posted live • 14 June 2012 (cd) Revision: prenatal testing available • 12 April 2012 (me) Review posted live • 31 October 2011 (ek) Original submission ## Acknowledgments Supported in part by a Center Grant from Foundation Fighting Blindness, Columbia, MD, and an unrestricted grant from Research to Prevent Blindness (New York, NY) ## Author History Edward J Kelly, PhD; University of Washington School of Pharmacy (2012-2019)Amanda Mitchell, MS, CGC (2019-present)Krystle A Okialda, BS; University of Washington Department of Pharmaceutics (2012-2019)Niamh B Stover, MS, CGC; Banner Health (2012-2019)Mauricio Vargas, MD, PhD (2019-present)Richard Weleber, MD, DABMG, FACMG (2012-present)Paul Yang, MD, PhD (2019-present) ## Revision History 7 February 2019 (sw) Comprehensive update posted live 14 June 2012 (cd) Revision: prenatal testing available 12 April 2012 (me) Review posted live 31 October 2011 (ek) Original submission • 7 February 2019 (sw) Comprehensive update posted live • 14 June 2012 (cd) Revision: prenatal testing available • 12 April 2012 (me) Review posted live • 31 October 2011 (ek) Original submission	[ "GDN Astuti, V Sun, M Bauwens, D Zobor, BP Leroy, A Omar, B Jurklies, I Lopez, H Ren, V Yazar, C Hamel, U Kellner, B Wissinger, S Kohl, ED Baere, RWJ Collin, RK Koenekoop. 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biotin	biotin	[ "Late-Onset Multiple Carboxylase Deficiency", "Late-Onset Multiple Carboxylase Deficiency", "Biotinidase", "BTD", "Biotinidase Deficiency" ]	Biotinidase Deficiency	Barry Wolf	Summary Individuals with biotinidase deficiency who are diagnosed before they have developed symptoms (e.g., by newborn screening) and who are treated with biotin have normal development. Symptoms including seizures, developmental delay, cutaneous manifestations (skin rash, alopecia), optic atrophy, hearing loss, and respiratory problems occur only in those individuals with biotinidase deficiency prior to biotin treatment. Symptoms of untreated profound biotinidase deficiency (<10% mean normal serum biotinidase activity) usually appear between ages one week and ten years, typically with optic atrophy, hypotonia, seizures, hair loss, and skin rash. Affected children often have ataxia and developmental delay. Individuals with partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection. Some symptoms, such as feeding issues, cutaneous manifestations, and respiratory issues, usually resolve with biotin therapy, whereas other manifestations presenting prior to biotin treatment, such as optic atrophy, hearing loss, and developmental delay, may improve but are usually not completely reversible with the initiation of biotin therapy. Untreated adolescents and adults usually exhibit myelopathy and optic neuropathy and are often initially diagnosed with multiple sclerosis. Most of these individuals experience improvement in their symptoms with biotin supplementation. The diagnosis of biotinidase deficiency is established in a proband whose newborn screening or biochemical findings indicate multiple carboxylase deficiency based on EITHER of the following: Detection of deficient biotinidase enzyme activity in serum/plasma Identification of biallelic pathogenic variants in Biotinidase deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis No consensus clinical diagnostic criteria for biotinidase deficiency have been published. NBS for biotinidase deficiency is primarily based on either fluorescent or colorimetric tests for biotinidase activity on dried blood spots. Putative positive samples have biotinidase activities below cutoff values established by the respective screening laboratory. Confirmational testing requires follow-up measurement of biotinidase activity in serum/plasma. Note: False positive newborn screening test results may occur in premature infants and in samples placed in plastic prior to sufficient drying. If the follow-up biotinidase enzyme activity supports the diagnosis of biotinidase deficiency, additional molecular genetic testing is available (see Biotin supplementation should begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine if it is a true positive NBS result and to establish the diagnosis of biotinidase deficiency definitively. A symptomatic individual may have either atypical findings associated with partial biotinidase deficiency or untreated profound biotinidase deficiency resulting from any of the following: NBS not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result. Biotinidase deficiency Features more specific to untreated profound biotinidase deficiency: Eczematous skin rash Alopecia Conjunctivitis Candidiasis Ataxia Other features of untreated profound biotinidase deficiency: Seizures Hypotonia Respiratory problems including hyperventilation, laryngeal stridor, and apnea Developmental delay Hearing loss Vision problems such as optic atrophy Features of Metabolic ketolactic acidosis Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency [see Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic. Hyperammonemia (usually mildly elevated up to several hundred µmol/L of ammonia in plasma) The diagnosis of biotinidase deficiency Detection of deficient biotinidase enzyme activity in serum/plasma 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 [ Profound biotinidase deficiency: <10% mean normal serum biotinidase activity Partial biotinidase deficiency: 10%-30% of mean normal serum biotinidase activity Note: (1) With appropriate controls, biochemical testing is definitive for confirming the diagnosis. It is important that a normal unrelated control sample and samples from the parent(s) accompany the serum/plasma sample from the proband to the diagnostic laboratory for accurate interpretation of enzymatic results [ Note: Targeted analysis for the pathogenic c.1330G>C (p.Asp444His) and c.1368A>C (p.Gln456His) variants can be performed first in individuals of Amish ancestry (see Molecular Genetic Testing Used in Biotinidase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Almost all individuals with partial biotinidase deficiency have the pathogenic variant Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Two large • Features more specific to untreated profound biotinidase deficiency: • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Other features of untreated profound biotinidase deficiency: • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Features of • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Metabolic ketolactic acidosis • Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency [see • Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic. • Hyperammonemia (usually mildly elevated up to several hundred µmol/L of ammonia in plasma) • Detection of deficient biotinidase enzyme activity in serum/plasma • Identification of biallelic pathogenic (or likely pathogenic) variants in • Profound biotinidase deficiency: <10% mean normal serum biotinidase activity • Partial biotinidase deficiency: 10%-30% of mean normal serum biotinidase activity • Note: (1) With appropriate controls, biochemical testing is definitive for confirming the diagnosis. It is important that a normal unrelated control sample and samples from the parent(s) accompany the serum/plasma sample from the proband to the diagnostic laboratory for accurate interpretation of enzymatic results [ ## Suggestive Findings NBS for biotinidase deficiency is primarily based on either fluorescent or colorimetric tests for biotinidase activity on dried blood spots. Putative positive samples have biotinidase activities below cutoff values established by the respective screening laboratory. Confirmational testing requires follow-up measurement of biotinidase activity in serum/plasma. Note: False positive newborn screening test results may occur in premature infants and in samples placed in plastic prior to sufficient drying. If the follow-up biotinidase enzyme activity supports the diagnosis of biotinidase deficiency, additional molecular genetic testing is available (see Biotin supplementation should begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine if it is a true positive NBS result and to establish the diagnosis of biotinidase deficiency definitively. A symptomatic individual may have either atypical findings associated with partial biotinidase deficiency or untreated profound biotinidase deficiency resulting from any of the following: NBS not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result. Biotinidase deficiency Features more specific to untreated profound biotinidase deficiency: Eczematous skin rash Alopecia Conjunctivitis Candidiasis Ataxia Other features of untreated profound biotinidase deficiency: Seizures Hypotonia Respiratory problems including hyperventilation, laryngeal stridor, and apnea Developmental delay Hearing loss Vision problems such as optic atrophy Features of Metabolic ketolactic acidosis Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency [see Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic. Hyperammonemia (usually mildly elevated up to several hundred µmol/L of ammonia in plasma) • Features more specific to untreated profound biotinidase deficiency: • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Other features of untreated profound biotinidase deficiency: • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Features of • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Metabolic ketolactic acidosis • Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency [see • Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic. • Hyperammonemia (usually mildly elevated up to several hundred µmol/L of ammonia in plasma) ## Scenario 1: Abnormal Newborn Screening (NBS) Result NBS for biotinidase deficiency is primarily based on either fluorescent or colorimetric tests for biotinidase activity on dried blood spots. Putative positive samples have biotinidase activities below cutoff values established by the respective screening laboratory. Confirmational testing requires follow-up measurement of biotinidase activity in serum/plasma. Note: False positive newborn screening test results may occur in premature infants and in samples placed in plastic prior to sufficient drying. If the follow-up biotinidase enzyme activity supports the diagnosis of biotinidase deficiency, additional molecular genetic testing is available (see Biotin supplementation should begin immediately on receipt of an abnormal NBS result while additional testing is performed to determine if it is a true positive NBS result and to establish the diagnosis of biotinidase deficiency definitively. ## Scenario 2: Symptomatic Individual A symptomatic individual may have either atypical findings associated with partial biotinidase deficiency or untreated profound biotinidase deficiency resulting from any of the following: NBS not performed, false negative NBS result, caregivers not adherent to recommended treatment following a positive NBS result. Biotinidase deficiency Features more specific to untreated profound biotinidase deficiency: Eczematous skin rash Alopecia Conjunctivitis Candidiasis Ataxia Other features of untreated profound biotinidase deficiency: Seizures Hypotonia Respiratory problems including hyperventilation, laryngeal stridor, and apnea Developmental delay Hearing loss Vision problems such as optic atrophy Features of Metabolic ketolactic acidosis Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency [see Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic. Hyperammonemia (usually mildly elevated up to several hundred µmol/L of ammonia in plasma) • Features more specific to untreated profound biotinidase deficiency: • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Other features of untreated profound biotinidase deficiency: • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Features of • Eczematous skin rash • Alopecia • Conjunctivitis • Candidiasis • Ataxia • Seizures • Hypotonia • Respiratory problems including hyperventilation, laryngeal stridor, and apnea • Developmental delay • Hearing loss • Vision problems such as optic atrophy • Metabolic ketolactic acidosis • Organic aciduria (usually with the metabolites commonly seen in multiple carboxylase deficiency [see • Note: Urinary organic acids can be normal even in individuals with biotinidase deficiency who are symptomatic. • Hyperammonemia (usually mildly elevated up to several hundred µmol/L of ammonia in plasma) ## Establishing the Diagnosis The diagnosis of biotinidase deficiency Detection of deficient biotinidase enzyme activity in serum/plasma 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 [ Profound biotinidase deficiency: <10% mean normal serum biotinidase activity Partial biotinidase deficiency: 10%-30% of mean normal serum biotinidase activity Note: (1) With appropriate controls, biochemical testing is definitive for confirming the diagnosis. It is important that a normal unrelated control sample and samples from the parent(s) accompany the serum/plasma sample from the proband to the diagnostic laboratory for accurate interpretation of enzymatic results [ Note: Targeted analysis for the pathogenic c.1330G>C (p.Asp444His) and c.1368A>C (p.Gln456His) variants can be performed first in individuals of Amish ancestry (see Molecular Genetic Testing Used in Biotinidase Deficiency See See Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include missense, nonsense, and splice site variants and small intragenic deletions/insertions; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click Almost all individuals with partial biotinidase deficiency have the pathogenic variant Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Two large • Detection of deficient biotinidase enzyme activity in serum/plasma • Identification of biallelic pathogenic (or likely pathogenic) variants in • Profound biotinidase deficiency: <10% mean normal serum biotinidase activity • Partial biotinidase deficiency: 10%-30% of mean normal serum biotinidase activity • Note: (1) With appropriate controls, biochemical testing is definitive for confirming the diagnosis. It is important that a normal unrelated control sample and samples from the parent(s) accompany the serum/plasma sample from the proband to the diagnostic laboratory for accurate interpretation of enzymatic results [ ## Clinical Characteristics Individuals with biotinidase deficiency who are diagnosed before they have developed symptoms (e.g., by newborn screening) and who are treated with biotin have normal development [ Some children with biotinidase deficiency manifest only a single finding, whereas others exhibit multiple neurologic and cutaneous findings. Individuals with untreated partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection. One child with partial biotinidase deficiency who was not treated with biotin exhibited hypotonia, skin rash, and hair loss during an episode of gastroenteritis at approximately age six months. When treated with biotin, the symptoms resolved. Because newborn screening (NBS) was rapidly incorporated into all state programs in the United States and in many countries, the window of opportunity to study symptomatic children has been limited compared to that of many other inherited metabolic disorders. Symptomatic children, if treated early enough, may experience reversal of all of their symptoms with biotin treatment. The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in children who have alopecia. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between their onset and the initiation of treatment. Some treated children have rapidly achieved developmental milestones, whereas others have continued to show delays. Many symptomatic children who experienced developmental delay, optic atrophy, and/or hearing loss prior to biotin treatment may find that the degree of the problem becomes static (i.e., does not progress), but also does not completely resolve. Children identified by NBS and treated shortly after birth, some in their fourth decade, have had successful outcomes [ Early reported deaths in a few symptomatic individuals were due to severe metabolic compromise. Diagnosis of biotinidase deficiency and/or treatment with biotin was usually too late. Currently, such cases are fortunately rare due to NBS or to inclusion of the disorder in the differential diagnosis of symptomatic children. A normal life span is expected for both initially symptomatic children and those identified by NBS as long as they continue lifelong biotin supplementation. One death initially thought to be caused by sudden infant death syndrome was subsequently attributed to biotinidase deficiency [ Genotype-phenotype correlations are not well established. However, certain genotypes correlate with profound biotinidase deficiency and others with partial biotinidase deficiency. There is a single report from Turkey in which symptomatic individuals with pathogenic null variants predicted to lead to profound enzyme deficiency had hearing loss, whereas those who had some residual enzyme activity did not [ Most Those with absence of all biotinidase enzyme activity are likely to be at increased risk for earlier onset of symptoms. In one study, children with symptoms of profound biotinidase deficiency with null pathogenic variants were more likely to develop hearing loss than those with pathogenic missense variants, even if those with pathogenic missense variants were not treated for a period of time [ Almost all children with profound biotinidase deficiency become symptomatic or are at risk of becoming symptomatic if not treated. Several reports describe adults with profound biotinidase deficiency who have offspring who also have profound biotinidase deficiency identified by NBS but who have never had symptoms [ Profound and partial biotinidase deficiency is the accepted nomenclature for this disorder. Individuals with partial biotinidase deficiency were previously described as having late-onset or juvenile multiple or combined carboxylase deficiency. Biotinidase deficiency should not be confused with holocarboxylase synthetase deficiency (see Based on the results of worldwide screening of biotinidase deficiency [ One in 137,401 for profound biotinidase deficiency; One in 109,921 for partial biotinidase deficiency; One in 61,067 for the combined incidence of profound and partial biotinidase deficiency. The incidence of biotinidase deficiency is generally higher in populations with a high rate of consanguinity (e.g., Turkey, Saudi Arabia). The incidence appears to be increased in the Hispanic population [ Carrier frequency in the general population is approximately one in 120. • The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. • Hair growth returns over a period of weeks to months in children who have alopecia. • Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between their onset and the initiation of treatment. • Some treated children have rapidly achieved developmental milestones, whereas others have continued to show delays. • Many symptomatic children who experienced developmental delay, optic atrophy, and/or hearing loss prior to biotin treatment may find that the degree of the problem becomes static (i.e., does not progress), but also does not completely resolve. Children identified by NBS and treated shortly after birth, some in their fourth decade, have had successful outcomes [ • Most • Those with absence of all biotinidase enzyme activity are likely to be at increased risk for earlier onset of symptoms. • In one study, children with symptoms of profound biotinidase deficiency with null pathogenic variants were more likely to develop hearing loss than those with pathogenic missense variants, even if those with pathogenic missense variants were not treated for a period of time [ • One in 137,401 for profound biotinidase deficiency; • One in 109,921 for partial biotinidase deficiency; • One in 61,067 for the combined incidence of profound and partial biotinidase deficiency. ## Clinical Description Individuals with biotinidase deficiency who are diagnosed before they have developed symptoms (e.g., by newborn screening) and who are treated with biotin have normal development [ Some children with biotinidase deficiency manifest only a single finding, whereas others exhibit multiple neurologic and cutaneous findings. Individuals with untreated partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection. One child with partial biotinidase deficiency who was not treated with biotin exhibited hypotonia, skin rash, and hair loss during an episode of gastroenteritis at approximately age six months. When treated with biotin, the symptoms resolved. Because newborn screening (NBS) was rapidly incorporated into all state programs in the United States and in many countries, the window of opportunity to study symptomatic children has been limited compared to that of many other inherited metabolic disorders. Symptomatic children, if treated early enough, may experience reversal of all of their symptoms with biotin treatment. The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in children who have alopecia. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between their onset and the initiation of treatment. Some treated children have rapidly achieved developmental milestones, whereas others have continued to show delays. Many symptomatic children who experienced developmental delay, optic atrophy, and/or hearing loss prior to biotin treatment may find that the degree of the problem becomes static (i.e., does not progress), but also does not completely resolve. Children identified by NBS and treated shortly after birth, some in their fourth decade, have had successful outcomes [ Early reported deaths in a few symptomatic individuals were due to severe metabolic compromise. Diagnosis of biotinidase deficiency and/or treatment with biotin was usually too late. Currently, such cases are fortunately rare due to NBS or to inclusion of the disorder in the differential diagnosis of symptomatic children. A normal life span is expected for both initially symptomatic children and those identified by NBS as long as they continue lifelong biotin supplementation. One death initially thought to be caused by sudden infant death syndrome was subsequently attributed to biotinidase deficiency [ • The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. • Hair growth returns over a period of weeks to months in children who have alopecia. • Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between their onset and the initiation of treatment. • Some treated children have rapidly achieved developmental milestones, whereas others have continued to show delays. • Many symptomatic children who experienced developmental delay, optic atrophy, and/or hearing loss prior to biotin treatment may find that the degree of the problem becomes static (i.e., does not progress), but also does not completely resolve. Children identified by NBS and treated shortly after birth, some in their fourth decade, have had successful outcomes [ ## Untreated Profound Biotinidase Deficiency Some children with biotinidase deficiency manifest only a single finding, whereas others exhibit multiple neurologic and cutaneous findings. ## Untreated Partial Biotinidase Deficiency Individuals with untreated partial biotinidase deficiency (10%-30% of mean normal serum biotinidase activity) may develop symptoms only when stressed, such as during infection. One child with partial biotinidase deficiency who was not treated with biotin exhibited hypotonia, skin rash, and hair loss during an episode of gastroenteritis at approximately age six months. When treated with biotin, the symptoms resolved. ## Prognosis Because newborn screening (NBS) was rapidly incorporated into all state programs in the United States and in many countries, the window of opportunity to study symptomatic children has been limited compared to that of many other inherited metabolic disorders. Symptomatic children, if treated early enough, may experience reversal of all of their symptoms with biotin treatment. The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in children who have alopecia. Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between their onset and the initiation of treatment. Some treated children have rapidly achieved developmental milestones, whereas others have continued to show delays. Many symptomatic children who experienced developmental delay, optic atrophy, and/or hearing loss prior to biotin treatment may find that the degree of the problem becomes static (i.e., does not progress), but also does not completely resolve. Children identified by NBS and treated shortly after birth, some in their fourth decade, have had successful outcomes [ Early reported deaths in a few symptomatic individuals were due to severe metabolic compromise. Diagnosis of biotinidase deficiency and/or treatment with biotin was usually too late. Currently, such cases are fortunately rare due to NBS or to inclusion of the disorder in the differential diagnosis of symptomatic children. A normal life span is expected for both initially symptomatic children and those identified by NBS as long as they continue lifelong biotin supplementation. One death initially thought to be caused by sudden infant death syndrome was subsequently attributed to biotinidase deficiency [ • The biochemical abnormalities and seizures rapidly resolve after biotin treatment, followed by improvement of the cutaneous abnormalities. • Hair growth returns over a period of weeks to months in children who have alopecia. • Optic atrophy and hearing loss may be resistant to therapy, especially if a long period has elapsed between their onset and the initiation of treatment. • Some treated children have rapidly achieved developmental milestones, whereas others have continued to show delays. • Many symptomatic children who experienced developmental delay, optic atrophy, and/or hearing loss prior to biotin treatment may find that the degree of the problem becomes static (i.e., does not progress), but also does not completely resolve. Children identified by NBS and treated shortly after birth, some in their fourth decade, have had successful outcomes [ ## Genotype-Phenotype Correlations Genotype-phenotype correlations are not well established. However, certain genotypes correlate with profound biotinidase deficiency and others with partial biotinidase deficiency. There is a single report from Turkey in which symptomatic individuals with pathogenic null variants predicted to lead to profound enzyme deficiency had hearing loss, whereas those who had some residual enzyme activity did not [ Most Those with absence of all biotinidase enzyme activity are likely to be at increased risk for earlier onset of symptoms. In one study, children with symptoms of profound biotinidase deficiency with null pathogenic variants were more likely to develop hearing loss than those with pathogenic missense variants, even if those with pathogenic missense variants were not treated for a period of time [ • Most • Those with absence of all biotinidase enzyme activity are likely to be at increased risk for earlier onset of symptoms. • In one study, children with symptoms of profound biotinidase deficiency with null pathogenic variants were more likely to develop hearing loss than those with pathogenic missense variants, even if those with pathogenic missense variants were not treated for a period of time [ ## Penetrance Almost all children with profound biotinidase deficiency become symptomatic or are at risk of becoming symptomatic if not treated. Several reports describe adults with profound biotinidase deficiency who have offspring who also have profound biotinidase deficiency identified by NBS but who have never had symptoms [ ## Nomenclature Profound and partial biotinidase deficiency is the accepted nomenclature for this disorder. Individuals with partial biotinidase deficiency were previously described as having late-onset or juvenile multiple or combined carboxylase deficiency. Biotinidase deficiency should not be confused with holocarboxylase synthetase deficiency (see ## Prevalence Based on the results of worldwide screening of biotinidase deficiency [ One in 137,401 for profound biotinidase deficiency; One in 109,921 for partial biotinidase deficiency; One in 61,067 for the combined incidence of profound and partial biotinidase deficiency. The incidence of biotinidase deficiency is generally higher in populations with a high rate of consanguinity (e.g., Turkey, Saudi Arabia). The incidence appears to be increased in the Hispanic population [ Carrier frequency in the general population is approximately one in 120. • One in 137,401 for profound biotinidase deficiency; • One in 109,921 for partial biotinidase deficiency; • One in 61,067 for the combined incidence of profound and partial biotinidase deficiency. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Clinical features including vomiting, hypotonia, and seizures accompanied by metabolic ketolactic acidosis or mild hyperammonemia are often observed in inherited metabolic diseases. Individuals with biotinidase deficiency may exhibit clinical features that are misdiagnosed as other disorders (e.g., isolated carboxylase deficiency) before they are correctly identified [ Organic acid abnormalities in biotinidase deficiency and holocarboxylase synthetase deficiency are similar and may be reported as consistent with multiple carboxylase deficiency. However, the tandem mass spectroscopic methodology that is being incorporated into many newborn screening programs should identify metabolites that are consistent with multiple carboxylase deficiency. Because most children with holocarboxylase synthetase deficiency excrete these metabolites in the newborn period, the disorder should be identifiable using this technology. Definitive enzyme determinations are required to distinguish between biotinidase deficiency and holocarboxylase synthetase deficiency (see Inherited Metabolic Disorders in the Differential Diagnosis of Biotinidase Deficiency The symptoms of biotinidase deficiency & HLCS deficiency are similar & clinical differentiation is often difficult. Age of onset of symptoms may be useful for distinguishing between the disorders: HLCS deficiency usually presents age 3 mos; however, there are exceptions for both disorders. Lactic acid 3-hydroxyisovaleric acid 3-methylcrotonic acid 3-methylcrotonylglycine 3-hydroxy-propionic acid Methylcitric acid Normal biotinidase enzyme activity Deficient activities of the 3 mitochondrial carboxylases in extracts of fibroblasts that are incubated in medium containing only the biotin contributed by fetal calf serum (low biotin), whereas persons w/biotinidase deficiency have normal carboxylase activities in fibroblasts The activities of the carboxylases in fibroblasts of persons w/HLCS deficiency become near-normal to normal when cultured in medium supplemented w/biotin (high biotin). Seizures, lethargy, hypotonia, developmental delay Metabolic acidosis 3-methylcrotonic acid 3-methylcrotonylglycine 3-hydroxyisovaleric acid Deficient enzyme activity of 1 of the 3 mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts grown in low biotin-containing medium; & Normal activity of the other 2 carboxylases. Seizures, lethargy, hypotonia, developmental delay Metabolic acidosis, hyperammonemia Lactate 3-hydroxy-propionic acid Methylcitric acid Seizures, lethargy, hypotonia, developmental delay Lactic acidosis, hypoglycemia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked A trial of biotin can be useful for discriminating between the disorders. Biotinidase enzyme activity is normal in serum of individuals with holocarboxylase synthetase deficiency; therefore, the enzymatic assay of biotinidase activity used in newborn screening is specific for biotinidase deficiency and does not identify children with holocarboxylase synthetase deficiency. Sensorineural hearing loss (see Older children, adolescents, and adults ultimately found to have biotinidase deficiency often exhibit symptoms different from those of younger children with the disorder [ • The symptoms of biotinidase deficiency & HLCS deficiency are similar & clinical differentiation is often difficult. • Age of onset of symptoms may be useful for distinguishing between the disorders: HLCS deficiency usually presents age 3 mos; however, there are exceptions for both disorders. • Lactic acid • 3-hydroxyisovaleric acid • 3-methylcrotonic acid • 3-methylcrotonylglycine • 3-hydroxy-propionic acid • Methylcitric acid • Normal biotinidase enzyme activity • Deficient activities of the 3 mitochondrial carboxylases in extracts of fibroblasts that are incubated in medium containing only the biotin contributed by fetal calf serum (low biotin), whereas persons w/biotinidase deficiency have normal carboxylase activities in fibroblasts • The activities of the carboxylases in fibroblasts of persons w/HLCS deficiency become near-normal to normal when cultured in medium supplemented w/biotin (high biotin). • Seizures, lethargy, hypotonia, developmental delay • Metabolic acidosis • 3-methylcrotonic acid • 3-methylcrotonylglycine • 3-hydroxyisovaleric acid • Deficient enzyme activity of 1 of the 3 mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts grown in low biotin-containing medium; & • Normal activity of the other 2 carboxylases. • Seizures, lethargy, hypotonia, developmental delay • Metabolic acidosis, hyperammonemia • Lactate • 3-hydroxy-propionic acid • Methylcitric acid • Seizures, lethargy, hypotonia, developmental delay • Lactic acidosis, hypoglycemia ## Inherited Metabolic Disorders Organic acid abnormalities in biotinidase deficiency and holocarboxylase synthetase deficiency are similar and may be reported as consistent with multiple carboxylase deficiency. However, the tandem mass spectroscopic methodology that is being incorporated into many newborn screening programs should identify metabolites that are consistent with multiple carboxylase deficiency. Because most children with holocarboxylase synthetase deficiency excrete these metabolites in the newborn period, the disorder should be identifiable using this technology. Definitive enzyme determinations are required to distinguish between biotinidase deficiency and holocarboxylase synthetase deficiency (see Inherited Metabolic Disorders in the Differential Diagnosis of Biotinidase Deficiency The symptoms of biotinidase deficiency & HLCS deficiency are similar & clinical differentiation is often difficult. Age of onset of symptoms may be useful for distinguishing between the disorders: HLCS deficiency usually presents age 3 mos; however, there are exceptions for both disorders. Lactic acid 3-hydroxyisovaleric acid 3-methylcrotonic acid 3-methylcrotonylglycine 3-hydroxy-propionic acid Methylcitric acid Normal biotinidase enzyme activity Deficient activities of the 3 mitochondrial carboxylases in extracts of fibroblasts that are incubated in medium containing only the biotin contributed by fetal calf serum (low biotin), whereas persons w/biotinidase deficiency have normal carboxylase activities in fibroblasts The activities of the carboxylases in fibroblasts of persons w/HLCS deficiency become near-normal to normal when cultured in medium supplemented w/biotin (high biotin). Seizures, lethargy, hypotonia, developmental delay Metabolic acidosis 3-methylcrotonic acid 3-methylcrotonylglycine 3-hydroxyisovaleric acid Deficient enzyme activity of 1 of the 3 mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts grown in low biotin-containing medium; & Normal activity of the other 2 carboxylases. Seizures, lethargy, hypotonia, developmental delay Metabolic acidosis, hyperammonemia Lactate 3-hydroxy-propionic acid Methylcitric acid Seizures, lethargy, hypotonia, developmental delay Lactic acidosis, hypoglycemia AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked A trial of biotin can be useful for discriminating between the disorders. Biotinidase enzyme activity is normal in serum of individuals with holocarboxylase synthetase deficiency; therefore, the enzymatic assay of biotinidase activity used in newborn screening is specific for biotinidase deficiency and does not identify children with holocarboxylase synthetase deficiency. • The symptoms of biotinidase deficiency & HLCS deficiency are similar & clinical differentiation is often difficult. • Age of onset of symptoms may be useful for distinguishing between the disorders: HLCS deficiency usually presents age 3 mos; however, there are exceptions for both disorders. • Lactic acid • 3-hydroxyisovaleric acid • 3-methylcrotonic acid • 3-methylcrotonylglycine • 3-hydroxy-propionic acid • Methylcitric acid • Normal biotinidase enzyme activity • Deficient activities of the 3 mitochondrial carboxylases in extracts of fibroblasts that are incubated in medium containing only the biotin contributed by fetal calf serum (low biotin), whereas persons w/biotinidase deficiency have normal carboxylase activities in fibroblasts • The activities of the carboxylases in fibroblasts of persons w/HLCS deficiency become near-normal to normal when cultured in medium supplemented w/biotin (high biotin). • Seizures, lethargy, hypotonia, developmental delay • Metabolic acidosis • 3-methylcrotonic acid • 3-methylcrotonylglycine • 3-hydroxyisovaleric acid • Deficient enzyme activity of 1 of the 3 mitochondrial carboxylases in peripheral blood leukocytes (prior to biotin therapy) or in cultured fibroblasts grown in low biotin-containing medium; & • Normal activity of the other 2 carboxylases. • Seizures, lethargy, hypotonia, developmental delay • Metabolic acidosis, hyperammonemia • Lactate • 3-hydroxy-propionic acid • Methylcitric acid • Seizures, lethargy, hypotonia, developmental delay • Lactic acidosis, hypoglycemia ## Sensorineural Hearing Loss Sensorineural hearing loss (see ## Late-Onset Biotinidase Deficiency Older children, adolescents, and adults ultimately found to have biotinidase deficiency often exhibit symptoms different from those of younger children with the disorder [ ## Management No clinical practice guidelines for biotinidase deficiency have been published. However, When biotinidase deficiency is suspected during the diagnostic evaluation (i.e., due to decreased biotinidase activity on a newborn blood spot), biotin treatment should be initiated immediately. Biotinidase deficiency or other biotin-related disorders, such as holocarboxylase synthetase deficiency (see To establish the extent of disease and needs in an Biotinidase Deficiency: Recommended Evaluations Following Initial Diagnosis Detected by Newborn Screening in an Asymptomatic Infant To incl assessment for hypotonia & seizures Consider EEG if seizures are a concern. Community or Social work involvement for parental support MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Newborn hearing screening should not be used as a substitute for this hearing evaluation. To establish the extent of disease and needs in Biotinidase Deficiency: Recommended Evaluations Following Initial Diagnosis in a Symptomatic Individual To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. To incl assessment for hypotonia, ataxia, & seizures Consider EEG if seizures are a concern. To incl motor & feeding-speech eval Eval for early intervention service needs 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 biotinidase deficiency. Biotin therapy is lifelong. All individuals with profound biotinidase deficiency (<10% mean normal serum enzyme activity) and those with partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated with oral biotin in the free form as opposed to the bound form (see Note: (1) Over the years it has become important, especially during infancy, to ensure that the child is ingesting a uniform and complete dose of the biotin. Various methods for administration of biotin to assure the appropriate dosage have been described [ Biotinidase Deficiency: Targeted Treatment Biotin is usually dispensed as a tablet or a capsule (most of which is filler: the quantity of biotin is minute relative to the quantity of filler). To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. Because there is no known toxicity for biotin, children w/partial biotinidase deficiency are usually treated. Different perspectives on biotin treatment exist; some centers treat partial biotinidase deficiency for only the first few months of life, while other centers do not treat partial biotinidase deficiency at all. The author recommends treatment for life [ More data are required to determine the dosage of biotin that is necessary for older children with either profound or partial biotinidase deficiency, but essentially all children have tolerated 10 mg/day of oral biotin with no side effects. Anecdotally, two girls with profound biotinidase deficiency developed hair loss during adolescence that resolved following an increase of their biotin dosages from 10 mg/day to 15 or 20 mg/day. There are no known adverse side effects from pharmacologic doses of biotin. Although biotin occasionally is dispensed as a solution or syrup, these liquid preparations are not recommended because the mixture – which is a suspension – tends to settle (especially upon refrigeration) and to grow bacteria upon storage. The liquid preparations usually do not provide a consistent dose and should not be added to milk in a bottle. The contents of the tablet or capsule should not be put into a bottle because the mixture will stick to the bottle and/or fail to pass through the nipple, thus delivering inconsistent doses. Only a few anecdotal reports exist regarding symptoms in children with partial biotinidase deficiency who were not treated with biotin. Note: High doses of biotin, such as that used to treat biotinidase deficiency, can interfere with laboratory tests that use biotin-streptavidin technologies [ Supportive care in Biotinidase Deficiency: Treatment of Manifestations in Symptomatic Individuals Hydration (typically intravenous) for dehydration Bicarbonate for acidosis Speech therapy, occupational therapy, & physical therapy may be beneficial, depending on specific needs. Consider referral to developmental specialist. Special education, incl IEP or 504 plans, may be considered. Children: through early intervention programs &/or school district Adults: Low vision clinic &/or community vision services / occupational therapy / mobility services Hearing aids may be helpful per otolaryngologist. In select instances, cochlear implants may be considered. Ensure appropriate social work involvement to connect families w/local resources& support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. IEP = individualized educational plan Although newborn screening for biotinidase deficiency has resulted in almost complete ascertainment of children with biotinidase deficiency in the United States and in many other countries, occasionally a child who has not been screened or has been mistakenly thought to have normal biotinidase activity on newborn screening will present with clinical symptoms. Individualized education plans (IEPs) are specific to the United States. An IEP provides specially designed instruction and related services to children who qualify. A 504 plan is specific to the United States (Section 504: a US federal statute that prohibits discrimination based on disability). It can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. Adherence to biotin therapy (see To monitor existing manifestations, the individual's response to targeted and supportive care, and the emergence of new manifestations, the evaluations summarized in Biotinidase Deficiency: Recommended Surveillance Annually for those w/profound biotinidase deficiency Every 2 yrs for those w/partial deficiency Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Annually for those w/profound biotinidase deficiency Every 2 yrs for those w/partial deficiency Measurement of biotin concentrations in blood or urine is not useful except to determine adherence to therapy. Raw eggs should be avoided because they contain avidin, an egg white protein that binds biotin, thus decreasing its bioavailability. However, thoroughly cooked eggs present no problem because heating inactivates avidin, rendering it incapable of binding biotin. See There have been females with profound biotinidase deficiency who are taking biotin therapy who have had normal pregnancies and offspring [ The only special pregnancy management considerations for a woman who is carrying a baby with biotinidase deficiency or is at risk of having a baby with biotinidase deficiency is consideration of biotin supplementation for the mother. An optimal prenatal dose has not been determined. See Search • To incl assessment for hypotonia & seizures • Consider EEG if seizures are a concern. • Community or • Social work involvement for parental support • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • To incl assessment for hypotonia, ataxia, & seizures • Consider EEG if seizures are a concern. • To incl motor & feeding-speech eval • Eval for early intervention service needs • Community or • Social work involvement for parental support • Biotin is usually dispensed as a tablet or a capsule (most of which is filler: the quantity of biotin is minute relative to the quantity of filler). • To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. • Because there is no known toxicity for biotin, children w/partial biotinidase deficiency are usually treated. • Different perspectives on biotin treatment exist; some centers treat partial biotinidase deficiency for only the first few months of life, while other centers do not treat partial biotinidase deficiency at all. The author recommends treatment for life [ • Hydration (typically intravenous) for dehydration • Bicarbonate for acidosis • Speech therapy, occupational therapy, & physical therapy may be beneficial, depending on specific needs. • Consider referral to developmental specialist. • Special education, incl IEP or 504 plans, may be considered. • Children: through early intervention programs &/or school district • Adults: Low vision clinic &/or community vision services / occupational therapy / mobility services • Hearing aids may be helpful per otolaryngologist. • In select instances, cochlear implants may be considered. • Ensure appropriate social work involvement to connect families w/local resources& support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. • Annually for those w/profound biotinidase deficiency • Every 2 yrs for those w/partial deficiency • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • Annually for those w/profound biotinidase deficiency • Every 2 yrs for those w/partial deficiency ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an Biotinidase Deficiency: Recommended Evaluations Following Initial Diagnosis Detected by Newborn Screening in an Asymptomatic Infant To incl assessment for hypotonia & seizures Consider EEG if seizures are a concern. Community or Social work involvement for parental support MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse Newborn hearing screening should not be used as a substitute for this hearing evaluation. To establish the extent of disease and needs in Biotinidase Deficiency: Recommended Evaluations Following Initial Diagnosis in a Symptomatic Individual To incl eval of aspiration risk & nutritional status Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. To incl assessment for hypotonia, ataxia, & seizures Consider EEG if seizures are a concern. To incl motor & feeding-speech eval Eval for early intervention service needs Community or Social work involvement for parental support MOI = mode of inheritance Medical geneticist, certified genetic counselor, certified advanced genetic nurse • To incl assessment for hypotonia & seizures • Consider EEG if seizures are a concern. • Community or • Social work involvement for parental support • To incl eval of aspiration risk & nutritional status • Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk. • To incl assessment for hypotonia, ataxia, & seizures • Consider EEG if seizures are a concern. • To incl motor & feeding-speech eval • Eval for early intervention service needs • Community or • Social work involvement for parental support ## Treatment of Manifestations There is no cure for biotinidase deficiency. Biotin therapy is lifelong. All individuals with profound biotinidase deficiency (<10% mean normal serum enzyme activity) and those with partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated with oral biotin in the free form as opposed to the bound form (see Note: (1) Over the years it has become important, especially during infancy, to ensure that the child is ingesting a uniform and complete dose of the biotin. Various methods for administration of biotin to assure the appropriate dosage have been described [ Biotinidase Deficiency: Targeted Treatment Biotin is usually dispensed as a tablet or a capsule (most of which is filler: the quantity of biotin is minute relative to the quantity of filler). To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. Because there is no known toxicity for biotin, children w/partial biotinidase deficiency are usually treated. Different perspectives on biotin treatment exist; some centers treat partial biotinidase deficiency for only the first few months of life, while other centers do not treat partial biotinidase deficiency at all. The author recommends treatment for life [ More data are required to determine the dosage of biotin that is necessary for older children with either profound or partial biotinidase deficiency, but essentially all children have tolerated 10 mg/day of oral biotin with no side effects. Anecdotally, two girls with profound biotinidase deficiency developed hair loss during adolescence that resolved following an increase of their biotin dosages from 10 mg/day to 15 or 20 mg/day. There are no known adverse side effects from pharmacologic doses of biotin. Although biotin occasionally is dispensed as a solution or syrup, these liquid preparations are not recommended because the mixture – which is a suspension – tends to settle (especially upon refrigeration) and to grow bacteria upon storage. The liquid preparations usually do not provide a consistent dose and should not be added to milk in a bottle. The contents of the tablet or capsule should not be put into a bottle because the mixture will stick to the bottle and/or fail to pass through the nipple, thus delivering inconsistent doses. Only a few anecdotal reports exist regarding symptoms in children with partial biotinidase deficiency who were not treated with biotin. Note: High doses of biotin, such as that used to treat biotinidase deficiency, can interfere with laboratory tests that use biotin-streptavidin technologies [ Supportive care in Biotinidase Deficiency: Treatment of Manifestations in Symptomatic Individuals Hydration (typically intravenous) for dehydration Bicarbonate for acidosis Speech therapy, occupational therapy, & physical therapy may be beneficial, depending on specific needs. Consider referral to developmental specialist. Special education, incl IEP or 504 plans, may be considered. Children: through early intervention programs &/or school district Adults: Low vision clinic &/or community vision services / occupational therapy / mobility services Hearing aids may be helpful per otolaryngologist. In select instances, cochlear implants may be considered. Ensure appropriate social work involvement to connect families w/local resources& support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. IEP = individualized educational plan Although newborn screening for biotinidase deficiency has resulted in almost complete ascertainment of children with biotinidase deficiency in the United States and in many other countries, occasionally a child who has not been screened or has been mistakenly thought to have normal biotinidase activity on newborn screening will present with clinical symptoms. Individualized education plans (IEPs) are specific to the United States. An IEP provides specially designed instruction and related services to children who qualify. A 504 plan is specific to the United States (Section 504: a US federal statute that prohibits discrimination based on disability). It can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Biotin is usually dispensed as a tablet or a capsule (most of which is filler: the quantity of biotin is minute relative to the quantity of filler). • To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. • Because there is no known toxicity for biotin, children w/partial biotinidase deficiency are usually treated. • Different perspectives on biotin treatment exist; some centers treat partial biotinidase deficiency for only the first few months of life, while other centers do not treat partial biotinidase deficiency at all. The author recommends treatment for life [ • Hydration (typically intravenous) for dehydration • Bicarbonate for acidosis • Speech therapy, occupational therapy, & physical therapy may be beneficial, depending on specific needs. • Consider referral to developmental specialist. • Special education, incl IEP or 504 plans, may be considered. • Children: through early intervention programs &/or school district • Adults: Low vision clinic &/or community vision services / occupational therapy / mobility services • Hearing aids may be helpful per otolaryngologist. • In select instances, cochlear implants may be considered. • Ensure appropriate social work involvement to connect families w/local resources& support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Targeted Therapy All individuals with profound biotinidase deficiency (<10% mean normal serum enzyme activity) and those with partial biotinidase deficiency (10%-30% of mean normal serum enzyme activity) should be treated with oral biotin in the free form as opposed to the bound form (see Note: (1) Over the years it has become important, especially during infancy, to ensure that the child is ingesting a uniform and complete dose of the biotin. Various methods for administration of biotin to assure the appropriate dosage have been described [ Biotinidase Deficiency: Targeted Treatment Biotin is usually dispensed as a tablet or a capsule (most of which is filler: the quantity of biotin is minute relative to the quantity of filler). To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. Because there is no known toxicity for biotin, children w/partial biotinidase deficiency are usually treated. Different perspectives on biotin treatment exist; some centers treat partial biotinidase deficiency for only the first few months of life, while other centers do not treat partial biotinidase deficiency at all. The author recommends treatment for life [ More data are required to determine the dosage of biotin that is necessary for older children with either profound or partial biotinidase deficiency, but essentially all children have tolerated 10 mg/day of oral biotin with no side effects. Anecdotally, two girls with profound biotinidase deficiency developed hair loss during adolescence that resolved following an increase of their biotin dosages from 10 mg/day to 15 or 20 mg/day. There are no known adverse side effects from pharmacologic doses of biotin. Although biotin occasionally is dispensed as a solution or syrup, these liquid preparations are not recommended because the mixture – which is a suspension – tends to settle (especially upon refrigeration) and to grow bacteria upon storage. The liquid preparations usually do not provide a consistent dose and should not be added to milk in a bottle. The contents of the tablet or capsule should not be put into a bottle because the mixture will stick to the bottle and/or fail to pass through the nipple, thus delivering inconsistent doses. Only a few anecdotal reports exist regarding symptoms in children with partial biotinidase deficiency who were not treated with biotin. Note: High doses of biotin, such as that used to treat biotinidase deficiency, can interfere with laboratory tests that use biotin-streptavidin technologies [ • Biotin is usually dispensed as a tablet or a capsule (most of which is filler: the quantity of biotin is minute relative to the quantity of filler). • To administer biotin to an infant or young child, the tablet can be crushed or the contents of the capsule can be mixed with breast milk or formula in a spoon, medicine dispenser, or syringe. • Because there is no known toxicity for biotin, children w/partial biotinidase deficiency are usually treated. • Different perspectives on biotin treatment exist; some centers treat partial biotinidase deficiency for only the first few months of life, while other centers do not treat partial biotinidase deficiency at all. The author recommends treatment for life [ ## Supportive Care Supportive care in Biotinidase Deficiency: Treatment of Manifestations in Symptomatic Individuals Hydration (typically intravenous) for dehydration Bicarbonate for acidosis Speech therapy, occupational therapy, & physical therapy may be beneficial, depending on specific needs. Consider referral to developmental specialist. Special education, incl IEP or 504 plans, may be considered. Children: through early intervention programs &/or school district Adults: Low vision clinic &/or community vision services / occupational therapy / mobility services Hearing aids may be helpful per otolaryngologist. In select instances, cochlear implants may be considered. Ensure appropriate social work involvement to connect families w/local resources& support. Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. IEP = individualized educational plan Although newborn screening for biotinidase deficiency has resulted in almost complete ascertainment of children with biotinidase deficiency in the United States and in many other countries, occasionally a child who has not been screened or has been mistakenly thought to have normal biotinidase activity on newborn screening will present with clinical symptoms. Individualized education plans (IEPs) are specific to the United States. An IEP provides specially designed instruction and related services to children who qualify. A 504 plan is specific to the United States (Section 504: a US federal statute that prohibits discrimination based on disability). It can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text. • Hydration (typically intravenous) for dehydration • Bicarbonate for acidosis • Speech therapy, occupational therapy, & physical therapy may be beneficial, depending on specific needs. • Consider referral to developmental specialist. • Special education, incl IEP or 504 plans, may be considered. • Children: through early intervention programs &/or school district • Adults: Low vision clinic &/or community vision services / occupational therapy / mobility services • Hearing aids may be helpful per otolaryngologist. • In select instances, cochlear implants may be considered. • Ensure appropriate social work involvement to connect families w/local resources& support. • Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies. ## Prevention of Primary Manifestations Adherence to biotin therapy (see ## Surveillance To monitor existing manifestations, the individual's response to targeted and supportive care, and the emergence of new manifestations, the evaluations summarized in Biotinidase Deficiency: Recommended Surveillance Annually for those w/profound biotinidase deficiency Every 2 yrs for those w/partial deficiency Monitor those w/seizures as clinically indicated. Assess for new manifestations such as seizures, changes in tone, & movement disorders. Annually for those w/profound biotinidase deficiency Every 2 yrs for those w/partial deficiency Measurement of biotin concentrations in blood or urine is not useful except to determine adherence to therapy. • Annually for those w/profound biotinidase deficiency • Every 2 yrs for those w/partial deficiency • Monitor those w/seizures as clinically indicated. • Assess for new manifestations such as seizures, changes in tone, & movement disorders. • Annually for those w/profound biotinidase deficiency • Every 2 yrs for those w/partial deficiency ## Agents/Circumstances to Avoid Raw eggs should be avoided because they contain avidin, an egg white protein that binds biotin, thus decreasing its bioavailability. However, thoroughly cooked eggs present no problem because heating inactivates avidin, rendering it incapable of binding biotin. ## Evaluation of Relatives at Risk See ## Pregnancy Management There have been females with profound biotinidase deficiency who are taking biotin therapy who have had normal pregnancies and offspring [ The only special pregnancy management considerations for a woman who is carrying a baby with biotinidase deficiency or is at risk of having a baby with biotinidase deficiency is consideration of biotin supplementation for the mother. An optimal prenatal dose has not been determined. See ## Therapies Under Investigation Search ## Genetic Counseling Biotinidase deficiency is inherited in an autosomal recessive manner. The parents of a child with biotinidase deficiency are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Sibs of an individual with biotinidase deficiency should be tested for the deficiency even if they do not exhibit symptoms (see Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has biotinidase deficiency or is a carrier (see Based on a carrier frequency of approximately one in 120 in the general population [ Note: Individuals with one profound or one partial biotinidase deficiency See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Two Differences in perspective may exist among medical professionals and in 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 biotinidase deficiency are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes 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 of an individual with biotinidase deficiency should be tested for the deficiency even if they do not exhibit symptoms (see • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has biotinidase deficiency or is a carrier (see • Based on a carrier frequency of approximately one in 120 in the general population [ • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Two ## Mode of Inheritance Biotinidase deficiency is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of a child with biotinidase deficiency are presumed to be heterozygous for a If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a One of the pathogenic variants identified in the proband occurred as a Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. Heterozygotes are asymptomatic and are not at risk of developing the disorder. If both parents are known to be heterozygous for a Sibs of an individual with biotinidase deficiency should be tested for the deficiency even if they do not exhibit symptoms (see Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. Unless an affected individual's reproductive partner also has biotinidase deficiency or is a carrier (see Based on a carrier frequency of approximately one in 120 in the general population [ • The parents of a child with biotinidase deficiency are presumed to be heterozygous for a • If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for a • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • One of the pathogenic variants identified in the proband occurred as a • Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband. • Heterozygotes 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 of an individual with biotinidase deficiency should be tested for the deficiency even if they do not exhibit symptoms (see • Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder. • Unless an affected individual's reproductive partner also has biotinidase deficiency or is a carrier (see • Based on a carrier frequency of approximately one in 120 in the general population [ ## Carrier Detection Note: Individuals with one profound or one partial biotinidase deficiency ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Two • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. • Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely and/or if both partners are of the same ethnic background. Two ## Prenatal Testing and Preimplantation Genetic Testing Differences in perspective may exist among medical professionals and in 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 Health Resources & Services Administration • • • • • • Health Resources & Services Administration • ## Molecular Genetics Biotinidase Deficiency: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Biotinidase Deficiency ( Biotinidase is a ubiquitously expressed enzyme essential for recycling the vitamin biotin, a water-soluble cofactor necessary for the function of several carboxylases. Biotinidase has been shown to have biotinyl-hydrolase and biotinyl-transferase activities. The enzyme is a monomeric sialylated glycoprotein with multiple isoforms resulting from differences in the degree of sialylation [ Selected Founder variant in Amish population [ Persons who are homozygous for this variant typically do not require treatment w/biotin. Variants listed in the table have been provided by the author. • Founder variant in Amish population [ • Persons who are homozygous for this variant typically do not require treatment w/biotin. ## Molecular Pathogenesis Biotinidase is a ubiquitously expressed enzyme essential for recycling the vitamin biotin, a water-soluble cofactor necessary for the function of several carboxylases. Biotinidase has been shown to have biotinyl-hydrolase and biotinyl-transferase activities. The enzyme is a monomeric sialylated glycoprotein with multiple isoforms resulting from differences in the degree of sialylation [ Selected Founder variant in Amish population [ Persons who are homozygous for this variant typically do not require treatment w/biotin. Variants listed in the table have been provided by the author. • Founder variant in Amish population [ • Persons who are homozygous for this variant typically do not require treatment w/biotin. ## Chapter Notes Dr Barry Wolf's laboratory was the first to describe biotinidase deficiency in individuals with late-onset multiple carboxylase deficiency and has characterized the clinical, biochemical, and molecular features of the disorder. They developed the method used to screen newborns for biotinidase deficiency and piloted the first newborn screening for the disorder. Safra Research Foundation at Henry Ford Hospital, Detroit, MI 25 May 2023 (ma) Comprehensive update posted live 9 June 2016 (bp) Comprehensive update posted live 5 December 2013 (me) Comprehensive update posted live 15 March 2011 Comprehensive update posted live 25 September 2008 (me) Comprehensive update posted live 2 March 2006 (me) Comprehensive update posted live 10 February 2005 (bw,cd) Revision: targeted mutation analysis clinically available 26 November 2003 (me) Comprehensive update posted live 27 September 2001 (me) Comprehensive update posted live 24 March 2000 (pb) Review posted live December 1999 (bw) Original submission • 25 May 2023 (ma) Comprehensive update posted live • 9 June 2016 (bp) Comprehensive update posted live • 5 December 2013 (me) Comprehensive update posted live • 15 March 2011 Comprehensive update posted live • 25 September 2008 (me) Comprehensive update posted live • 2 March 2006 (me) Comprehensive update posted live • 10 February 2005 (bw,cd) Revision: targeted mutation analysis clinically available • 26 November 2003 (me) Comprehensive update posted live • 27 September 2001 (me) Comprehensive update posted live • 24 March 2000 (pb) Review posted live • December 1999 (bw) Original submission ## Author Notes Dr Barry Wolf's laboratory was the first to describe biotinidase deficiency in individuals with late-onset multiple carboxylase deficiency and has characterized the clinical, biochemical, and molecular features of the disorder. They developed the method used to screen newborns for biotinidase deficiency and piloted the first newborn screening for the disorder. ## Acknowledgments Safra Research Foundation at Henry Ford Hospital, Detroit, MI ## Revision History 25 May 2023 (ma) Comprehensive update posted live 9 June 2016 (bp) Comprehensive update posted live 5 December 2013 (me) Comprehensive update posted live 15 March 2011 Comprehensive update posted live 25 September 2008 (me) Comprehensive update posted live 2 March 2006 (me) Comprehensive update posted live 10 February 2005 (bw,cd) Revision: targeted mutation analysis clinically available 26 November 2003 (me) Comprehensive update posted live 27 September 2001 (me) Comprehensive update posted live 24 March 2000 (pb) Review posted live December 1999 (bw) Original submission • 25 May 2023 (ma) Comprehensive update posted live • 9 June 2016 (bp) Comprehensive update posted live • 5 December 2013 (me) Comprehensive update posted live • 15 March 2011 Comprehensive update posted live • 25 September 2008 (me) Comprehensive update posted live • 2 March 2006 (me) Comprehensive update posted live • 10 February 2005 (bw,cd) Revision: targeted mutation analysis clinically available • 26 November 2003 (me) Comprehensive update posted live • 27 September 2001 (me) Comprehensive update posted live • 24 March 2000 (pb) Review posted live • December 1999 (bw) Original submission ## Key Sections in this ## References Strovel ET, Cowan TM, Scott AI, Wolf B. Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19. Available • Strovel ET, Cowan TM, Scott AI, Wolf B. Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19. Available ## Published Guidelines / Consensus Statements Strovel ET, Cowan TM, Scott AI, Wolf B. Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19. Available • Strovel ET, Cowan TM, Scott AI, Wolf B. Laboratory diagnosis of biotinidase deficiency, 2017 update: a technical standard and guideline of the American College of Medical Genetics and Genomics. Genet Med. 2017;19. Available ## Literature Cited The biotin cycle Free biotin enters the cycle from dietary sources or from the cleavage of biocytin or biotinyl-peptides by the action of biotinidase. The free biotin is then covalently attached to the various apocarboxylases, propionyl-CoA carboxylase (PCC), beta-methylcrotonyl-CoA carboxylase (MCC), pyruvate carboxylase (PC), and acetyl-CoA carboxylase (ACC) by the action of biotin holocarboxylase synthetase, thereby forming active holocarboxylases. The holocarboxylases are subsequently proteolyzed to biocytin and/or biotinyl-peptides, which are then further cleaved by biotinidase, thus recycling the biotin. The liberated biotin can then enter the free biotin pool. Isolated deficiencies of each of the carboxylases and deficiencies of both holocarboxylase synthetase and biotinidase can occur.	[]	24/3/2000	25/5/2023	10/2/2005	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bloom	bloom	[ "RecQ-like DNA helicase BLM", "BLM", "Bloom Syndrome" ]	Bloom Syndrome	Katherine Langer, Christopher M Cunniff, Nicole Kucine	Summary Bloom syndrome (BSyn) is characterized by severe pre- and postnatal growth deficiency, immune abnormalities, sensitivity to sunlight, insulin resistance, and a high risk for many cancers that occur at an early age. Despite their very small head circumference, most affected individuals have normal intellectual ability. Women may be fertile but often have early menopause, and men tend to be infertile, with only one confirmed case of paternity. Serious medical complications that are more common than in the general population and that also appear at unusually early ages include cancer of a wide variety of types and anatomic sites, diabetes mellitus as a result of insulin resistance, chronic obstructive pulmonary disease, and hypothyroidism. The diagnosis of BSyn is established in a proband with characteristic clinical features and biallelic pathogenic variants in BSyn is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a	## Diagnosis Bloom syndrome (BSyn) Prenatal-onset growth deficiency that usually affects linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population The diagnosis of BSyn Note: (1) An increased frequency of SCEs on specialized cytogenetic studies may be helpful in circumstances where 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 Bloom Syndrome See 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. • Prenatal-onset growth deficiency that usually affects linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood • Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution • Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population ## Suggestive Findings Bloom syndrome (BSyn) Prenatal-onset growth deficiency that usually affects linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population • Prenatal-onset growth deficiency that usually affects linear growth, weight gain, and head circumference and that persists into infancy, childhood, and adulthood • Moderate-to-severe growth deficiency and a sun-sensitive, erythematous rash that commonly involves the face and appears in a butterfly distribution • Moderate-to-severe growth deficiency and a diagnosis of cancer, usually occurring at an earlier age than in the general population ## Establishing the Diagnosis The diagnosis of BSyn Note: (1) An increased frequency of SCEs on specialized cytogenetic studies may be helpful in circumstances where 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 Bloom Syndrome See 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 For an introduction to multigene panels click ## Option 2 For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Bloom Syndrome See 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. ## Other Testing ## Clinical Characteristics The range of clinical features in persons with Bloom syndrome (BSyn) has been tracked through the The affected fetus is smaller than normal for gestational age. The mean birth weight of affected males is 1,760 g (range: 900-3,189 g) and of affected females, 1,754 g (range: 700-2,892 g). The average adult height of men is 149 cm (range: 128-164 cm) and of women, 138 cm (range: 115-160 cm). Plasma growth hormone concentration is normal. Growth hormone therapy has not consistently increased growth rate in most persons, but some have experienced improved linear growth. Subcutaneous adipose tissue is sparse throughout childhood and adolescence, but adults may develop central obesity. Providing increased calories in childhood and adolescence does not usually result in substantial changes in growth parameters, particularly linear growth. Studies of small cohorts have shown that supplemental feeding may result in increased fat deposition in individuals with BSyn. In addition, lipid profile abnormalities were identified in five of ten individuals tested [ Serial measurements of 136 individuals with BSyn (81 male, 55 female) showed that mean head circumference was below normal at all ages [ Additional dermatologic manifestations include cheilitis, blistering and fissuring of the lips, eyebrow and eyelash hair loss, alopecia areata, and vesicular and bullous lesions with excessive or intense sun exposure. Café au lait macules and areas of hypopigmented skin are more numerous and larger than in those without BSyn. Malignant Neoplasms Diagnosed in Persons in the Bloom Syndrome Registry (1954-2022) Adapted from GI = gastrointestinal; NA = not applicable No genotype-phenotype correlations have been identified. Few individuals with BSyn have been reported in the medical literature since its description half a century ago [ Although rare in all populations, BSyn is relatively less rare among individuals of Ashkenazi Jewish descent. The predominant ## Clinical Description The range of clinical features in persons with Bloom syndrome (BSyn) has been tracked through the The affected fetus is smaller than normal for gestational age. The mean birth weight of affected males is 1,760 g (range: 900-3,189 g) and of affected females, 1,754 g (range: 700-2,892 g). The average adult height of men is 149 cm (range: 128-164 cm) and of women, 138 cm (range: 115-160 cm). Plasma growth hormone concentration is normal. Growth hormone therapy has not consistently increased growth rate in most persons, but some have experienced improved linear growth. Subcutaneous adipose tissue is sparse throughout childhood and adolescence, but adults may develop central obesity. Providing increased calories in childhood and adolescence does not usually result in substantial changes in growth parameters, particularly linear growth. Studies of small cohorts have shown that supplemental feeding may result in increased fat deposition in individuals with BSyn. In addition, lipid profile abnormalities were identified in five of ten individuals tested [ Serial measurements of 136 individuals with BSyn (81 male, 55 female) showed that mean head circumference was below normal at all ages [ Additional dermatologic manifestations include cheilitis, blistering and fissuring of the lips, eyebrow and eyelash hair loss, alopecia areata, and vesicular and bullous lesions with excessive or intense sun exposure. Café au lait macules and areas of hypopigmented skin are more numerous and larger than in those without BSyn. Malignant Neoplasms Diagnosed in Persons in the Bloom Syndrome Registry (1954-2022) Adapted from GI = gastrointestinal; NA = not applicable ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been identified. ## Prevalence Few individuals with BSyn have been reported in the medical literature since its description half a century ago [ Although rare in all populations, BSyn is relatively less rare among individuals of Ashkenazi Jewish descent. The predominant ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis Genetic disorders of interest in the differential diagnosis of Bloom syndrome are listed in Genetic Disorders of Interest in the Differential Diagnosis of Bloom Syndrome To date, cancer not observed, but reported persons are all relatively young. No abnormal skin findings Small size Café au lait macules Small size Café au lait macules 1 person w/cervical cancer in early adulthood No malar rash Cardiomyopathy Small stature Evidence of excessive genomic instability Telangiectasias Sinopulmonary infection Immunodeficiency Progressive cerebellar ataxia from early childhood ↑ alpha-fetoprotein levels Small stature Evidence of excessive genomic instability ↑ cancer susceptibility Café au lait macules, hyper- or hypopigmentation ↓ fertility Endocrinopathy Skeletal malformations Bone marrow failure Small stature Evidence of excessive genomic instability Progressive cerebellar degeneration No telangiectasias or immunodeficiency Small stature Evidence of excessive genomic instability Immunodeficiency Café au lait macules Predisposition to lymphoid malignancy Decline in intellectual performance No telangiectasias Small stature Evidence of excessive genomic instability ↑ incidence of diabetes Premature atherosclerosis Prematurely aged appearance Small stature ↑ cancer susceptibility Alopecia Juvenile cataracts True poikiloderma (not sun-sensitive rash) Premature aging AD = autosomal dominant; AR = autosomal recessive; BSyn = Bloom syndrome; matUPD7 = maternal uniparental disomy for chromosome 7; MOI = mode of inheritance; SCE = sister-chromatid exchange; XL = X-linked Accurate assessment of Silver-Russell syndrome (SRS) recurrence risk requires identification of the causative genetic mechanism in the proband. In most families, a proband with SRS represents a simplex case and has SRS as the result of an apparent Listed genes represent the most common genetic causes of Fanconi anemia. For other genes associated with this phenotype, see Fanconi anemia (FA) can be inherited in an autosomal recessive manner, an autosomal dominant manner ( • To date, cancer not observed, but reported persons are all relatively young. • No abnormal skin findings • Small size • Café au lait macules • Small size • Café au lait macules • 1 person w/cervical cancer in early adulthood • No malar rash • Cardiomyopathy • Small stature • Evidence of excessive genomic instability • Telangiectasias • Sinopulmonary infection • Immunodeficiency • Progressive cerebellar ataxia from early childhood • ↑ alpha-fetoprotein levels • Small stature • Evidence of excessive genomic instability • ↑ cancer susceptibility • Café au lait macules, hyper- or hypopigmentation • ↓ fertility • Endocrinopathy • Skeletal malformations • Bone marrow failure • Small stature • Evidence of excessive genomic instability • Progressive cerebellar degeneration • No telangiectasias or immunodeficiency • Small stature • Evidence of excessive genomic instability • Immunodeficiency • Café au lait macules • Predisposition to lymphoid malignancy • Decline in intellectual performance • No telangiectasias • Small stature • Evidence of excessive genomic instability • ↑ incidence of diabetes • Premature atherosclerosis • Prematurely aged appearance • Small stature • ↑ cancer susceptibility • Alopecia • Juvenile cataracts • True poikiloderma (not sun-sensitive rash) • Premature aging ## Management Health supervision recommendations that address diagnosis, treatment, and surveillance for complications in persons with Bloom syndrome (BSyn) have been published [ To establish the extent of disease and needs in an individual diagnosed with BSyn, in addition to the routine medical history, family history, and physical examination, the evaluations summarized in Bloom Syndrome: Recommended Evaluations Following Initial Diagnosis Immunodeficiency screening incl immunoglobulin level, antibody responses to vaccines, & quantitative B & T lymphocytes Referral to immunologist as needed Men: semen analysis to assess for azoospermia, oligospermia, or asthenospermia Women: assessment for signs of early menopause Fasting blood glucose & hemoglobin A1c concentration Assessment for polyuria, polydipsia, weight loss BSyn = Bloom syndrome; MOI = mode of inheritance; TSH = thyroid-stimulating hormone Treatment recommendations for persons with BSyn have been published [ Bloom Syndrome: Treatment of Manifestations If GH is prescribed, growth response, serum IGF-1, & IGFBP-3 should be closely monitored. GH should be discontinued if growth velocity does not ↑ w/GH treatment. Standard treatment for feeding issues incl high-calorie diet Consider consultation w/gastroenterologist or feeding specialist. Reflux precautions & anti-reflux medications as needed Dietary treatment of dyslipidemia according to standard protocols ↓ excessive exposure to sunlight by seeking shade, particularly 10 am to 4 pm. Use sun-protective clothing, incl broad-brimmed hat. UV-blocking sunglasses Use broad-spectrum sunscreen w/SPF 30 2x daily, or every 2-3 hrs when outdoors. Standard treatments for precancerous lesions & skin cancers Mgmt per immunologist Recurrent infections & defects in humoral immunity: treatment w/immunoglobulins Physical, occupational, & speech therapy as needed Educational support as needed Family & teachers are encouraged to relate to persons w/BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. Modification of standard cancer treatment regimens, usually incl reduction of both dosage & duration Full weight-based dosing may be appropriate for some chemotherapeutic drugs (e.g., steroids, tyrosine kinase inhibitors). Nonmyeloablative transplantation is likely to be tolerated more than other regimens; required ablative therapy prior to HSCT may require modification of standard protocols because of hypersensitivity to DNA-damaging agents. HSCT has been performed in 3 persons w/leukemia in the Bloom Syndrome Registry. 1 person had >5 yrs disease-free survival before succumbing to another cancer; the other 2 died in immediate post-transplant period. Men can consider consulting a fertility specialist. It is unclear if ART is helpful in persons w/oligospermia or other abnormalities. Women: consider oocyte cryopreservation in those w/early menopause; ART may be beneficial if natural conception is not possible. ART = assisted reproductive technology; BSyn = Bloom syndrome; GH = growth hormone; HSCT = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3 Health supervision recommendations for surveillance in persons with BSyn have been published [ Bloom Syndrome: Recommended Surveillance Monitor growth. Assess for feeding issues & gastroesophageal reflux. Abdominal ultrasound Screen for signs/symptoms incl hematuria & painless abdominal mass Fasting blood glucose & hemoglobin A1c Screening & family education on signs/symptoms of polyuria, polydipsia, weight loss Serum TSH w/reflex to thyroxine Screening & family education on signs/symptoms incl fatigue, constipation, cold sensitivity, weight gain TSH = thyroid-stimulating hormone Sun exposure to the face and other exposed skin, particularly in infancy and early childhood, should be avoided. Exposure to ionizing radiation should be minimized. People with BSyn should avoid unnecessary radiographs and CT scans; MRI and ultrasound are preferred imaging modalities when able to be used. Chemotherapy can have significant side effects and toxicity (including secondary malignancies). Dose reductions and shortened courses of treatment are generally utilized for individuals with BSyn. Alkylating agents and radiation therapy are considered high risk and are avoided when possible in those with BSyn. It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from avoidance of sun exposure and early surveillance for cancer (see Molecular genetic testing for the An unusually low birth weight followed by short stature throughout childhood is typically present in affected sibs; sibs of normal stature are likely unaffected and may not need further testing. See Eleven women with BSyn followed in the Bloom Syndrome Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size. See Search • Immunodeficiency screening incl immunoglobulin level, antibody responses to vaccines, & quantitative B & T lymphocytes • Referral to immunologist as needed • Men: semen analysis to assess for azoospermia, oligospermia, or asthenospermia • Women: assessment for signs of early menopause • Fasting blood glucose & hemoglobin A1c concentration • Assessment for polyuria, polydipsia, weight loss • If GH is prescribed, growth response, serum IGF-1, & IGFBP-3 should be closely monitored. • GH should be discontinued if growth velocity does not ↑ w/GH treatment. • Standard treatment for feeding issues incl high-calorie diet • Consider consultation w/gastroenterologist or feeding specialist. • Reflux precautions & anti-reflux medications as needed • Dietary treatment of dyslipidemia according to standard protocols • ↓ excessive exposure to sunlight by seeking shade, particularly 10 am to 4 pm. • Use sun-protective clothing, incl broad-brimmed hat. • UV-blocking sunglasses • Use broad-spectrum sunscreen w/SPF 30 2x daily, or every 2-3 hrs when outdoors. • Standard treatments for precancerous lesions & skin cancers • Mgmt per immunologist • Recurrent infections & defects in humoral immunity: treatment w/immunoglobulins • Physical, occupational, & speech therapy as needed • Educational support as needed • Family & teachers are encouraged to relate to persons w/BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. • Modification of standard cancer treatment regimens, usually incl reduction of both dosage & duration • Full weight-based dosing may be appropriate for some chemotherapeutic drugs (e.g., steroids, tyrosine kinase inhibitors). • Nonmyeloablative transplantation is likely to be tolerated more than other regimens; required ablative therapy prior to HSCT may require modification of standard protocols because of hypersensitivity to DNA-damaging agents. • HSCT has been performed in 3 persons w/leukemia in the Bloom Syndrome Registry. 1 person had >5 yrs disease-free survival before succumbing to another cancer; the other 2 died in immediate post-transplant period. • Men can consider consulting a fertility specialist. It is unclear if ART is helpful in persons w/oligospermia or other abnormalities. • Women: consider oocyte cryopreservation in those w/early menopause; ART may be beneficial if natural conception is not possible. • Monitor growth. • Assess for feeding issues & gastroesophageal reflux. • Abdominal ultrasound • Screen for signs/symptoms incl hematuria & painless abdominal mass • Fasting blood glucose & hemoglobin A1c • Screening & family education on signs/symptoms of polyuria, polydipsia, weight loss • Serum TSH w/reflex to thyroxine • Screening & family education on signs/symptoms incl fatigue, constipation, cold sensitivity, weight gain • Molecular genetic testing for the • An unusually low birth weight followed by short stature throughout childhood is typically present in affected sibs; sibs of normal stature are likely unaffected and may not need further testing. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with BSyn, in addition to the routine medical history, family history, and physical examination, the evaluations summarized in Bloom Syndrome: Recommended Evaluations Following Initial Diagnosis Immunodeficiency screening incl immunoglobulin level, antibody responses to vaccines, & quantitative B & T lymphocytes Referral to immunologist as needed Men: semen analysis to assess for azoospermia, oligospermia, or asthenospermia Women: assessment for signs of early menopause Fasting blood glucose & hemoglobin A1c concentration Assessment for polyuria, polydipsia, weight loss BSyn = Bloom syndrome; MOI = mode of inheritance; TSH = thyroid-stimulating hormone • Immunodeficiency screening incl immunoglobulin level, antibody responses to vaccines, & quantitative B & T lymphocytes • Referral to immunologist as needed • Men: semen analysis to assess for azoospermia, oligospermia, or asthenospermia • Women: assessment for signs of early menopause • Fasting blood glucose & hemoglobin A1c concentration • Assessment for polyuria, polydipsia, weight loss ## Treatment of Manifestations Treatment recommendations for persons with BSyn have been published [ Bloom Syndrome: Treatment of Manifestations If GH is prescribed, growth response, serum IGF-1, & IGFBP-3 should be closely monitored. GH should be discontinued if growth velocity does not ↑ w/GH treatment. Standard treatment for feeding issues incl high-calorie diet Consider consultation w/gastroenterologist or feeding specialist. Reflux precautions & anti-reflux medications as needed Dietary treatment of dyslipidemia according to standard protocols ↓ excessive exposure to sunlight by seeking shade, particularly 10 am to 4 pm. Use sun-protective clothing, incl broad-brimmed hat. UV-blocking sunglasses Use broad-spectrum sunscreen w/SPF 30 2x daily, or every 2-3 hrs when outdoors. Standard treatments for precancerous lesions & skin cancers Mgmt per immunologist Recurrent infections & defects in humoral immunity: treatment w/immunoglobulins Physical, occupational, & speech therapy as needed Educational support as needed Family & teachers are encouraged to relate to persons w/BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. Modification of standard cancer treatment regimens, usually incl reduction of both dosage & duration Full weight-based dosing may be appropriate for some chemotherapeutic drugs (e.g., steroids, tyrosine kinase inhibitors). Nonmyeloablative transplantation is likely to be tolerated more than other regimens; required ablative therapy prior to HSCT may require modification of standard protocols because of hypersensitivity to DNA-damaging agents. HSCT has been performed in 3 persons w/leukemia in the Bloom Syndrome Registry. 1 person had >5 yrs disease-free survival before succumbing to another cancer; the other 2 died in immediate post-transplant period. Men can consider consulting a fertility specialist. It is unclear if ART is helpful in persons w/oligospermia or other abnormalities. Women: consider oocyte cryopreservation in those w/early menopause; ART may be beneficial if natural conception is not possible. ART = assisted reproductive technology; BSyn = Bloom syndrome; GH = growth hormone; HSCT = hematopoietic stem cell transplantation; IGF-1 = insulin-like growth factor 1; IGFBP-3 = insulin-like growth factor binding protein 3 • If GH is prescribed, growth response, serum IGF-1, & IGFBP-3 should be closely monitored. • GH should be discontinued if growth velocity does not ↑ w/GH treatment. • Standard treatment for feeding issues incl high-calorie diet • Consider consultation w/gastroenterologist or feeding specialist. • Reflux precautions & anti-reflux medications as needed • Dietary treatment of dyslipidemia according to standard protocols • ↓ excessive exposure to sunlight by seeking shade, particularly 10 am to 4 pm. • Use sun-protective clothing, incl broad-brimmed hat. • UV-blocking sunglasses • Use broad-spectrum sunscreen w/SPF 30 2x daily, or every 2-3 hrs when outdoors. • Standard treatments for precancerous lesions & skin cancers • Mgmt per immunologist • Recurrent infections & defects in humoral immunity: treatment w/immunoglobulins • Physical, occupational, & speech therapy as needed • Educational support as needed • Family & teachers are encouraged to relate to persons w/BSyn appropriately for their chronologic age rather than the younger age suggested by their unusually small size. • Modification of standard cancer treatment regimens, usually incl reduction of both dosage & duration • Full weight-based dosing may be appropriate for some chemotherapeutic drugs (e.g., steroids, tyrosine kinase inhibitors). • Nonmyeloablative transplantation is likely to be tolerated more than other regimens; required ablative therapy prior to HSCT may require modification of standard protocols because of hypersensitivity to DNA-damaging agents. • HSCT has been performed in 3 persons w/leukemia in the Bloom Syndrome Registry. 1 person had >5 yrs disease-free survival before succumbing to another cancer; the other 2 died in immediate post-transplant period. • Men can consider consulting a fertility specialist. It is unclear if ART is helpful in persons w/oligospermia or other abnormalities. • Women: consider oocyte cryopreservation in those w/early menopause; ART may be beneficial if natural conception is not possible. ## Surveillance Health supervision recommendations for surveillance in persons with BSyn have been published [ Bloom Syndrome: Recommended Surveillance Monitor growth. Assess for feeding issues & gastroesophageal reflux. Abdominal ultrasound Screen for signs/symptoms incl hematuria & painless abdominal mass Fasting blood glucose & hemoglobin A1c Screening & family education on signs/symptoms of polyuria, polydipsia, weight loss Serum TSH w/reflex to thyroxine Screening & family education on signs/symptoms incl fatigue, constipation, cold sensitivity, weight gain TSH = thyroid-stimulating hormone • Monitor growth. • Assess for feeding issues & gastroesophageal reflux. • Abdominal ultrasound • Screen for signs/symptoms incl hematuria & painless abdominal mass • Fasting blood glucose & hemoglobin A1c • Screening & family education on signs/symptoms of polyuria, polydipsia, weight loss • Serum TSH w/reflex to thyroxine • Screening & family education on signs/symptoms incl fatigue, constipation, cold sensitivity, weight gain ## Agents/Circumstances to Avoid Sun exposure to the face and other exposed skin, particularly in infancy and early childhood, should be avoided. Exposure to ionizing radiation should be minimized. People with BSyn should avoid unnecessary radiographs and CT scans; MRI and ultrasound are preferred imaging modalities when able to be used. Chemotherapy can have significant side effects and toxicity (including secondary malignancies). Dose reductions and shortened courses of treatment are generally utilized for individuals with BSyn. Alkylating agents and radiation therapy are considered high risk and are avoided when possible in those with BSyn. ## Evaluation of Relatives at Risk It is appropriate to evaluate sibs of a proband in order to identify as early as possible those who would benefit from avoidance of sun exposure and early surveillance for cancer (see Molecular genetic testing for the An unusually low birth weight followed by short stature throughout childhood is typically present in affected sibs; sibs of normal stature are likely unaffected and may not need further testing. See • Molecular genetic testing for the • An unusually low birth weight followed by short stature throughout childhood is typically present in affected sibs; sibs of normal stature are likely unaffected and may not need further testing. ## Pregnancy Management Eleven women with BSyn followed in the Bloom Syndrome Registry have become pregnant at least once; seven of them have delivered a total of 11 healthy babies of normal size. See ## Therapies Under Investigation Search ## Genetic Counseling Bloom syndrome (BSyn) is inherited in an autosomal recessive manner. The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [ Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of If both parents are known to be heterozygous for a Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of Children born to a female with BSyn are usually heterozygous for a Children born to a female with BSyn and a reproductive partner who is a carrier of a pathogenic variant have a 50% chance of having BSyn and a 50% chance of being carriers. Males with BSyn tend to be infertile. Carrier testing for at-risk relatives requires prior identification of the See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers. Carrier testing should be offered for the reproductive partners of individuals known to be carriers of BSyn. Note: Ultrasound measurements are not reliable for estimating gestation age if prenatal diagnosis confirms the diagnosis of BSyn in the fetus. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [ • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [ • Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of • 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 not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of • Children born to a female with BSyn are usually heterozygous for a • Children born to a female with BSyn and a reproductive partner who is a carrier of a pathogenic variant have a 50% chance of having BSyn and a 50% chance of being carriers. • Males with BSyn tend to be infertile. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 offered for the reproductive partners of individuals known to be carriers of BSyn. ## Mode of Inheritance Bloom syndrome (BSyn) is inherited in an autosomal recessive manner. ## Risk to Family Members The parents of an affected individual are presumed to be heterozygous for a Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [ Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of If both parents are known to be heterozygous for a Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of Children born to a female with BSyn are usually heterozygous for a Children born to a female with BSyn and a reproductive partner who is a carrier of a pathogenic variant have a 50% chance of having BSyn and a 50% chance of being carriers. Males with BSyn tend to be infertile. • The parents of an affected individual are presumed to be heterozygous for a • Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a • If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [ • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity; • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband [ • Heterozygotes (carriers) are not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of • 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 not at risk of developing BSyn. The cancer risk of heterozygotes as a group remains unclear. Some studies have identified a higher rate of • Children born to a female with BSyn are usually heterozygous for a • Children born to a female with BSyn and a reproductive partner who is a carrier of a pathogenic variant have a 50% chance of having BSyn and a 50% chance of being carriers. • Males with BSyn tend to be infertile. ## Carrier Detection Carrier testing for at-risk relatives requires prior identification of the ## Population Screening ## 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 offered for the reproductive partners of individuals known to be carriers of BSyn. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 offered for the reproductive partners of individuals known to be carriers of BSyn. ## Prenatal Testing and Preimplantation Genetic Testing Note: Ultrasound measurements are not reliable for estimating gestation age if prenatal diagnosis confirms the diagnosis of BSyn in the fetus. 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 Weill Cornell Medicine • • • • Weill Cornell Medicine • ## Molecular Genetics Bloom Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Bloom Syndrome ( Bloom syndrome (BSyn) is the prototype of the class of human diseases sometimes referred to as the chromosome breakage syndromes [ Molecular and genetic evidence implicates RecQ-like DNA helicase BLM (BLM) in the cellular mechanisms that maintain genomic stability [ Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Also known as the blm ## Molecular Pathogenesis Bloom syndrome (BSyn) is the prototype of the class of human diseases sometimes referred to as the chromosome breakage syndromes [ Molecular and genetic evidence implicates RecQ-like DNA helicase BLM (BLM) in the cellular mechanisms that maintain genomic stability [ Variants listed in the table have been provided by the authors. Variant designation that does not conform to current naming conventions Also known as the blm ## Chapter Notes The Bloom Syndrome Registry is a long-term surveillance program in which the clinical courses of persons diagnosed with Bloom syndrome (BSyn) and close members of their families are followed. The Bloom Syndrome Registry includes individuals with confirmed BSyn living in various parts of the world. The registry is the source of much of the data included in this The authors would like to acknowledge Dr James L German III (b. January 2, 1926, d. April 21, 2018), who founded the Bloom Syndrome Registry and who dedicated much of his career to the understanding of BSyn and the support of affected persons and their families. They would also like to thank the New York Community Trust and Weill Cornell Medicine's Clinical and Translational Science Center for providing funding. Christopher Cunniff, MD, FACMG (2016-present)Maeve Flanagan, BA; Weill Cornell Medical College (2019-2023)James German, MD, FACMG (hon); Weill Cornell Medical College (2006-2019) Nicole Kucine, MD, MS (2023-present) Katherine Langer, BA (2023-present)Maureen M Sanz, PhD, FACMG; Molloy College (2006-2019) 12 October 2023 (sw) Comprehensive update posted live 14 February 2019 (sw) Comprehensive update posted live 7 April 2016 (sw) Comprehensive update posted live 28 March 2013 (me) Comprehensive update posted live 24 August 2010 (me) Comprehensive update posted live 22 March 2006 (me) Review posted live 10 December 2004 (ms) Original submission • 12 October 2023 (sw) Comprehensive update posted live • 14 February 2019 (sw) Comprehensive update posted live • 7 April 2016 (sw) Comprehensive update posted live • 28 March 2013 (me) Comprehensive update posted live • 24 August 2010 (me) Comprehensive update posted live • 22 March 2006 (me) Review posted live • 10 December 2004 (ms) Original submission ## Author Notes The Bloom Syndrome Registry is a long-term surveillance program in which the clinical courses of persons diagnosed with Bloom syndrome (BSyn) and close members of their families are followed. The Bloom Syndrome Registry includes individuals with confirmed BSyn living in various parts of the world. The registry is the source of much of the data included in this ## Acknowledgments The authors would like to acknowledge Dr James L German III (b. January 2, 1926, d. April 21, 2018), who founded the Bloom Syndrome Registry and who dedicated much of his career to the understanding of BSyn and the support of affected persons and their families. They would also like to thank the New York Community Trust and Weill Cornell Medicine's Clinical and Translational Science Center for providing funding. ## Author History Christopher Cunniff, MD, FACMG (2016-present)Maeve Flanagan, BA; Weill Cornell Medical College (2019-2023)James German, MD, FACMG (hon); Weill Cornell Medical College (2006-2019) Nicole Kucine, MD, MS (2023-present) Katherine Langer, BA (2023-present)Maureen M Sanz, PhD, FACMG; Molloy College (2006-2019) ## Revision History 12 October 2023 (sw) Comprehensive update posted live 14 February 2019 (sw) Comprehensive update posted live 7 April 2016 (sw) Comprehensive update posted live 28 March 2013 (me) Comprehensive update posted live 24 August 2010 (me) Comprehensive update posted live 22 March 2006 (me) Review posted live 10 December 2004 (ms) Original submission • 12 October 2023 (sw) Comprehensive update posted live • 14 February 2019 (sw) Comprehensive update posted live • 7 April 2016 (sw) Comprehensive update posted live • 28 March 2013 (me) Comprehensive update posted live • 24 August 2010 (me) Comprehensive update posted live • 22 March 2006 (me) Review posted live • 10 December 2004 (ms) Original submission ## References ## Literature Cited Individual with Bloom syndrome showing characteristic long, narrow face and erythematous rash. Reproduced with permission from	[]	22/3/2006	12/10/2023		GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bofs	bofs	[ "BOF Syndrome", "BOF Syndrome", "Transcription factor AP-2-alpha", "TFAP2A", "Branchiooculofacial Syndrome" ]	Branchiooculofacial Syndrome	Chad R Haldeman-Englert, Angela E Lin, Jeff M Milunsky	Summary Branchiooculofacial syndrome (BOFS) is characterized by branchial (cervical or infra- or supra-auricular) skin defects that range from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; ocular anomalies that can include microphthalmia, anophthalmia, coloboma, cataract, and nasolacrimal duct stenosis/atresia; and facial anomalies that can include dolichocephaly, hypertelorism or telecanthus, broad nasal tip, upslanted palpebral fissures, cleft lip or prominent philtral pillars that give the appearance of a repaired cleft lip (formerly called "pseudocleft lip") with or without cleft palate, upper lip pits, and lower facial weakness (asymmetric crying face or partial weakness of cranial nerve VII). Malformed and prominent pinnae and hearing loss from inner ear and/or petrous bone anomalies are common. Intellect is usually normal. The diagnosis of BOFS is established in a proband with characteristic clinical findings and a heterozygous pathogenic variant in BOFS is inherited in an autosomal dominant manner.	## Diagnosis There are no formal diagnostic guidelines for branchiooculofacial syndrome (BOFS) developed by consensus panels, algorithms using a hierarchy of clinical findings, or evidence-based test standards. Diagnostic criteria have been proposed (see Table I in BOFS Vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; Are most distinctive when they are bilateral and anterior cervical in location, and may be described as "cutis aplasia" [ Differ from the punctuate sinus tracts of the If very mild, may be unrecognized and heal spontaneously, but tend to "weep." Microphthalmia, anophthalmia Coloboma Cataract Ptosis Nasolacrimal duct stenosis/atresia Strabismus Characteristic appearance with dolichocephaly, hypertelorism or telecanthus, broad nasal tip, and upslanted palpebral fissures (See Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]), with or without cleft palate (Isolated cleft palate has not been reported.) Upper lip pits Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct Malformed and prominent pinnae Hearing loss (conductive, sensorineural, mixed) The clinical diagnosis of BOFS can be 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 [ All three of the main features are present: Branchial (cutaneous) skin defect Ocular anomaly Facial anomalies (characteristic facial appearance) OR Two of the three main features plus one of the following are present: Affected first-degree relative, independently diagnosed Ectopic thymus (dermal) 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 Branchiooculofacial 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. • Vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; • Are most distinctive when they are bilateral and anterior cervical in location, and may be described as "cutis aplasia" [ • Differ from the punctuate sinus tracts of the • If very mild, may be unrecognized and heal spontaneously, but tend to "weep." • Microphthalmia, anophthalmia • Coloboma • Cataract • Ptosis • Nasolacrimal duct stenosis/atresia • Strabismus • Characteristic appearance with dolichocephaly, hypertelorism or telecanthus, broad nasal tip, and upslanted palpebral fissures (See • Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]), with or without cleft palate (Isolated cleft palate has not been reported.) • Upper lip pits • Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Malformed and prominent pinnae • Hearing loss (conductive, sensorineural, mixed) • Branchial (cutaneous) skin defect • Ocular anomaly • Facial anomalies (characteristic facial appearance) • Affected first-degree relative, independently diagnosed • Ectopic thymus (dermal) • For an introduction to multigene panels click ## Suggestive Findings BOFS Vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; Are most distinctive when they are bilateral and anterior cervical in location, and may be described as "cutis aplasia" [ Differ from the punctuate sinus tracts of the If very mild, may be unrecognized and heal spontaneously, but tend to "weep." Microphthalmia, anophthalmia Coloboma Cataract Ptosis Nasolacrimal duct stenosis/atresia Strabismus Characteristic appearance with dolichocephaly, hypertelorism or telecanthus, broad nasal tip, and upslanted palpebral fissures (See Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]), with or without cleft palate (Isolated cleft palate has not been reported.) Upper lip pits Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct Malformed and prominent pinnae Hearing loss (conductive, sensorineural, mixed) • Vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions; • Are most distinctive when they are bilateral and anterior cervical in location, and may be described as "cutis aplasia" [ • Differ from the punctuate sinus tracts of the • If very mild, may be unrecognized and heal spontaneously, but tend to "weep." • Microphthalmia, anophthalmia • Coloboma • Cataract • Ptosis • Nasolacrimal duct stenosis/atresia • Strabismus • Characteristic appearance with dolichocephaly, hypertelorism or telecanthus, broad nasal tip, and upslanted palpebral fissures (See • Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]), with or without cleft palate (Isolated cleft palate has not been reported.) • Upper lip pits • Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Malformed and prominent pinnae • Hearing loss (conductive, sensorineural, mixed) ## Establishing the Diagnosis The clinical diagnosis of BOFS can be 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 [ All three of the main features are present: Branchial (cutaneous) skin defect Ocular anomaly Facial anomalies (characteristic facial appearance) OR Two of the three main features plus one of the following are present: Affected first-degree relative, independently diagnosed Ectopic thymus (dermal) 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 Branchiooculofacial 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. • Branchial (cutaneous) skin defect • Ocular anomaly • Facial anomalies (characteristic facial appearance) • Affected first-degree relative, independently diagnosed • Ectopic thymus (dermal) • For an introduction to multigene panels click ## Clinical Diagnosis All three of the main features are present: Branchial (cutaneous) skin defect Ocular anomaly Facial anomalies (characteristic facial appearance) OR Two of the three main features plus one of the following are present: Affected first-degree relative, independently diagnosed Ectopic thymus (dermal) • Branchial (cutaneous) skin defect • Ocular anomaly • Facial anomalies (characteristic facial appearance) • Affected first-degree relative, independently diagnosed • Ectopic thymus (dermal) ## Molecular Diagnosis 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 Branchiooculofacial 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. • For an introduction to multigene panels click ## Clinical Characteristics Most individuals with branchiooculofacial syndrome (BOFS) can be diagnosed in infancy on the basis of their clinical features. Females and males are affected equally. Although the facial features are generally recognizable, some individuals may have subtle differences [Authors, personal observation]. Defects vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions. The mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract that may appear to "weep," revealing the patency. Structural eye malformations can include microphthalmia, anophthalmia, coloboma, or cataract. Periorbital abnormalities include nasolacrimal duct stenosis/atresia leading to weeping eyes and ptosis. Visual concerns include strabismus and significant visual impairment. Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]) Occurring with or without cleft palate (99%) No instances of isolated cleft palate reported Upper lip pits Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) Ear anomalies Malformed and prominent pinnae Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct Hearing loss (70%) (conductive, sensorineural, mixed) Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip Structural anomalies (35%) (e.g., dysplastic, absent, multicystic) Vesicoureteral reflux Premature hair graying, poliosis (forelock or patchy) (35%) Hypoplastic teeth Dysplastic nails Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly other areas of the head and neck) Visual and hearing handicaps (frequent) Autism spectrum disorder, intellectual disability (rare) Heterochromia irides Congenital heart defect (atrial septal defect, tetralogy of Fallot) Polydactyly (bilateral, usually postaxial) Medulloblastoma (1 individual) [ Trigonocephaly (1 individual) [ No clear genotype-phenotype correlation exists. Significant inter- and intrafamilial variability have been observed with the same pathogenic variants [ The majority of individuals with a deletion involving BOFS has shown almost complete penetrance. Careful examination of individuals identified in a family with BOFS with a The prevalence of BOFS is not known. It is a rare condition, with fewer than 150 individuals having a well-described clinical and/or molecular diagnosis. An informal survey of clinical geneticists who attended a 2017 dysmorphology conference identified an additional 27 unpublished individuals (18 with a clinical diagnosis and nine with a molecular diagnosis). While these numbers are insufficient to calculate a population-based prevalence, they support the impression that BOFS remains a rare disorder. • Defects vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions. • The mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract that may appear to "weep," revealing the patency. • Structural eye malformations can include microphthalmia, anophthalmia, coloboma, or cataract. • Periorbital abnormalities include nasolacrimal duct stenosis/atresia leading to weeping eyes and ptosis. • Visual concerns include strabismus and significant visual impairment. • Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]) • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Upper lip pits • Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) • Ear anomalies • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Structural anomalies (35%) (e.g., dysplastic, absent, multicystic) • Vesicoureteral reflux • Premature hair graying, poliosis (forelock or patchy) (35%) • Hypoplastic teeth • Dysplastic nails • Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly other areas of the head and neck) • Visual and hearing handicaps (frequent) • Autism spectrum disorder, intellectual disability (rare) • Heterochromia irides • Congenital heart defect (atrial septal defect, tetralogy of Fallot) • Polydactyly (bilateral, usually postaxial) • Medulloblastoma (1 individual) [ • Trigonocephaly (1 individual) [ ## Clinical Description Most individuals with branchiooculofacial syndrome (BOFS) can be diagnosed in infancy on the basis of their clinical features. Females and males are affected equally. Although the facial features are generally recognizable, some individuals may have subtle differences [Authors, personal observation]. Defects vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions. The mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract that may appear to "weep," revealing the patency. Structural eye malformations can include microphthalmia, anophthalmia, coloboma, or cataract. Periorbital abnormalities include nasolacrimal duct stenosis/atresia leading to weeping eyes and ptosis. Visual concerns include strabismus and significant visual impairment. Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]) Occurring with or without cleft palate (99%) No instances of isolated cleft palate reported Upper lip pits Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) Ear anomalies Malformed and prominent pinnae Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct Hearing loss (70%) (conductive, sensorineural, mixed) Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip Structural anomalies (35%) (e.g., dysplastic, absent, multicystic) Vesicoureteral reflux Premature hair graying, poliosis (forelock or patchy) (35%) Hypoplastic teeth Dysplastic nails Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly other areas of the head and neck) Visual and hearing handicaps (frequent) Autism spectrum disorder, intellectual disability (rare) Heterochromia irides Congenital heart defect (atrial septal defect, tetralogy of Fallot) Polydactyly (bilateral, usually postaxial) Medulloblastoma (1 individual) [ Trigonocephaly (1 individual) [ • Defects vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions. • The mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract that may appear to "weep," revealing the patency. • Structural eye malformations can include microphthalmia, anophthalmia, coloboma, or cataract. • Periorbital abnormalities include nasolacrimal duct stenosis/atresia leading to weeping eyes and ptosis. • Visual concerns include strabismus and significant visual impairment. • Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]) • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Upper lip pits • Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) • Ear anomalies • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Structural anomalies (35%) (e.g., dysplastic, absent, multicystic) • Vesicoureteral reflux • Premature hair graying, poliosis (forelock or patchy) (35%) • Hypoplastic teeth • Dysplastic nails • Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly other areas of the head and neck) • Visual and hearing handicaps (frequent) • Autism spectrum disorder, intellectual disability (rare) • Heterochromia irides • Congenital heart defect (atrial septal defect, tetralogy of Fallot) • Polydactyly (bilateral, usually postaxial) • Medulloblastoma (1 individual) [ • Trigonocephaly (1 individual) [ ## Classic BOFS Findings Defects vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions. The mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract that may appear to "weep," revealing the patency. Structural eye malformations can include microphthalmia, anophthalmia, coloboma, or cataract. Periorbital abnormalities include nasolacrimal duct stenosis/atresia leading to weeping eyes and ptosis. Visual concerns include strabismus and significant visual impairment. Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]) Occurring with or without cleft palate (99%) No instances of isolated cleft palate reported Upper lip pits Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) Ear anomalies Malformed and prominent pinnae Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct Hearing loss (70%) (conductive, sensorineural, mixed) Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip • Defects vary from barely perceptible thin skin or hair patch to erythematous "hemangiomatous" lesions to large weeping erosions. • The mildest defects may be unrecognized and in rare cases heal completely spontaneously. There may be a small residual sinus or tract that may appear to "weep," revealing the patency. • Structural eye malformations can include microphthalmia, anophthalmia, coloboma, or cataract. • Periorbital abnormalities include nasolacrimal duct stenosis/atresia leading to weeping eyes and ptosis. • Visual concerns include strabismus and significant visual impairment. • Cleft lip or prominent philtral pillars (technically known as a lesser-form cleft lip [formerly "pseudocleft lip"]) • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Upper lip pits • Lower facial nerve and/or muscle hypoplasia (asymmetric crying face, partial weakness of cranial nerve VII) • Ear anomalies • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) • Broad nose with full nasal tip, which is distinct from the appearance of the nose in other individuals with cleft lip • Occurring with or without cleft palate (99%) • No instances of isolated cleft palate reported • Malformed and prominent pinnae • Inner ear and petrous bone anomalies such as cochlear dysplasia, Mondini dysplasia, and enlarged vestibular aqueduct • Hearing loss (70%) (conductive, sensorineural, mixed) ## Additional Findings Observed in BOFS Structural anomalies (35%) (e.g., dysplastic, absent, multicystic) Vesicoureteral reflux Premature hair graying, poliosis (forelock or patchy) (35%) Hypoplastic teeth Dysplastic nails Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly other areas of the head and neck) Visual and hearing handicaps (frequent) Autism spectrum disorder, intellectual disability (rare) Heterochromia irides Congenital heart defect (atrial septal defect, tetralogy of Fallot) Polydactyly (bilateral, usually postaxial) Medulloblastoma (1 individual) [ Trigonocephaly (1 individual) [ • Structural anomalies (35%) (e.g., dysplastic, absent, multicystic) • Vesicoureteral reflux • Premature hair graying, poliosis (forelock or patchy) (35%) • Hypoplastic teeth • Dysplastic nails • Cysts, subcutaneous (dermoid-like, often on the scalp; less commonly other areas of the head and neck) • Visual and hearing handicaps (frequent) • Autism spectrum disorder, intellectual disability (rare) • Heterochromia irides • Congenital heart defect (atrial septal defect, tetralogy of Fallot) • Polydactyly (bilateral, usually postaxial) • Medulloblastoma (1 individual) [ • Trigonocephaly (1 individual) [ ## Genotype-Phenotype Correlations No clear genotype-phenotype correlation exists. Significant inter- and intrafamilial variability have been observed with the same pathogenic variants [ The majority of individuals with a deletion involving ## Penetrance BOFS has shown almost complete penetrance. Careful examination of individuals identified in a family with BOFS with a ## Prevalence The prevalence of BOFS is not known. It is a rare condition, with fewer than 150 individuals having a well-described clinical and/or molecular diagnosis. An informal survey of clinical geneticists who attended a 2017 dysmorphology conference identified an additional 27 unpublished individuals (18 with a clinical diagnosis and nine with a molecular diagnosis). While these numbers are insufficient to calculate a population-based prevalence, they support the impression that BOFS remains a rare disorder. ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis The branchiooculofacial syndrome phenotype is distinctive and can typically be differentiated on a clinical basis from disorders with overlapping features (see Disorders of Interest in the Differential Diagnosis of Branchiooculofacial Syndrome Eye abnormalities Ear abnormalities Branchial abnormalities Renal abnormalities Orofacial cleft Cardiac defects common No BOFS facial features Eye abnormalities Ear abnormalities Orofacial cleft No skin defects No premature gray hair Frequent posterior segment coloboma & choanal atresia No BOFS facial features Premature graying of hair Telecanthus Hearing loss No renal abnormalities No BOFS facial features Ear abnormalities Branchial abnormalities Renal abnormalities Branchial pits (vs draining sinuses w/overlying skin defects in BOFS) No BOFS facial features Orofacial cleft Ectodermal abnormalities Ectrodactyly No BOFS facial features AD = autosomal dominant; AR = autosomal recessive; BOFS = branchiooculofacial syndrome; MOI = mode of inheritance Although • Eye abnormalities • Ear abnormalities • Branchial abnormalities • Renal abnormalities • Orofacial cleft • Cardiac defects common • No BOFS facial features • Eye abnormalities • Ear abnormalities • Orofacial cleft • No skin defects • No premature gray hair • Frequent posterior segment coloboma & choanal atresia • No BOFS facial features • Premature graying of hair • Telecanthus • Hearing loss • No renal abnormalities • No BOFS facial features • Ear abnormalities • Branchial abnormalities • Renal abnormalities • Branchial pits (vs draining sinuses w/overlying skin defects in BOFS) • No BOFS facial features • Orofacial cleft • Ectodermal abnormalities • Ectrodactyly • No BOFS facial features ## Management To establish the extent of disease and needs of an individual diagnosed with branchiooculofacial syndrome (BOFS), the evaluations summarized in Branchiooculofacial Syndrome: Recommended Evaluations Following Initial Diagnosis Hearing eval CT imaging of temporal bone to anticipate optimal hearing correction Developmental assessment particularly for children w/visual &/or hearing problems Assessment for depression, attention dysregulation, autism, intellectual disability Community or Social work involvement for parental support; Home nursing referral. BOFS = branchiooculofacial syndrome; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Note: (1) Motor delays are not part of BOFS; thus, physical and occupational therapy is not anticipated. (2) The role of cancer surveillance is not established. Branchiooculofacial Syndrome: Treatment of Manifestations Most larger skin defects require surgical excision. Note: Skin defects should not be cauterized. Sinus tracts must be dissected by experienced pediatric plastic surgeon. Exploration for a thymic remnant may be necessary; such tissue should be sent for histopathologic exam. If dermal thymic tissue is present, evaluate for mediastinal thymic tissue prior to excision of ectopic thymus. Obstruction from nasolacrimal duct stenosis or atresia must be relieved & affected persons monitored for restenosis. Severe microphthalmia or anophthalmia may be managed by inserting a conformer into the eye socket to encourage its growth. Surgical treatment by pediatric plastic surgeon experienced in treating cleft lip In addition to the nasal tip flattening or asymmetry that may be assoc w/cleft lip, a characteristic full, flat nasal tip may need a corrective procedure. Affected persons may need reconstruction of malformed protruding pinnae. Hearing loss is treated routinely (see Adapted from To monitor existing manifestations and the individual's response to supportive care, the evaluations summarized in Branchiooculofacial Syndrome: Recommended Surveillance It is appropriate to evaluate 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 treatment of hearing, vision, renal, and other manifestations. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; A careful physical examination to look for subtle physical findings of BOFS if the pathogenic variant in the family is not known. See Search • Hearing eval • CT imaging of temporal bone to anticipate optimal hearing correction • Developmental assessment particularly for children w/visual &/or hearing problems • Assessment for depression, attention dysregulation, autism, intellectual disability • Community or • Social work involvement for parental support; • Home nursing referral. • Most larger skin defects require surgical excision. • Note: Skin defects should not be cauterized. • Exploration for a thymic remnant may be necessary; such tissue should be sent for histopathologic exam. • If dermal thymic tissue is present, evaluate for mediastinal thymic tissue prior to excision of ectopic thymus. • Obstruction from nasolacrimal duct stenosis or atresia must be relieved & affected persons monitored for restenosis. • Severe microphthalmia or anophthalmia may be managed by inserting a conformer into the eye socket to encourage its growth. • Surgical treatment by pediatric plastic surgeon experienced in treating cleft lip • In addition to the nasal tip flattening or asymmetry that may be assoc w/cleft lip, a characteristic full, flat nasal tip may need a corrective procedure. • Affected persons may need reconstruction of malformed protruding pinnae. • Hearing loss is treated routinely (see • Molecular genetic testing if the pathogenic variant in the family is known; • A careful physical examination to look for subtle physical findings of BOFS 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 branchiooculofacial syndrome (BOFS), the evaluations summarized in Branchiooculofacial Syndrome: Recommended Evaluations Following Initial Diagnosis Hearing eval CT imaging of temporal bone to anticipate optimal hearing correction Developmental assessment particularly for children w/visual &/or hearing problems Assessment for depression, attention dysregulation, autism, intellectual disability Community or Social work involvement for parental support; Home nursing referral. BOFS = branchiooculofacial syndrome; MOI = mode of inheritance Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Note: (1) Motor delays are not part of BOFS; thus, physical and occupational therapy is not anticipated. (2) The role of cancer surveillance is not established. • Hearing eval • CT imaging of temporal bone to anticipate optimal hearing correction • Developmental assessment particularly for children w/visual &/or hearing problems • Assessment for depression, attention dysregulation, autism, intellectual disability • Community or • Social work involvement for parental support; • Home nursing referral. ## Treatment of Manifestations Branchiooculofacial Syndrome: Treatment of Manifestations Most larger skin defects require surgical excision. Note: Skin defects should not be cauterized. Sinus tracts must be dissected by experienced pediatric plastic surgeon. Exploration for a thymic remnant may be necessary; such tissue should be sent for histopathologic exam. If dermal thymic tissue is present, evaluate for mediastinal thymic tissue prior to excision of ectopic thymus. Obstruction from nasolacrimal duct stenosis or atresia must be relieved & affected persons monitored for restenosis. Severe microphthalmia or anophthalmia may be managed by inserting a conformer into the eye socket to encourage its growth. Surgical treatment by pediatric plastic surgeon experienced in treating cleft lip In addition to the nasal tip flattening or asymmetry that may be assoc w/cleft lip, a characteristic full, flat nasal tip may need a corrective procedure. Affected persons may need reconstruction of malformed protruding pinnae. Hearing loss is treated routinely (see Adapted from • Most larger skin defects require surgical excision. • Note: Skin defects should not be cauterized. • Exploration for a thymic remnant may be necessary; such tissue should be sent for histopathologic exam. • If dermal thymic tissue is present, evaluate for mediastinal thymic tissue prior to excision of ectopic thymus. • Obstruction from nasolacrimal duct stenosis or atresia must be relieved & affected persons monitored for restenosis. • Severe microphthalmia or anophthalmia may be managed by inserting a conformer into the eye socket to encourage its growth. • Surgical treatment by pediatric plastic surgeon experienced in treating cleft lip • In addition to the nasal tip flattening or asymmetry that may be assoc w/cleft lip, a characteristic full, flat nasal tip may need a corrective procedure. • Affected persons may need reconstruction of malformed protruding pinnae. • Hearing loss is treated routinely (see ## Surveillance To monitor existing manifestations and the individual's response to supportive care, the evaluations summarized in Branchiooculofacial Syndrome: Recommended Surveillance ## Evaluation of Relatives at Risk It is appropriate to evaluate 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 treatment of hearing, vision, renal, and other manifestations. Evaluations can include: Molecular genetic testing if the pathogenic variant in the family is known; A careful physical examination to look for subtle physical findings of BOFS if the pathogenic variant in the family is not known. See • Molecular genetic testing if the pathogenic variant in the family is known; • A careful physical examination to look for subtle physical findings of BOFS if the pathogenic variant in the family is not known. ## Therapies Under Investigation Search ## Genetic Counseling Branchiooculofacial syndrome (BOFS) is inherited in an autosomal dominant manner. Approximately 40%-50% of individuals diagnosed with BOFS have an affected parent [ Approximately 50%-60% of individuals diagnosed with BOFS have the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with BOFS may appear to be negative because of failure to recognize the disorder in family members or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without molecular genetic testing to establish 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. BOFS is associated with almost complete penetrance; however, significant intrafamilial variability has been observed [ If the proband has a known If the parents appear to be clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of a milder phenotypic presentation in a heterozygous parent and the possibility of parental 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. 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 40%-50% of individuals diagnosed with BOFS have an affected parent [ • Approximately 50%-60% of individuals diagnosed with BOFS have the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The family history of some individuals diagnosed with BOFS may appear to be negative because of failure to recognize the disorder in family members or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without molecular genetic testing to establish 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. • * A parent with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. BOFS is associated with almost complete penetrance; however, significant intrafamilial variability has been observed [ • If the proband has a known • If the parents appear to be clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of a milder phenotypic presentation in a heterozygous parent and the possibility of parental 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 Branchiooculofacial syndrome (BOFS) is inherited in an autosomal dominant manner. ## Risk to Family Members Approximately 40%-50% of individuals diagnosed with BOFS have an affected parent [ Approximately 50%-60% of individuals diagnosed with BOFS have the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: The proband has a The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. * A parent with somatic and germline mosaicism for a The family history of some individuals diagnosed with BOFS may appear to be negative because of failure to recognize the disorder in family members or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without molecular genetic testing to establish 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. BOFS is associated with almost complete penetrance; however, significant intrafamilial variability has been observed [ If the proband has a known If the parents appear to be clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of a milder phenotypic presentation in a heterozygous parent and the possibility of parental mosaicism. • Approximately 40%-50% of individuals diagnosed with BOFS have an affected parent [ • Approximately 50%-60% of individuals diagnosed with BOFS have the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status and inform recurrence risk assessment. • If the pathogenic variant identified in the proband is not identified in either parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered: • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The proband has a • The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only. • * A parent with somatic and germline mosaicism for a • The family history of some individuals diagnosed with BOFS may appear to be negative because of failure to recognize the disorder in family members or a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without molecular genetic testing to establish 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. • * A parent with somatic and germline mosaicism for a • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. BOFS is associated with almost complete penetrance; however, significant intrafamilial variability has been observed [ • If the proband has a known • If the parents appear to be clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of a milder phenotypic presentation in a heterozygous parent and the possibility of parental 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 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 Branchiooculofacial Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Branchiooculofacial Syndrome ( TFAP2A is a retinoic acid-responsive member of the AP-2 family of transcription factors that regulate gene expression during embryogenesis of the eye, ear, face, body wall, limbs, and neural tube [ Although the pathogenic variants occur throughout the gene, a hot spot region in exons 6 and 7 that contains missense variants in about 90% of probands/families with BOFS has been identified [ ## Molecular Pathogenesis TFAP2A is a retinoic acid-responsive member of the AP-2 family of transcription factors that regulate gene expression during embryogenesis of the eye, ear, face, body wall, limbs, and neural tube [ Although the pathogenic variants occur throughout the gene, a hot spot region in exons 6 and 7 that contains missense variants in about 90% of probands/families with BOFS has been identified [ ## Chapter Notes As of January 2018, there is no disease advocacy organization ("support group") for BOFS. Through Dr Lin, several parents of children with BOFS have reached out to the families of newly diagnosed individuals. We thank the many families and international colleagues who have supported our research. 14 August 2025 (aa) Revision: 28 September 2023 (sw) Comprehensive update posted live 29 March 2018 (ha) Comprehensive update posted live 31 May 2011 (me) Review posted live 11 January 2011 (al) Original submission • 14 August 2025 (aa) Revision: • 28 September 2023 (sw) Comprehensive update posted live • 29 March 2018 (ha) Comprehensive update posted live • 31 May 2011 (me) Review posted live • 11 January 2011 (al) Original submission ## Author Notes As of January 2018, there is no disease advocacy organization ("support group") for BOFS. Through Dr Lin, several parents of children with BOFS have reached out to the families of newly diagnosed individuals. ## Acknowledgments We thank the many families and international colleagues who have supported our research. ## Revision History 14 August 2025 (aa) Revision: 28 September 2023 (sw) Comprehensive update posted live 29 March 2018 (ha) Comprehensive update posted live 31 May 2011 (me) Review posted live 11 January 2011 (al) Original submission • 14 August 2025 (aa) Revision: • 28 September 2023 (sw) Comprehensive update posted live • 29 March 2018 (ha) Comprehensive update posted live • 31 May 2011 (me) Review posted live • 11 January 2011 (al) Original submission ## References Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, Mortier GR, Parkash S, Ray CR, Roberts A, Roberts A, Reardon W, Schnur RE, Smith R, Splitt M, Tezcan K, Whiteford ML, Wong DA, Zori R, Lin AE. Genotype-phenotype analysis of the branchio-oculo-facial syndrome. Am J Med Genet A. 2011;155A:22-32. [ • Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, Mortier GR, Parkash S, Ray CR, Roberts A, Roberts A, Reardon W, Schnur RE, Smith R, Splitt M, Tezcan K, Whiteford ML, Wong DA, Zori R, Lin AE. Genotype-phenotype analysis of the branchio-oculo-facial syndrome. Am J Med Genet A. 2011;155A:22-32. [ ## Published Guidelines / Consensus Statements Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, Mortier GR, Parkash S, Ray CR, Roberts A, Roberts A, Reardon W, Schnur RE, Smith R, Splitt M, Tezcan K, Whiteford ML, Wong DA, Zori R, Lin AE. Genotype-phenotype analysis of the branchio-oculo-facial syndrome. Am J Med Genet A. 2011;155A:22-32. [ • Milunsky JM, Maher TM, Zhao G, Wang Z, Mulliken JB, Chitayat D, Clemens M, Stalker HJ, Bauer M, Burch M, Chénier S, Cunningham ML, Drack AV, Janssens S, Karlea A, Klatt R, Kini U, Klein O, Lachmeijer AM, Megarbane A, Mendelsohn NJ, Meschino WS, Mortier GR, Parkash S, Ray CR, Roberts A, Roberts A, Reardon W, Schnur RE, Smith R, Splitt M, Tezcan K, Whiteford ML, Wong DA, Zori R, Lin AE. Genotype-phenotype analysis of the branchio-oculo-facial syndrome. Am J Med Genet A. 2011;155A:22-32. [ ## Literature Cited Photo of a boy age five years with branchiooculofacial syndrome syndrome (BOFS). Details of the molecular findings are reported in Photo generously provided by this child's mother.	[]	31/5/2011	28/9/2023	14/8/2025	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bohring-opitz	bohring-opitz	[ "Oberklaid-Danks Syndrome", "Oberklaid-Danks Syndrome", "Polycomb group protein ASXL1", "ASXL1", "Bohring-Opitz Syndrome" ]	Bohring-Opitz Syndrome	Bianca Russell, Wen-Hann Tan, John M Graham	Summary Bohring-Opitz syndrome (BOS) is characterized by distinctive facial features and posture, growth failure, variable but usually severe intellectual disability, and variable anomalies. The facial features may include microcephaly or trigonocephaly / prominent (but not fused) metopic ridge, hypotonic facies with full cheeks, synophrys, glabellar and eyelid nevus flammeus (simplex), prominent globes, widely set eyes, palate anomalies, and micrognathia. The 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. Feeding difficulties in early childhood, including cyclic vomiting, have a significant impact on overall health; feeding tends to improve with age. Seizures are common and typically responsive to standard epileptic medications. Minor cardiac anomalies and transient bradycardia and apnea may be present. Affected individuals may experience recurrent infections, which also tend to improve with age. Isolated case reports suggest that individuals with BOS are at greater risk for Wilms tumor than the general population, but large-scale epidemiologic studies have not been conducted. The diagnosis of Bohring-Opitz syndrome (BOS) is established in a proband with suggestive clinical features and/or the identification of a constitutional heterozygous pathogenic variant in Bohring-Opitz syndrome (BOS) is typically the result of a	## Diagnosis Prior to the identification of the molecular cause of Bohring-Opitz syndrome (BOS), Bohring-Opitz syndrome Microcephaly or trigonocephaly / prominent (but not necessarily fused) metopic ridge Glabellar and eyelid nevus flammeus (simplex) that fades with age Prominent globes Cleft lip Palatal anomalies: cleft palate, high arched palate, or prominent palatine ridges Micrognathia and/or retrognathia Intrauterine growth restriction Severe feeding difficulties with chronic emesis that typically improves with age Poor postnatal weight gain and linear growth, often exacerbated by severe feeding intolerance Developmental delay or intellectual disability in the severe-to-profound range with minimal or complete lack of expressive language Seizures Sleep disturbance Obstructive sleep apnea High myopia presenting in infancy that may worsen over the first years of life Variable optic nerve and retinal anomalies Flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints; most noticeable in early childhood and usually less obvious with age Truncal hypotonia with hypertonia of the extremities The diagnosis of Bohring-Opitz 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 Bohring-Opitz 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 The denominator represents only those individuals in the literature who have undergone sequence analysis of Somatic mosaicism for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. In four individuals with features suggestive of BOS molecular genetic testing of • Microcephaly or trigonocephaly / prominent (but not necessarily fused) metopic ridge • Glabellar and eyelid nevus flammeus (simplex) that fades with age • Prominent globes • Cleft lip • Palatal anomalies: cleft palate, high arched palate, or prominent palatine ridges • Micrognathia and/or retrognathia • Intrauterine growth restriction • Severe feeding difficulties with chronic emesis that typically improves with age • Poor postnatal weight gain and linear growth, often exacerbated by severe feeding intolerance • Developmental delay or intellectual disability in the severe-to-profound range with minimal or complete lack of expressive language • Seizures • Sleep disturbance • Obstructive sleep apnea • High myopia presenting in infancy that may worsen over the first years of life • Variable optic nerve and retinal anomalies • Flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints; most noticeable in early childhood and usually less obvious with age • Truncal hypotonia with hypertonia of the extremities • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings Bohring-Opitz syndrome Microcephaly or trigonocephaly / prominent (but not necessarily fused) metopic ridge Glabellar and eyelid nevus flammeus (simplex) that fades with age Prominent globes Cleft lip Palatal anomalies: cleft palate, high arched palate, or prominent palatine ridges Micrognathia and/or retrognathia Intrauterine growth restriction Severe feeding difficulties with chronic emesis that typically improves with age Poor postnatal weight gain and linear growth, often exacerbated by severe feeding intolerance Developmental delay or intellectual disability in the severe-to-profound range with minimal or complete lack of expressive language Seizures Sleep disturbance Obstructive sleep apnea High myopia presenting in infancy that may worsen over the first years of life Variable optic nerve and retinal anomalies Flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints; most noticeable in early childhood and usually less obvious with age Truncal hypotonia with hypertonia of the extremities • Microcephaly or trigonocephaly / prominent (but not necessarily fused) metopic ridge • Glabellar and eyelid nevus flammeus (simplex) that fades with age • Prominent globes • Cleft lip • Palatal anomalies: cleft palate, high arched palate, or prominent palatine ridges • Micrognathia and/or retrognathia • Intrauterine growth restriction • Severe feeding difficulties with chronic emesis that typically improves with age • Poor postnatal weight gain and linear growth, often exacerbated by severe feeding intolerance • Developmental delay or intellectual disability in the severe-to-profound range with minimal or complete lack of expressive language • Seizures • Sleep disturbance • Obstructive sleep apnea • High myopia presenting in infancy that may worsen over the first years of life • Variable optic nerve and retinal anomalies • Flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints; most noticeable in early childhood and usually less obvious with age • Truncal hypotonia with hypertonia of the extremities ## Establishing the Diagnosis The diagnosis of Bohring-Opitz 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 Bohring-Opitz 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 The denominator represents only those individuals in the literature who have undergone sequence analysis of Somatic mosaicism for Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. No data on detection rate of gene-targeted deletion/duplication analysis are available. In four individuals with features suggestive of BOS molecular genetic testing of • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Bohring-Opitz syndrome (BOS) is a rare condition characterized by distinctive facial features and posture, variable but usually severe intellectual disability, growth failure, and variable anomalies. Feeding difficulties have a significant impact on overall health in early childhood; feeding tends to improve with age. This section summarizes clinical data from numerous case reports and case series; see Other features widely, but variably, reported include cleft lip with or without cleft palate, high arched palate, widely spaced eyes (hypertelorism), depressed and wide nasal bridge, anteverted nares, and low-set ears with increased posterior angulation. The only other neoplastic process reported was medulloblastoma in a child age five years with clinical features of BOS in whom a pathogenic Annular pancreas has been described in some affected individuals. Gallstones have been reported in several affected individuals [Author, personal observation]. Historically, this condition had been associated with high infant mortality (27% based on data published before 2015), but the current survival rate is likely to be much better due to advances in pediatric care and more aggressive interventions [ No genotype-phenotype correlations have been reported to date, but the total number of individuals in whom BOS is occasionally known as Oberklaid-Danks syndrome after F Oberklaid and DM Danks, who described one of the early cases of BOS [ The prevalence of BOS is unknown; out of 46 clinically diagnosed individuals reported in the literature, 20 had the diagnosis molecularly confirmed. Note: Not all clinically diagnosed individuals reported in the literature have undergone molecular genetic testing of • Annular pancreas has been described in some affected individuals. • Gallstones have been reported in several affected individuals [Author, personal observation]. • Historically, this condition had been associated with high infant mortality (27% based on data published before 2015), but the current survival rate is likely to be much better due to advances in pediatric care and more aggressive interventions [ ## Clinical Description Bohring-Opitz syndrome (BOS) is a rare condition characterized by distinctive facial features and posture, variable but usually severe intellectual disability, growth failure, and variable anomalies. Feeding difficulties have a significant impact on overall health in early childhood; feeding tends to improve with age. This section summarizes clinical data from numerous case reports and case series; see Other features widely, but variably, reported include cleft lip with or without cleft palate, high arched palate, widely spaced eyes (hypertelorism), depressed and wide nasal bridge, anteverted nares, and low-set ears with increased posterior angulation. The only other neoplastic process reported was medulloblastoma in a child age five years with clinical features of BOS in whom a pathogenic Annular pancreas has been described in some affected individuals. Gallstones have been reported in several affected individuals [Author, personal observation]. Historically, this condition had been associated with high infant mortality (27% based on data published before 2015), but the current survival rate is likely to be much better due to advances in pediatric care and more aggressive interventions [ • Annular pancreas has been described in some affected individuals. • Gallstones have been reported in several affected individuals [Author, personal observation]. • Historically, this condition had been associated with high infant mortality (27% based on data published before 2015), but the current survival rate is likely to be much better due to advances in pediatric care and more aggressive interventions [ ## Genotype-Phenotype Correlations No genotype-phenotype correlations have been reported to date, but the total number of individuals in whom ## Nomenclature BOS is occasionally known as Oberklaid-Danks syndrome after F Oberklaid and DM Danks, who described one of the early cases of BOS [ ## Prevalence The prevalence of BOS is unknown; out of 46 clinically diagnosed individuals reported in the literature, 20 had the diagnosis molecularly confirmed. Note: Not all clinically diagnosed individuals reported in the literature have undergone molecular genetic testing of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this Sporadic malignancies (including myelodysplastic syndrome) occurring in the absence of any other findings of Bohring-Opitz syndrome frequently contain a somatic variant in ## Differential Diagnosis Disorders to Consider in the Differential Diagnosis of Bohring-Opitz Syndrome (BOS) Severe DD/ID Microcephaly Trigonocephaly Upslanting palpebral fissures Retrognathia Low-set ears Nevus flammeus (simplex) over glabella BOS posture Poor linear growth Feeding difficulties High myopia DD Hypotonia Feeding difficulties in infancy Nevus flammeus (simplex) over the glabella Facial characteristics (particularly widely spaced eyes, prominent globes, & low-set or posteriorly rotated ears) Hypertrichosis (2 of 6 reported cases) Severe to profound ID Microcephaly BOS posture Variable ID (borderline to severe) Macrocephaly Lesser feeding difficulties & normal weight gain Episodic hypoglycemia of unknown etiology Severe DD/ID w/minimal speech Hypotonia Feeding difficulties Poor linear growth & weight gain Microcephaly IUGR Nevus flammeus (simplex) over the glabella Prominent globes Typical BOS posture DD/ID Prenatal and postnatal growth restriction Microcephaly Hypertrichosis Small feet In More severe feeding intolerance High myopia BOS posture Prominent globes Small hands & feet sometimes w/upper-limb reduction defects DD/ID Feeding difficulties IUGR Seizures Microcephaly Hypoplastic corpus callosum Facial characteristics: prominent eyes, anteverted nares Facial nevus flammeus (simplex) Hypertrichosis Joint contractures BOS posture Absence of high myopia & retinal/optic nerve atrophy Retinitis pigmentosa in childhood Hyperthermia Oropharyngeal muscle contraction AD = autosomal dominant; AR = autosomal recessive; DD/ID = developmental delay / intellectual disability; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked The phenotypic spectrum of C syndrome is not well defined, apart from the reportedly more common features. The mode of inheritance is also unclear since the molecular etiology remains elusive. A Japanese individual with a clinical diagnosis of C syndrome had a chromosomal translocation that disrupted Pathogenic variants in • Severe DD/ID • Microcephaly • Trigonocephaly • Upslanting palpebral fissures • Retrognathia • Low-set ears • Nevus flammeus (simplex) over glabella • BOS posture • Poor linear growth • Feeding difficulties • High myopia • DD • Hypotonia • Feeding difficulties in infancy • Nevus flammeus (simplex) over the glabella • Facial characteristics (particularly widely spaced eyes, prominent globes, & low-set or posteriorly rotated ears) • Hypertrichosis (2 of 6 reported cases) • Severe to profound ID • Microcephaly • BOS posture • Variable ID (borderline to severe) • Macrocephaly • Lesser feeding difficulties & normal weight gain • Episodic hypoglycemia of unknown etiology • Severe DD/ID w/minimal speech • Hypotonia • Feeding difficulties • Poor linear growth & weight gain • Microcephaly • IUGR • Nevus flammeus (simplex) over the glabella • Prominent globes • Typical BOS posture • DD/ID • Prenatal and postnatal growth restriction • Microcephaly • Hypertrichosis • Small feet • In • More severe feeding intolerance • High myopia • BOS posture • Prominent globes • Small hands & feet sometimes w/upper-limb reduction defects • DD/ID • Feeding difficulties • IUGR • Seizures • Microcephaly • Hypoplastic corpus callosum • Facial characteristics: prominent eyes, anteverted nares • Facial nevus flammeus (simplex) • Hypertrichosis • Joint contractures • BOS posture • Absence of high myopia & retinal/optic nerve atrophy • Retinitis pigmentosa in childhood • Hyperthermia • Oropharyngeal muscle contraction ## Management To establish the spectrum of manifestations and medical needs in an individual diagnosed with Bohring-Opitz syndrome (BOS), the following evaluations are recommended if they have not already been completed. Recommended Evaluations Following Initial Diagnosis of Bohring-Opitz Syndrome Goal: normal weight-for-length or body mass index Expected final adult height: <2nd centile Feeding evaluation (w/consideration of swallowing study) to assess for chronic emesis & aspiration risk Consideration of gastric emptying time to assess for poor gastric motility Treatment of Manifestations in Individuals with BOS For cyclic vomiting: identification & avoidance of triggers, G-tubes or GJ-tubes often decrease aspiration & improve nutrition; Primary closure of cleft lip along standard timeline Consider leaving cleft palates unrepaired when speech is lacking. Palate repair in a child at risk for obstructive apnea may ↑ risk. Assess language & mobility to determine plan for palate closure & alveolar bone grafting. Palate repair may be warranted in individuals w/language skills. Urinalysis & urine culture for possible urinary tract infection Evaluation for other possible sources of infection, pain, or exposure Creating a safe airway Treating aspiration → lung disease Treating severe obstructive sleep apnea not controlled by noninvasive pressure support (e.g., CPAP, BiPAP) or surgical management (e.g., adenoidectomy, mandibular distraction) Inhaled albuterol & inhaled steroids have improved respiratory status in some, although typical findings for reactive airway disease were lacking [ Descending aspiration of saliva can often be managed w/glycopyrrolate or salivary Botox injections. If vomiting is well controlled, growth typically improves, hospitalizations for dehydration and aspiration decrease, and overall health and well-being improve, although the rate of linear growth and weight gain remains poor. Lifelong feeding interventions may not be required, so periodic reexamination is appropriate. Triggers such as vaccines, infections, and anesthesia have been reported, although this is not a reason to avoid vaccination and anesthesia: all children with BOS should receive the full course of standard vaccinations as recommended by the local authorities. Cyproheptadine has been used for daily maintenance therapy. Prophylactic treatment prior to a trigger exposure with antiemetics has been beneficial. Abortive treatment includes lorazepam, ondansetron, and acetaminophen or some combination of an antiemetic, pain reliever, and sedative. Most affected individuals with feeding difficulties require a permanent feeding tube (G-tube or GJ-tube). Thickened feeds can help with emesis, and while G-tubes often do not stop emesis completely, they can limit the amount of nutrition lost through vomiting. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). Adequate treatment of severe emesis can decrease hospitalizations, infectious exposures, and aspiration. The following are appropriate: Renal ultrasound every three months from birth to age eight years to screen for the development of Wilms tumor [ Frequent monitoring of growth and development with interventions as needed (see Close management of feeding intolerance with a gastroenterology specialist Regular follow up with an ophthalmologist for vision optimization Triggers for vomiting should be avoided and managed with prophylactic antiemetics prior to the exposure (see See Search • Goal: normal weight-for-length or body mass index • Expected final adult height: <2nd centile • Feeding evaluation (w/consideration of swallowing study) to assess for chronic emesis & aspiration risk • Consideration of gastric emptying time to assess for poor gastric motility • For cyclic vomiting: identification & avoidance of triggers, • G-tubes or GJ-tubes often decrease aspiration & improve nutrition; • Primary closure of cleft lip along standard timeline • Consider leaving cleft palates unrepaired when speech is lacking. • Palate repair in a child at risk for obstructive apnea may ↑ risk. • Assess language & mobility to determine plan for palate closure & alveolar bone grafting. • Palate repair may be warranted in individuals w/language skills. • Urinalysis & urine culture for possible urinary tract infection • Evaluation for other possible sources of infection, pain, or exposure • Creating a safe airway • Treating aspiration → lung disease • Treating severe obstructive sleep apnea not controlled by noninvasive pressure support (e.g., CPAP, BiPAP) or surgical management (e.g., adenoidectomy, mandibular distraction) • Inhaled albuterol & inhaled steroids have improved respiratory status in some, although typical findings for reactive airway disease were lacking [ • Descending aspiration of saliva can often be managed w/glycopyrrolate or salivary Botox injections. • 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). • Renal ultrasound every three months from birth to age eight years to screen for the development of Wilms tumor [ • Frequent monitoring of growth and development with interventions as needed (see • Close management of feeding intolerance with a gastroenterology specialist • Regular follow up with an ophthalmologist for vision optimization ## Evaluations Following Initial Diagnosis To establish the spectrum of manifestations and medical needs in an individual diagnosed with Bohring-Opitz syndrome (BOS), the following evaluations are recommended if they have not already been completed. Recommended Evaluations Following Initial Diagnosis of Bohring-Opitz Syndrome Goal: normal weight-for-length or body mass index Expected final adult height: <2nd centile Feeding evaluation (w/consideration of swallowing study) to assess for chronic emesis & aspiration risk Consideration of gastric emptying time to assess for poor gastric motility • Goal: normal weight-for-length or body mass index • Expected final adult height: <2nd centile • Feeding evaluation (w/consideration of swallowing study) to assess for chronic emesis & aspiration risk • Consideration of gastric emptying time to assess for poor gastric motility ## Treatment of Manifestations Treatment of Manifestations in Individuals with BOS For cyclic vomiting: identification & avoidance of triggers, G-tubes or GJ-tubes often decrease aspiration & improve nutrition; Primary closure of cleft lip along standard timeline Consider leaving cleft palates unrepaired when speech is lacking. Palate repair in a child at risk for obstructive apnea may ↑ risk. Assess language & mobility to determine plan for palate closure & alveolar bone grafting. Palate repair may be warranted in individuals w/language skills. Urinalysis & urine culture for possible urinary tract infection Evaluation for other possible sources of infection, pain, or exposure Creating a safe airway Treating aspiration → lung disease Treating severe obstructive sleep apnea not controlled by noninvasive pressure support (e.g., CPAP, BiPAP) or surgical management (e.g., adenoidectomy, mandibular distraction) Inhaled albuterol & inhaled steroids have improved respiratory status in some, although typical findings for reactive airway disease were lacking [ Descending aspiration of saliva can often be managed w/glycopyrrolate or salivary Botox injections. If vomiting is well controlled, growth typically improves, hospitalizations for dehydration and aspiration decrease, and overall health and well-being improve, although the rate of linear growth and weight gain remains poor. Lifelong feeding interventions may not be required, so periodic reexamination is appropriate. Triggers such as vaccines, infections, and anesthesia have been reported, although this is not a reason to avoid vaccination and anesthesia: all children with BOS should receive the full course of standard vaccinations as recommended by the local authorities. Cyproheptadine has been used for daily maintenance therapy. Prophylactic treatment prior to a trigger exposure with antiemetics has been beneficial. Abortive treatment includes lorazepam, ondansetron, and acetaminophen or some combination of an antiemetic, pain reliever, and sedative. Most affected individuals with feeding difficulties require a permanent feeding tube (G-tube or GJ-tube). Thickened feeds can help with emesis, and while G-tubes often do not stop emesis completely, they can limit the amount of nutrition lost through vomiting. The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • For cyclic vomiting: identification & avoidance of triggers, • G-tubes or GJ-tubes often decrease aspiration & improve nutrition; • Primary closure of cleft lip along standard timeline • Consider leaving cleft palates unrepaired when speech is lacking. • Palate repair in a child at risk for obstructive apnea may ↑ risk. • Assess language & mobility to determine plan for palate closure & alveolar bone grafting. • Palate repair may be warranted in individuals w/language skills. • Urinalysis & urine culture for possible urinary tract infection • Evaluation for other possible sources of infection, pain, or exposure • Creating a safe airway • Treating aspiration → lung disease • Treating severe obstructive sleep apnea not controlled by noninvasive pressure support (e.g., CPAP, BiPAP) or surgical management (e.g., adenoidectomy, mandibular distraction) • Inhaled albuterol & inhaled steroids have improved respiratory status in some, although typical findings for reactive airway disease were lacking [ • Descending aspiration of saliva can often be managed w/glycopyrrolate or salivary Botox injections. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Developmental Delay / Intellectual Disability Management Issues The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States; standard recommendations may vary from country to country. Consideration of private supportive therapies based on the affected individual's needs is recommended. Specific recommendations regarding type of therapy can be made by a developmental pediatrician. In the US: Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. • Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities. • Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability. ## Motor Dysfunction Physical therapy is recommended to maximize mobility. Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). • Physical therapy is recommended to maximize mobility. • Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers). ## Prevention of Primary Manifestations Adequate treatment of severe emesis can decrease hospitalizations, infectious exposures, and aspiration. ## Surveillance The following are appropriate: Renal ultrasound every three months from birth to age eight years to screen for the development of Wilms tumor [ Frequent monitoring of growth and development with interventions as needed (see Close management of feeding intolerance with a gastroenterology specialist Regular follow up with an ophthalmologist for vision optimization • Renal ultrasound every three months from birth to age eight years to screen for the development of Wilms tumor [ • Frequent monitoring of growth and development with interventions as needed (see • Close management of feeding intolerance with a gastroenterology specialist • Regular follow up with an ophthalmologist for vision optimization ## Agents/Circumstances to Avoid Triggers for vomiting should be avoided and managed with prophylactic antiemetics prior to the exposure (see ## Evaluation of Relatives at Risk See ## Therapies Under Investigation Search ## Genetic Counseling Bohring-Opitz syndrome (BOS) is inherited in an autosomal dominant manner. Note: A previously published sib pair identified as having BOS (which could have implied either autosomal recessive inheritance or germline mosaicism in a parent) have subsequently been identified as having another genetic condition [ Most probands with BOS reported to date have the disorder as a result of a Recommendations for the evaluation of parents of a proband with an apparent Most affected individuals reported to date have had a If the The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. Once the • Most probands with BOS reported to date have the disorder as a result of a • Recommendations for the evaluation of parents of a proband with an apparent • Most affected individuals reported to date have had a • If the • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to parents of affected individuals. ## Mode of Inheritance Bohring-Opitz syndrome (BOS) is inherited in an autosomal dominant manner. Note: A previously published sib pair identified as having BOS (which could have implied either autosomal recessive inheritance or germline mosaicism in a parent) have subsequently been identified as having another genetic condition [ ## Risk to Family Members Most probands with BOS reported to date have the disorder as a result of a Recommendations for the evaluation of parents of a proband with an apparent Most affected individuals reported to date have had a If the • Most probands with BOS reported to date have the disorder as a result of a • Recommendations for the evaluation of parents of a proband with an apparent • Most affected individuals reported to date have had a • If the ## Related Genetic Counseling Issues The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to 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 ## Resources • • • • • • • • • ## Molecular Genetics Bohring-Opitz Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Bohring-Opitz Syndrome ( NOTE: Sporadic malignancies (including myelodysplastic syndrome) occurring in the absence of any other findings of BOS frequently contain a somatic variant in Somatic ## Molecular Pathogenesis NOTE: ## Cancer and Benign Tumors Sporadic malignancies (including myelodysplastic syndrome) occurring in the absence of any other findings of BOS frequently contain a somatic variant in Somatic ## Chapter Notes Dr Bianca Russell is a clinical geneticist at Cincinnati Children's Hospital who has been studying and caring for patients with Bohring-Opitz Syndrome since meeting two patients with the condition in 2012. She met these patients while under the mentorship of Dr John Graham at Cedars Sinai Medical Center. Dr Graham has been a leader in the field of clinical dysmorphology for decades and an outstanding mentor. Dr Wen-Hann Tan is a clinical geneticist at Boston Children's Hospital who cares for several patients with BOS and was an integral part of their 2015 publication on clinical management of BOS. Dr Russell and Dr Tan are continuing their work with the BOS community through a registry for disorders caused by pathogenic variants in the The authors would like to thank the BOS families and community for their commitment to understanding BOS and providing outstanding care for their children. They continue to be a true inspiration to the authors of this review. 15 February 2018 (ma) Review posted live 13 March 2017 (br) Initial submission • 15 February 2018 (ma) Review posted live • 13 March 2017 (br) Initial submission ## Author Notes Dr Bianca Russell is a clinical geneticist at Cincinnati Children's Hospital who has been studying and caring for patients with Bohring-Opitz Syndrome since meeting two patients with the condition in 2012. She met these patients while under the mentorship of Dr John Graham at Cedars Sinai Medical Center. Dr Graham has been a leader in the field of clinical dysmorphology for decades and an outstanding mentor. Dr Wen-Hann Tan is a clinical geneticist at Boston Children's Hospital who cares for several patients with BOS and was an integral part of their 2015 publication on clinical management of BOS. Dr Russell and Dr Tan are continuing their work with the BOS community through a registry for disorders caused by pathogenic variants in the ## Acknowledgments The authors would like to thank the BOS families and community for their commitment to understanding BOS and providing outstanding care for their children. They continue to be a true inspiration to the authors of this review. ## Revision History 15 February 2018 (ma) Review posted live 13 March 2017 (br) Initial submission • 15 February 2018 (ma) Review posted live • 13 March 2017 (br) Initial submission ## References ## Literature Cited Facial features of individuals with BOS at varying ages A-B. 2 years C. 18 months D. 2 years E-F. Infant and 12 years Facial features include glabellar and eyelid nevus flammeus (simplex) that fades with age, synophrys, facial hypotonia with full cheeks, prominent globes, widely spaced eyes (hypertelorism), depressed and wide nasal bridge, anteverted nares, palatal anomalies (cleft palate, high arched palate or prominent palatine ridges), cleft lip, micrognathia and/or retrognathia, low-set ears with increased posterior angulation, variable trigonocephaly, microcephaly, or normocephaly. Republished with permission from Typical BOS posture with flexion at the elbows, ulnar deviation, flexion of the wrists and metacarpophalangeal joints, and hypertonic extremities with central hypotonia Republished with permission from	[]	15/2/2018			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bor	bor	[ "Branchiootorenal Syndrome (BORS)", "Branchiootic Syndrome (BOS)", "Homeobox protein SIX1", "Protein phosphatase EYA1", "EYA1", "SIX1", "Branchiootorenal Spectrum Disorder" ]	Branchiootorenal Spectrum Disorder	Richard JH Smith, Hela Azaiez	Summary Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g., preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle, and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment. Congenital anomalies of the kidney and urinary tract (CAKUT) include kidney agenesis, hypoplasia, and dysplasia as well as urinary tract anomalies such as ureteropelvic junction (UPJ) obstruction, calyceal cysts and/or diverticula, and/or vesicoureteral reflux (VUR). Glomerular pathology that includes proteinuria and glomerulosclerosis has been reported. Some individuals progress to end-stage kidney disease (ESKD) depending on the severity of the kidney involvement. The clinical diagnosis of BORSD is established in an individual based on the presence of three or more major criteria OR two major criteria and two minor criteria OR one major criterion and a first-degree relative with BORSD. The molecular diagnosis of BORSD is established in a proband with suggestive findings and a heterozygous pathogenic variant in either BORSD is inherited in an autosomal dominant manner. Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of	Branchiootorenal syndrome (BORS) Branchiootic syndrome (BOS) • Branchiootorenal syndrome (BORS) • Branchiootic syndrome (BOS) ## Diagnosis The clinical diagnostic criteria for branchiootorenal spectrum disorder (BORSD) outlined by Branchiootorenal spectrum disorder (BORSD) Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. Severity ranges from mild to profound. Hearing loss can be progressive [ Kidney: agenesis, hypoplasia, dysplasia Urinary tract: Ureteropelvic junction (UPJ) obstruction Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) Preauricular tags External auditory canal anomalies (atresia or stenosis) Middle ear anomalies Malformation, malposition, dislocation, or fixation of the ossicles Reduction in size or malformation of the middle ear space Inner ear anomalies Cochlear abnormalities Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an Cochlear hypoplasia Thorny apical turn of the cochlea [ Enlargement of the cochlear and vestibular aqueducts Enlarged vestibular aqueduct (EVA) (see Hypoplasia of the lateral semicircular canal [ Widening of the internal auditory canal [ Membranous labyrinth dysplasia seen on MRI [ Other Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ Cleft/high-arched palate The Three or more major criteria OR Two major criteria and two minor criteria OR One major criterion and a first-degree relative with BORSD The A heterozygous pathogenic (or likely pathogenic) variant in either A heterozygous copy number abnormality (most commonly deletion) or structural variant of 8q13.2-13.3 involving Note: Copy number abnormalities involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic findings suggest the diagnosis of BORSD, 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 Branchiootorenal Spectrum Disorder 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 and contiguous gene deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (CGH), and 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. • • Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see • A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. • Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see • A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. • Severity ranges from mild to profound. • Hearing loss can be progressive [ • Severity ranges from mild to profound. • Hearing loss can be progressive [ • • Kidney: agenesis, hypoplasia, dysplasia • Urinary tract: • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Kidney: agenesis, hypoplasia, dysplasia • Urinary tract: • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see • A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. • Severity ranges from mild to profound. • Hearing loss can be progressive [ • Kidney: agenesis, hypoplasia, dysplasia • Urinary tract: • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Preauricular tags • External auditory canal anomalies (atresia or stenosis) • Middle ear anomalies • Malformation, malposition, dislocation, or fixation of the ossicles • Reduction in size or malformation of the middle ear space • Malformation, malposition, dislocation, or fixation of the ossicles • Reduction in size or malformation of the middle ear space • Inner ear anomalies • Cochlear abnormalities • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Enlarged vestibular aqueduct (EVA) (see • Hypoplasia of the lateral semicircular canal [ • Widening of the internal auditory canal [ • Membranous labyrinth dysplasia seen on MRI [ • Cochlear abnormalities • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Enlarged vestibular aqueduct (EVA) (see • Hypoplasia of the lateral semicircular canal [ • Widening of the internal auditory canal [ • Membranous labyrinth dysplasia seen on MRI [ • Other • Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ • Cleft/high-arched palate • Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ • Cleft/high-arched palate • Malformation, malposition, dislocation, or fixation of the ossicles • Reduction in size or malformation of the middle ear space • Cochlear abnormalities • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Enlarged vestibular aqueduct (EVA) (see • Hypoplasia of the lateral semicircular canal [ • Widening of the internal auditory canal [ • Membranous labyrinth dysplasia seen on MRI [ • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ • Cleft/high-arched palate • Three or more major criteria • OR • Two major criteria and two minor criteria • OR • One major criterion and a first-degree relative with BORSD • A heterozygous pathogenic (or likely pathogenic) variant in either • A heterozygous copy number abnormality (most commonly deletion) or structural variant of 8q13.2-13.3 involving • Note: Copy number abnormalities involving • For an introduction to multigene panels click ## Suggestive Findings Branchiootorenal spectrum disorder (BORSD) Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. Severity ranges from mild to profound. Hearing loss can be progressive [ Kidney: agenesis, hypoplasia, dysplasia Urinary tract: Ureteropelvic junction (UPJ) obstruction Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) Preauricular tags External auditory canal anomalies (atresia or stenosis) Middle ear anomalies Malformation, malposition, dislocation, or fixation of the ossicles Reduction in size or malformation of the middle ear space Inner ear anomalies Cochlear abnormalities Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an Cochlear hypoplasia Thorny apical turn of the cochlea [ Enlargement of the cochlear and vestibular aqueducts Enlarged vestibular aqueduct (EVA) (see Hypoplasia of the lateral semicircular canal [ Widening of the internal auditory canal [ Membranous labyrinth dysplasia seen on MRI [ Other Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ Cleft/high-arched palate • • Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see • A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. • Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see • A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. • Severity ranges from mild to profound. • Hearing loss can be progressive [ • Severity ranges from mild to profound. • Hearing loss can be progressive [ • • Kidney: agenesis, hypoplasia, dysplasia • Urinary tract: • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Kidney: agenesis, hypoplasia, dysplasia • Urinary tract: • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Branchial cleft sinus tracts appear as small (sometimes even pinpoint) openings anterior to the sternocleidomastoid muscle usually above the level of the hyoid bone, typically in the lower third of the neck (see • A branchial cleft cyst (typically in the same location as branchial cleft sinus tracts) forms when a branchial cleft sinus (also called a cervical fistula) does not have either an external opening in the skin or an internal opening in the mucosa. • Severity ranges from mild to profound. • Hearing loss can be progressive [ • Kidney: agenesis, hypoplasia, dysplasia • Urinary tract: • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Ureteropelvic junction (UPJ) obstruction • Calyceal cyst/diverticulum (cystic outpouching of a renal calyx communicating with the renal collecting system, lined with transitional epithelium and filled with urine) • Calyectasis (enlargement of renal calyces), pelviectasis (dilatation of the renal pelvis), hydronephrosis, and/or vesicoureteral reflux (VUR) • Preauricular tags • External auditory canal anomalies (atresia or stenosis) • Middle ear anomalies • Malformation, malposition, dislocation, or fixation of the ossicles • Reduction in size or malformation of the middle ear space • Malformation, malposition, dislocation, or fixation of the ossicles • Reduction in size or malformation of the middle ear space • Inner ear anomalies • Cochlear abnormalities • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Enlarged vestibular aqueduct (EVA) (see • Hypoplasia of the lateral semicircular canal [ • Widening of the internal auditory canal [ • Membranous labyrinth dysplasia seen on MRI [ • Cochlear abnormalities • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Enlarged vestibular aqueduct (EVA) (see • Hypoplasia of the lateral semicircular canal [ • Widening of the internal auditory canal [ • Membranous labyrinth dysplasia seen on MRI [ • Other • Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ • Cleft/high-arched palate • Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ • Cleft/high-arched palate • Malformation, malposition, dislocation, or fixation of the ossicles • Reduction in size or malformation of the middle ear space • Cochlear abnormalities • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Enlarged vestibular aqueduct (EVA) (see • Hypoplasia of the lateral semicircular canal [ • Widening of the internal auditory canal [ • Membranous labyrinth dysplasia seen on MRI [ • Offset cochlear turns (unwound cochlea) are measured via turn alignment ratio (TAR). TAR ratios <0.476 are considered diagnostic for an • Cochlear hypoplasia • Thorny apical turn of the cochlea [ • Enlargement of the cochlear and vestibular aqueducts • Mild facial asymmetry (due to underdevelopment of the mandible or cheek on one side, which often makes the face appear long and narrow) [ • Cleft/high-arched palate ## Establishing the Diagnosis The Three or more major criteria OR Two major criteria and two minor criteria OR One major criterion and a first-degree relative with BORSD The A heterozygous pathogenic (or likely pathogenic) variant in either A heterozygous copy number abnormality (most commonly deletion) or structural variant of 8q13.2-13.3 involving Note: Copy number abnormalities involving Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [ Molecular genetic testing approaches can include a combination of When the phenotypic findings suggest the diagnosis of BORSD, 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 Branchiootorenal Spectrum Disorder 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 and contiguous gene deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (CGH), and 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. • Three or more major criteria • OR • Two major criteria and two minor criteria • OR • One major criterion and a first-degree relative with BORSD • A heterozygous pathogenic (or likely pathogenic) variant in either • A heterozygous copy number abnormality (most commonly deletion) or structural variant of 8q13.2-13.3 involving • Note: Copy number abnormalities involving • For an introduction to multigene panels click ## Option 1 When the phenotypic findings suggest the diagnosis of BORSD, 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 Branchiootorenal Spectrum Disorder 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 and contiguous gene deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), array comparative genomic hybridization (CGH), and 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 Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g., preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle, and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment. Congenital anomalies of the kidney and urinary tract (CAKUT) include kidney agenesis, hypoplasia, and dysplasia as well as urinary tract anomalies such as ureteropelvic junction (UPJ) obstruction, calyceal cysts and/or diverticula, and/or vesicoureteral reflux (VUR). Glomerular pathology that includes proteinuria and glomerulosclerosis has been reported. Some individuals progress to end-stage kidney disease (ESKD) depending on the severity of the kidney involvement. Extreme variability can be observed in the presence, severity, and type of branchial arch and otologic anomalies and CAKUT between the right and left sides of an affected individual. Similarly, marked interfamilial variability and intrafamilial variability are observed. To date, more than 400 individuals with BORSD have been described in the literature [ Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) Severity: mild (27%), moderate (22%), severe (33%), profound (16%) Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ Renal agenesis (29%), hypoplasia (19%), dysplasia (14%) Ureteropelvic junction (UPJ) obstruction (10%) Calyceal cyst/diverticulum (10%) Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux (VUR) (5% each) CAKUT can be unilateral or bilateral and can occur in any combination. The most severe anomalies (i.e., bilateral renal agenesis) result in pregnancy loss (due to miscarriage) or neonatal death. The less severe findings – that are nonetheless medically significant – can result in progressive kidney dysfunction and may lead to ESKD. If kidney function is sufficiently impaired, kidney replacement therapy (KRT) may be required. KRT refers to medical treatments that substitute for the normal kidney function and includes dialysis (hemodialysis and peritoneal dialysis) and kidney transplantation (see Lacrimal duct aplasia (absence or hypoplasia of the lacrimal ducts) presents as epiphora due to absence or hypoplasia of the nasolacrimal or tear duct, a tiny tube that carries tears from the eye to the nose [ Short or cleft palate may contribute to feeding or speech difficulties [ Retrognathia (posteriorly positioned mandible) may contribute to airway or feeding difficulties [ Facial nerve paralysis (inability to move one side of the face) may occasionally be seen [ Facial asymmetry is often mild and may involve mandibular hypoplasia or hemifacial microsomia, which may contribute to feeding or speech difficulties in infancy and childhood [ Gustatory lacrimation (also known as "crocodile tears"), involuntary tearing while eating or drinking, is occasionally seen. Congenital anterior segment anomalies of the eye with or without cataract have been reported in two individuals with other features of BORSD, suggesting that congenital eye anomalies may be an occasional feature of BORSD [ Euthyroid goiter, enlargement of the thyroid gland associated with normal levels of thyroid hormone, has been reported. In a small Tunisian family, five persons heterozygous for a Clinically actionable genotype-phenotype correlations for Based on clinical studies of large pedigrees, BORSD appears to have 100% penetrance; however, intrafamilial variability and interfamilial variability are high [ Branchiootorenal spectrum disorder (BORSD) encompasses branchiootorenal syndrome (BORS) and branchiootic syndrome (BOS), which differ primarily by the presence (BORS) or absence (BOS) of renal abnormalities. Individuals with a confirmed molecular diagnosis within the same family often exhibit features consistent with either BORS or BOS, highlighting the intrafamilial variability in phenotypic expression [ BORS was originally known eponymously as Melnick-Fraser syndrome. Large-scale prevalence data for BORSD are lacking. In the authors' experience at the Molecular Otolaryngology and Renal Research Laboratories (MORL), as of January 2025, 3,376 of 8,032 persons (42%) screened for genetic causes of hearing loss (no exclusionary criteria) had an identified genetic cause of hearing loss. Of persons with a genetic diagnosis, 58 persons (0.72%) had BORSD [H Azaiez & R Smith, unpublished data]. A comprehensive nationwide survey in Japan estimated that only 250 individuals with BORSD (95% confidence interval: 170-320) were identified in clinics in 2009-2010, suggesting that the prevalence of BORSD is lower in Japan than in Western countries [ • Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) • Severity: mild (27%), moderate (22%), severe (33%), profound (16%) • Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ • Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) • Severity: mild (27%), moderate (22%), severe (33%), profound (16%) • Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ • Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) • Severity: mild (27%), moderate (22%), severe (33%), profound (16%) • Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ • Renal agenesis (29%), hypoplasia (19%), dysplasia (14%) • Ureteropelvic junction (UPJ) obstruction (10%) • Calyceal cyst/diverticulum (10%) • Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux (VUR) (5% each) • Lacrimal duct aplasia (absence or hypoplasia of the lacrimal ducts) presents as epiphora due to absence or hypoplasia of the nasolacrimal or tear duct, a tiny tube that carries tears from the eye to the nose [ • Short or cleft palate may contribute to feeding or speech difficulties [ • Retrognathia (posteriorly positioned mandible) may contribute to airway or feeding difficulties [ • Facial nerve paralysis (inability to move one side of the face) may occasionally be seen [ • Facial asymmetry is often mild and may involve mandibular hypoplasia or hemifacial microsomia, which may contribute to feeding or speech difficulties in infancy and childhood [ • Gustatory lacrimation (also known as "crocodile tears"), involuntary tearing while eating or drinking, is occasionally seen. • Congenital anterior segment anomalies of the eye with or without cataract have been reported in two individuals with other features of BORSD, suggesting that congenital eye anomalies may be an occasional feature of BORSD [ • Euthyroid goiter, enlargement of the thyroid gland associated with normal levels of thyroid hormone, has been reported. ## Clinical Description Branchiootorenal spectrum disorder (BORSD) is characterized by second branchial arch anomalies (e.g., preauricular pits and branchial cleft sinuses or cysts) and malformations of the outer, middle, and inner ear associated with conductive, sensorineural, and/or mixed hearing impairment. Congenital anomalies of the kidney and urinary tract (CAKUT) include kidney agenesis, hypoplasia, and dysplasia as well as urinary tract anomalies such as ureteropelvic junction (UPJ) obstruction, calyceal cysts and/or diverticula, and/or vesicoureteral reflux (VUR). Glomerular pathology that includes proteinuria and glomerulosclerosis has been reported. Some individuals progress to end-stage kidney disease (ESKD) depending on the severity of the kidney involvement. Extreme variability can be observed in the presence, severity, and type of branchial arch and otologic anomalies and CAKUT between the right and left sides of an affected individual. Similarly, marked interfamilial variability and intrafamilial variability are observed. To date, more than 400 individuals with BORSD have been described in the literature [ Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) Severity: mild (27%), moderate (22%), severe (33%), profound (16%) Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ Renal agenesis (29%), hypoplasia (19%), dysplasia (14%) Ureteropelvic junction (UPJ) obstruction (10%) Calyceal cyst/diverticulum (10%) Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux (VUR) (5% each) CAKUT can be unilateral or bilateral and can occur in any combination. The most severe anomalies (i.e., bilateral renal agenesis) result in pregnancy loss (due to miscarriage) or neonatal death. The less severe findings – that are nonetheless medically significant – can result in progressive kidney dysfunction and may lead to ESKD. If kidney function is sufficiently impaired, kidney replacement therapy (KRT) may be required. KRT refers to medical treatments that substitute for the normal kidney function and includes dialysis (hemodialysis and peritoneal dialysis) and kidney transplantation (see Lacrimal duct aplasia (absence or hypoplasia of the lacrimal ducts) presents as epiphora due to absence or hypoplasia of the nasolacrimal or tear duct, a tiny tube that carries tears from the eye to the nose [ Short or cleft palate may contribute to feeding or speech difficulties [ Retrognathia (posteriorly positioned mandible) may contribute to airway or feeding difficulties [ Facial nerve paralysis (inability to move one side of the face) may occasionally be seen [ Facial asymmetry is often mild and may involve mandibular hypoplasia or hemifacial microsomia, which may contribute to feeding or speech difficulties in infancy and childhood [ Gustatory lacrimation (also known as "crocodile tears"), involuntary tearing while eating or drinking, is occasionally seen. Congenital anterior segment anomalies of the eye with or without cataract have been reported in two individuals with other features of BORSD, suggesting that congenital eye anomalies may be an occasional feature of BORSD [ Euthyroid goiter, enlargement of the thyroid gland associated with normal levels of thyroid hormone, has been reported. In a small Tunisian family, five persons heterozygous for a • Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) • Severity: mild (27%), moderate (22%), severe (33%), profound (16%) • Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ • Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) • Severity: mild (27%), moderate (22%), severe (33%), profound (16%) • Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ • Type: conductive due to middle ear abnormalities (33%), sensorineural due to inner ear abnormalities (29%), and mixed due to both middle ear and inner ear abnormalities (52%) • Severity: mild (27%), moderate (22%), severe (33%), profound (16%) • Non-progressive (~70%) and progressive (~30%), which correlates with presence of a dilated vestibular aqueduct (DVA) [ • Renal agenesis (29%), hypoplasia (19%), dysplasia (14%) • Ureteropelvic junction (UPJ) obstruction (10%) • Calyceal cyst/diverticulum (10%) • Calyectasis, pelviectasis, hydronephrosis, and vesicoureteral reflux (VUR) (5% each) • Lacrimal duct aplasia (absence or hypoplasia of the lacrimal ducts) presents as epiphora due to absence or hypoplasia of the nasolacrimal or tear duct, a tiny tube that carries tears from the eye to the nose [ • Short or cleft palate may contribute to feeding or speech difficulties [ • Retrognathia (posteriorly positioned mandible) may contribute to airway or feeding difficulties [ • Facial nerve paralysis (inability to move one side of the face) may occasionally be seen [ • Facial asymmetry is often mild and may involve mandibular hypoplasia or hemifacial microsomia, which may contribute to feeding or speech difficulties in infancy and childhood [ • Gustatory lacrimation (also known as "crocodile tears"), involuntary tearing while eating or drinking, is occasionally seen. • Congenital anterior segment anomalies of the eye with or without cataract have been reported in two individuals with other features of BORSD, suggesting that congenital eye anomalies may be an occasional feature of BORSD [ • Euthyroid goiter, enlargement of the thyroid gland associated with normal levels of thyroid hormone, has been reported. ## Genotype-Phenotype Correlations Clinically actionable genotype-phenotype correlations for ## Penetrance Based on clinical studies of large pedigrees, BORSD appears to have 100% penetrance; however, intrafamilial variability and interfamilial variability are high [ ## Nomenclature Branchiootorenal spectrum disorder (BORSD) encompasses branchiootorenal syndrome (BORS) and branchiootic syndrome (BOS), which differ primarily by the presence (BORS) or absence (BOS) of renal abnormalities. Individuals with a confirmed molecular diagnosis within the same family often exhibit features consistent with either BORS or BOS, highlighting the intrafamilial variability in phenotypic expression [ BORS was originally known eponymously as Melnick-Fraser syndrome. ## Prevalence Large-scale prevalence data for BORSD are lacking. In the authors' experience at the Molecular Otolaryngology and Renal Research Laboratories (MORL), as of January 2025, 3,376 of 8,032 persons (42%) screened for genetic causes of hearing loss (no exclusionary criteria) had an identified genetic cause of hearing loss. Of persons with a genetic diagnosis, 58 persons (0.72%) had BORSD [H Azaiez & R Smith, unpublished data]. A comprehensive nationwide survey in Japan estimated that only 250 individuals with BORSD (95% confidence interval: 170-320) were identified in clinics in 2009-2010, suggesting that the prevalence of BORSD is lower in Japan than in Western countries [ ## Genetically Related (Allelic) Disorders Although a heterozygous canonic splice donor variant in Note: (1) Nonsyndromic ## Differential Diagnosis At the time of this writing, Genes of Interest in the Differential Diagnosis of Branchiootorenal Spectrum Disorder AD = autosomal dominant; AR = autosomal recessive; BOSRD = branchiootorenal spectrum disorder; EVA = enlarged vestibular aqueduct; MOI = mode of inheritance; SNHL = sensorineural hearing loss; XL = X-linked See ## Management No consensus clinical practice guidelines for branchiootorenal spectrum disorder (BORSD) have been published. The following recommendations are based on the authors' personal experience managing individuals with BORSD. To establish the extent of disease and needs in an individual diagnosed with BORSD, the evaluations summarized in Branchiootorenal Spectrum Disorder: Recommended Evaluations Following Initial Diagnosis Consider imaging study (CT or MRI) of neck if a mass is palpable under sternocleidomastoid muscle. It may be helpful to obtain a fistulogram by using a contrast agent to visualize the path of the tract connecting the skin on the neck to the tonsillar fossa. Kidney ultrasound exam to detect agenesis, hypoplasia, & dysplasia DMSA kidney scan to evaluate kidney scarring BUN & blood creatinine concentration to assess GFR Urinalysis to detect proteinuria & hematuria Excretory urography (intravenous pyelography) to visualize urinary tract, incl kidneys, ureters, & bladder MAG3 diuretic kidney scan to evaluate UPJ obstruction & drainage efficiency VCUG to assess VUR Community or Social work involvement for parental support Home nursing referral ABR = auditory brain stem response; BORSD = branchiootorenal spectrum disorder; BUN = blood urea nitrogen; CAKUT = congenital anomalies of the kidney and urinary tract; DMSA = dimercaptosuccinic acid; GFR = glomerular filtration rate; MOI = mode of inheritance; OAE = otoacoustic emissions; UPJ = ureteropelvic junction; VCUG = voiding cystourethrogram; VUR = vesicoureteral reflux See Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) Supportive care ideally involves coordinated care by a multidisciplinary team including an otolaryngologist, audiologist, speech-language pathologist, nephrologist, urologist, clinical geneticist, and genetic counselor (see Branchiootorenal Spectrum Disorder: Treatment of Manifestations Hearing aids are appropriate for persons with mild-to-moderate sensorineural or mixed hearing loss. CI is indicated for persons w/bilateral severe-to-profound hearing loss. CI = cochlear implantation; UPJ = ureteropelvic junction; VUR = vesicoureteral reflux The only contraindication to the use of either hearing aids or CI is cochlear nerve aplasia [ While inner ear malformations do not preclude candidacy for CI, preoperative imaging and planning is required [ To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Branchiootorenal Spectrum Disorder: Recommended Surveillance Annually More frequently if fluctuation or progression of hearing loss is described by affected person BORSD = branchiootorenal spectrum disorder For individuals with CAKUT, it is recommended that kidney function be evaluated at least annually, especially if the CAKUT involves unilateral kidney dysplasia. Follow up as recommended by a pediatric nephologist is essential for detecting potential complications and for monitoring the long-term effects of kidney abnormalities. Most important for persons with mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises, particularly secondary to earbud use. The headphone safety feature built into most smartphones can be set to a maximum limit of 75 decibels (dB). Headphone/earbud safety features can be found in the phone settings menu: In iPhones, under Settings > Sounds & Haptics > Headphone Safety In Android phones, under Settings > Sounds & Vibrations > Volume > Media volume limit Also see these general resources on noise reduction: Anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing has led some providers to recommend avoiding activities such as weightlifting and contact sports [ It is appropriate to evaluate apparently asymptomatic relatives at risk for BORSD to determine if treatable and/or possibly progressive otologic and/or kidney abnormalities are present. Evaluations can include: Molecular genetic testing if the BORSD-related genetic alteration in the family is known; Comprehensive physical examination (to include hearing evaluation and kidney imaging and function studies) if the genetic alteration in the family is not known. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ See A pregnant woman with BORSD who has known kidney involvement should consider seeking care from a maternal-fetal medicine specialist. These specialists have additional training and board certification in managing pregnancies with complex medical problems. Search • Consider imaging study (CT or MRI) of neck if a mass is palpable under sternocleidomastoid muscle. • It may be helpful to obtain a fistulogram by using a contrast agent to visualize the path of the tract connecting the skin on the neck to the tonsillar fossa. • Kidney ultrasound exam to detect agenesis, hypoplasia, & dysplasia • DMSA kidney scan to evaluate kidney scarring • BUN & blood creatinine concentration to assess GFR • Urinalysis to detect proteinuria & hematuria • Excretory urography (intravenous pyelography) to visualize urinary tract, incl kidneys, ureters, & bladder • MAG3 diuretic kidney scan to evaluate UPJ obstruction & drainage efficiency • VCUG to assess VUR • Community or • Social work involvement for parental support • Home nursing referral • Hearing aids are appropriate for persons with mild-to-moderate sensorineural or mixed hearing loss. • CI is indicated for persons w/bilateral severe-to-profound hearing loss. • Annually • More frequently if fluctuation or progression of hearing loss is described by affected person • In iPhones, under Settings > Sounds & Haptics > Headphone Safety • In Android phones, under Settings > Sounds & Vibrations > Volume > Media volume limit • • • Molecular genetic testing if the BORSD-related genetic alteration in the family is known; • Comprehensive physical examination (to include hearing evaluation and kidney imaging and function studies) if the genetic alteration in the family is not known. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with BORSD, the evaluations summarized in Branchiootorenal Spectrum Disorder: Recommended Evaluations Following Initial Diagnosis Consider imaging study (CT or MRI) of neck if a mass is palpable under sternocleidomastoid muscle. It may be helpful to obtain a fistulogram by using a contrast agent to visualize the path of the tract connecting the skin on the neck to the tonsillar fossa. Kidney ultrasound exam to detect agenesis, hypoplasia, & dysplasia DMSA kidney scan to evaluate kidney scarring BUN & blood creatinine concentration to assess GFR Urinalysis to detect proteinuria & hematuria Excretory urography (intravenous pyelography) to visualize urinary tract, incl kidneys, ureters, & bladder MAG3 diuretic kidney scan to evaluate UPJ obstruction & drainage efficiency VCUG to assess VUR Community or Social work involvement for parental support Home nursing referral ABR = auditory brain stem response; BORSD = branchiootorenal spectrum disorder; BUN = blood urea nitrogen; CAKUT = congenital anomalies of the kidney and urinary tract; DMSA = dimercaptosuccinic acid; GFR = glomerular filtration rate; MOI = mode of inheritance; OAE = otoacoustic emissions; UPJ = ureteropelvic junction; VCUG = voiding cystourethrogram; VUR = vesicoureteral reflux See Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant) • Consider imaging study (CT or MRI) of neck if a mass is palpable under sternocleidomastoid muscle. • It may be helpful to obtain a fistulogram by using a contrast agent to visualize the path of the tract connecting the skin on the neck to the tonsillar fossa. • Kidney ultrasound exam to detect agenesis, hypoplasia, & dysplasia • DMSA kidney scan to evaluate kidney scarring • BUN & blood creatinine concentration to assess GFR • Urinalysis to detect proteinuria & hematuria • Excretory urography (intravenous pyelography) to visualize urinary tract, incl kidneys, ureters, & bladder • MAG3 diuretic kidney scan to evaluate UPJ obstruction & drainage efficiency • VCUG to assess VUR • Community or • Social work involvement for parental support • Home nursing referral ## Treatment of Manifestations Supportive care ideally involves coordinated care by a multidisciplinary team including an otolaryngologist, audiologist, speech-language pathologist, nephrologist, urologist, clinical geneticist, and genetic counselor (see Branchiootorenal Spectrum Disorder: Treatment of Manifestations Hearing aids are appropriate for persons with mild-to-moderate sensorineural or mixed hearing loss. CI is indicated for persons w/bilateral severe-to-profound hearing loss. CI = cochlear implantation; UPJ = ureteropelvic junction; VUR = vesicoureteral reflux The only contraindication to the use of either hearing aids or CI is cochlear nerve aplasia [ While inner ear malformations do not preclude candidacy for CI, preoperative imaging and planning is required [ • Hearing aids are appropriate for persons with mild-to-moderate sensorineural or mixed hearing loss. • CI is indicated for persons w/bilateral severe-to-profound hearing loss. ## Surveillance To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in Branchiootorenal Spectrum Disorder: Recommended Surveillance Annually More frequently if fluctuation or progression of hearing loss is described by affected person BORSD = branchiootorenal spectrum disorder For individuals with CAKUT, it is recommended that kidney function be evaluated at least annually, especially if the CAKUT involves unilateral kidney dysplasia. Follow up as recommended by a pediatric nephologist is essential for detecting potential complications and for monitoring the long-term effects of kidney abnormalities. • Annually • More frequently if fluctuation or progression of hearing loss is described by affected person ## Agents/Circumstances to Avoid Most important for persons with mild-to-moderate hearing loss is avoidance of repeated overexposure to loud noises, particularly secondary to earbud use. The headphone safety feature built into most smartphones can be set to a maximum limit of 75 decibels (dB). Headphone/earbud safety features can be found in the phone settings menu: In iPhones, under Settings > Sounds & Haptics > Headphone Safety In Android phones, under Settings > Sounds & Vibrations > Volume > Media volume limit Also see these general resources on noise reduction: Anecdotal reports that increased intracranial pressure in individuals with enlarged vestibular aqueduct (EVA) can occasionally trigger a decline in hearing has led some providers to recommend avoiding activities such as weightlifting and contact sports [ • In iPhones, under Settings > Sounds & Haptics > Headphone Safety • In Android phones, under Settings > Sounds & Vibrations > Volume > Media volume limit • • ## Evaluation of Relatives at Risk It is appropriate to evaluate apparently asymptomatic relatives at risk for BORSD to determine if treatable and/or possibly progressive otologic and/or kidney abnormalities are present. Evaluations can include: Molecular genetic testing if the BORSD-related genetic alteration in the family is known; Comprehensive physical examination (to include hearing evaluation and kidney imaging and function studies) if the genetic alteration in the family is not known. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ See • Molecular genetic testing if the BORSD-related genetic alteration in the family is known; • Comprehensive physical examination (to include hearing evaluation and kidney imaging and function studies) if the genetic alteration in the family is not known. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ ## Pregnancy Management A pregnant woman with BORSD who has known kidney involvement should consider seeking care from a maternal-fetal medicine specialist. These specialists have additional training and board certification in managing pregnancies with complex medical problems. ## Therapies Under Investigation Search ## Genetic Counseling Branchiootorenal spectrum disorder (BORSD) is inherited in an autosomal dominant manner. An individual diagnosed with BORSD may represent a simplex case (i.e., the only affected family member). Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of If the proband appears to be the only affected family member, evaluation of the parents of the proband is recommended to determine their clinical/genetic status and inform recurrence risk assessment. Evaluations include the following: Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 Note: If the proband has a copy number variant or complex structural rearrangement involving Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. Although most individuals diagnosed with BORSD have an affected parent, the proband may appear to be the only affected family member because of failure to recognize the disorder in relatives. Therefore, appropriate evaluation of the parents (i.e., molecular genetic testing if the proband has a molecular diagnosis and/or clinical evaluation of the parents) is necessary to establish the family history. If a parent has a clinical and/or molecular diagnosis of BORSD, the risk to the sibs is 50%. BOSRD appears to have 100% penetrance; however phenotypic expressivity is highly variable. Disease phenotype and severity in affected sibs cannot be accurately predicted and is extremely variable even within the same family. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ If a molecular diagnosis has been established in the proband and the BORSD-related genetic alteration 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 proband represents a simplex case and the parents are unaffected based on appropriate clinical evaluation, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism. See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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. • An individual diagnosed with BORSD may represent a simplex case (i.e., the only affected family member). Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of • If the proband appears to be the only affected family member, evaluation of the parents of the proband is recommended to determine their clinical/genetic status and inform recurrence risk assessment. Evaluations include the following: • Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 • Note: If the proband has a copy number variant or complex structural rearrangement involving • Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. • Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 • Note: If the proband has a copy number variant or complex structural rearrangement involving • Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. • Although most individuals diagnosed with BORSD have an affected parent, the proband may appear to be the only affected family member because of failure to recognize the disorder in relatives. Therefore, appropriate evaluation of the parents (i.e., molecular genetic testing if the proband has a molecular diagnosis and/or clinical evaluation of the parents) is necessary to establish the family history. • Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 • Note: If the proband has a copy number variant or complex structural rearrangement involving • Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. • If a parent has a clinical and/or molecular diagnosis of BORSD, the risk to the sibs is 50%. BOSRD appears to have 100% penetrance; however phenotypic expressivity is highly variable. Disease phenotype and severity in affected sibs cannot be accurately predicted and is extremely variable even within the same family. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ • If a molecular diagnosis has been established in the proband and the BORSD-related genetic alteration 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 proband represents a simplex case and the parents are unaffected based on appropriate clinical evaluation, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk. ## Mode of Inheritance Branchiootorenal spectrum disorder (BORSD) is inherited in an autosomal dominant manner. ## Risk to Family Members An individual diagnosed with BORSD may represent a simplex case (i.e., the only affected family member). Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of If the proband appears to be the only affected family member, evaluation of the parents of the proband is recommended to determine their clinical/genetic status and inform recurrence risk assessment. Evaluations include the following: Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 Note: If the proband has a copy number variant or complex structural rearrangement involving Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. Although most individuals diagnosed with BORSD have an affected parent, the proband may appear to be the only affected family member because of failure to recognize the disorder in relatives. Therefore, appropriate evaluation of the parents (i.e., molecular genetic testing if the proband has a molecular diagnosis and/or clinical evaluation of the parents) is necessary to establish the family history. If a parent has a clinical and/or molecular diagnosis of BORSD, the risk to the sibs is 50%. BOSRD appears to have 100% penetrance; however phenotypic expressivity is highly variable. Disease phenotype and severity in affected sibs cannot be accurately predicted and is extremely variable even within the same family. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ If a molecular diagnosis has been established in the proband and the BORSD-related genetic alteration 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 proband represents a simplex case and the parents are unaffected based on appropriate clinical evaluation, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism. • An individual diagnosed with BORSD may represent a simplex case (i.e., the only affected family member). Of individuals with a molecular diagnosis of BORSD, approximately 10%-20% have the disorder as the result of • If the proband appears to be the only affected family member, evaluation of the parents of the proband is recommended to determine their clinical/genetic status and inform recurrence risk assessment. Evaluations include the following: • Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 • Note: If the proband has a copy number variant or complex structural rearrangement involving • Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. • Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 • Note: If the proband has a copy number variant or complex structural rearrangement involving • Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. • Although most individuals diagnosed with BORSD have an affected parent, the proband may appear to be the only affected family member because of failure to recognize the disorder in relatives. Therefore, appropriate evaluation of the parents (i.e., molecular genetic testing if the proband has a molecular diagnosis and/or clinical evaluation of the parents) is necessary to establish the family history. • Molecular genetic testing if a molecular diagnosis has been established in the proband. If the proband has a BORSD-related pathogenic variant that 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 • Note: If the proband has a copy number variant or complex structural rearrangement involving • Examination of the parents for hearing loss, preauricular pits, lacrimal duct stenosis, branchial fistulae and/or cysts, and kidney anomalies if a molecular diagnosis has not been established in the proband. • If a parent has a clinical and/or molecular diagnosis of BORSD, the risk to the sibs is 50%. BOSRD appears to have 100% penetrance; however phenotypic expressivity is highly variable. Disease phenotype and severity in affected sibs cannot be accurately predicted and is extremely variable even within the same family. Note: Individuals with an affected family member need only one major BORSD criterion to establish the diagnosis of BORSD [ • If a molecular diagnosis has been established in the proband and the BORSD-related genetic alteration 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 proband represents a simplex case and the parents are unaffected based on appropriate clinical evaluation, the recurrence risk to sibs is estimated to be 1% because of the possibility of parental gonadal mosaicism. ## Related Genetic Counseling Issues See Management, The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected 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: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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 Canada • • • • • • • • • • • • • United Kingdom • • • Canada • • • • • ## Molecular Genetics Branchiootorenal Spectrum Disorder: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Branchiootorenal Spectrum Disorder ( The ClinGen Hearing Loss Gene Curation Expert Panel has classified the association between See See • See • See ## Molecular Pathogenesis The ClinGen Hearing Loss Gene Curation Expert Panel has classified the association between See See • See • See ## Chapter Notes Supported in part by grants DC02842, DC012049, and DC017955 from the NIDCD (RJHS). Hela Azaiez, MS, PhD (2025-present)Glenn E Green, MD; Arizona Health Sciences Center (1999-2001)Sai D Prasad; University of Iowa (1999-2001)Richard JH Smith, MD (1999-present) 26 June 2025 (bp) Comprehensive update posted live 6 September 2018 (ha) Comprehensive update posted live 22 October 2015 (me) Comprehensive update posted live 20 June 2013 (me) Comprehensive update posted live 27 August 2009 (me) Comprehensive update posted live 24 January 2006 (me) Comprehensive update posted live 30 October 2003 (me) Comprehensive update posted live 28 November 2001 (me) Comprehensive update posted live 19 March 1999 (pb) Review posted live 6 January 1999 (rjhs) Original submission • 26 June 2025 (bp) Comprehensive update posted live • 6 September 2018 (ha) Comprehensive update posted live • 22 October 2015 (me) Comprehensive update posted live • 20 June 2013 (me) Comprehensive update posted live • 27 August 2009 (me) Comprehensive update posted live • 24 January 2006 (me) Comprehensive update posted live • 30 October 2003 (me) Comprehensive update posted live • 28 November 2001 (me) Comprehensive update posted live • 19 March 1999 (pb) Review posted live • 6 January 1999 (rjhs) Original submission ## Author Notes ## Acknowledgments Supported in part by grants DC02842, DC012049, and DC017955 from the NIDCD (RJHS). ## Author History Hela Azaiez, MS, PhD (2025-present)Glenn E Green, MD; Arizona Health Sciences Center (1999-2001)Sai D Prasad; University of Iowa (1999-2001)Richard JH Smith, MD (1999-present) ## Revision History 26 June 2025 (bp) Comprehensive update posted live 6 September 2018 (ha) Comprehensive update posted live 22 October 2015 (me) Comprehensive update posted live 20 June 2013 (me) Comprehensive update posted live 27 August 2009 (me) Comprehensive update posted live 24 January 2006 (me) Comprehensive update posted live 30 October 2003 (me) Comprehensive update posted live 28 November 2001 (me) Comprehensive update posted live 19 March 1999 (pb) Review posted live 6 January 1999 (rjhs) Original submission • 26 June 2025 (bp) Comprehensive update posted live • 6 September 2018 (ha) Comprehensive update posted live • 22 October 2015 (me) Comprehensive update posted live • 20 June 2013 (me) Comprehensive update posted live • 27 August 2009 (me) Comprehensive update posted live • 24 January 2006 (me) Comprehensive update posted live • 30 October 2003 (me) Comprehensive update posted live • 28 November 2001 (me) Comprehensive update posted live • 19 March 1999 (pb) Review posted live • 6 January 1999 (rjhs) Original submission ## References American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available American College of Medical Genetics. Statement on universal newborn hearing screening. Available • American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available • American College of Medical Genetics. Statement on universal newborn hearing screening. Available ## Published Guidelines / Consensus Statements American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available American College of Medical Genetics. Statement on universal newborn hearing screening. Available • American College of Medical Genetics. Genetics evaluation guidelines for the etiologic diagnosis of congenital hearing loss. Genetic evaluation of congenital hearing loss expert panel. Available • American College of Medical Genetics. Statement on universal newborn hearing screening. Available ## Literature Cited A second branchial arch fistula or sinus tract appears as a small opening in the skin on the side of the neck anterior to the sternocleidomastoid muscle (black arrow). It can extend internally to open into the tonsillar fossa or tonsillar pillars, or it may end as a blind pouch. A branchial cyst forms when neither an external opening in the skin nor an internal opening in the mucosa are present. Branchial cysts typically present as non-tender masses in the neck just anterior to the sternocleidomastoid muscle. Preauricular pit. The pinna forms from six small prominences known as the hillocks of His. These hillocks develop around the 6th week of embryonic life from the first and second pharyngeal arches and fuse together to form the structured shape of the pinna. Improper fusion of these hillocks can lead to preauricular pits. Anteverted pinna (posterior lateral views of left and right ear). An anteverted pinna or cupped ear is characteristic of BORSD and develops when the helix and antihelix are malformed or absent.	[]	19/3/1999	26/6/2025	27/3/2008	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bpan	bpan	[ "BPAN", "Neurodegeneration with Brain Iron Accumulation 5 (NBIA5)", "BPAN", "Neurodegeneration with Brain Iron Accumulation 5 (NBIA5)", "WD repeat domain phosphoinositide-interacting protein 4", "WDR45", "Beta-Propeller Protein-Associated Neurodegeneration" ]	Beta-Propeller Protein-Associated Neurodegeneration	Allison Gregory, Manju A Kurian, Tobias Haack, Susan J Hayflick, Penelope Hogarth	Summary Beta-propeller protein-associated neurodegeneration (BPAN) is typically characterized by early-onset seizures, infantile-onset developmental delay, intellectual disability, absent-to-limited expressive language, motor dysfunction (ataxia), and abnormal behaviors often similar to autism spectrum disorder. Seizure types including generalized (absence, tonic, atonic, tonic-clonic and myoclonic), focal with impaired consciousness, and epileptic spasms, as well as epileptic syndromes (West syndrome and Lennox-Gastaut syndrome) can be seen. With age seizures tend to resolve or become less prominent, whereas cognitive decline and movement disorders (progressive parkinsonism and dystonia) emerge as characteristic findings. The diagnosis of BPAN is established by identifying on molecular genetic testing: In females. A heterozygous In males. Either a hemizygous Somatic mosaicism has been reported in rare females (and possibly in 1 male). BPAN is inherited in an X-linked manner; to date, most affected individuals have been female, and the vast majority are simplex cases (i.e., a single occurrence in a family) resulting from a	## Diagnosis No formal diagnostic criteria for beta-propeller protein-associated neurodegeneration (BPAN) have been published. BPAN Onset in early childhood Development of multiple seizure types Seizures worse in early childhood, lessening with age Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) Focal seizures with impaired consciousness Epileptic spasms West syndrome Lennox-Gastaut syndrome Early-onset epilepsy with intellectual disability Nonspecific hypomyelination and thin corpus callosum are seen in early childhood [ T T Cerebellar or cerebral atrophy may also be present at any age. The diagnosis of BPAN The diagnosis of BPAN A In three families with recurrence of BPAN in sibs, affected males had inherited a germline pathogenic variant [ Apparent somatic mosaicism for a Molecular genetic testing approaches can include a combination of Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. In some cases, the phenotype of BPAN may be distinctive enough to warrant single gene-targeted testing (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Beta Propeller Protein-Associated Neurodegeneration (BPAN) 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 failure to detect a pathogenic variant in a proband using sequence-based testing could be due to somatic mosaicism in a male or female or – theoretically – a heterozygous (multi)exon Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 • • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • T • T • A • In three families with recurrence of BPAN in sibs, affected males had inherited a germline pathogenic variant [ • Apparent somatic mosaicism for a • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Suggestive Findings BPAN Onset in early childhood Development of multiple seizure types Seizures worse in early childhood, lessening with age Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) Focal seizures with impaired consciousness Epileptic spasms West syndrome Lennox-Gastaut syndrome Early-onset epilepsy with intellectual disability Nonspecific hypomyelination and thin corpus callosum are seen in early childhood [ T T Cerebellar or cerebral atrophy may also be present at any age. • • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • T • T ## Clinical Findings Onset in early childhood Development of multiple seizure types Seizures worse in early childhood, lessening with age Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) Focal seizures with impaired consciousness Epileptic spasms West syndrome Lennox-Gastaut syndrome Early-onset epilepsy with intellectual disability • • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability • Onset in early childhood • Development of multiple seizure types • Seizures worse in early childhood, lessening with age • Generalized (absence, tonic, atonic, tonic-clonic and myoclonic) • Focal seizures with impaired consciousness • Epileptic spasms • West syndrome • Lennox-Gastaut syndrome • Early-onset epilepsy with intellectual disability ## MRI Findings Nonspecific hypomyelination and thin corpus callosum are seen in early childhood [ T T Cerebellar or cerebral atrophy may also be present at any age. • T • T ## Establishing the Diagnosis The diagnosis of BPAN The diagnosis of BPAN A In three families with recurrence of BPAN in sibs, affected males had inherited a germline pathogenic variant [ Apparent somatic mosaicism for a Molecular genetic testing approaches can include a combination of Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. In some cases, the phenotype of BPAN may be distinctive enough to warrant single gene-targeted testing (see For an introduction to multigene panels click For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in Beta Propeller Protein-Associated Neurodegeneration (BPAN) 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 failure to detect a pathogenic variant in a proband using sequence-based testing could be due to somatic mosaicism in a male or female or – theoretically – a heterozygous (multi)exon Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as 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 • A • In three families with recurrence of BPAN in sibs, affected males had inherited a germline pathogenic variant [ • Apparent somatic mosaicism for a • For an introduction to multigene panels click • For an introduction to comprehensive genomic testing click ## Clinical Characteristics Beta-propeller protein-associated neurodegeneration (BPAN) typically presents with seizures, infantile-onset developmental delay, intellectual disability, absent-to-limited expressive language, and abnormal behaviors with Rett syndrome-like features. During adolescence and early adulthood (mean age 25 years; range 15-37 years) some of the hallmark childhood features (e.g., seizures) resolve or become less prominent, while cognitive decline and progressive parkinsonism and dystonia emerge as characteristic findings [ The majority of individuals with BPAN are female; however, some males have been reported. Significant phenotypic variability is observed in both males and females. With increasing use of genomic testing, individuals with BPAN now tend to be identified at younger ages than those originally described by One young boy included in a cohort of children with early-onset epileptic encephalopathy had a Although seizures often require pharmacologic treatment and may be intractable, they often resolve or become less prominent with age. Onset of progressive dementia occurs between adolescence and early to middle adulthood (mean age 25 years; range 15-37 years) [ In some instances, parents of children with BPAN have reported regression during early childhood; however, it is not clear whether this is due to the underlying disease, unrecognized seizures, or both [Hogarth, personal communication]. The aggressive epilepsy profile eventually seen in some children with BPAN may itself contribute to cognitive dysfunction, as in other epileptic encephalopathies. Fine motor skills are also impaired. Some also have limited purposeful hand use (reminiscent of Dystonia often starts in the upper extremities. Parkinsonism is characterized by prominent bradykinesia, rigidity, freezing of gait, and postural instability. Tremor is not as common as in other forms of parkinsonism. Some adults with BPAN continue to have sleep difficulties or develop new manifestations such as waking and vocalizing during the night. Two of seven Japanese women had sleep problems as adults [ Bilateral optic atrophy has been described in one individual who also had bilateral sensorineural hearing loss [ In a second, more advanced case the findings were similar, but with more extensive neuronal loss and tau pathology [ Although In the original report of 20 individuals, the three affected males had pathogenic variants predicted to render the protein nonfunctional (all frameshifts leading to premature stop codons). One of these males had evidence suggestive of somatic mosaicism [ Males with germline pathogenic variants in The overall paucity of affected males relative to females suggests that germline pathogenic variants are rare in males and that affected male conceptuses are less likely to survive than female conceptuses. In two sets of male-female sibs with inherited In summary, the following factors are all proposed to contribute to the variability in phenotype and to the predominance of affected females relative to males: Somatic mosaicism in both sexes Skewed X-chromosome inactivation in females The specific type of pathogenic variant Germline nonsense variants are predicted to lead to non-viable males. The vast majority of pathogenic variants are The BPAN phenotype was recognized in the initial (2002) version of Although referenced in the literature, the term SENDA (static encephalopathy with neurodegeneration in adulthood) is no longer favored [ Similar to other forms of • Somatic mosaicism in both sexes • Skewed X-chromosome inactivation in females • The specific type of pathogenic variant ## Clinical Description Beta-propeller protein-associated neurodegeneration (BPAN) typically presents with seizures, infantile-onset developmental delay, intellectual disability, absent-to-limited expressive language, and abnormal behaviors with Rett syndrome-like features. During adolescence and early adulthood (mean age 25 years; range 15-37 years) some of the hallmark childhood features (e.g., seizures) resolve or become less prominent, while cognitive decline and progressive parkinsonism and dystonia emerge as characteristic findings [ The majority of individuals with BPAN are female; however, some males have been reported. Significant phenotypic variability is observed in both males and females. With increasing use of genomic testing, individuals with BPAN now tend to be identified at younger ages than those originally described by One young boy included in a cohort of children with early-onset epileptic encephalopathy had a Although seizures often require pharmacologic treatment and may be intractable, they often resolve or become less prominent with age. Onset of progressive dementia occurs between adolescence and early to middle adulthood (mean age 25 years; range 15-37 years) [ In some instances, parents of children with BPAN have reported regression during early childhood; however, it is not clear whether this is due to the underlying disease, unrecognized seizures, or both [Hogarth, personal communication]. The aggressive epilepsy profile eventually seen in some children with BPAN may itself contribute to cognitive dysfunction, as in other epileptic encephalopathies. Fine motor skills are also impaired. Some also have limited purposeful hand use (reminiscent of Dystonia often starts in the upper extremities. Parkinsonism is characterized by prominent bradykinesia, rigidity, freezing of gait, and postural instability. Tremor is not as common as in other forms of parkinsonism. Some adults with BPAN continue to have sleep difficulties or develop new manifestations such as waking and vocalizing during the night. Two of seven Japanese women had sleep problems as adults [ Bilateral optic atrophy has been described in one individual who also had bilateral sensorineural hearing loss [ In a second, more advanced case the findings were similar, but with more extensive neuronal loss and tau pathology [ Although In the original report of 20 individuals, the three affected males had pathogenic variants predicted to render the protein nonfunctional (all frameshifts leading to premature stop codons). One of these males had evidence suggestive of somatic mosaicism [ Males with germline pathogenic variants in The overall paucity of affected males relative to females suggests that germline pathogenic variants are rare in males and that affected male conceptuses are less likely to survive than female conceptuses. In two sets of male-female sibs with inherited In summary, the following factors are all proposed to contribute to the variability in phenotype and to the predominance of affected females relative to males: Somatic mosaicism in both sexes Skewed X-chromosome inactivation in females The specific type of pathogenic variant • Somatic mosaicism in both sexes • Skewed X-chromosome inactivation in females • The specific type of pathogenic variant ## Core Clinical Features One young boy included in a cohort of children with early-onset epileptic encephalopathy had a Although seizures often require pharmacologic treatment and may be intractable, they often resolve or become less prominent with age. Onset of progressive dementia occurs between adolescence and early to middle adulthood (mean age 25 years; range 15-37 years) [ In some instances, parents of children with BPAN have reported regression during early childhood; however, it is not clear whether this is due to the underlying disease, unrecognized seizures, or both [Hogarth, personal communication]. The aggressive epilepsy profile eventually seen in some children with BPAN may itself contribute to cognitive dysfunction, as in other epileptic encephalopathies. Fine motor skills are also impaired. Some also have limited purposeful hand use (reminiscent of Dystonia often starts in the upper extremities. Parkinsonism is characterized by prominent bradykinesia, rigidity, freezing of gait, and postural instability. Tremor is not as common as in other forms of parkinsonism. ## Other Features Some adults with BPAN continue to have sleep difficulties or develop new manifestations such as waking and vocalizing during the night. Two of seven Japanese women had sleep problems as adults [ Bilateral optic atrophy has been described in one individual who also had bilateral sensorineural hearing loss [ In a second, more advanced case the findings were similar, but with more extensive neuronal loss and tau pathology [ ## BPAN in Affected Males and Females Although In the original report of 20 individuals, the three affected males had pathogenic variants predicted to render the protein nonfunctional (all frameshifts leading to premature stop codons). One of these males had evidence suggestive of somatic mosaicism [ Males with germline pathogenic variants in The overall paucity of affected males relative to females suggests that germline pathogenic variants are rare in males and that affected male conceptuses are less likely to survive than female conceptuses. In two sets of male-female sibs with inherited In summary, the following factors are all proposed to contribute to the variability in phenotype and to the predominance of affected females relative to males: Somatic mosaicism in both sexes Skewed X-chromosome inactivation in females The specific type of pathogenic variant • Somatic mosaicism in both sexes • Skewed X-chromosome inactivation in females • The specific type of pathogenic variant ## Genotype-Phenotype Correlations Germline nonsense variants are predicted to lead to non-viable males. The vast majority of pathogenic variants are ## Nomenclature The BPAN phenotype was recognized in the initial (2002) version of Although referenced in the literature, the term SENDA (static encephalopathy with neurodegeneration in adulthood) is no longer favored [ ## Prevalence Similar to other forms of ## Genetically Related (Allelic) Disorders No phenotypes other than those discussed in this ## Differential Diagnosis In childhood, the core clinical features of BPAN – seizures, developmental delay / intellectual disability, movement disorders, and behavioral abnormalities – are highly variable between individuals and lack specificity, overlapping with many other genetic and sporadic (non-genetic) disorders. Early in the disease course, imaging abnormalities are similarly nonspecific, particularly if iron-sensitive sequences are not employed. The differential diagnosis at this stage is therefore broad, and includes Dravet syndrome (See West syndrome Lennox-Gastaut syndrome Epilepsy with electrical status during slow-wave sleep Gelastic epilepsy Kozhevnikov-Rasmussen syndrome Landau-Kleffner syndrome Early-infantile epileptic encephalopathy (See Note: Like BPAN, the epileptic encephalopathies present with multiple seizure types in the first months or years of life and are associated with severe neurocognitive deficits. Note that specific eponyms are applied to a particular clinical and electrographic profile and do not imply a specific etiology: many genetic and non-genetic etiologies can result in a given epilepsy syndrome. If imaging reveals basal ganglia hypointensity on iron-sensitive sequences, the differential diagnosis narrows to the NBIA disorders and imaging phenocopies. These disorders can generally be distinguished from BPAN and each other by specific clinical and imaging features. See Clinical features and the presence of high brain iron on MRI distinguish BPAN from other forms of childhood- or early adult-onset dystonia-parkinsonism, such as Neuropathologic findings (see Clinical Description, In BPAN the pathologic changes found in the substantia nigra dominate those found in the globus pallidus (consistent with MRI findings), in contrast to other forms of NBIA in which the globus pallidus is more involved. BPAN can be distinguished by the lack of α-synuclein pathology that is abundant in MPAN and PLAN. • Dravet syndrome (See • West syndrome • Lennox-Gastaut syndrome • Epilepsy with electrical status during slow-wave sleep • Gelastic epilepsy • Kozhevnikov-Rasmussen syndrome • Landau-Kleffner syndrome • Early-infantile epileptic encephalopathy (See • Note: Like BPAN, the epileptic encephalopathies present with multiple seizure types in the first months or years of life and are associated with severe neurocognitive deficits. Note that specific eponyms are applied to a particular clinical and electrographic profile and do not imply a specific etiology: many genetic and non-genetic etiologies can result in a given epilepsy syndrome. • In BPAN the pathologic changes found in the substantia nigra dominate those found in the globus pallidus (consistent with MRI findings), in contrast to other forms of NBIA in which the globus pallidus is more involved. • BPAN can be distinguished by the lack of α-synuclein pathology that is abundant in MPAN and PLAN. ## Management To establish the extent of disease and needs in an individual diagnosed with beta-propeller protein-associated neurodegeneration (BPAN), the following evaluations are recommended: Complete neurologic examination and developmental assessment including evaluation of motor function, speech/language, swallowing, and sleep EEG monitoring, including sleep EEG, for any child with features (by history or observation) to suggest overt or occult seizures. Early referral to a neurology epilepsy sub-specialist is recommended if hypsarrhythmia or another aggressive electrographic pattern is found on EEG. Assessments by specialists in physical, occupational, and/or speech therapy Ophthalmologic examination Assessment of nutrition by a nutritionist or dietician Consultation with a clinical geneticist and/or genetic counselor Some children with BPAN may have no evidence of seizures or experience only rare febrile events and require no ongoing pharmacologic intervention. Others have severe, refractory epilepsy with multiple seizure types warranting the involvement of specialists in pediatric epilepsy and consideration of multiple therapeutic modalities, including anti-seizure medication, ketogenic diet, and/or vagus nerve stimulation. Short-term treatment with ACTH, prednisolone, or vigabatrin should be considered early in the care of a child with epileptic spasms, based on the guidelines in the US consensus report from the International League Against Epilepsy [ 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. Consultation with a developmental pediatrician is recommended to ensure that appropriate community, state, and educational agencies are involved and to support parents in maximizing quality of life. Developmental pediatricians can also 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. Consider use of durable medical equipment 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, Botox In the treatment of parkinsonism, dystonia, and spasticity the usual pharmacologic agents can be considered with the caveat that these therapies could exacerbate the cognitive deficits that also occur in this age group. Pharmacologic treatment of parkinsonism with dopaminergic medications usually has an initial striking benefit in males and females with improved motor function, affect, appetite, and interest in activities, followed by equally consistent disabling motor fluctuations ("on-off" phenomena) and dyskinesias [ As cognitive deficits progress in those with advanced disease, carbidopa/levodopa formulations may carry a lower risk of adverse neuropsychiatric effects than dopamine agonists. Amantadine may be helpful for dyskinesias, but also carries a risk (especially in higher doses) of adverse psychiatric effects such as hallucinations and agitation. Pharmacologic treatment of dystonia and spasticity can include (if indicated) clonazepam or other benzodiazepines, oral baclofen, intramuscular botulinum toxin, and a trial of intrathecal baclofen. Trihexyphenydyl may also be useful for dystonia but may worsen cognitive dysfunction in advanced stages of the disease. 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 when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Use of a liquid nutritional supplement to help maintain weight as needed A gastric feeding tube to help maintain adequate weight (which becomes more difficult with disease progression) and to reduce the risk of aspiration pneumonia, if indicated Monitoring for complications of gastroesophageal reflux disease with institution of pharmacologic management if indicated. There are no data on the efficacy of fundoplication in BPAN. Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications Regular pulmonary hygiene to manage risk for pulmonary complications; tracheostomy as indicated when secretions are difficult to manage The following are appropriate: Routine follow up by a neurologist for medication management and interval assessment of ambulation, seizure activity, speech, and swallowing. Often done every three to six months, follow up may be annual for those who are more stable. For those receiving dopaminergic drugs (for parkinsonism), monitoring for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesias Follow-up ophthalmologic examination every one to two years See Because women with mild manifestations of BPAN could potentially reproduce, the potential for teratogenic effects of medication taken during pregnancy needs to be considered. Because BPAN falls in the category of Search • Complete neurologic examination and developmental assessment including evaluation of motor function, speech/language, swallowing, and sleep • EEG monitoring, including sleep EEG, for any child with features (by history or observation) to suggest overt or occult seizures. Early referral to a neurology epilepsy sub-specialist is recommended if hypsarrhythmia or another aggressive electrographic pattern is found on EEG. • Assessments by specialists in physical, occupational, and/or speech therapy • Ophthalmologic examination • Assessment of nutrition by a nutritionist or dietician • Consultation with a clinical geneticist and/or genetic counselor • 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. • Use of a liquid nutritional supplement to help maintain weight as needed • A gastric feeding tube to help maintain adequate weight (which becomes more difficult with disease progression) and to reduce the risk of aspiration pneumonia, if indicated • Monitoring for complications of gastroesophageal reflux disease with institution of pharmacologic management if indicated. There are no data on the efficacy of fundoplication in BPAN. • Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications • Regular pulmonary hygiene to manage risk for pulmonary complications; tracheostomy as indicated when secretions are difficult to manage • Routine follow up by a neurologist for medication management and interval assessment of ambulation, seizure activity, speech, and swallowing. Often done every three to six months, follow up may be annual for those who are more stable. • For those receiving dopaminergic drugs (for parkinsonism), monitoring for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesias • Follow-up ophthalmologic examination every one to two years ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with beta-propeller protein-associated neurodegeneration (BPAN), the following evaluations are recommended: Complete neurologic examination and developmental assessment including evaluation of motor function, speech/language, swallowing, and sleep EEG monitoring, including sleep EEG, for any child with features (by history or observation) to suggest overt or occult seizures. Early referral to a neurology epilepsy sub-specialist is recommended if hypsarrhythmia or another aggressive electrographic pattern is found on EEG. Assessments by specialists in physical, occupational, and/or speech therapy Ophthalmologic examination Assessment of nutrition by a nutritionist or dietician Consultation with a clinical geneticist and/or genetic counselor • Complete neurologic examination and developmental assessment including evaluation of motor function, speech/language, swallowing, and sleep • EEG monitoring, including sleep EEG, for any child with features (by history or observation) to suggest overt or occult seizures. Early referral to a neurology epilepsy sub-specialist is recommended if hypsarrhythmia or another aggressive electrographic pattern is found on EEG. • Assessments by specialists in physical, occupational, and/or speech therapy • Ophthalmologic examination • Assessment of nutrition by a nutritionist or dietician • Consultation with a clinical geneticist and/or genetic counselor ## Treatment of Manifestations Some children with BPAN may have no evidence of seizures or experience only rare febrile events and require no ongoing pharmacologic intervention. Others have severe, refractory epilepsy with multiple seizure types warranting the involvement of specialists in pediatric epilepsy and consideration of multiple therapeutic modalities, including anti-seizure medication, ketogenic diet, and/or vagus nerve stimulation. Short-term treatment with ACTH, prednisolone, or vigabatrin should be considered early in the care of a child with epileptic spasms, based on the guidelines in the US consensus report from the International League Against Epilepsy [ 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. Consultation with a developmental pediatrician is recommended to ensure that appropriate community, state, and educational agencies are involved and to support parents in maximizing quality of life. Developmental pediatricians can also 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. Consider use of durable medical equipment 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, Botox In the treatment of parkinsonism, dystonia, and spasticity the usual pharmacologic agents can be considered with the caveat that these therapies could exacerbate the cognitive deficits that also occur in this age group. Pharmacologic treatment of parkinsonism with dopaminergic medications usually has an initial striking benefit in males and females with improved motor function, affect, appetite, and interest in activities, followed by equally consistent disabling motor fluctuations ("on-off" phenomena) and dyskinesias [ As cognitive deficits progress in those with advanced disease, carbidopa/levodopa formulations may carry a lower risk of adverse neuropsychiatric effects than dopamine agonists. Amantadine may be helpful for dyskinesias, but also carries a risk (especially in higher doses) of adverse psychiatric effects such as hallucinations and agitation. Pharmacologic treatment of dystonia and spasticity can include (if indicated) clonazepam or other benzodiazepines, oral baclofen, intramuscular botulinum toxin, and a trial of intrathecal baclofen. Trihexyphenydyl may also be useful for dystonia but may worsen cognitive dysfunction in advanced stages of the disease. 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 when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. Use of a liquid nutritional supplement to help maintain weight as needed A gastric feeding tube to help maintain adequate weight (which becomes more difficult with disease progression) and to reduce the risk of aspiration pneumonia, if indicated Monitoring for complications of gastroesophageal reflux disease with institution of pharmacologic management if indicated. There are no data on the efficacy of fundoplication in BPAN. Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications Regular pulmonary hygiene to manage risk for pulmonary complications; tracheostomy as indicated when secretions are difficult to manage • 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. • Use of a liquid nutritional supplement to help maintain weight as needed • A gastric feeding tube to help maintain adequate weight (which becomes more difficult with disease progression) and to reduce the risk of aspiration pneumonia, if indicated • Monitoring for complications of gastroesophageal reflux disease with institution of pharmacologic management if indicated. There are no data on the efficacy of fundoplication in BPAN. • Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications • Regular pulmonary hygiene to manage risk for pulmonary complications; tracheostomy as indicated when secretions are difficult to manage ## Developmental Delay / Intellectual Disability 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. Consultation with a developmental pediatrician is recommended to ensure that appropriate community, state, and educational agencies are involved and to support parents in maximizing quality of life. Developmental pediatricians can also 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. • 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 Consider use of durable medical equipment 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, Botox In the treatment of parkinsonism, dystonia, and spasticity the usual pharmacologic agents can be considered with the caveat that these therapies could exacerbate the cognitive deficits that also occur in this age group. Pharmacologic treatment of parkinsonism with dopaminergic medications usually has an initial striking benefit in males and females with improved motor function, affect, appetite, and interest in activities, followed by equally consistent disabling motor fluctuations ("on-off" phenomena) and dyskinesias [ As cognitive deficits progress in those with advanced disease, carbidopa/levodopa formulations may carry a lower risk of adverse neuropsychiatric effects than dopamine agonists. Amantadine may be helpful for dyskinesias, but also carries a risk (especially in higher doses) of adverse psychiatric effects such as hallucinations and agitation. Pharmacologic treatment of dystonia and spasticity can include (if indicated) clonazepam or other benzodiazepines, oral baclofen, intramuscular botulinum toxin, and a trial of intrathecal baclofen. Trihexyphenydyl may also be useful for dystonia but may worsen cognitive dysfunction in advanced stages of the disease. ## 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 when necessary. Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist. ## Other Features Use of a liquid nutritional supplement to help maintain weight as needed A gastric feeding tube to help maintain adequate weight (which becomes more difficult with disease progression) and to reduce the risk of aspiration pneumonia, if indicated Monitoring for complications of gastroesophageal reflux disease with institution of pharmacologic management if indicated. There are no data on the efficacy of fundoplication in BPAN. Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications Regular pulmonary hygiene to manage risk for pulmonary complications; tracheostomy as indicated when secretions are difficult to manage • Use of a liquid nutritional supplement to help maintain weight as needed • A gastric feeding tube to help maintain adequate weight (which becomes more difficult with disease progression) and to reduce the risk of aspiration pneumonia, if indicated • Monitoring for complications of gastroesophageal reflux disease with institution of pharmacologic management if indicated. There are no data on the efficacy of fundoplication in BPAN. • Over-the-counter fiber supplements and/or stool softeners to treat constipation, which is likely caused by a combination of immobility, diet, and medications • Regular pulmonary hygiene to manage risk for pulmonary complications; tracheostomy as indicated when secretions are difficult to manage ## Surveillance The following are appropriate: Routine follow up by a neurologist for medication management and interval assessment of ambulation, seizure activity, speech, and swallowing. Often done every three to six months, follow up may be annual for those who are more stable. For those receiving dopaminergic drugs (for parkinsonism), monitoring for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesias Follow-up ophthalmologic examination every one to two years • Routine follow up by a neurologist for medication management and interval assessment of ambulation, seizure activity, speech, and swallowing. Often done every three to six months, follow up may be annual for those who are more stable. • For those receiving dopaminergic drugs (for parkinsonism), monitoring for adverse neuropsychiatric effects and disabling motor fluctuations and dyskinesias • Follow-up ophthalmologic examination every one to two years ## Evaluation of Relatives at Risk See ## Pregnancy Management Because women with mild manifestations of BPAN could potentially reproduce, the potential for teratogenic effects of medication taken during pregnancy needs to be considered. ## Therapies Under Investigation Because BPAN falls in the category of Search ## Genetic Counseling Beta-propeller protein-associated neurodegeneration (BPAN) is inherited in an X-linked manner. To date, most individuals with BPAN have been female. Data suggest that one male with BPAN had apparent somatic mosaicism for a Recommended parental molecular genetic testing when a proband has an identified If a woman has more than one affected child and no other affected relatives, she most likely has germline (and possibly somatic) mosaicism. Presumed maternal germline mosaicism has been reported in a family with two affected sibs [ In a second family, a phenotypically normal mother had the same If a proband represents a simplex case (i.e., a single occurrence in a family) and if the One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal 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 parents of affected individuals. Once the • Presumed maternal germline mosaicism has been reported in a family with two affected sibs [ • In a second family, a phenotypically normal mother had the same • One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ • One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal • One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ • One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal • One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ • One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal • 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 parents of affected individuals. ## Mode of Inheritance Beta-propeller protein-associated neurodegeneration (BPAN) is inherited in an X-linked manner. To date, most individuals with BPAN have been female. Data suggest that one male with BPAN had apparent somatic mosaicism for a ## Risk to Family Members Recommended parental molecular genetic testing when a proband has an identified If a woman has more than one affected child and no other affected relatives, she most likely has germline (and possibly somatic) mosaicism. Presumed maternal germline mosaicism has been reported in a family with two affected sibs [ In a second family, a phenotypically normal mother had the same If a proband represents a simplex case (i.e., a single occurrence in a family) and if the One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal • Presumed maternal germline mosaicism has been reported in a family with two affected sibs [ • In a second family, a phenotypically normal mother had the same • One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ • One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal • One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ • One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal • One very mildly affected female with somatic and, presumably, germline mosaicism has reproduced [ • One very mildly affected female with skewed X-chromosome inactivation in leukocyte DNA favoring the normal ## Related Genetic Counseling Issues 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 parents of affected individuals. • 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 parents of affected individuals. ## Prenatal Testing and Preimplantation Genetic Testing Once the ## Resources Center of Excellence for NBIA Clinical Care and Research International Registry for NBIA and Related Disorders Oregon Health & Science University Germany • • • • • • Center of Excellence for NBIA Clinical Care and Research • International Registry for NBIA and Related Disorders • Oregon Health & Science University • • • Germany • ## Molecular Genetics Beta-Propeller Protein-Associated Neurodegeneration: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Beta-Propeller Protein-Associated Neurodegeneration ( The majority of reported variants are predicted to be loss-of-function variants [ Additionally, a 19.9-kb Nearly all pathogenic variants are ## Chapter Notes The NBIAcure website, developed and maintained by Drs Susan Hayflick and Penny Hogarth and their team, contains up-to-date information about BPAN and the other NBIA disorders, geared for lay persons, clinicians, and researchers. Information about current research and opportunities to enroll online are available Research reported in this publication was supported by a grant awarded to Dr Hogarth by the 16 February 2017 (bp) Review posted live 9 February 2016 (ag) Original submission • 16 February 2017 (bp) Review posted live • 9 February 2016 (ag) Original submission ## Author Notes The NBIAcure website, developed and maintained by Drs Susan Hayflick and Penny Hogarth and their team, contains up-to-date information about BPAN and the other NBIA disorders, geared for lay persons, clinicians, and researchers. Information about current research and opportunities to enroll online are available ## Acknowledgments Research reported in this publication was supported by a grant awarded to Dr Hogarth by the ## Revision History 16 February 2017 (bp) Review posted live 9 February 2016 (ag) Original submission • 16 February 2017 (bp) Review posted live • 9 February 2016 (ag) Original submission ## References ## Literature Cited T T	[ "A Abidi, C Mignon-Ravix, P Cacciagli, N Girard, M Milh, L Villard. Early-onset epileptic encephalopathy as the initial clinical presentation of WDR45 deletion in a male patient.. Eur J Hum Genet. 2016;24:615-8", "C Behrends, ME Sowa, SP Gygi, JW Harper. Network organization of the human autophagy system.. Nature. 2010;466:68-76", "A Gregory, SJ Hayflick. Genetics of neurodegeneration with brain iron accumulation.. Curr Neurol Neurosci Rep. 2011;11:254-61", "A Gregory, BJ Polster, SJ Hayflick. Clinical and genetic delineation of neurodegeneration with brain iron accumulation.. J Med Genet. 2009;46:73-80", "TB Haack, P Hogarth, MC Kruer, A Gregory, T Wieland, T Schwarzmayr, E Graf, L Sanford, E Meyer, E Kara, SM Cuno, SI Harik, VH Dandu, N Nardocci, G Zorzi, T Dunaway, M Tarnopolsky, S Skinner, S Frucht, E Hanspal, C Schrander-Stumpel, D Héron, C Mignot, B Garavaglia, K Bhatia, J Hardy, TM Strom, N Boddaert, HH Houlden, MA Kurian, T Meitinger, H Prokisch, SJ Hayflick. Exome sequencing reveals de novo WDR45 mutations causing a phenotypically distinct, X-linked dominant form of NBIA.. Am J Hum Genet. 2012;91:1144-9", "TB Haack, P Hogarth, A Gregory, H Prokisch, SJ Hayflick. BPAN: the only X-linked dominant NBIA disorder.. Int Rev Neurobiol. 2013;110:85-90", "SJ Hayflick, MC Kruer, A Gregory, TB Haack, MA Kurian, HH Houlden, J Anderson, N Boddaert, L Sanford, SI Harik, VH Dandu, N Nardocci, G Zorzi, T Dunaway, M Tarnopolsky, S Skinner, KR Holden, S Frucht, E Hanspal, C Schrander-Stumpel, C Mignot, D Héron, DE Saunders, M Kaminska, JP Lin, K Lascelles, SM Cuno, E Meyer, B Garavaglia, K Bhatia, R de Silva, S Crisp, P Lunt, M Carey, J Hardy, T Meitinger, H Prokisch, P Hogarth. β-propeller protein-associated neurodegeneration: a new X-linked dominant disorder with brain iron accumulation.. Brain. 2013;136:1708-17", "P. Hogarth. Neurodegeneration with brain iron accumulation: diagnosis and management.. J Mov Disord. 2015;8:1-13", "Y Ichinose, M Miwa, A Onohara, K Obi, K Shindo, H Saitsu, N Matsumoto, Y. Takiyama. Characteristic MRI findings in beta-propeller protein-associated neurodegeneration (BPAN).. Neurol Clin Pract. 2014;4:175-7", "M Khalifa, L Naffaa. Exome sequencing reveals a novel WDR45 frameshift mutation and inherited POLR3A heterozygous variants in a female with a complex phenotype and mixed brain MRI findings.. Eur J Med Genet. 2015;58:381-6", "MC Kruer, N Boddaert, SA Schneider, H Houlden, KP Bhatia, A Gregory, JC Anderson, WD Rooney, P Hogarth, SJ Hayflick. Neuroimaging features of neurodegeneration with brain iron accumulation.. AJNR Am J Neuroradiol. 2012;33:407-14", "D Li, R. Roberts. WD-repeat proteins: structure characteristics, biological function, and their involvement in human diseases.. Cell Mol Life Sci. 2001;58:2085-97", "M Long, N Abdeen, MT Geraghty, P Hogarth, S Hayflick, S Venkateswaran. Novel WDR45 mutation and pathognomonic BPAN imaging in a young female with mild cognitive delay.. Pediatrics. 2015;136:e714-7", "M Nakashima, K Takano, Y Tsuyusaki, S Yoshitomi, M Shimono, Y Aoki, M Kato, N Aida, T Mizuguchi, S Miyatake, N Miyake, H Osaka, H Saitsu, N. Matsumoto. WDR45 mutations in three male patients with West syndrome.. J Hum Genet. 2016;61:653-61", "M Nassif, C. Hetz. Autophagy impairment: a crossroad between neurodegeneration and tauopathies.. BMC Biol. 2012;10:78", "K Nishioka, G Oyama, H Yoshino, Y Li, T Matsushima, C Takeuchi, Y Mochizuki, M Mori-Yoshimura, M Murata, C Yamasita, N Nakamura, Y Konishi, K Ohi, K Ichikawa, T Terada, T Obi, M Funayama, S Saiki, N Hattori. High frequency of beta-propeller protein-associated neurodegeneration (BPAN) among patients with intellectual disability and young-onset parkinsonism.. Neurobiol Aging. 2015;36:2004.e9-15", "RA Nixon. The role of autophagy in neurodegenerative disease.. Nat Med. 2013;19:983-97", "C Ohba, S Nabatame, Y Iijima, K Nishiyama, Y Tsurusaki, M Nakashima, N Miyake, F Tanaka, K Ozono, H Saitsu, N. Matsumoto. De novo WDR45 mutation in a patient showing clinically Rett syndrome with childhood iron deposition in brain.. J Hum Genet. 2014;59:292-5", "R Paudel, A Li, S Wiethoff, R Bandopadhyay, K Bhatia, R de Silva, H Houlden, JL Holton. Neuropathology of Beta-propeller protein associated neurodegeneration (BPAN): a new tauopathy.. Acta Neuropathol Commun. 2015;3:39", "JM Pellock, R Hrachovy, S Shinnar, TZ Baram, D Bettis, DJ Dlugos, WD Gaillard, PA Gibson, GL Holmes, DR Nordl, C O'Dell, WD Shields, E Trevathan, JW Wheless. Infantile spasms: a U.S. consensus report.. Epilepsia. 2010;51:2175-89", "G Pont-Kingdon, F Gedge, W Wooderchak-Donahue, I Schrijver, KE Weck, JA Kant, D Oglesbee, P Bayrak-Toydemir, E Lyon. Design and analytical validation of clinical DNA sequencing assays.. Arch Pathol Lab Med. 2012;136:41-6", "T Proikas-Cezanne, S Waddell, A Gaugel, T Frickey, A Lupas, A. Nordheim. WIPI-1alpha (WIPI49), a member of the novel 7-bladed WIPI protein family, is aberrantly expressed in human cancer and is linked to starvation-induced autophagy.. Oncogene. 2004;23:9314-25", "GS Rathore, CP Schaaf, AJ Stocco. Novel mutation of the WDR45 gene causing beta-propeller protein-associated neurodegeneration.. Mov Disord. 2014;29:574-5", "H Saitsu, T Nishimura, K Muramatsu, H Kodera, S Kumada, K Sugai, E Kasai-Yoshida, N Sawaura, H Nishida, A Hoshino, F Ryujin, S Yoshioka, K Nishiyama, Y Kondo, Y Tsurusaki, M Nakashima, N Miyake, H Arakawa, M Kato, N Mizushima, N. Matsumoto. De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood.. Nat Genet. 2013;45:445-9", "WM Verhoeven, JI Egger, DA Koolen, H Yntema, S Olgiati, GJ Breedveld, V Bonifati, BP van de Warrenburg. Beta-propeller protein-associated neurodegeneration (BPAN), a rare form of NBIA: novel mutations and neuropsychiatric phenotype in three adult patients.. Parkinsonism Relat Disord. 2014;20:332-6", "YA Zarate, JR Jones, MA Jones, F Millan, J Juusola, A Vertino-Bell, GB Schaefer, MC Kruer. Lessons from a pair of siblings with BPAN.. Eur J Hum Genet. 2016;24:1080-3" ]	16/2/2017			GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]
bpes	bpes	[ "Blepharophimosis Syndrome", "BPES", "BPES", "Blepharophimosis Syndrome", "Forkhead box protein L2", "FOXL2", "Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome" ]	Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome	Hannah Verdin, Charlotte Matton, Elfride De Baere	Summary The diagnosis of BPES is established in a proband with suggestive findings and a heterozygous pathogenic variant in BPES is almost always inherited in an autosomal dominant manner. More than half of individuals diagnosed with BPES have the disorder as the result of a pathogenic variant inherited from an affected parent. Each child of an individual with BPES has a 50% chance of inheriting the pathogenic variant. Once the BPES-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BPES are possible.	## Diagnosis No consensus clinical diagnostic criteria for BPES Additionally, primary ovarian insufficiency is present in individuals with BEPS type 1. The diagnosis of BPES Note: Identification of a heterozygous variant 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. Individuals with the distinctive findings described in If no variant is detected using exome or genome sequencing, the next step is to perform gene-targeted deletion/duplication analysis of the For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in BPES See See Several additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, and nonsense variants; typically, partial 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. Individuals with BPES and an apparently balanced chromosome translocation and no evidence for a sequence variant or copy number variant in MLPA and other methods for deletion/duplication analysis (see footnote 6) may detect partial-, whole-, or contiguous-gene deletions or upstream or downstream regulatory deletions, depending on the experimental design [ ## Suggestive Findings BPES Additionally, primary ovarian insufficiency is present in individuals with BEPS type 1. ## Establishing the Diagnosis The diagnosis of BPES Note: Identification of a heterozygous variant 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. Individuals with the distinctive findings described in If no variant is detected using exome or genome sequencing, the next step is to perform gene-targeted deletion/duplication analysis of the For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in BPES See See Several additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, and nonsense variants; typically, partial 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. Individuals with BPES and an apparently balanced chromosome translocation and no evidence for a sequence variant or copy number variant in MLPA and other methods for deletion/duplication analysis (see footnote 6) may detect partial-, whole-, or contiguous-gene deletions or upstream or downstream regulatory deletions, depending on the experimental design [ ## Option 1 ## Option 2 If no variant is detected using exome or genome sequencing, the next step is to perform gene-targeted deletion/duplication analysis of the For an introduction to comprehensive genomic testing click Molecular Genetic Testing Used in BPES See See Several additional individuals with contiguous gene deletions (not included in these calculations) have been reported (see Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, and nonsense variants; typically, partial 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. Individuals with BPES and an apparently balanced chromosome translocation and no evidence for a sequence variant or copy number variant in MLPA and other methods for deletion/duplication analysis (see footnote 6) may detect partial-, whole-, or contiguous-gene deletions or upstream or downstream regulatory deletions, depending on the experimental design [ ## Clinical Characteristics Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is defined by complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. Two types of BPES have been described [ BPES type I includes the four major features and female infertility caused by primary ovarian insufficiency. BPES type II includes only the four major features. Use the Tilt their head backward into a chin-up position. Dysplastic eyelids (lack of eyelid folds and thin skin) S-shaped border of the upper eyelid and abnormal downward concavity of the lower eyelid with lateral ectropion Nasolacrimal drainage problems caused by lateral displacement, duplication, or stenosis of the lacrimal puncta Note: A study of ten individuals with molecularly confirmed BPES showed that all had lateral displacement of the inferior punctum (i.e., in the lower eyelid) resulting from a temporal displacement of the entire lower eyelid. This proved to be an important anatomic hallmark in the diagnosis of BPES [ Strabismus, refractive errors (anisometropic hypermetropia and myopia), and amblyopia are more common in individuals with BPES than in the general population [ Secondary sexual characteristics are usually normal in both BPES type I and BPES type II. In BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea. Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ Pathogenic variants predicted to result in proteins truncated before the polyalanine tract preferentially lead to POI (BPES type I). Note: The need for careful interpretation of genotype-phenotype correlations is illustrated by the co-occurrence of BPES type I and isolated POI in a three-generation family [ Polyalanine expansions preferentially lead to BPES type II. All individuals heterozygous for a The exception is a consanguineous Indian family in which heterozygotes for a short polyalanine expansion of 19 alanines are unaffected, but homozygotes have typical BPES (with documented POI in 1 female) [ The prevalence of BPES is estimated at 1:50,000 births in the general population. No differences in prevalence based on sex, race, or ethnicity have been reported. • BPES type I includes the four major features and female infertility caused by primary ovarian insufficiency. • BPES type II includes only the four major features. • Use the • Tilt their head backward into a chin-up position. • Use the • Tilt their head backward into a chin-up position. • Use the • Tilt their head backward into a chin-up position. • Dysplastic eyelids (lack of eyelid folds and thin skin) • S-shaped border of the upper eyelid and abnormal downward concavity of the lower eyelid with lateral ectropion • Nasolacrimal drainage problems caused by lateral displacement, duplication, or stenosis of the lacrimal puncta • Note: A study of ten individuals with molecularly confirmed BPES showed that all had lateral displacement of the inferior punctum (i.e., in the lower eyelid) resulting from a temporal displacement of the entire lower eyelid. This proved to be an important anatomic hallmark in the diagnosis of BPES [ • Strabismus, refractive errors (anisometropic hypermetropia and myopia), and amblyopia are more common in individuals with BPES than in the general population [ • Secondary sexual characteristics are usually normal in both BPES type I and BPES type II. • In BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea. • Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. • Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ • Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ • Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. • Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ • Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ • Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. • Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ • Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ ## Clinical Description Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is defined by complex eyelid malformation characterized by four major features, all present at birth: blepharophimosis, ptosis, epicanthus inversus, and telecanthus. Two types of BPES have been described [ BPES type I includes the four major features and female infertility caused by primary ovarian insufficiency. BPES type II includes only the four major features. Use the Tilt their head backward into a chin-up position. Dysplastic eyelids (lack of eyelid folds and thin skin) S-shaped border of the upper eyelid and abnormal downward concavity of the lower eyelid with lateral ectropion Nasolacrimal drainage problems caused by lateral displacement, duplication, or stenosis of the lacrimal puncta Note: A study of ten individuals with molecularly confirmed BPES showed that all had lateral displacement of the inferior punctum (i.e., in the lower eyelid) resulting from a temporal displacement of the entire lower eyelid. This proved to be an important anatomic hallmark in the diagnosis of BPES [ Strabismus, refractive errors (anisometropic hypermetropia and myopia), and amblyopia are more common in individuals with BPES than in the general population [ Secondary sexual characteristics are usually normal in both BPES type I and BPES type II. In BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea. Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ • BPES type I includes the four major features and female infertility caused by primary ovarian insufficiency. • BPES type II includes only the four major features. • Use the • Tilt their head backward into a chin-up position. • Use the • Tilt their head backward into a chin-up position. • Use the • Tilt their head backward into a chin-up position. • Dysplastic eyelids (lack of eyelid folds and thin skin) • S-shaped border of the upper eyelid and abnormal downward concavity of the lower eyelid with lateral ectropion • Nasolacrimal drainage problems caused by lateral displacement, duplication, or stenosis of the lacrimal puncta • Note: A study of ten individuals with molecularly confirmed BPES showed that all had lateral displacement of the inferior punctum (i.e., in the lower eyelid) resulting from a temporal displacement of the entire lower eyelid. This proved to be an important anatomic hallmark in the diagnosis of BPES [ • Strabismus, refractive errors (anisometropic hypermetropia and myopia), and amblyopia are more common in individuals with BPES than in the general population [ • Secondary sexual characteristics are usually normal in both BPES type I and BPES type II. • In BPES type I, menarche is usually normal, followed by oligomenorrhea and secondary amenorrhea. • Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. • Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ • Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ • Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. • Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ • Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ • Hypoplastic uterus and small ovaries may be found in some individuals with BPES type I on pelvic ultrasound. • Ovarian reserve is decreased (characterized by a low atrial follicle count of <4 and decreased serum levels of anti-müllerian hormone) [ • Endocrinologic findings of hypergonadotropic hypogonadism include: elevated serum concentrations of follicle-stimulating hormone (>25 IU/L, measured on 2 occasions >4 weeks apart); elevated luteinizing hormone [ ## Genotype-Phenotype Correlations Pathogenic variants predicted to result in proteins truncated before the polyalanine tract preferentially lead to POI (BPES type I). Note: The need for careful interpretation of genotype-phenotype correlations is illustrated by the co-occurrence of BPES type I and isolated POI in a three-generation family [ Polyalanine expansions preferentially lead to BPES type II. ## Penetrance All individuals heterozygous for a The exception is a consanguineous Indian family in which heterozygotes for a short polyalanine expansion of 19 alanines are unaffected, but homozygotes have typical BPES (with documented POI in 1 female) [ ## Prevalence The prevalence of BPES is estimated at 1:50,000 births in the general population. No differences in prevalence based on sex, race, or ethnicity have been reported. ## Genetically Related (Allelic) Disorders ## Differential Diagnosis Because of its characteristic phenotype and the absence of extraocular manifestations other than primary ovarian insufficiency, BPES can be distinguished relatively easily from other conditions in which ptosis or blepharophimosis is a major feature (e.g., ## Management No clinical practice guidelines for blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) have been published. To establish the extent of disease and needs in an individual diagnosed with BPES, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with BPES For females w/BPES during late childhood or early puberty to assess gonadal function & assess/discuss onset & course of POI See also To inform affected persons & their families re nature, MOI, & implications of BPES to facilitate medical & personal decision making In females w/BPES, family history can indicate type of BPES (type I inferred by assoc w/subfertility or infertility). MOI = mode of inheritance; POI = primary ovarian insufficiency Medical geneticist, certified genetic counselor, certified advanced genetic nurse Management requires the input of a multidisciplinary team with specialists including a clinical geneticist, genetic counselor, pediatric ophthalmologist, oculoplastic surgeon, (pediatric or adult) endocrinologist, reproductive endocrinologist, and gynecologist. Treatment of Manifestations in Individuals with BPES Age 3-5 yrs: medial canthoplasty for correction of blepharophimosis, epicanthus inversus, & telecanthus ~1 yr later: ptosis correction, usually requiring brow suspension procedure Hormone replacement therapy Monitoring & optimizing bone health Eval of options for parenthood (adoption, foster parenthood, embryo donation, egg donation, ovary cryopreservation) POI = primary ovarian insufficiency Current management practices for primary ovarian insufficiency have been reviewed in Recommended Surveillance for Individuals with BPES Endocrinologic & gynecologic follow up to monitor ovarian status Assess effects of hormone replacement therapy for adjustments as needed. Psychological follow up POI = primary ovarian insufficiency It is appropriate to clarify the status of older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from ophthalmic surveillance and, in female relatives, endocrinologic surveillance to monitor ovarian status (see Molecular genetic testing if a Clinical examination for features of BPES if the pathogenic variant in the family is not known. See Search • For females w/BPES during late childhood or early puberty to assess gonadal function & assess/discuss onset & course of POI • See also • To inform affected persons & their families re nature, MOI, & implications of BPES to facilitate medical & personal decision making • In females w/BPES, family history can indicate type of BPES (type I inferred by assoc w/subfertility or infertility). • Age 3-5 yrs: medial canthoplasty for correction of blepharophimosis, epicanthus inversus, & telecanthus • ~1 yr later: ptosis correction, usually requiring brow suspension procedure • Hormone replacement therapy • Monitoring & optimizing bone health • Eval of options for parenthood (adoption, foster parenthood, embryo donation, egg donation, ovary cryopreservation) • Endocrinologic & gynecologic follow up to monitor ovarian status • Assess effects of hormone replacement therapy for adjustments as needed. • Psychological follow up • Molecular genetic testing if a • Clinical examination for features of BPES if the pathogenic variant in the family is not known. ## Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with BPES, the evaluations summarized in Recommended Evaluations Following Initial Diagnosis in Individuals with BPES For females w/BPES during late childhood or early puberty to assess gonadal function & assess/discuss onset & course of POI See also To inform affected persons & their families re nature, MOI, & implications of BPES to facilitate medical & personal decision making In females w/BPES, family history can indicate type of BPES (type I inferred by assoc w/subfertility or infertility). MOI = mode of inheritance; POI = primary ovarian insufficiency Medical geneticist, certified genetic counselor, certified advanced genetic nurse • For females w/BPES during late childhood or early puberty to assess gonadal function & assess/discuss onset & course of POI • See also • To inform affected persons & their families re nature, MOI, & implications of BPES to facilitate medical & personal decision making • In females w/BPES, family history can indicate type of BPES (type I inferred by assoc w/subfertility or infertility). ## Treatment of Manifestations Management requires the input of a multidisciplinary team with specialists including a clinical geneticist, genetic counselor, pediatric ophthalmologist, oculoplastic surgeon, (pediatric or adult) endocrinologist, reproductive endocrinologist, and gynecologist. Treatment of Manifestations in Individuals with BPES Age 3-5 yrs: medial canthoplasty for correction of blepharophimosis, epicanthus inversus, & telecanthus ~1 yr later: ptosis correction, usually requiring brow suspension procedure Hormone replacement therapy Monitoring & optimizing bone health Eval of options for parenthood (adoption, foster parenthood, embryo donation, egg donation, ovary cryopreservation) POI = primary ovarian insufficiency Current management practices for primary ovarian insufficiency have been reviewed in • Age 3-5 yrs: medial canthoplasty for correction of blepharophimosis, epicanthus inversus, & telecanthus • ~1 yr later: ptosis correction, usually requiring brow suspension procedure • Hormone replacement therapy • Monitoring & optimizing bone health • Eval of options for parenthood (adoption, foster parenthood, embryo donation, egg donation, ovary cryopreservation) ## Surveillance Recommended Surveillance for Individuals with BPES Endocrinologic & gynecologic follow up to monitor ovarian status Assess effects of hormone replacement therapy for adjustments as needed. Psychological follow up POI = primary ovarian insufficiency • Endocrinologic & gynecologic follow up to monitor ovarian status • Assess effects of hormone replacement therapy for adjustments as needed. • Psychological follow up ## Evaluation of Relatives at Risk It is appropriate to clarify the status of older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from ophthalmic surveillance and, in female relatives, endocrinologic surveillance to monitor ovarian status (see Molecular genetic testing if a Clinical examination for features of BPES if the pathogenic variant in the family is not known. See • Molecular genetic testing if a • Clinical examination for features of BPES if the pathogenic variant in the family is not known. ## Therapies Under Investigation Search ## Genetic Counseling Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is almost always inherited in an autosomal dominant manner. BPES associated with biallelic More than half of individuals diagnosed with BPES have an affected parent. A recent study showed more female than male probands and a highly significant bias in the parental origin of inherited pathogenic variants, with 20/21 pathogenic variants found to be paternal in origin (95%). The latter may be due to the association of BPES and primary ovarian insufficiency (POI) [ Some probands with BPES have the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has BPES as the result of a cytogenetic rearrangement involving 3q23, recommendations for the evaluation of asymptomatic parents include genomic testing to determine if a balanced chromosome rearrangement involving the 3q23 region is present. If the pathogenic variant identified in the proband is not found 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. Parental mosaicism has been observed in BPES [ The family history of some individuals diagnosed with BPES 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 without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of the BPES eyelid phenotype in heterozygous family members is 100%. If the proband has a known BPES-causing 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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. If a parent has a balanced structural chromosome rearrangement involving the 3q23 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. 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. Women with BPES should be informed regarding the risk of POI and recommendations for endocrinologic surveillance to monitor ovarian status (see Once the BPES-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BPES 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. • More than half of individuals diagnosed with BPES have an affected parent. • A recent study showed more female than male probands and a highly significant bias in the parental origin of inherited pathogenic variants, with 20/21 pathogenic variants found to be paternal in origin (95%). The latter may be due to the association of BPES and primary ovarian insufficiency (POI) [ • Some probands with BPES have the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the proband has BPES as the result of a cytogenetic rearrangement involving 3q23, recommendations for the evaluation of asymptomatic parents include genomic testing to determine if a balanced chromosome rearrangement involving the 3q23 region is present. • If the pathogenic variant identified in the proband is not found 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. • Parental mosaicism has been observed in BPES [ • 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 has been observed in BPES [ • The family history of some individuals diagnosed with BPES 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 without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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. • Parental mosaicism has been observed in BPES [ • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of the BPES eyelid phenotype in heterozygous family members is 100%. • If the proband has a known BPES-causing 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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. • If a parent has a balanced structural chromosome rearrangement involving the 3q23 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. • The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy. • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected. • Women with BPES should be informed regarding the risk of POI and recommendations for endocrinologic surveillance to monitor ovarian status (see ## Mode of Inheritance Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is almost always inherited in an autosomal dominant manner. BPES associated with biallelic ## Risk to Family Members (Autosomal Dominant Inheritance) More than half of individuals diagnosed with BPES have an affected parent. A recent study showed more female than male probands and a highly significant bias in the parental origin of inherited pathogenic variants, with 20/21 pathogenic variants found to be paternal in origin (95%). The latter may be due to the association of BPES and primary ovarian insufficiency (POI) [ Some probands with BPES have the disorder as the result of a If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. If the proband has BPES as the result of a cytogenetic rearrangement involving 3q23, recommendations for the evaluation of asymptomatic parents include genomic testing to determine if a balanced chromosome rearrangement involving the 3q23 region is present. If the pathogenic variant identified in the proband is not found 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. Parental mosaicism has been observed in BPES [ The family history of some individuals diagnosed with BPES 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 without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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 pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of the BPES eyelid phenotype in heterozygous family members is 100%. If the proband has a known BPES-causing 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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. If a parent has a balanced structural chromosome rearrangement involving the 3q23 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. • More than half of individuals diagnosed with BPES have an affected parent. • A recent study showed more female than male probands and a highly significant bias in the parental origin of inherited pathogenic variants, with 20/21 pathogenic variants found to be paternal in origin (95%). The latter may be due to the association of BPES and primary ovarian insufficiency (POI) [ • Some probands with BPES have the disorder as the result of a • If a molecular diagnosis has been established in the proband and the proband appears to be the only affected family member (i.e., a simplex case), molecular genetic testing is recommended for the parents of the proband to confirm their genetic status and to allow reliable recurrence risk counseling. • If the proband has BPES as the result of a cytogenetic rearrangement involving 3q23, recommendations for the evaluation of asymptomatic parents include genomic testing to determine if a balanced chromosome rearrangement involving the 3q23 region is present. • If the pathogenic variant identified in the proband is not found 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. • Parental mosaicism has been observed in BPES [ • 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 has been observed in BPES [ • The family history of some individuals diagnosed with BPES 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 without appropriate clinical evaluation of the parents and/or molecular genetic testing (to establish 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. • Parental mosaicism has been observed in BPES [ • If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to the sibs is 50%. The penetrance of the BPES eyelid phenotype in heterozygous family members is 100%. • If the proband has a known BPES-causing 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 are clinically unaffected but their genetic status is unknown, the risk to the sibs of a proband appears to be low but increased over that of the general population because of the possibility of parental germline mosaicism. • If a parent has a balanced structural chromosome rearrangement involving the 3q23 region, the risk to sibs is increased. The estimated risk depends on the specific chromosome rearrangement. ## 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. Women with BPES should be informed regarding the risk of POI and recommendations for endocrinologic surveillance to monitor ovarian status (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. • Women with BPES should be informed regarding the risk of POI and recommendations for endocrinologic surveillance to monitor ovarian status (see ## Prenatal Testing and Preimplantation Genetic Testing Once the BPES-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing for BPES 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 • ## Molecular Genetics Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome: Genes and Databases Data are compiled from the following standard references: gene from OMIM Entries for Blepharophimosis, Ptosis, and Epicanthus Inversus Syndrome ( The FOXL2 protein of 376 amino acids belongs to the large family of winged-helix/forkhead transcription factors. Forkhead proteins are present in all eukaryotes and have important functions in the establishment of the body axis and the development of tissues from all three layers in animals. Rearrangements outside the FOXL2 contains a polyalanine tract of 14 residues, the role of which has not yet been elucidated. Expansions from 14 to 24 alanine residues in this region represent about 30% of all intragenic Notable Variants listed in the table have been provided by the authors. • Rearrangements outside the • FOXL2 contains a polyalanine tract of 14 residues, the role of which has not yet been elucidated. Expansions from 14 to 24 alanine residues in this region represent about 30% of all intragenic ## Molecular Pathogenesis The FOXL2 protein of 376 amino acids belongs to the large family of winged-helix/forkhead transcription factors. Forkhead proteins are present in all eukaryotes and have important functions in the establishment of the body axis and the development of tissues from all three layers in animals. Rearrangements outside the FOXL2 contains a polyalanine tract of 14 residues, the role of which has not yet been elucidated. Expansions from 14 to 24 alanine residues in this region represent about 30% of all intragenic Notable Variants listed in the table have been provided by the authors. • Rearrangements outside the • FOXL2 contains a polyalanine tract of 14 residues, the role of which has not yet been elucidated. Expansions from 14 to 24 alanine residues in this region represent about 30% of all intragenic ## Chapter Notes Author websites: 10 March 2022 (ha) Comprehensive update posted live 5 February 2015 (me) Comprehensive update posted live 12 November 2009 (me) Comprehensive update posted live 15 February 2006 (cd) Revision: prenatal diagnosis available 12 July 2005 (me) Comprehensive update posted live 8 July 2004 (me) Review posted live 1 March 2004 (edb) Original submission • 10 March 2022 (ha) Comprehensive update posted live • 5 February 2015 (me) Comprehensive update posted live • 12 November 2009 (me) Comprehensive update posted live • 15 February 2006 (cd) Revision: prenatal diagnosis available • 12 July 2005 (me) Comprehensive update posted live • 8 July 2004 (me) Review posted live • 1 March 2004 (edb) Original submission ## Author Notes Author websites: ## Revision History 10 March 2022 (ha) Comprehensive update posted live 5 February 2015 (me) Comprehensive update posted live 12 November 2009 (me) Comprehensive update posted live 15 February 2006 (cd) Revision: prenatal diagnosis available 12 July 2005 (me) Comprehensive update posted live 8 July 2004 (me) Review posted live 1 March 2004 (edb) Original submission • 10 March 2022 (ha) Comprehensive update posted live • 5 February 2015 (me) Comprehensive update posted live • 12 November 2009 (me) Comprehensive update posted live • 15 February 2006 (cd) Revision: prenatal diagnosis available • 12 July 2005 (me) Comprehensive update posted live • 8 July 2004 (me) Review posted live • 1 March 2004 (edb) Original submission ## References ## Literature Cited	[ "PS Beckingsale, TJ Sullivan, VA Wong, C Oley. Blepharophimosis: a recommendation for early surgery in patients with severe ptosis.. Clin Experiment Ophthalmol 2003;31:138-42", "D Beysen, S De Jaegere, D Mowat, R Laframboise, G Gillessen-Kaesbach, M Fellous, RA Veitia, P Boucard, P Touraine, BP Leroy, C De Cock, P Delbeke, K Leppig, R Ensenauer, F Ebinger, D Barel, A Plomp, V Kimonis, Y Hendriks, J Clayton-Smith, AW Grix, N Van Regemorter, R Hennekam, F Meire, N Oyen, LC Wilson, A De Paepe, E De Baere. Mutation in brief: identification of 34 novel and 56 known. Hum Mutat 2008;29:E205-19", "D Beysen, A De Paepe, E De Baere. Mutation update:. Hum Mutat 2009;30:158-69", "D Beysen, J Raes, BP Leroy, A Lucassen, JR Yates, J Clayton-Smith, H Ilyina, SS Brooks, S Christin-Maitre, M Fellous, JP Fryns, JR Kim, P Lapunzina, E Lemyre, F Meire, LM Messiaen, C Oley, M Splitt, J Thomson, Y Van de Peer, RA Veitia, A De Paepe, E De Baere. 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The incidence of strabismus and refractive error in patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES).. Strabismus. 2003;11:173-7", "E De Baere, D Beysen, C Oley, B Lorenz, J Cocquet, P De Sutter, K Devriendt, M Dixon, M Fellous, JP Fryns, A Garza, C Jonsrud, PA Koivisto, A Krause, BP Leroy, F Meire, A Plomp, L Van Maldergem, A De Paepe, R Veitia, L Messiaen. FOXL2 and BPES: mutational hotspots, phenotypic variability, and revision of the genotype-phenotype correlation.. Am J Hum Genet 2003;72:478-87", "CE Decock, I Claerhout, BP Leroy, P Kesteleyn, AD Shah, E De Baere. Correction of the lower eyelid malpositioning in the blepharophimosis-ptosis-epicanthus inversus syndrome.. Ophthal Plast Reconstr Surg. 2011;27:368-70", "B D'haene, C Attanasio, D Beysen, J Dostie, E Lemire, P Bouchard, M Field, K Jones, B Lorenz, B Menten, K Buysse, F Pattyn, M Friedli, C Ucla, C Rossier, C Wyss, F Speleman, A De Paepe, J Dekker, SE Antonarakis, E De Baere. Disease-causing 7.4 kb cis-regulatory deletion disrupting conserved non-coding sequences and their interaction with the FOXL2 promotor: implications for mutation screening.. PLoS Genet. 2009;5", "B D'haene, J Nevado, M Pugeat, G Pierquin, RB Lowry, W Reardon, A Delicado, S García-Miñaur, M Palomares, W Courtens, M Stefanova, S Wallace, W Watkins, AN Shelling, D Wieczorek, RA Veitia, A De Paepe, P Lapunzina, E De Baere. FOXL2 copy number changes in the molecular pathogenesis of BPES: unique cohort of 17 deletions.. Hum Mutat. 2010;31:E1332-47", "SE Harris, AL Chand, IM Winship, K Gersak, K Aittomaki, AN Shelling. Identification of novel mutations in FOXL2 associated with premature ovarian failure.. Mol Hum Reprod. 2002;8:729-33", "I Huhtaniemi, O Hovatta, A La Marca, G Livera, D Monniaux, L Persani, A Heddar, K Jarzabek, T Laisk-Podar, A Salumets, JS Tapanainen, RA Veitia, JA Visser, P Wieacker, S Wolczynski, M Misrahi. Advances in the molecular pathophysiology, genetics, and treatment of primary ovarian insufficiency.. Trends Endocrinol Metab. 2018;29:400-19", "RV Kanj, NA Ofei-Tenkorang, M Altaye, CM Gordon. Evaluation and management of primary ovarian insufficiency in adolescents and young adults.. J Pediatr Adolesc Gynecol. 2018;31:13-18", "P Laissue, B Lakhal, BA Benayoun, A Dipietromaria, R Braham, H Elghezal, P Philibert, A Saâd, C Sultan, M Fellous, R Veitia. Functional evidence implicating FOXL2 in non syndromic premature ovarian failure and in the regulation of the transcription factor OSR2.. J Med Genet 2009;46:455-7", "AM Moreira, PM Spritzer. Primary ovarian insufficiency: different approaches in three cases and a review of literature.. Endocrinol Diabetes Metab Case Rep. 2016;2016", "J Nallathambi, L Moumné, E De Baere, D Beysen, K Usha, P Sundaresan, R Veitia. A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction.. Hum Genet 2007;121:107-12", "PD Stenson, M Mort, EV Ball, M Chapman, K Evans, L Azevedo, M Hayden, S Heywood, DS Millar, AD Phillips, DN Cooper. The Human Gene Mutation Database (HGMD®): optimizing its use in a clinical diagnostic or research setting.. Hum Genet. 2020;139:1197-207", "H Verdin, B D'haene, D Beysen, Y Novikova, B Menten, T Sante, P Lapunzina, J Nevado, C Carvalho, JR Lupski, E De Baere. Microhomology-mediated replication-based mechanisms underly non-recurrent pathogenic microdeletions of the FOXL2 gene or its regulatory domain.. PLoS Genet. 2013;9", "L Yang, T Li, Y Xing. Identification of a novel FOXL2 mutation in a single family with both types of blepharophimosis-ptosis-epicanthus inversus syndrome.. Mol Med Rep. 2017;16:5529-32", "Y Yang, C Yang, Y Zhu, H Chen, R Zhao, X He, L Tao, P Wang, L Zhou, L Zhao, M Tu, Z Dong, H Chen, Z Xie. Intragenic and extragenic disruptions of FOXL2 mapped by whole genome low-coverage sequencing in two BPES families with chromosome reciprocal translocation.. Genomics. 2014;104:170-6", "J Zlotogora, M Sagi, T Cohen. The blepharophimosis, ptosis, and epicanthus inversus syndrome: delineation of two types.. Am J Hum Genet 1983;35:1020-7" ]	8/7/2004	10/3/2022	15/2/2006	GeneReviews®	https://www.ncbi.nlm.nih.gov/books/NBK1116/	[ "Review", "Clinical Review" ]

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