MedGen

The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). Enzyme replacement therapy (ERT) is currently FDA approved for the non-central nervous system manifestations of ASMD, regardless of type. As more affected individuals are treated with ERT for longer periods of time, the natural history of ASMD is likely to change. The most common presenting symptom in untreated NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Growth failure typically becomes evident by the second year of life. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. This feature may not be amenable to ERT. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children, although it is unclear if ERT will have an impact on this. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most untreated children succumb before the third year of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized in untreated individuals by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some central nervous system manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B, even when untreated. [from GeneReviews]

Pyruvate carboxylase (PC) deficiency is characterized in most affected individuals by failure to gain weight and/or linear growth failure, developmental delay, epilepsy, and metabolic acidosis. Three clinical phenotypes are recognized. Type A (infantile form) is characterized by infantile onset of metabolic and lactic acidosis, delayed motor development, intellectual disability, poor linear growth and/or weight gain, and neurologic findings (apathy, hypotonia, pyramidal and extrapyramidal signs, ataxia, and seizures). Brain anomalies can be noted. Most affected children die in infancy or early childhood. Type B (severe neonatal form) is characterized by neonatal or infantile onset of hypothermia, respiratory distress/failure, vomiting, severe lactic acidosis, hyperammonemia, and often hypoglycemia. Neurologic findings include brain abnormalities, lethargy, hypotonia, and pyramidal and extrapyramidal signs. Death typically occurs by age eight months. Type C (intermittent/attenuated form) is characterized by relatively normal or mildly delayed neurologic development, motor and/or gait abnormalities, (rarely) seizures, episodic movement disorders, and metabolic acidosis. Life span is unknown but survival into adulthood has been reported. [from GeneReviews]

3-methylglutaconyl-CoA hydratase deficiency is an inherited condition that causes neurological problems. Beginning in infancy to early childhood, children with this condition often have delayed development of mental and motor skills (psychomotor delay), speech delay, involuntary muscle cramping (dystonia), and spasms and weakness of the arms and legs (spastic quadriparesis). Affected individuals can also have optic atrophy, which is the breakdown (atrophy) of nerve cells that carry visual information from the eyes to the brain.

In some cases, signs and symptoms of 3-methylglutaconyl-CoA hydratase deficiency begin in adulthood, often in a person's twenties or thirties. These individuals have damage to a type of brain tissue called white matter (leukoencephalopathy). This damage likely contributes to progressive problems with speech (dysarthria), difficulty coordinating movements (ataxia), stiffness (spasticity), optic atrophy, and a decline in intellectual function (dementia).

Affected individuals who show symptoms of 3-methylglutaconyl-CoA hydratase deficiency in childhood often go on to develop leukoencephalopathy and other neurological problems in adulthood.

All people with 3-methylglutaconyl-CoA hydratase deficiency accumulate large amounts of a substance called 3-methylglutaconic acid in their body fluids. As a result, they have elevated levels of acid in their blood (metabolic acidosis) and excrete large amounts of acid in their urine (aciduria). 3-methylglutaconyl-CoA hydratase deficiency is one of a group of metabolic disorders that can be diagnosed by the presence of increased levels 3-methylglutaconic acid in urine (3-methylglutaconic aciduria). People with 3-methylglutaconyl-CoA hydratase deficiency also have high urine levels of another acid called 3-methylglutaric acid. [from MedlinePlus Genetics]

Free sialic acid storage disorders (FSASDs) are a spectrum of neurodegenerative disorders resulting from increased lysosomal storage of free sialic acid. Historically, FSASD was divided into separate allelic disorders: Salla disease, intermediate severe Salla disease, and infantile free sialic acid storage disease (ISSD). The mildest type was Salla disease, characterized by normal appearance and absence of neurologic findings at birth, followed by slowly progressive neurologic deterioration resulting in mild-to-moderate psychomotor delays, spasticity, athetosis, and epileptic seizures. Salla disease was named for a municipality in Finnish Lapland where a specific founder variant is relatively prevalent. However, the term Salla has been used in the literature to refer to less severe FSASD. More severe FSASD is historically referred to as ISSD, and is characterized by severe developmental delay, coarse facial features, hepatosplenomegaly, and cardiomegaly; death usually occurs in early childhood. [from GeneReviews]

Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities. [from GeneReviews]

Mitochondrial DNA depletion syndrome-7 is an autosomal recessive severe neurodegenerative disorder characterized primarily by hypotonia, ataxia, ophthalmoplegia, hearing loss, seizures, and sensory axonal neuropathy. Although originally classified as a form of spinocerebellar ataxia (see, e.g., SCA1, 164400) (Koskinen et al., 1994), it has been reclassified as a mitochondrial DNA depletion syndrome (Hakonen et al., 2008) based on the finding of mtDNA depletion in the brain and liver of affected individuals. For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041). [from OMIM]

SUCLA2-related mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria (SUCLA2-related mtDNA depletion syndrome) is characterized by onset of the following features in infancy: developmental delay, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, growth failure, and feeding difficulties. Other less frequent features include choreoathetosis, muscle weakness, recurrent vomiting, ptosis, and kyphoscoliosis. The median survival is age 20 years; approximately 30% of affected individuals succumb during childhood. [from GeneReviews]

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. [from GeneReviews]

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. [from GeneReviews]

De Barsy syndrome, or autosomal recessive cutis laxa type III (ARCL3), is characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (summary by Kivuva et al., 2008). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219100. Genetic Heterogeneity of de Barsy Syndrome Also see ARCL3B (614438), caused by mutation in the PYCR1 gene (179035) on chromosome 17q25. [from OMIM]

FOXG1 syndrome is characterized by moderate-to-profound developmental delay and intellectual disability, postnatal growth deficiency, congenital or postnatal microcephaly, hyperkinetic/dyskinetic movement disorder, hypotonia, neurobehavioral/psychiatric manifestations (motor stereotypies, impairment of social interaction, abnormal sleep patterns, unexplained episodes of crying, restlessness, and bruxism), feeding difficulties with poor weight gain, strabismus, seizures, spasticity, gastroesophageal reflux, and aspiration. Some individuals have cortical visual impairment, kyphosis, scoliosis, and/or abnormal breathing. Characteristic neuroimaging findings include corpus callosum anomalies (especially a marked, filiform thinning of the rostrum of the corpus callosum), a simplified gyral pattern, and hyperplasia of the fornices. [from GeneReviews]

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord. [from GeneReviews]

Hereditary folate malabsorption (HFM) is characterized by folate deficiency due to impaired intestinal folate absorption and impaired folate transport into the central nervous system. Findings include poor feeding, failure to thrive, and anemia. There can be leukopenia and thrombocytopenia, diarrhea and/or oral mucositis, hypoimmunoglobulinemia, and other immunologic dysfunction resulting in infections, most often Pneumocystis jirovecii pneumonia. Neurologic manifestations include developmental delays, cognitive and motor disorders, behavioral disorders, and seizures. [from GeneReviews]

De Barsy syndrome, also known as autosomal recessive cutis laxa type III (ARCL3), is a rare autosomal recessive disorder characterized by an aged appearance with distinctive facial features, sparse hair, ophthalmologic abnormalities, intrauterine growth retardation (IUGR), and cutis laxa (summary by Lin et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of de Barsy syndrome, see 219150. For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see 219200. [from OMIM]

Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016). Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36. [from OMIM]

The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (summary by Steinberg et al., 2006). For a complete phenotypic description and a discussion of genetic heterogeneity of Zellweger syndrome, see 214100. Individuals with PBDs of complementation group 5 (CG5, equivalent to CG10 and CGF) have mutations in the PEX2 gene. For information on the history of PBD complementation groups, see 214100. [from OMIM]

Hyperphosphatasia with impaired intellectual development syndrome-1 (HPMRS1) is an autosomal recessive disorder characterized by impaired intellectual development, various neurologic abnormalities such as seizures and hypotonia, and hyperphosphatasia. Other features include facial dysmorphism and variable degrees of brachytelephalangy (summary by Krawitz et al., 2010). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Hyperphosphatasia with Impaired Intellectual Development Syndrome See also HPMRS2 (614749), caused by mutation in the PIGO gene (614730) on chromosome 9p13; HPMRS3 (614207), caused by mutation in the PGAP2 gene (615187) on chromosome 11p15; HPMRS4 (615716), caused by mutation in the PGAP3 gene (611801) on chromosome 17q12; HPMRS5 (616025), caused by mutation in the PIGW gene (610275) on chromosome 17q12; and HPMRS6 (616809), caused by mutation in the PIGY gene (610662) on chromosome 4q22. Knaus et al. (2018) provided a review of the main clinical features of the different types of HPMRS, noting that some patients have a distinct pattern of facial anomalies that can be detected by computer-assisted comparison, particularly those with mutations in the PIGV and PGAP3 genes. Individuals with HPMRS have variable increased in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between HPMRS and MCAHS (see, e.g., 614080), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified under the more encompassing term of 'GPI biosynthesis defects' (GPIBD). [from OMIM]

Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the UBQLN2 gene. [from MONDO]

Infantile cerebellar-retinal degeneration (ICRD) is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (summary by Spiegel et al., 2012). A subset of patients may have a milder phenotype with variable features, including ataxia, developmental delay, and behavioral abnormalities (Blackburn et al., 2020). Mutation in the ACO2 gene also causes isolated optic atrophy (OPA9; 616289). [from OMIM]

Autosomal recessive limb-girdle muscular dystrophy-18 (LGMDR18) is characterized by childhood-onset of proximal muscle weakness resulting in gait abnormalities and scapular winging. Serum creatine kinase is increased. A subset of patients may show a hyperkinetic movement disorder with chorea, ataxia, or dystonia and global developmental delay (summary by Bogershausen et al., 2013). Additional more variable features include alacrima, achalasia, cataracts, or hepatic steatosis (Liang et al., 2015; Koehler et al., 2017). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600). [from OMIM]