Classic ataxia-telangiectasia (A-T) is characterized by progressive cerebellar ataxia beginning between ages one and four years, oculomotor apraxia, choreoathetosis, telangiectasias of the conjunctivae, immunodeficiency, frequent infections, and an increased risk for malignancy, particularly leukemia and lymphoma. Individuals with A-T are unusually sensitive to ionizing radiation. Non-classic forms of A-T have included adult-onset A-T and A-T with early-onset dystonia.

X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in 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 six months to two years. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. Adrenomyeloneuropathy (AMN) manifests most commonly in an individual in his twenties or middle age as progressive stiffness and weakness of the legs, 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 by middle age. More than 20% of female carriers develop mild-to-moderate spastic paraparesis in middle age or later. Adrenal function is usually normal.

EZH2-related overgrowth includes EZH2-related Weaver syndrome at one end of the spectrum and tall stature at the other. Although most individuals diagnosed with a heterozygous EZH2 pathogenic variant have been identified because of a clinical suspicion of Weaver syndrome, a minority have been identified through molecular genetic testing of family members of probands or individuals with overgrowth who did not have a clinical diagnosis of Weaver syndrome. Thus, the extent of the phenotypic spectrum associated with a heterozygous EZH2 pathogenic variant is not yet known. Weaver syndrome is characterized by tall stature, variable intellect (ranging from normal intellect to severe intellectual disability), characteristic facial appearance, and a range of associated clinical features including advanced bone age, poor coordination, soft doughy skin, camptodactyly of the fingers and/or toes, umbilical hernia, abnormal tone, and hoarse low cry in infancy. Brain MRI has identified abnormalities in a few individuals with EZH2-related overgrowth. Neuroblastoma occurs at a slightly increased frequency in individuals with a heterozygous EZH2 pathogenic variant but data are insufficient to determine absolute risk. There is currently no evidence that additional malignancies (including hematologic malignancies) occur with increased frequency.

GLB1-related disorders comprise two phenotypically distinct lysosomal storage disorders: GM1 gangliosidosis and mucopolysaccharidosis type IVB (MPS IVB). The phenotype of GM1 gangliosidosis constitutes a spectrum ranging from severe (infantile) to intermediate (late-infantile and juvenile) to mild (chronic/adult). Type I (infantile) GM1 gangliosidosis begins before age 12 months. Prenatal manifestations may include nonimmune hydrops fetalis, intrauterine growth restriction, and placental vacuolization; congenital dermal melanocytosis (Mongolian spots) may be observed. Macular cherry-red spot is detected on eye exam. Progressive central nervous system dysfunction leads to spasticity and rapid regression; blindness, deafness, decerebrate rigidity, seizures, feeding difficulties, and oral secretions are observed. Life expectancy is two to three years. Type II can be subdivided into the late-infantile (onset age 1-3 years) and juvenile (onset age 3-10 years) phenotypes. Central nervous system dysfunction manifests as progressive cognitive, motor, and speech decline as measured by psychometric testing. There may be mild corneal clouding, hepatosplenomegaly, and/or cardiomyopathy; the typical course is characterized by progressive neurologic decline, progressive skeletal disease in some individuals (including kyphosis and avascular necrosis of the femoral heads), and progressive feeding difficulties leading to aspiration risk. Type III begins in late childhood to the third decade with generalized dystonia leading to unsteady gait and speech disturbance followed by extrapyramidal signs including akinetic-rigid parkinsonism. Cardiomyopathy develops in some and skeletal involvement occurs in most. Intellectual impairment is common late in the disease with prognosis directly related to the degree of neurologic impairment. MPS IVB is characterized by skeletal dysplasia with specific findings of axial and appendicular dysostosis multiplex, short stature (below 15th centile in adults), kyphoscoliosis, coxa/genu valga, joint laxity, platyspondyly, and odontoid hypoplasia. First signs and symptoms may be apparent at birth. Bony involvement is progressive, with more than 84% of adults requiring ambulation aids; life span does not appear to be limited. Corneal clouding is detected in some individuals and cardiac valvular disease may develop.

Gillespie syndrome (GLSP) is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (summary by Gerber et al., 2016 and McEntagart et al., 2016).

Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The age of onset ranges from 19 to 73 years; mean age of onset is between 43 and 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved.

Episodic ataxia type 1 (EA1) is a potassium channelopathy characterized by constant myokymia and dramatic episodes of spastic contractions of the skeletal muscles of the head, arms, and legs with loss of both motor coordination and balance. During attacks individuals may experience a number of variable symptoms including vertigo, blurred vision, diplopia, nausea, headache, diaphoresis, clumsiness, stiffening of the body, dysarthric speech, and difficulty in breathing, among others. EA1 may be associated with epilepsy. Other possible associations include delayed motor development, cognitive disability, choreoathetosis, and carpal spasm. Usually, onset is in childhood or early adolescence.

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").

The Hedera type of X-linked syndromic intellectual developmental disorder (MRXSH) is characterized by global developmental delay apparent from infancy and progressive neurologic decline with abnormal movements, spasticity, and seizures. Brain imaging shows volume loss of cortical white and gray matter, thin corpus callosum, and myelination defects, consistent with a neurodegenerative process. Only males are affected (summary by Hirose et al., 2019).

Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral leg weakness and spasticity. Most affected individuals have decreased vibration sense and cerebellar signs. Onset is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years. Additional features including ataxia (gait and limbs), spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, ptosis, hearing loss, motor and sensory neuropathy, amyotrophy, scoliosis, pes cavus, and urinary sphincter disturbances may be observed.

A rare syndromic renal disorder characterized by renal, neurologic and thyroid disease, associated with thrombocytopenia. There have been no further descriptions in the literature since 1978.

An exceedingly rare form of hereditary episodic ataxia with varying degrees of ataxia and associated findings including slurred speech, headache, confusion and hemiplegia.

Cerebellar ataxia, impaired intellectual development, and dysequilibrium syndrome (CAMRQ) is a genetically heterogeneous disorder characterized by congenital cerebellar ataxia and mental retardation (summary by Gulsuner et al., 2011). For a discussion of genetic heterogeneity of CAMRQ, see CAMRQ1 (224050).

A rare hereditary ataxia characterized by recurrent episodes of ataxia with variable frequency and duration, associated with slurred speech, generalized muscle weakness and balance disturbance. Other symptoms may occur between episodes, including intention tremor, gait ataxia, mild dysarthria, myokymia, migraine and nystagmus.

Luscan-Lumish syndrome (LLS) is characterized by macrocephaly, intellectual disability, speech delay, low sociability, and behavioral problems. More variable features include postnatal overgrowth, obesity, advanced carpal ossification, developmental delay, and seizures (Luscan et al., 2014; Lumish et al., 2015)

Sialidosis is an autosomal recessive disorder characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. Common to the sialidoses is the accumulation and/or excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins (summary by Lowden and O'Brien, 1979). The sialidoses are distinct from the sialurias in which there is storage and excretion of 'free' sialic acid, rather than 'bound' sialic acid; neuraminidase activity in sialuria is normal or elevated. Salla disease (604369) is a form of 'free' sialic acid disease. Classification Lowden and O'Brien (1979) provided a logical nosology of neuraminidase deficiency into sialidosis type I and type II. Type I is the milder form, also known as the 'normosomatic' type or the cherry red spot-myoclonus syndrome. Sialidosis type II is the more severe form with an earlier onset, and is also known as the 'dysmorphic' type. Type II has been subdivided into juvenile and infantile forms. Other terms for sialidosis type II are mucolipidosis I and lipomucopolysaccharidosis.

Congenital bile acid synthesis defect-6 (CBAS6) is characterized by persistent hypertransaminasemia and accumulation of C27 bile acids (summary by Alonso-Pena et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of congenital bile acid synthesis defects, see CBAS1 (607765).

Autosomal dominant striatal degeneration is a neurologic disorder characterized by variable movement abnormalities due to dysfunction in the striatal part of the basal ganglia (summary by Kuhlenbaumer et al., 2004). Genetic Heterogeneity of Autosomal Dominant Striatal Degeneration See also ADSD2 (616922), caused by mutation in the PDE10A gene (610652) on chromosome 6q27.

Autosomal recessive idiopathic basal ganglia calcification-7 is a neurologic disorder characterized by onset of symptoms in adulthood. Patients present with dysarthria, gait abnormalities, various movement abnormalities, and often cognitive decline. Brain imaging shows abnormal accumulation of calcium deposits in deep brain regions, including the basal ganglia, thalamus, dentate nuclei, cerebellum, and sometimes other areas of the brain and spinal cord. Some patients with brain imaging abnormalities may be clinically asymptomatic (summary by Yao et al., 2018). For a detailed phenotypic description and a discussion of genetic heterogeneity of IBGC, see IBGC1 (213600).

Combined oxidative phosphorylation deficiency-44 (COXPD44) is an autosomal recessive mitochondrial disorder with multisystemic manifestations. Most affected individuals present in infancy or early childhood with global developmental delay, hypotonia, and abnormal movements. Most patients develop seizures, often associated with status epilepticus, and some patients may have optic atrophy. One patient with hypertrophic cardiomyopathy has been reported. Serum lactate may be increased, although that finding is inconsistent. Detailed biochemical analysis shows variable combined deficiencies of mitochondrial oxidative complexes that appear to be tissue-specific (summary by Wei et al., 2020). For discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Neurodevelopmental disorder with seizures and gingival overgrowth (NEDSGO) is an autosomal recessive disorder with a highly variable phenotype. Some patients have early normal development with developmental regression apparent in the first years of life, whereas others present with hypotonia or delayed development. Most patients develop significant gingival hypertrophy associated with a prominent mandible or cherubism in the first years of life. Other more variable features may include coarse facial features, optic atrophy, sensorineural hearing loss, ataxia, and seizures. Brain imaging may show cerebellar or cerebral atrophy and enlarged ventricles. There is a wide phenotypic spectrum with features that may develop with age; the disorder appears to comprise a continuum of evolving neurologic manifestations (Harms et al., 2020).

Hatipoglu immunodeficiency syndrome (HATIS) is an autosomal recessive immunologic disorder characterized by childhood onset of failure to thrive, skin manifestations, pancytopenia, and susceptibility to recurrent infections (Harapas et al., 2022).