Fabry disease is the most common of the lysosomal storage disorders and results from deficient activity of the enzyme alpha-galactosidase A (a-Gal A), leading to progressive lysosomal deposition of globotriaosylceramide and its derivatives in cells throughout the body. The classic form, occurring in males with less than 1% a-Gal A enzyme activity, usually has its onset in childhood or adolescence with periodic crises of severe pain in the extremities (acroparesthesia), the appearance of vascular cutaneous lesions (angiokeratomas), sweating abnormalities (anhidrosis, hypohidrosis, and rarely hyperhidrosis), characteristic corneal and lenticular opacities, and proteinuria. Gradual deterioration of renal function to end-stage renal disease (ESRD) usually occurs in men in the third to fifth decade. In middle age, most males successfully treated for ESRD develop cardiac and/or cerebrovascular disease, a major cause of morbidity and mortality. Heterozygous females typically have milder symptoms at a later age of onset than males. Rarely, females may be relatively asymptomatic throughout a normal life span or may have symptoms as severe as those observed in males with the classic phenotype. In contrast, late-onset forms occur in males with greater than 1% a-Gal A activity. Clinical manifestations include cardiac disease, which usually presents in the sixth to eighth decade with left ventricular hypertrophy, cardiomyopathy, arrhythmia, and proteinuria; renal failure, associated with ESRD but without the skin lesions or pain; or cerebrovascular disease presenting as stroke or transient ischemic attack.

Acute intermittent porphyria (AIP), an autosomal dominant disorder, occurs in heterozygotes for an HMBS pathogenic variant that causes reduced activity of the enzyme porphobilinogen deaminase. AIP is considered "overt" in a heterozygote who was previously or is currently symptomatic; AIP is considered "latent" in a heterozygote who has never had symptoms, and typically has been identified during molecular genetic testing of at-risk family members. Note that GeneReviews does not use the term "carrier" for an individual who is heterozygous for an autosomal dominant pathogenic variant; GeneReviews reserves the term "carrier" for an individual who is heterozygous for an autosomal recessive disorder and thus is not expected to ever develop manifestations of the disorder. Overt AIP is characterized clinically by life-threatening acute neurovisceral attacks of severe abdominal pain without peritoneal signs, often accompanied by nausea, vomiting, tachycardia, and hypertension. Attacks may be complicated by neurologic findings (mental changes, convulsions, and peripheral neuropathy that may progress to respiratory paralysis), and hyponatremia. Acute attacks, which may be provoked by certain drugs, alcoholic beverages, endocrine factors, calorie restriction, stress, and infections, usually resolve within two weeks. Most individuals with AIP have one or a few attacks; about 3%-8% (mainly women) have recurrent attacks (defined as >3 attacks/year) that may persist for years. Other long-term complications are chronic renal failure, hepatocellular carcinoma (HCC), and hypertension. Attacks, which are very rare before puberty, are more common in women than men. Latent AIP. While all individuals heterozygous for an HMBS pathogenic variant that predisposes to AIP are at risk of developing overt AIP, most have latent AIP and never have symptoms.

ALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (Jaffe and Stith, 2007).

Gitelman syndrome (GTLMNS) is an autosomal recessive renal tubular salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. It is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most patients have onset of symptoms as adults, but some present in childhood. Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis (summary by Glaudemans et al., 2012). Gitelman syndrome is sometimes referred to as a mild variant of classic Bartter syndrome (607364). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.

For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

A mild subtype of autosomal recessive limb girdle muscular dystrophy characterized by slowly progressive proximal muscle weakness and wasting of the pelvic and shoulder girdles with onset that usually occurs during the second or third decade of life. Clinical presentation is variable and can include calf psuedohypertrophy, joint contractures, scapular winging, muscle cramping and/or facial and respiratory muscle involvement.

Cronkhite-Canada syndrome is characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, skin hyperpigmentation, and diarrhea. It is associated with high morbidity (summary by Sweetser et al., 2012).

Autosomal dominant hypocalcemia-1 (HYPOC1) is associated with low or normal serum parathyroid hormone concentrations (PTH). Approximately 50% of patients have mild or asymptomatic hypocalcemia; about 50% have paresthesias, carpopedal spasm, and seizures; about 10% have hypercalciuria with nephrocalcinosis or kidney stones; and more than 35% have ectopic and basal ganglia calcifications (summary by Nesbit et al., 2013). Thakker (2001) noted that patients with gain-of-function mutations in the CASR gene, resulting in generally asymptomatic hypocalcemia with hypercalciuria, have low-normal serum PTH concentrations and have often been diagnosed with hypoparathyroidism because of the insensitivity of earlier PTH assays. Because treatment with vitamin D to correct the hypocalcemia in these patients causes hypercalciuria, nephrocalcinosis, and renal impairment, these patients need to be distinguished from those with other forms of hypoparathyroidism (see 146200). Thakker (2001) suggested the designation 'autosomal dominant hypocalcemic hypercalciuria' for this CASR-related disorder. Genetic Heterogeneity of Autosomal Dominant Hypocalcemia Autosomal dominant hypocalcemia-2 (HYPOC2; 615361) is caused by mutation in the GNA11 gene (139313) on chromosome 19p13.

A rare, genetic, benign disorder of cobalamin transport, due to variable degrees of transcobalamin I deficiency, characterized by mildly low to almost undetectable plasma transcobalamin I levels and slighly low to absent serum cobalamin levels. Normal methylmalonic acid and homocysteine serum values and absence of megaloblastic anemia are reported. No specific clinical manifestations are associated and patients are typically asymptomatic.

Arnold-Chiari type I malformation refers to a relatively mild degree of herniation of the posteroinferior region of the cerebellum (the cerebellar tonsils) into the cervical canal with little or no displacement of the fourth ventricle. It is characterized by one or both pointed (not rounded) cerebellar tonsils that project 5 mm below the foramen magnum, measured by a line drawn from the basion to the opisthion (McRae Line)

Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of up-gaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late-adult onset have been reported. Those with onset after age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy.

Intrinsic factor deficiency (IFD), or congenital pernicious anemia, is a rare disorder characterized by the lack of gastric intrinsic factor in the presence of normal acid secretion and mucosal cytology and the absence of GIF antibodies that are found in the acquired form of pernicious anemia (170900). See also pernicious anemia due to defect in the receptor for vitamin B12/intrinsic factor (261100).

Episodic ataxia is a genetically heterogeneous neurologic condition characterized by spells of incoordination and imbalance, often associated with progressive ataxia. Episodic ataxia type 2 is the most common form of EA (Jen et al., 2007). For a discussion of genetic heterogeneity of episodic ataxia, see EA1 (160120).

The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started.

Most individuals with classic GBE1 adult polyglucosan body disease (GBE1-APBD) present after age 40 years with unexplained 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, autonomic dysfunction (associated with orthostatic hypotension and constipation), and mild cognitive difficulties (often executive dysfunction). Some affected individuals without classic GBE1-APBD have atypical phenotypes including Alzheimer disease-like dementia and axonal neuropathy, stroke-like episodes, and diaphragmatic failure; others may have a history of infantile liver disease.

Hereditary sensory and autonomic neuropathy type II (HSAN2) is characterized by progressively reduced sensation to pain, temperature, and touch. Onset can be at birth and is often before puberty. The sensory deficit is predominantly distal with the lower limbs more severely affected than the upper limbs. Over time sensory function becomes severely reduced. Unnoticed injuries and neuropathic skin promote ulcerations and infections that result in spontaneous amputation of digits or the need for surgical amputation. Osteomyelitis is common. Painless fractures can complicate the disease. Autonomic disturbances are variable and can include hyperhidrosis, tonic pupils, and urinary incontinence in those with more advanced disease.

Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.

Methylenetetrahydrofolate reductase deficiency is a common inborn error of folate metabolism. The phenotypic spectrum ranges from severe neurologic deterioration and early death to asymptomatic adults. In the classic form, both thermostable and thermolabile enzyme variants have been identified (Rosenblatt et al., 1992).

Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disorder of the central nervous system (CNS) with various degrees of axonal damage. MS affects mainly young adults with predominance for females. The disorder often leads to substantial disability (summary by Bomprezzi et al., 2003). Genetic Heterogeneity of Susceptibility to Multiple Sclerosis Additional MS susceptibility loci include MS2 (612594) on chromosome 10p15, MS3 (612595) on chromosome 5p13, MS4 (612596) on chromosome 1p36, and MS5 (614810), conferred by variation in the TNFRSF1A gene (191190) on chromosome 12p13.

Restless legs syndrome (RLS) is a neurologic sleep/wake disorder characterized by uncomfortable and unpleasant sensations in the legs that appear at rest, usually at night, inducing an irresistible desire to move the legs. The disorder results in nocturnal insomnia and chronic sleep deprivation (Bonati et al., 2003). Genetic Heterogeneity of Restless Legs Syndrome RLS1 has been mapped to chromosome 12q. Other susceptibility loci for RLS include RLS2 (608831) on chromosome 14q13-q31; RLS3 (610438) on chromosome 9p24-p22; RLS4 (610439) on chromosome 2q33; RLS5 (611242) on chromosome 20p13; RLS6 (611185) on chromosome 6p21; RLS7 (612853) on chromosome 2p14; and RLS8 (615197) on chromosome 5q31.

Cerebral amyloid angiopathy, or cerebroarterial amyloidosis, refers to a pathologic process in which amyloid protein progressively deposits in cerebral blood vessel walls with subsequent degenerative vascular changes that usually result in spontaneous cerebral hemorrhage, ischemic lesions, and progressive dementia. APP-related CAA is the most common form of CAA (Revesz et al., 2003, 2009).

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in all affected individuals, these findings occur in a minority of individuals with SPG3A. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. Most persons with early-onset ATL1-HSP have a "pure" ("uncomplicated") HSP; however, complicated HSP with axonal motor neuropathy and/or distal amyotrophy with lower motor neuron involvement (Silver syndrome phenotype) has been observed. The rate of progression in ATL1-HSP is slow, and wheelchair dependency or need for a walking aid (cane, walker, or wheelchair) is relatively rare.

An autosomal dominant hypocalcemia disease that has material basis in heterozygous mutation in the GNA11 gene on chromosome 19p13.

3-Methylglutaconic aciduria type I (MGCA1) is a rare autosomal recessive disorder of leucine catabolism. The metabolic landmark is urinary excretion of 3-methylglutaconic acid (3-MGA) and its derivatives 3-methylglutaric acid (3-MG) and 3-hydroxyisovaleric acid (3-HIVA). Two main presentations have been described: one with onset in childhood associated with the nonspecific finding of psychomotor retardation, and the other with onset in adulthood of a progressive neurodegenerative disorder characterized by ataxia, spasticity, and sometimes dementia; these patients develop white matter lesions in the brain. However, some asymptomatic pediatric patients have been identified by newborn screening and show no developmental abnormalities when reexamined later in childhood (summary by Wortmann et al., 2010). Genetic Heterogeneity and Classification of Methylglutaconic Aciduria Methylglutaconic aciduria is a clinically and genetically heterogeneous disorder. Type II MGCA (MGCA2), also known as Barth syndrome (BTHS; 302060), is caused by mutation in the tafazzin gene (TAZ; 300394) on chromosome Xq28. It is characterized by mitochondrial cardiomyopathy, short stature, skeletal myopathy, and recurrent infections; cognitive development is normal. Type III MGCA (MGCA3; 258501), caused by mutation in the OPA3 gene (606580) on chromosome 19q13, involves optic atrophy, movement disorder, and spastic paraplegia. In types II and III, the elevations of 3-methylglutaconate and 3-methylglutarate in urine are modest. Type IV MGCA (MGCA4; 250951) represents an unclassified group of patients who have severe psychomotor retardation and cerebellar dysgenesis. Type V MGCA (MGCA5; 610198), caused by mutation in the DNAJC19 gene (608977) on chromosome 3q26, is characterized by early-onset dilated cardiomyopathy with conduction defects, nonprogressive cerebellar ataxia, testicular dysgenesis, and growth failure in addition to 3-methylglutaconic aciduria (Chitayat et al., 1992; Davey et al., 2006). Type VI MGCA (MGCA6; 614739), caused by mutation in the SERAC1 gene (614725) on chromosome 6q25, includes deafness, encephalopathy, and a Leigh-like syndrome. Type VII MGCA (MGCA7B, 616271 and MGCA7A, 619835), caused by mutation in the CLPB gene (616254) on chromosome 11q13, includes cataracts, neurologic involvement, and neutropenia. Type VIII MGCA (MGCA8; 617248) is caused by mutation in the HTRA2 gene (606441) on chromosome 2p13. Type IX MGCA (MGCA9; 617698) is caused by mutation in the TIMM50 gene (607381) on chromosome 19q13. Eriguchi et al. (2006) noted that type I MGCA is very rare, with only 13 patients reported in the literature as of 2003. Wortmann et al. (2013) proposed a pathomechanism-based classification for 'inborn errors of metabolism with 3-methylglutaconic aciduria as discriminative feature.'

Syringomyelia (Greek: 'syrinx,' pipe, and 'myelos,' marrow) is a tubular cavity in the spinal cord. It can occur sporadically in association with spinal cord tumors, inflammatory arachnoiditis, or posttraumatically. It is rarely idiopathic (less than 1% of cases). The vast majority of cases of syringomyelia are cervical, noncommunicating, and associated with an abnormality at the foramen magnum, particularly the Chiari malformation type I (CM1; 118420), as well as basilar impression (109500) and Dandy-Walker malformation (220200) (Speer et al., 2003; Levine, 2004); these cases have shown familial segregation. The form of syringomyelia discussed here is 'noncommunicating' with the fourth ventricle, but may communicate with the subarachnoid space. In contrast, 'communicating' syringomyelia, or 'hydromelia,' opens rostrally into the fourth ventricle and almost always occurs in children with hydrocephalus, Chiari malformation type II (CM2; 207950), and spina bifida (see 182940) (Levine, 2004).

Autosomal recessive spastic paraplegia-83 (SPG83) is a neurologic disorder characterized by progressive lower limb spasticity resulting in gait instability. Patients develop symptoms in the second decade, consistent with juvenile onset. Some patients may have myalgia or mild dysarthria, but the phenotype is considered to be a pure type of SPG with no additional neurologic abnormalities (summary by Husain et al., 2020). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Autosomal recessive distal hereditary motor neuronopathy-7 (HMNR7) is characterized by onset of lower leg weakness in the first decade. Affected individuals have difficulty climbing stairs and problems standing on the heels. Some patients have later onset well into the adult years. Most patients have foot deformities, and some may have leg muscle atrophy. The disorder is slowly progressive and often involves the upper limbs. Muscle biopsy and electrophysiologic studies are consistent with both a myopathic process and an axonal motor neuropathy. Sensory abnormalities are not typically present, and patients remain ambulatory. The phenotype shows phenotypic overlap with distal hereditary motor neuropathy, but can distinguished by the presence of myopathic features (summary by Deschauer et al., 2021 and Pagnamenta et al., 2021). For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).

A rare axonal hereditary motor and sensory neuropathy characterized by adult onset of recurrent pain in legs with or without cramps, progressive loss of deep tendon reflexes and vibration sense, paresthesia in the feet and later in the hands. Patients often experience sleep disturbances and mild sensory ataxia.

Autosomal recessive spinocerebellar ataxia-21 (SCAR21) is a neurologic disorder characterized by onset of cerebellar ataxia associated with cerebellar atrophy in early childhood. Affected individuals also have recurrent episodes of liver failure in the first decade, resulting in chronic liver fibrosis, as well as later onset of a peripheral neuropathy. Mild learning disabilities may also occur (summary by Schmidt et al., 2015). The phenotype is highly variable: all patients appear to have episodic and severe liver dysfunction in early childhood that tends to resolve with age. Affected individuals also show mild developmental or language delay and/or later onset of variable neurologic features, such as motor dysfunction (summary by Lenz et al., 2018).

Spastic paraplegia-18A (SPG18A) is an autosomal dominant disorder characterized by a pure form of hereditary spastic paraplegia phenotype (summary by Rydning et al., 2018).