Hereditary sensory and autonomic neuropathy type V (HSAN5) is a condition that primarily affects the sensory nerve cells (sensory neurons), which transmit information about sensations such as pain, temperature, and touch. These sensations are impaired in people with HSAN5.\n\nThe signs and symptoms of HSAN5 appear early, usually at birth or during infancy. People with HSAN5 lose the ability to feel pain, heat, and cold. Deep pain perception, the feeling of pain from injuries to bones, ligaments, or muscles, is especially affected in people with HSAN5. Because of the inability to feel deep pain, affected individuals suffer repeated severe injuries such as bone fractures and joint injuries that go unnoticed. Repeated trauma can lead to a condition called Charcot joints, in which the bones and tissue surrounding joints are destroyed.

PNPLA6 disorders span a phenotypic continuum characterized by variable combinations of cerebellar ataxia; upper motor neuron involvement manifesting as spasticity and/or brisk reflexes; chorioretinal dystrophy associated with variable degrees of reduced visual function; and hypogonadotropic hypogonadism (delayed puberty and lack of secondary sex characteristics). The hypogonadotropic hypogonadism occurs either in isolation or as part of anterior hypopituitarism (growth hormone, thyroid hormone, or gonadotropin deficiencies). Common but less frequent features are peripheral neuropathy (usually of axonal type manifesting as reduced distal reflexes, diminished vibratory sensation, and/or distal muscle wasting); hair anomalies (long eyelashes, bushy eyebrows, or scalp alopecia); short stature; and impaired cognitive functioning (learning disabilities in children; deficits in attention, visuospatial abilities, and recall in adults). Some of these features can occur in distinct clusters on the phenotypic continuum: Boucher-Neuhäuser syndrome (cerebellar ataxia, chorioretinal dystrophy, and hypogonadotropic hypogonadism); Gordon Holmes syndrome (cerebellar ataxia, hypogonadotropic hypogonadism, and – to a variable degree – brisk reflexes); Oliver-McFarlane syndrome (trichomegaly, chorioretinal dystrophy, short stature, intellectual disability, and hypopituitarism); Laurence-Moon syndrome; and spastic paraplegia type 39 (SPG39) (upper motor neuron involvement, peripheral neuropathy, and sometimes reduced cognitive functioning and/or cerebellar ataxia).

Multiple symmetric lipomatosis (MSL) is an autosomal recessive metabolic disorder characterized by the growth of unencapsulated masses of adipose tissue with predilection for the cervical and thoracic regions. The lipoma growth is striking and disfiguring, and growth around the neck may cause difficulty swallowing or breathing. The age at onset ranges from childhood to young adulthood. Most, but not all, patients develop axonal peripheral neuropathy, which can appear at any age and varies in severity. Laboratory studies in MSL show low leptin (164160), low adiponectin (605441), variably increased lactate, and increased FGF21 (609436). Some patients may have insulin resistance. The disorder is exclusively associated with a particular MFN2 mutation (R707W; 608507.0013), usually in the homozygous state, but sometimes in the compound heterozygous state (Rocha et al., 2017; Capel et al., 2018).

Neurofibromatosis 2 (NF2) is characterized by bilateral vestibular schwannomas with associated symptoms of tinnitus, hearing loss, and balance dysfunction. The average age of onset is 18 to 24 years. Almost all affected individuals develop bilateral vestibular schwannomas by age 30 years. Affected individuals may also develop schwannomas of other cranial and peripheral nerves, meningiomas, ependymomas, and, very rarely, astrocytomas. Because NF2 is considered an adult-onset disease, it may be underrecognized in children, in whom skin tumors and ocular findings (retinal hamartoma, thickened optic nerves, cortical wedge cataracts, third cranial nerve palsy) may be the first manifestations. Mononeuropathy that occurs in childhood is an increasingly recognized finding; it frequently presents as a persistent facial palsy or hand/foot drop.

Hereditary coproporphyria (HCP) is an acute (hepatic) porphyria in which the acute symptoms are neurovisceral and occur in discrete episodes. Attacks typically start in the abdomen with low-grade pain that slowly increases over a period of days (not hours) with nausea progressing to vomiting. In some individuals, the pain is predominantly in the back or extremities. When an acute attack is untreated, a motor neuropathy may develop over a period of days or a few weeks. The neuropathy first appears as weakness proximally in the arms and legs, then progresses distally to involve the hands and feet. Some individuals experience respiratory insufficiency due to loss of innervation of the diaphragm and muscles of respiration. Acute attacks are associated commonly with use of certain medications, caloric deprivation, and changes in female reproductive hormones. About 20% of those with an acute attack also experience photosensitivity associated with bullae and skin fragility.

Variegate porphyria (VP) is both a cutaneous porphyria (with chronic blistering skin lesions) and an acute porphyria (with severe episodic neurovisceral symptoms). The most common manifestation of VP is adult-onset cutaneous blistering lesions (subepidermal vesicles, bullae, and erosions that crust over and heal slowly) of sun-exposed skin, especially the hands and face. Other chronic skin findings include milia, scarring, thickening, and areas of decreased and increased skin pigmentation. Facial hyperpigmentation and hypertrichosis may occur. Cutaneous manifestations may improve in winter and be less prevalent in northern regions and in dark-skinned individuals. Acute neurovisceral symptoms can occur any time after puberty, but less often in the elderly. Acute manifestations are highly variable, but may be similar from episode to episode in a person with recurrent attacks; not all manifestations are present in a single episode; and acute symptoms may become chronic. Symptoms are more common in women than men. The most common manifestations are abdominal pain; constipation; pain in the back, chest, and extremities; anxiety; seizures; and a primarily motor neuropathy resulting in muscle weakness that may progress to quadriparesis and respiratory paralysis. Psychiatric disturbances and autonomic neuropathy can also be observed. Acute attacks may be severe and are potentially fatal.

The most basic description of Moebius syndrome is a congenital facial palsy with impairment of ocular abduction. The facial nerve (cranial nerve VII) and abducens nerve (CN VI) are most frequently involved, but other cranial nerves may be involved as well. Other variable features include orofacial dysmorphism and limb malformations. Mental retardation has been reported in a subset of patients. Most cases of Moebius syndrome are sporadic, but familial occurrence has been reported (Verzijl et al., 2003). The definition of and diagnostic criteria for Moebius syndrome have been controversial and problematic. The syndrome has most frequently been confused with hereditary congenital facial paresis (HCFP; see 601471), which is restricted to involvement of the facial nerve and no other abnormalities. Verzijl et al. (2003) and Verzijl et al. (2005) concluded that HCFP and Moebius syndrome are distinct disorders, and that Moebius syndrome is a complex developmental disorder of the brainstem. Moebius syndrome was defined at the Moebius Syndrome Foundation Research Conference in 2007 as congenital, nonprogressive facial weakness with limited abduction of one or both eyes. Additional features can include hearing loss and other cranial nerve dysfunction, as well as motor, orofacial, musculoskeletal, neurodevelopmental, and social problems (summary by Webb et al., 2012). Kumar (1990) provided a review of Moebius syndrome, which was critiqued by Lipson et al. (1990). Briegel (2006) provided a review of Moebius sequence with special emphasis on neuropsychiatric findings.

'Behr syndrome' is a clinical term that refers to the constellation of early-onset optic atrophy accompanied by neurologic features, including ataxia, pyramidal signs, spasticity, and mental retardation (Behr, 1909; Thomas et al., 1984). Patients with mutations in genes other than OPA1 can present with clinical features reminiscent of Behr syndrome. Mutations in one of these genes, OPA3 (606580), result in type III 3-methylglutaconic aciduria (MGCA3; 258501). Lerman-Sagie (1995) noted that the abnormal urinary pattern in MGCA3 may not be picked up by routine organic acid analysis, suggesting that early reports of Behr syndrome with normal metabolic features may actually have been 3-methylglutaconic aciduria type III.

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease characterized by infantile-onset diarrhea, childhood-onset cataract, adolescent- to young adult-onset tendon xanthomas, and adult-onset progressive neurologic dysfunction (dementia, psychiatric disturbances, pyramidal and/or cerebellar signs, dystonia, atypical parkinsonism, peripheral neuropathy, and seizures). Chronic diarrhea from infancy and/or neonatal cholestasis may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Xanthomas appear in the second or third decade; they occur on the Achilles tendon, the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons. Xanthomas have been reported in the lung, bones, and central nervous system. Some individuals show cognitive impairment from early infancy, whereas the majority have normal or only slightly impaired intellectual function until puberty; dementia with slow deterioration in intellectual abilities occurs in the third decade in more than 50% of individuals. Neuropsychiatric symptoms such as behavioral changes, hallucinations, agitation, aggression, depression, and suicide attempts may be prominent. Pyramidal signs (i.e., spasticity) and/or cerebellar signs almost invariably become evident between ages 20 and 30 years. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas include high plasma and tissue cholestanol concentration, normal-to-low plasma cholesterol concentration, decreased chenodeoxycholic acid (CDCA), increased concentration of bile alcohols and their glyconjugates, and increased concentrations of cholestanol and apolipoprotein B in cerebrospinal fluid.

A rare autosomal recessive inherited syndrome. It is characterized by xeroderma pigmentosum, mental retardation, dwarfism, hypogonadism, and neurologic abnormalities.

Primary hyperoxaluria type 1 (PH1) is caused by a deficiency of the liver peroxisomal enzyme alanine:glyoxylate-aminotransferase (AGT), which catalyzes the conversion of glyoxylate to glycine. When AGT activity is absent, glyoxylate is converted to oxalate, which forms insoluble calcium oxalate crystals that accumulate in the kidney and other organs. Individuals with PH1 are at risk for recurrent nephrolithiasis (deposition of calcium oxalate in the renal pelvis / urinary tract), nephrocalcinosis (deposition of calcium oxalate in the renal parenchyma), or end-stage renal disease (ESRD). Age at onset of symptoms ranges from infancy to the sixth decade. Approximately 10% of affected individuals present in infancy or early childhood with nephrocalcinosis, with or without nephrolithiasis, and failure to thrive related to renal failure. The majority of individuals with PH1 present in childhood or early adolescence, usually with symptomatic nephrolithiasis and normal or reduced kidney function. The remainder of affected individuals present in adulthood with recurrent renal stones and a mild-to-moderate reduction in kidney function. The natural history of untreated PH1 is one of progressive decline in renal function as a result of calcium oxalate deposits in kidney tissue and complications of nephrolithiasis (e.g., obstruction and infection) with eventual progression to oxalosis (widespread tissue deposition of calcium oxalate) and death from ESRD and/or complications of oxalosis.

The adult form of metachromatic leukodystrophy affects approximately 15 to 20 percent of individuals with the disorder. In this form, the first symptoms appear during the teenage years or later. Often behavioral problems such as alcohol use disorder, drug abuse, or difficulties at school or work are the first symptoms to appear. The affected individual may experience psychiatric symptoms such as delusions or hallucinations. People with the adult form of metachromatic leukodystrophy may survive for 20 to 30 years after diagnosis. During this time there may be some periods of relative stability and other periods of more rapid decline.\n\nMetachromatic leukodystrophy gets its name from the way cells with an accumulation of sulfatides appear when viewed under a microscope. The sulfatides form granules that are described as metachromatic, which means they pick up color differently than surrounding cellular material when stained for examination.\n\nIn 20 to 30 percent of individuals with metachromatic leukodystrophy, onset occurs between the age of 4 and adolescence. In this juvenile form, the first signs of the disorder may be behavioral problems and increasing difficulty with schoolwork. Progression of the disorder is slower than in the late infantile form, and affected individuals may survive for about 20 years after diagnosis.\n\nThe most common form of metachromatic leukodystrophy, affecting about 50 to 60 percent of all individuals with this disorder, is called the late infantile form. This form of the disorder usually appears in the second year of life. Affected children lose any speech they have developed, become weak, and develop problems with walking (gait disturbance). As the disorder worsens, muscle tone generally first decreases, and then increases to the point of rigidity. Individuals with the late infantile form of metachromatic leukodystrophy typically do not survive past childhood.\n\nIn people with metachromatic leukodystrophy, white matter damage causes progressive deterioration of intellectual functions and motor skills, such as the ability to walk. Affected individuals also develop loss of sensation in the extremities (peripheral neuropathy), incontinence, seizures, paralysis, an inability to speak, blindness, and hearing loss. Eventually they lose awareness of their surroundings and become unresponsive. While neurological problems are the primary feature of metachromatic leukodystrophy, effects of sulfatide accumulation on other organs and tissues have been reported, most often involving the gallbladder.\n\nMetachromatic leukodystrophy is an inherited disorder characterized by the accumulation of fats called sulfatides in cells. This accumulation especially affects cells in the nervous system that produce myelin, the substance that insulates and protects nerves. Nerve cells covered by myelin make up a tissue called white matter. Sulfatide accumulation in myelin-producing cells causes progressive destruction of white matter (leukodystrophy) throughout the nervous system, including in the brain and spinal cord (the central nervous system) and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system).

A group of rare renal diseases, characterized by amyloid fibril deposition of apolipoprotein A-I or A-II (AApoAI or AApoAII amyloidosis), lysozyme (ALys amyloidosis) or fibrinogen A-alpha chain (AFib amyloidosis) in one or several organs. Renal involvement leading to chronic renal disease and renal failure is a common sign. Additional manifestations depend on the organ involved and the type of amyloid fibrils deposited.

For a general phenotypic description and a discussion of genetic heterogeneity of Charcot-Marie-Tooth disease type 1, see CMT1B (118200). CMT1A is the most common form of CMT. The average age of onset of clinical symptoms is 12.2 +/- 7.3 years. Slow nerve conduction velocity (NCV) less than 38 m/s is highly diagnostic and is a 100% penetrant phenotype independent of age (Lupski et al., 1991, 1992).

Charcot-Marie-Tooth disease is a sensorineural peripheral polyneuropathy. Affecting approximately 1 in 2,500 individuals, Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system (Skre, 1974). Autosomal dominant, autosomal recessive, and X-linked forms have been recognized. Classification On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1, or HMSNI) and primary peripheral axonal (type 2, or HMSNII) neuropathies. The demyelinating neuropathies classified as CMT type 1 are characterized by severely reduced motor NCVs (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy. The axonal neuropathies classified as CMT type 2 are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (see CMT2A1; 118210). Distal hereditary motor neuropathy (dHMN) (see 158590), or spinal CMT, is characterized by exclusive motor involvement and sparing of sensory nerves (Pareyson, 1999). McAlpine (1989) proposed that the forms of CMT with very slow nerve conduction be given the gene symbol CMT1A (118220) and CMT1B, CMT1A being the gene on chromosome 17 and CMT1B being the gene on chromosome 1. CMT2 was the proposed symbol for the autosomal locus responsible for the moderately slow nerve conduction form of the disease (axonal). For a phenotypic description and discussion of genetic heterogeneity of the various subtypes of CMT, see CMTX1 (302800), CMT2A1 (118210), CMT3 (DSS; 145900), CMT4A (214400), and CMTDIB (606482). Genetic Heterogeneity of Autosomal Dominant Demyelinating CMT1 Autosomal dominant demyelinating CMT1 is a genetically heterogeneous disorder and can be caused by mutations in different genes; see CMT1A (118220), CMT1C (601098), CMT1D (607678), CMT1E (607734), CMT1F (607734), CMT1G (618279), CMT1H (619764), CMT1I (619742), and CMT1J (620111). See also 608236 for a related phenotype characterized by isolated slowed nerve conduction velocities (NCVs).

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.

A rare genetic disease characterized by childhood onset of bilateral progressive sensorineural hearing loss, ocular anomalies (myopia, cataract, retinitis pigmentosa), central and peripheral nervous system features (dementia, epilepsy, ataxia, peripheral neuropathy), ectodermal features (skin atrophy, alopecia, dental caries), and skeletal anomalies (bone cysts, joint stiffness, scoliosis, kyphosis). Laboratory examination may reveal elevated cerebrospinal fluid protein.

GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic. Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction).

Hereditary neuropathy with liability to pressure palsies (HNPP) is characterized by recurrent acute sensory and motor neuropathy in a single or multiple nerves. The most common initial manifestation is the acute onset of a non-painful focal sensory and motor neuropathy in a single nerve (mononeuropathy). The first attack usually occurs in the second or third decade but earlier onset is possible. Neuropathic pain is increasingly recognized as a common manifestation. Recovery from acute neuropathy is usually complete; when recovery is not complete, the resulting disability is mild. Some affected individuals also demonstrate a mild-to-moderate peripheral neuropathy.

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.

Smith-Magenis syndrome (SMS) is characterized by distinctive physical features (particularly coarse facial features that progress with age), developmental delay, cognitive impairment, behavioral abnormalities, sleep disturbance, and childhood-onset abdominal obesity. Infants have feeding difficulties, failure to thrive, hypotonia, hyporeflexia, prolonged napping or need to be awakened for feeds, and generalized lethargy. The majority of individuals function in the mild-to-moderate range of intellectual disability. The behavioral phenotype, including significant sleep disturbance, stereotypies, and maladaptive and self-injurious behaviors, is generally not recognized until age 18 months or older and continues to change until adulthood. Sensory issues are frequently noted; these may include avoidant behavior, as well as repetitive seeking of textures, sounds, and experiences. Toileting difficulties are common. Significant anxiety is common as are problems with executive functioning, including inattention, distractibility, hyperactivity, and impulsivity. Maladaptive behaviors include frequent outbursts / temper tantrums, attention-seeking behaviors, opposition, aggression, and self-injurious behaviors including self-hitting, self-biting, skin picking, inserting foreign objects into body orifices (polyembolokoilamania), and yanking fingernails and/or toenails (onychotillomania). Among the stereotypic behaviors described, the spasmodic upper-body squeeze or "self-hug" seems to be highly associated with SMS. An underlying developmental asynchrony, specifically emotional maturity delayed beyond intellectual functioning, may also contribute to maladaptive behaviors in people with SMS.

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.

Spastic paraplegia-23 (SPG23) is an autosomal recessive neurologic disorder characterized by childhood-onset spastic paraplegia resulting in gait difficulties and associated with pigmentary abnormalities, including premature graying of the hair and vitiligo-like or hyperpigmented skin lesions. Some patients may also have a peripheral neuropathy (summary by Lee et al., 2017).

Arts syndrome, which is part of the spectrum of PRPS1-related disorders, is characterized by profound congenital sensorineural hearing impairment, early-onset hypotonia, delayed motor development, mild to moderate intellectual disability, ataxia, and increased risk of infection, all of which – with the exception of optic atrophy – present before age two years. Signs of peripheral neuropathy develop during early childhood. Twelve of 15 boys from the two Dutch families reported with Arts syndrome died before age six years of complications of infection. Carrier females can show late-onset (age >20 years) hearing impairment and other findings.

Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (summary by Green et al., 2010). Genetic Heterogeneity of Brown-Vialetto-Van Laere Syndrome See also BVVLS2 (614707), caused by mutation in the SLC52A2 gene (607882) on chromosome 8q.

Autosomal recessive keratitis-ichthyosis-deafness syndrome (KIDAR) is characterized by neonatal-onset ichthyotic erythroderma and profound sensorineural deafness, with failure to thrive and developmental delay in childhood. Severe corneal scarring with vision loss has been observed in adulthood. Low plasma copper and ceruloplasmin levels have been reported in some patients (Alsaif et al., 2019; Boyden et al., 2019). An autosomal dominant form of KID syndrome (KIDAD; 148210) is caused by mutation in the GJB2 gene (121011) on chromosome 13q12. Mutation in the AP1S1 gene (603531) causes a disorder with overlapping features (MEDNIK; 609313).

A severe form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy. Onset in the second or third decade has manifestations of ulceration and infection of the feet. Symmetric and distal weakness develops mostly in the legs together with a severe symmetric distal sensory loss. Tendon reflexes are only reduced at ankles and foot deformities including pes cavus or planus and hammer toes, appear in childhood.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant form of recurrent focal neuropathy characterized clinically by acute, recurrent episodes of brachial plexus neuropathy with muscle weakness and atrophy preceded by severe pain in the affected arm.

Autosomal dominant distal hereditary motor neuronopathy-7 (HMND7) is a neurologic disorder characterized by onset in the second decade of progressive distal muscle wasting and weakness affecting the upper and lower limbs and resulting in walking difficulties and hand grip. There is significant muscle atrophy of the hands and lower limbs. The disorder is associated with vocal cord paresis due to involvement of the tenth cranial nerve (summary by Barwick et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).

Cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma syndrome (CEDNIK) refers to a unique constellation of clinical manifestations including global developmental delay with hypotonia, roving eye movements or nystagmus, poor motor skills, and impaired intellectual development with speech delay. More variable features include microcephaly, feeding difficulties, seizures, ocular anomalies, hearing loss, and nonspecific dysmorphic facial features. Palmoplantar keratoderma and ichthyosis or neuropathy develop in some patients. Brain magnetic resonance imaging (MRI) shows varying degrees of cerebral dysgenesis, including absence of the corpus callosum and cortical dysplasia, as well as hypomyelination, white matter loss, and white matter signal anomalies suggestive of a leukodystrophy. Some patients may show developmental regression; many die in childhood (Fuchs-Telem et al., 2011; Mah-Som et al., 2021). With more patients being reported, several authors (Diggle et al., 2017; Llaci et al., 2019; Mah-Som et al., 2021) have observed that the dermatologic features and peripheral neuropathy show reduced penetrance and are more variable manifestations of this disorder, as they are not observed in all patients with biallelic SNAP29 mutations.

MEDNIK syndrome is a severe multisystem disorder characterized by impaired intellectual development, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma (summary by Montpetit et al., 2008). Patients with MEDNIK exhibit distinct dysmorphic features, including high forehead, upslanting palpebral fissures, depressed nasal bridge, and low-set ears, as well as growth retardation and moderate to severe intellectual disability, with brain atrophy on imaging. Other features include sensorineural deafness, enteropathy with congenital diarrhea, abnormalities of copper metabolism associated with liver disease, and ichthyosis, hyperkeratosis, and erythroderma. Peripheral neuropathy has also been observed in adult patients (Martinelli et al., 2013). MEDNIK syndrome shows phenotypic similarities to CEDNIK syndrome (609528).

SCA8 is a slowly progressive ataxia with onset typically in the third to fifth decade but with a range from before age one year to after age 60 years. Common initial manifestations are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Over the disease course other findings can include eye movement abnormalities (nystagmus, abnormal pursuit and abnormal saccades, and, rarely, ophthalmoplegia); upper motor neuron involvement; extrapyramidal signs; brain stem signs (dysphagia and poor cough reflex); sensory neuropathy; and cognitive impairment (e.g., executive dysfunction, psychomotor slowing and other features of cerebellar cognitive-affective disorder in some). Life span is typically not shortened.

Spinal and bulbar muscular atrophy (SBMA) is a gradually progressive neuromuscular disorder in which degeneration of lower motor neurons results in muscle weakness, muscle atrophy, and fasciculations. SBMA occurs only in males. Affected individuals often show gynecomastia, testicular atrophy, and reduced fertility as a result of mild androgen insensitivity.

FMR1 disorders include fragile X syndrome (FXS), fragile X-associated tremor/ataxia syndrome (FXTAS), and fragile X-associated primary ovarian insufficiency (FXPOI). Fragile X syndrome occurs in individuals with an FMR1 full mutation or other loss-of-function variant and is nearly always characterized in affected males by developmental delay and intellectual disability along with a variety of behavioral issues. Autism spectrum disorder is present in 50%-70% of individuals with FXS. Affected males may have characteristic craniofacial features (which become more obvious with age) and medical problems including hypotonia, gastroesophageal reflux, strabismus, seizures, sleep disorders, joint laxity, pes planus, scoliosis, and recurrent otitis media. Adults may have mitral valve prolapse or aortic root dilatation. The physical and behavioral features seen in males with FXS have been reported in females heterozygous for the FMR1 full mutation, but with lower frequency and milder involvement. FXTAS occurs in individuals who have an FMR1 premutation and is characterized by late-onset, progressive cerebellar ataxia and intention tremor followed by cognitive impairment. Psychiatric disorders are common. Age of onset is typically between 60 and 65 years and is more common among males who are hemizygous for the premutation (40%) than among females who are heterozygous for the premutation (16%-20%). FXPOI, defined as hypergonadotropic hypogonadism before age 40 years, has been observed in 20% of women who carry a premutation allele compared to 1% in the general population.

GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.

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

A rare genetic peripheral sensorimotor neuropathy with an X-linked recessive inheritance pattern and the infantile to childhood-onset of progressive, distal muscle weakness and atrophy (more prominent in the lower extremities than in the upper extremities), pes cavus, and absent tendon reflexes. Sensory impairment and intellectual disability has been reported in some individuals.

An extremely rare autosomal recessively inherited neuromuscular disease characterised by ocular manifestations such as ptosis and diplopia followed by chronic diarrhoea, malnutrition and intestinal pseudo-obstruction.

MPV17-related mitochondrial DNA (mtDNA) maintenance defect presents in the vast majority of affected individuals as an early-onset encephalohepatopathic (hepatocerebral) disease that is typically associated with mtDNA depletion, particularly in the liver. A later-onset neuromyopathic disease characterized by myopathy and neuropathy, and associated with multiple mtDNA deletions in muscle, has also rarely been described. MPV17-related mtDNA maintenance defect, encephalohepatopathic form is characterized by: Hepatic manifestations (liver dysfunction that typically progresses to liver failure, cholestasis, hepatomegaly, and steatosis); Neurologic involvement (developmental delay, hypotonia, microcephaly, and motor and sensory peripheral neuropathy); Gastrointestinal manifestations (gastrointestinal dysmotility, feeding difficulties, and failure to thrive); and Metabolic derangements (lactic acidosis and hypoglycemia). Less frequent manifestations include renal tubulopathy, nephrocalcinosis, and hypoparathyroidism. Progressive liver disease often leads to death in infancy or early childhood. Hepatocellular carcinoma has been reported.

HMSNR is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy (summary by Sevilla et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (214400).

Mast syndrome (MASTS) is an autosomal recessive complicated form of hereditary spastic paraplegia in which progressive spastic paraparesis is associated in more advanced cases with cognitive decline, dementia, and other neurologic abnormalities. Symptom onset usually occurs in adulthood, and the disorder is progressive with variable severity. Brain imaging shows thinning of the corpus callosum. The disorder occurs with high frequency in the Old Order Amish (summary by Simpson et al., 2003). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Autosomal recessive familial visceral neuropathy-1 (VSCN1) is characterized by a broad spectrum of developmental anomalies associating neural crest and extraneural crest features, including intestinal dysmotility due to aganglionosis (Hirschsprung disease), hypoganglionosis, and/or chronic intestinal pseudoobstruction. Some patients develop progressive peripheral neuropathy, and arthrogryposis has been observed. Hypoplasia or aplasia of the olfactory bulb and of the external auditory canals, as well as microtia or anotia, have been reported. Patients also exhibit facial dysmorphisms, including microretrognathia in most; other variable features include structural cardiac anomalies and arthrogryposis with multiple pterygia (Le et al., 2021). Genetic Heterogeneity of Familial Visceral Neuropathy Autosomal recessive familial visceral neuropathy-2 (VSCN2; 619465) is caused by mutation in the ERBB2 gene (164870) on chromosome 17q12. Also see VSCN3 (609629) for an autosomal dominant form of the disorder.

Syndrome with characteristics of progressive sensorineural deafness, progressive sensory neuropathy and gastrointestinal abnormalities (progressive loss of gastric motility, small bowel diverticulosis). It has been described in five patients (three sisters in a family and two sisters born to consanguineous parents). This syndrome is transmitted as an autosomal recessive trait.

Okinawa-type hereditary motor and sensory neuropathy (HMSNO) is an autosomal dominant neurodegenerative disorder characterized by young adult onset of proximal or distal muscle weakness and atrophy, muscle cramps, and fasciculations, with later onset of distal sensory impairment. The disorder is slowly progressive and clinically resembles amyotrophic lateral sclerosis (ALS; see 105400) (summary by Ishiura et al., 2012).

Triosephosphate isomerase deficiency (TPID) is an autosomal recessive multisystem disorder characterized by congenital hemolytic anemia, and progressive neuromuscular dysfunction beginning in early childhood. Many patients die from respiratory failure in childhood. The neurologic syndrome is variable, but usually includes lower motor neuron dysfunction with hypotonia, muscle weakness and atrophy, and hyporeflexia. Some patients may show additional signs such as dystonic posturing and/or spasticity. Laboratory studies show intracellular accumulation of dihydroxyacetone phosphate (DHAP), particularly in red blood cells (summary by Fermo et al., 2010).

Stiff skin syndrome (SSKS) is characterized by hard, thick skin, usually over the entire body, which limits joint mobility and causes flexion contractures. Other occasional findings include lipodystrophy and muscle weakness (Loeys et al., 2010). Patients with similar phenotypes involving stiff skin have been described; see, e.g., familial progressive scleroderma (181750), symmetric lipomatosis (151800), and congenital fascial dystrophy (228020).

Charcot-Marie-Tooth disease-deafness-intellectual disability syndrome is a rare demyelinating hereditary motor and sensory neuropathy characterized by early-onset, slowly progressive, distal muscular weakness and atrophy with no sensory impairment, congenital sensorineural deafness and mild intellectual disability (with absence of normal speech development). The absence of large myelinated fibers on sural nerve biopsy is equally characteristic of the disease.

MFN2 hereditary motor and sensory neuropathy (MFN2-HMSN) is a classic axonal peripheral sensorimotor neuropathy, inherited in either an autosomal dominant (AD) manner (~90%) or an autosomal recessive (AR) manner (~10%). MFN2-HMSN is characterized by more severe involvement of the lower extremities than the upper extremities, distal upper-extremity involvement as the neuropathy progresses, more prominent motor deficits than sensory deficits, and normal (>42 m/s) or only slightly decreased nerve conduction velocities (NCVs). Postural tremor is common. Median onset is age 12 years in the AD form and age eight years in the AR form. The prevalence of optic atrophy is approximately 7% in the AD form and approximately 20% in the AR form.

Long-chain hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency and trifunctional protein (TFP) deficiency are caused by impairment of mitochondrial TFP. TFP has three enzymatic activities – long-chain enoyl-CoA hydratase, long-chain 3-hydroxyacyl-CoA dehydrogenase, and long-chain 3-ketoacyl-CoA thiolase. In individuals with LCHAD deficiency, there is isolated deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase, while deficiency of all three enzymes occurs in individuals with TFP deficiency. Individuals with TFP deficiency can present with a severe-to-mild phenotype, while individuals with LCHAD deficiency typically present with a severe-to-intermediate phenotype. Neonates with the severe phenotype present within a few days of birth with hypoglycemia, hepatomegaly, encephalopathy, and often cardiomyopathy. The intermediate phenotype is characterized by hypoketotic hypoglycemia precipitated by infection or fasting in infancy. The mild (late-onset) phenotype is characterized by myopathy and/or neuropathy. Long-term complications include peripheral neuropathy and retinopathy.

Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria. The mild phenotype (~75% of affected males) with onset in the second or third decade of life is typically limited to these biochemical findings, whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia. In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled.

Onset of distal hereditary motor neuropathy, type II ranges from the teenage years through mid-adulthood. The initial symptoms of the disorder are cramps or weakness in the muscles of the big toe and later, the entire foot. Over a period of approximately 5 to 10 years, affected individuals experience a gradual loss of muscle tissue (atrophy) in the lower legs. They begin to have trouble walking and running, and eventually may have complete paralysis of the lower legs. The thigh muscles may also be affected, although generally this occurs later and is less severe.\n\nSome individuals with distal hereditary motor neuropathy, type II have weakening of the muscles in the hands and forearms. This weakening is less pronounced than in the lower limbs and does not usually result in paralysis.\n\nDistal hereditary motor neuropathy, type II is a progressive disorder that affects nerve cells in the spinal cord. It results in muscle weakness and affects movement, primarily in the legs.

POLR3-related leukodystrophy, a hypomyelinating leukodystrophy with specific features on brain MRI, is characterized by varying combinations of four major clinical findings: Neurologic dysfunction, typically predominated by motor dysfunction (progressive cerebellar dysfunction, and to a lesser extent extrapyramidal [i.e., dystonia], pyramidal [i.e., spasticity] and cognitive dysfunctions). Abnormal dentition (delayed dentition, hypodontia, oligodontia, and abnormally placed or shaped teeth). Endocrine abnormalities such as short stature (in ~50% of individuals) with or without growth hormone deficiency, and more commonly, hypogonadotropic hypogonadism manifesting as delayed, arrested, or absent puberty. Ocular abnormality in the form of myopia, typically progressing over several years and becoming severe. POLR3-related leukodystrophy and 4H leukodystrophy are the two recognized terms for five previously described overlapping clinical phenotypes (initially described as distinct entities before their molecular basis was known). These include: Hypomyelination, hypodontia, hypogonadotropic hypogonadism (4H syndrome); Ataxia, delayed dentition, and hypomyelination (ADDH); Tremor-ataxia with central hypomyelination (TACH); Leukodystrophy with oligodontia (LO); Hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum (HCAHC). Age of onset is typically in early childhood but later-onset cases have also been reported. An infant with Wiedemann-Rautenstrauch syndrome (neonatal progeroid syndrome) was recently reported to have pathogenic variants in POLR3A on exome sequencing. Confirmation of this as a very severe form of POLR3-related leukodystrophy awaits replication in other individuals with a clinical diagnosis of Wiedemann-Rautenstrauch syndrome.

Spastic paraplegia-43 (SPG43) is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive spasticity affecting the lower and upper limbs (summary by Meilleur et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.

SUCLA2-related mitochondrial DNA (mtDNA) depletion syndrome, encephalomyopathic form with methylmalonic aciduria is characterized by onset of the following features in infancy or childhood (median age of onset 2 months; range of onset birth to 6 years): psychomotor retardation, hypotonia, dystonia, muscular atrophy, sensorineural hearing impairment, postnatal growth retardation, and feeding difficulties. Other less frequent features include distinctive facial features, contractures, kyphoscoliosis, gastroesophageal reflux, ptosis, choreoathetosis, ophthalmoplegia, and epilepsy (infantile spasms or generalized convulsions). The median survival is 20 years; approximately 30% of affected individuals succumb during childhood. Affected individuals may have hyperintensities in the basal ganglia, cerebral atrophy, and leukoencephalopathy on head MRI. Elevation of methylmalonic acid (MMA) in the urine and plasma is found in a vast majority of affected individuals, although at levels that are far below those typically seen in individuals with classic methylmalonic aciduria.

Hereditary transthyretin (ATTR) amyloidosis is characterized by a slowly progressive peripheral sensorimotor and/or autonomic neuropathy as well as non-neuropathic changes of cardiomyopathy, nephropathy, vitreous opacities, and CNS amyloidosis. The disease usually begins in the third to fifth decade in persons from endemic foci in Portugal and Japan; onset is later in persons from other areas. Typically, sensory neuropathy starts in the lower extremities with paresthesias and hypesthesias of the feet, followed within a few years by motor neuropathy. In some persons, particularly those with early-onset disease, autonomic neuropathy is the first manifestation of the condition; findings can include: orthostatic hypotension, constipation alternating with diarrhea, attacks of nausea and vomiting, delayed gastric emptying, sexual impotence, anhidrosis, and urinary retention or incontinence. Cardiac amyloidosis is mainly characterized by progressive cardiomyopathy. Individuals with leptomeningeal amyloidosis may have the following CNS findings: dementia, psychosis, visual impairment, headache, seizures, motor paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage.

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.

Any neuronopathy, distal hereditary motor in which the cause of the disease is a mutation in the HSPB3 gene.

Spastic paraplegia-48 (SPG48) is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment (summary by Hirst et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).

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.

Leukoencephalopathy-dystonia-motor neuropathy syndrome is a peroxisomal neurodegenerative disorder characterized by spasmodic torticollis, dystonic head tremor, intention tremor, nystagmus, hyposmia, and hypergonadotrophic hypogonadism with azoospermia. Slight cerebellar signs (left-sided intention tremor, balance and gait impairment) are also noted. Magnetic resonance imaging (MRI) shows bilateral hyperintense signals in the thalamus, butterfly-like lesions in the pons, and lesions in the occipital region, whereas nerve conduction studies of the lower extremities shows a predominantly motor and slight sensory neuropathy.

A syndromic X-linked intellectual disability characterized by moderate intellectual disability, seizures, dysmorphic facial features and in some older patients slowly progressive unsteady gait and progressive weakness that has material basis in variation in the chromosomal region Xq21.33-q23.

Syndromic optic atrophy, also known as DOA+ syndrome, is a neurologic disorder characterized most commonly by an insidious onset of visual loss and sensorineural hearing loss in childhood with variable presentation of other clinical manifestations including progressive external ophthalmoplegia (PEO), muscle cramps, hyperreflexia, and ataxia. There appears to be a wide range of intermediate phenotypes (Yu-Wai-Man et al., 2010).

Mitochondrial complex V (ATP synthase) deficiency, nuclear type 3 (MC5DN3) is an autosomal recessive disorder with variable manifestations. Affected individuals present soon after birth or in early infancy with hypotonia, respiratory distress, and poor sucking. They have global developmental delay with mildly impaired intellectual disability. Additional features may include dystonia, ataxia, peripheral neuropathy, and seizures. Congenital cataracts, hearing impairment, and mild left cardiac ventricular hypertrophy have been reported in 1 patient each. Laboratory studies show increased lactate; some patients have hyperammonemia, 3-methylglutaconic aciduria, and hyperCKemia (Mayr et al., 2010; Zech et al., 2022). For a general phenotypic description of the nuclear type of mitochondrial complex V deficiency and a discussion of genetic heterogeneity of mitochondrial complex V deficiency, see 604273.

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.

A rare genetic subtype of autosomal dominant Charcot-Marie-Tooth disease type 2 with characteristics of early childhood-onset of slowly progressive, predominantly distal, lower limb muscle weakness and atrophy, delayed motor development, variable sensory loss and pes cavus in the presence of normal or near-normal nerve conduction velocities. Additional variable features may include proximal muscle weakness, abnormal gait, arthrogryposis, scoliosis, cognitive impairment, and spasticity. Caused by heterozygous mutation in the DYNC1H1 gene on chromosome 14q32.

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome is a rare, syndromic genetic deafness characterized by a combination of muscle weakness, chronic neuropathic and myopathic features, hoarseness and sensorineural hearing loss. A wide range of disease onset and severity has been reported even within the same family.

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive adult-onset, slowly progressive neurologic disorder characterized by imbalance due to cerebellar gait and limb ataxia, impaired vestibular function bilaterally, and non-length-dependent sensory neuropathy (summary by Szmulewicz et al., 2011).

Primary coenzyme Q10 (CoQ10) deficiency is usually associated with multisystem involvement, including neurologic manifestations such as fatal neonatal encephalopathy with hypotonia; a late-onset slowly progressive multiple-system atrophy-like phenotype (neurodegeneration with autonomic failure and various combinations of parkinsonism and cerebellar ataxia, and pyramidal dysfunction); and dystonia, spasticity, seizures, and intellectual disability. Steroid-resistant nephrotic syndrome (SRNS), the hallmark renal manifestation, is often the initial manifestation either as isolated renal involvement that progresses to end-stage renal disease (ESRD), or associated with encephalopathy (seizures, stroke-like episodes, severe neurologic impairment) resulting in early death. Hypertrophic cardiomyopathy (HCM), retinopathy or optic atrophy, and sensorineural hearing loss can also be seen.

Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by Bricker et al., 2012).

The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX16 gene have cells of complementation group 9 (CG9, equivalent to CGD). For information on the history of PBD complementation groups, see 214100.

A rare genetic principally axonal peripheral sensorimotor neuropathy with an X-linked dominant inheritance pattern and the childhood-onset of slowly progressive, moderate to severe, distal muscle weakness and atrophy of the lower extremities, as well as distal, pan modal sensory abnormalities, bilateral foot deformities (pes cavus, clawed toes), absent ankle reflexes and gait abnormalities (steppage gait). Females are usually asymptomatic or only present mild manifestations (mild postural hand tremor, mild wasting of hand intrinsic muscles).

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 ADA2 pathogenic variants may remain asymptomatic until adulthood or may never develop clinical manifestations of DADA2.

CAGSSS, which comprises cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysplasia, is an autosomal recessive multisystemic disorder with a highly variable phenotypic spectrum. Not all of these features are always present, and almost all the features may present at different times and/or become more apparent with age. The skeletal features are consistent with spondyloepimetaphyseal dysplasia (SEMD) (summary by Vona et al., 2018). One family had a distinctive presentation with infantile-onset intractable seizures and cortical abnormalities reminiscent of Leigh syndrome (see 256000). The correlation between genotype and phenotype remains unclear, but since the IARS2 gene is involved in mitochondrial function, heterogeneous manifestations can be expected (Takezawa et al., 2018).

Combined cerebellar and peripheral ataxia with hearing loss and diabetes mellitus (ACPHD) is an autosomal recessive multisystem disorder including defects in glucose metabolism, diffuse neurodegeneration, multiple hormone deficiencies, severe growth retardation with possible growth hormone deficiencies, and subtle osseous changes suggesting early-onset bone dysplasia (summary by Ozon et al., 2020).

Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life (summary by Wanders and Waterham, 2005). For a discussion of genetic heterogeneity of rhizomelic chondrodysplasia punctata, see 215100.

Charcot-Marie-Tooth disease type 4K is an autosomal recessive demyelinating peripheral neuropathy characterized by onset in the first decade of distal muscle weakness and atrophy associated with impaired distal sensation. Both upper and lower limbs are affected. Affected individuals may also have nystagmus and late-onset cerebellar ataxia. Laboratory studies show increased serum lactate and isolated mitochondrial complex IV deficiency (summary by Echaniz-Laguna et al., 2013). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).

Spastic paraplegia-75 (SPG75) is an autosomal recessive, slowly progressive neurodegenerative disorder characterized by onset of spastic paraplegia and cognitive impairment in childhood (summary by Lossos et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).

Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-2 (PEOB2) is a mitochondrial disorder characterized by adult onset of progressive external ophthalmoplegia, exercise intolerance, muscle weakness, and signs and symptoms of spinocerebellar ataxia, such as impaired gait and dysarthria. Some patients may have respiratory insufficiency. Laboratory studies are consistent with a defect in mtDNA replication (summary by Reyes et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).

Developmental and epileptic encephalopathy-29 (DEE29) is an autosomal recessive neurologic disorder characterized by the onset of refractory myoclonic seizures in the first months of life. Affected individuals have poor overall growth, congenital microcephaly with cerebral atrophy and impaired myelination on brain imaging, spasticity with abnormal movements, peripheral neuropathy, and poor visual fixation (summary by Simons et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Ataxia-oculomotor apraxia-4 (AOA4) is an autosomal recessive neurologic disorder characterized by onset of dystonia and ataxia in the first decade. Additional features include oculomotor apraxia and peripheral neuropathy. Some patients may show cognitive impairment. The disorder is progressive, and most patients become wheelchair-bound in the second or third decade (summary by Bras et al., 2015). For a discussion of genetic heterogeneity of ataxia-oculomotor apraxia, see AOA1 (208920).

Autosomal dominant intermediate Charcot-Marie-Tooth disease E with focal segmental glomerulonephritis is characterized by the neurologic features of CMT, including distal muscle weakness and atrophy and distal sensory loss, and the features of FSGS, including proteinuria, progression to end-stage renal disease, and a characteristic histologic pattern on renal biopsy (summary by Boyer et al., 2011). Isolated focal segmental glomerulosclerosis-5 (FSGS5; 613237) is also caused by heterozygous mutation in the INF2 gene. For a discussion of genetic heterogeneity of CMTDI, see 606482.

Encephalopathy due to defective mitochondrial and peroxisomal fission-2 (EMPF2) is an autosomal recessive disorder characterized by delayed psychomotor development, severe hypotonia with inability to walk, microcephaly, and abnormal signals in the basal ganglia. More variable features include early-onset seizures, optic atrophy, and peripheral neuropathy (summary by Koch et al., 2016). For a discussion of genetic heterogeneity of EMPF, see EMPF1 (614388).

A rare genetic disorder with characteristics of infantile onset of stagnation and regression of motor and language development resulting in complete lack of communication and purposeful movement. Further neurological manifestations include truncal hypotonia, appendicular spasticity, dystonia, optic disc pallor, peripheral neuropathy and neurogenic bladder. Patients also present multiple contractures, late-onset relative macrocephaly, short stature and facial dysmorphism (including coarse facial features, sloping forehead, thick eyebrows, low-set ears, prominent nose, flat philtrum, and prominent lower lip). Brain imaging at advanced stages shows diffuse abnormal white matter signal and severe atrophy. Sural nerve biopsy reveals decreased myelination.

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset), primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, hypothyroidism, ichthyosis, lymphopenia/immunodeficiency, and neurologic abnormalities that can include developmental delay, regression / progressive neurologic involvement, cranial nerve deficits, and peripheral motor and sensory neuropathy.

CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is characterized by mid-adult onset of recurrent ischemic stroke, cognitive decline progressing to dementia, a history of migraine with aura, mood disturbance, apathy, and diffuse white matter lesions and subcortical infarcts on neuroimaging.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by progressive gastrointestinal dysmotility (manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea); cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; and demyelinating peripheral neuropathy (manifesting as paresthesias (tingling, numbness, and pain) and symmetric and distal weakness more prominently affecting the lower extremities). The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years.

CMTDIG is an autosomal dominant neurologic disorder with a highly variable phenotype. Most affected individuals have onset in the first or second decades of slowly progressive distal motor weakness and atrophy, resulting in gait instability and distal upper limb impairment, as well as distal sensory impairment. More severely affected individuals may have pes cavus and claw hands and become wheelchair-bound, whereas other affected individuals have later onset with a milder disease course. Electrophysiologic studies tend to show median motor nerve conduction velocities (NCV) in the 'intermediate' range, between 25 and 45 m/s (summary by Berciano et al., 2017). In a review of intermediate CMT, Berciano et al. (2017) noted that advanced axonal degeneration may induce secondary demyelinating changes resulting in decreased NCV and attenuated compound muscle action potential (CMAP) in median nerve conduction studies. They thus suggested that testing the upper arm, axilla to elbow, may provide more accurate assessment of NCV and CMAP and reveal an intermediate phenotype (review by Berciano et al., 2017). For a discussion of genetic heterogeneity of CMTDI, see 606482.

Congenital hypomyelinating neuropathy (CHN) is characterized clinically by onset of hypotonia at birth, areflexia, distal muscle weakness, and very slow nerve conduction velocities (often less than 10 m/s). Warner et al. (1997, 1998) noted that pathologic findings on sural nerve biopsies show hypomyelination of most or all fibers. Based on these findings, CHN is considered to be a result of congenital impairment in myelin formation. There has been some controversy and difficulty in differentiating congenital hypomyelination from Dejerine-Sottas syndrome (DSS; 145900) because there is considerable overlap in clinical presentation. Based on pathologic findings of sural nerve biopsies (the absence of active myelin breakdown and the paucity of the onion bulbs in CHN and the presence of demyelination/remyelination and an abundance of well-organized onion bulbs in DSS; see Balestrini et al., 1991), CHN is considered to result from a congenital impairment in myelin formation, whereas DSS is thought to be due to aberrant demyelination and subsequent remyelination of the peripheral nerve. There is also variation in the prognosis of patients diagnosed with CHN. In patients with CHN, Harati and Butler (1985) showed correlation of morbidity and mortality with the presence/absence of onion bulbs: patients with few onion bulbs died in early infancy, usually because of difficulty in swallowing and respiration after birth. Patients with atypical onion bulbs survived but were affected with severe motor and sensory impairment. These differences in outcome may represent genetic heterogeneity such that mutations in essential early myelin gene(s) cause a severe phenotype, whereas mutations in other, possibly later acting gene(s), such as MPZ, lead to a less severe outcome. Genetic Heterogeneity of Congenital Hypomyelinating Neuropathy See also CHN2 (618184), caused by mutation in the MPZ gene (159440) on chromosome 1q23; and CHN3 (618186), caused by mutation in the CNTNAP1 gene (602346) on chromosome 17q21.

Combined oxidative phosphorylation deficiency-21 (COXPD11) is a severe multisystemic autosomal recessive disorder characterized by neonatal hypotonia and lactic acidosis. Affected individuals may have respiratory insufficiency, foot deformities, or seizures, and all reported patients have died in infancy. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes (summary by Garcia-Diaz et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Developmental and epileptic encephalopathy-81 (DEE81) is an autosomal recessive neurodevelopmental disorder typically characterized by onset of severe refractory seizures soon after birth or in the first months of life. Affected individuals show little developmental progress with no eye contact and no motor or cognitive development. Other features may include facial dysmorphism, such as hypotonic facies and epicanthal folds, as well as sensorineural hearing loss and peripheral neuropathy. Brain imaging shows cerebral atrophy, impaired myelination, thin corpus callosum, and progressive leukoencephalopathy (summary by Esposito et al., 2019; Maddirevula et al., 2019). For a discussion of genetic heterogeneity of DEE, see 308350.

The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait.

Sodium-dependent multivitamin transporter deficiency (SMVTD) is an autosomal recessive multisystemic metabolic disorder with highly variable manifestations. Affected individuals usually present at birth or in infancy with severe feeding problems, gastrointestinal reflux, cyclic vomiting, and diarrhea associated with failure to thrive. Gastrointestinal hemorrhage may occur; tube-feeding is often required for a short time. The course and severity of the disease varies: some patients have episodes of acute metabolic decompensation during infection that respond well to treatment, whereas others show more permanent neurologic regression with loss of early motor and cognitive milestones in the first year or so of life. Less severely affected patients have normal development or mild growth and motor delays, whereas more severely affected individuals may have seizures, ataxia, spasticity, peripheral neuropathy, immune defects, and osteopenia. In severely affected patients, brain imaging shows cerebral, cerebellar, and brainstem atrophy and thin corpus callosum. Treatment with biotin, pantothenic acid, and alpha-lipoic acid has been shown to result in significant clinical improvement (Byrne et al., 2019; Hauth et al., 2022).

Neurodevelopmental disorder with microcephaly, language delay, and gait abnormalities (NEDMILG) is an autosomal recessive disorder characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. More variable features include hypotonia, early-onset seizures, and a peripheral demyelinating or axonal peripheral sensorimotor neuropathy. The disease follows a neurodegenerative course in many patients; clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).

Neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities (NEDMILEG) is characterized by global developmental delay apparent in infancy. Affected individuals have delayed walking with variable gait abnormalities, including ataxia and spasticity, impaired intellectual development with poor or absent speech and language, and progressive microcephaly. Dysmorphic facial features may also be observed. Most patients have early-onset seizures; some may develop a demyelinating peripheral neuropathy. The clinical features suggest involvement of both the central and peripheral nervous systems (Manole et al., 2020).

Aicardi-Goutieres syndrome-9 (AGS9) is a type I interferonopathy characterized by severe developmental delay and progressive neurologic deterioration. Patients present in infancy with irritability and spasticity. Brain imaging shows diffusely abnormal white matter, cerebral atrophy, and intracranial calcification. Premature death has been associated with renal and/or hepatic failure (Uggenti et al., 2020). For a general phenotypic description and discussion of genetic heterogeneity of Aicardi-Goutieres syndrome, see AGS1 (225750).

Charcot-Marie-Tooth disease type 2FF (CMT2FF) is an autosomal dominant progressive axonal sensorimotor peripheral neuropathy characterized by early-childhood onset of difficulties walking or running due to atrophy and weakness of the lower limbs. Most patients have foot and ankle deformities, requiring surgery or walking aids. Some patients lose independent ambulation. There is also prominent involvement of the upper limbs, with weakness and atrophy of the forearm, wrist, and intrinsic hand muscles. Proximal muscle function is preserved. Affected individuals have variable distal sensory impairment. Most patients have hyporeflexia, although brisk reflexes, suggesting upper motor involvement, have been described in 1 family. Sural nerve biopsy showed abnormal myelination (Rebelo et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).

Spastic paraplegia-76 is an autosomal recessive neurologic disorder characterized by young-adult onset of slowly progressive spasticity of the lower limbs resulting in gait difficulties. Most affected individuals have upper limb involvement and additional features such as foot deformities and dysarthria. Cognition is unaffected (summary by Gan-Or et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Charcot-Marie-Tooth disease type 2W is an autosomal dominant neurologic disorder characterized by a peripheral neuropathy mainly affecting the lower limbs and resulting in gait difficulties and distal sensory impairment, although most patients also have upper limb involvement. The age at onset is highly variable, ranging from childhood to late adulthood (summary by Safka Brozkova et al., 2015). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

A rare mitochondrial oxidative phosphorylation disorder with characteristics of microcephaly, global developmental delay, spastic-dystonic movement disorder, intractable seizures, optic atrophy, autonomic dysfunction and peripheral neuropathy. Serum lactate is increased, and muscle biopsy shows decreased activity of mitochondrial respiratory complexes I and III. Brain imaging reveals progressive cerebellar atrophy and delayed myelination.

Peripheral neuropathy with variable spasticity, exercise intolerance, and developmental delay (PNSED) is an autosomal recessive multisystemic disorder with highly variable manifestations, even within the same family. Some patients present in infancy with hypotonia and global developmental delay with poor or absent motor skill acquisition and poor growth, whereas others present as young adults with exercise intolerance and muscle weakness. All patients have signs of a peripheral neuropathy, usually demyelinating, with distal muscle weakness and atrophy and distal sensory impairment; many become wheelchair-bound. Additional features include spasticity, extensor plantar responses, contractures, cerebellar signs, seizures, short stature, and rare involvement of other organ systems, including the heart, pancreas, and kidney. Biochemical analysis may show deficiencies in mitochondrial respiratory complex enzyme activities in patient tissue, although this is not always apparent. Lactate is frequently increased, suggesting mitochondrial dysfunction (Powell et al., 2015; Argente-Escrig et al., 2022). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

A rare hereditary motor and sensory neuropathy with characteristics of childhood onset of unsteady gait, pes cavus, frequent falls and foot dorsiflexor weakness slowly progressing to distal upper and lower limb muscle weakness and atrophy, distal sensory impairment and reduced tendon reflexes. Additional symptoms may include bilateral sensorineural hearing impairment and neuropathic pain.

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 distal hereditary motor neuronopathy-6 (HMNR6) is a neuromuscular disorder characterized by onset of distal muscle weakness in early infancy. Affected individuals often present at birth with distal joint contractures or foot deformities and show delayed motor development, often with inability to walk or frequent falls. Hypo- or hyperreflexia may be observed; limb muscle atrophy may also be present. Patients often show respiratory distress or diaphragmatic palsy. Electrophysiologic studies are consistent with a peripheral motor neuropathy without sensory involvement (Maroofian et al., 2019). For a discussion of genetic heterogeneity of autosomal recessive distal HMN, see HMNR1 (604320).

Autosomal dominant distal hereditary motor neuronopathy-10 (HMND10) is a neurologic disorder of the peripheral nerves characterized clinically by length-dependent motor neuropathy primarily affecting the lower limbs. Affected individuals have onset of distal muscle weakness and atrophy in early childhood that results in walking difficulties and gait abnormalities. Some have pyramidal signs, including hyperreflexia, suggesting the involvement of upper motor neurons. Electrophysiologic studies are consistent with a neurogenic process. More variable features may include mild intellectual disability, minor gyration defects on brain imaging, foot deformities, and connective tissue defects (1 family) (Capuano et al., 2016; Iacomino et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).

Childhood-onset neurodegeneration with multisystem involvement due to mitochondrial dysfunction (CONDMIM) is an autosomal recessive syndromic disorder characterized primarily by neurologic deficits. Patients show global developmental delay and variably impaired intellectual development with speech delay apparent from infancy. Affected individuals have hypotonia, poor feeding, poor overall growth, and respiratory distress early in life. Other features include visual impairment due to optic atrophy, sensorineural hearing loss, and neuromuscular abnormalities. The severity is highly variable. The disorder is progressive; about half of patients show developmental regression with loss of previous skills. Features suggestive of a mitochondrial disorder include cataracts, cardiomyopathy, diabetes mellitus, combined oxidative phosphorylation deficiency, and increased lactate. Some patients develop seizures, some have dysmorphic facial features, and some have nonspecific abnormalities on brain imaging. Death in childhood may occur (Kaiyrzhanov et al., 2022).

Charcot-Marie-Tooth disease type 1J (CMT1J) is an autosomal dominant sensorimotor peripheral neuropathy characterized by distal muscle weakness and atrophy, as well as distal sensory impairment, predominantly affecting the lower limbs and resulting in gait abnormalities. The age at onset is highly variable, ranging from early childhood to mid-adulthood, and the disorder is progressive, although the severity is also variable. Additional features may include foot deformities, upper limb or hand involvement, and decreased or absent deep tendon reflexes. Electrophysiologic studies tend to show nerve conduction velocities in the demyelinating range, although some patients may have results in the intermediate range, likely reflecting secondary axonal degeneration (summary by Ronkko et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

Carpal tunnel syndrome-1 (CTS1) is characterized by hand pain and numbness in the distribution of the median nerve, with onset in the sixth decade of life. Amyloid deposits are observed in synovial tissue of the wrist and in the transverse carpal ligament (Murakami et al., 1994). Genetic Heterogeneity of Carpal Tunnel Syndrome CTS2 (619161) is caused by mutation in the COMP gene (600310) on chromosome 19p13. Susceptibility to the development of mononeuropathy of the median (MNMN; 613353) may be conferred by heterozygous mutation in the SH3TC2 gene (608206) on chromosome 5q32. Carpal tunnel syndrome has been described as a feature in amyloid neuropathy (see 176300) and in mucopolysaccharidoses (e.g., 253200) and mucolipidoses (252600).

The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death (SIDS; 272120), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy (summary by Spiekerkoetter et al., 2003). Some patients with MTP deficiency show a protracted progressive course associated with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy. These patients tend to survive into adolescence and adulthood (den Boer et al., 2003). See mitochondrial trifunctional protein deficiency-1 (609015), caused by mutation in the HADHA gene (600890), the alpha subunit of mitochondrial trifunctional protein.

Individuals with NGLY1-related congenital disorder of deglycosylation (NGLY1-CDDG) typically display a clinical tetrad of developmental delay / intellectual disability in the mild to profound range, hypo- or alacrima, elevated liver transaminases that may spontaneously resolve in childhood, and a complex hyperkinetic movement disorder that can include choreiform, athetoid, dystonic, myoclonic, action tremor, and dysmetric movements. About half of affected individuals will develop clinical seizures. Other findings may include obstructive and/or central sleep apnea, oral motor defects that affect feeding ability, auditory neuropathy, constipation, scoliosis, and peripheral neuropathy.