Chediak-Higashi syndrome (CHS) is characterized by partial oculocutaneous albinism, immunodeficiency, and a mild bleeding tendency. Approximately 85% of affected individuals develop the accelerated phase, or hemophagocytic lymphohistiocytosis, a life-threatening, hyperinflammatory condition. All affected individuals including adolescents and adults with atypical CHS and children with classic CHS who have successfully undergone allogenic hematopoietic stem cell transplantation (HSCT) develop neurologic findings during early adulthood.

Dejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (summary by Baets et al., 2011).

The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated DCM when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.

Familial dysautonomia, which affects the development and survival of sensory, sympathetic, and parasympathetic neurons, is a debilitating disorder present from birth. Neuronal degeneration progresses throughout life. Affected individuals have gastrointestinal dysfunction, autonomic crises (i.e., hypertensive vomiting attacks), recurrent pneumonia, altered pain sensitivity, altered temperature perception, and blood pressure instability. Hypotonia contributes to delay in acquisition of motor milestones. Optic neuropathy results in progressive vision loss. Older individuals often have a broad-based and ataxic gait that deteriorates over time. Developmental delay / intellectual disability occur in about 21% of individuals. Life expectancy is decreased.

Pompe disease is classified by age of onset, organ involvement, severity, and rate of progression. Infantile-onset Pompe disease (IOPD; individuals with onset before age 12 months with cardiomyopathy) may be apparent in utero but more typically onset is at the median age of four months with hypotonia, generalized muscle weakness, feeding difficulties, failure to thrive, respiratory distress, and hypertrophic cardiomyopathy. Without treatment by enzyme replacement therapy (ERT), IOPD commonly results in death by age two years from progressive left ventricular outflow obstruction and respiratory insufficiency. Late-onset Pompe disease (LOPD; including: (a) individuals with onset before age 12 months without cardiomyopathy; and (b) all individuals with onset after age 12 months) is characterized by proximal muscle weakness and respiratory insufficiency; clinically significant cardiac involvement is uncommon.

The clinical manifestations of glycogen storage disease type IV (GSD IV) discussed in this entry span a continuum of different subtypes with variable ages of onset, severity, and clinical features. Clinical findings vary extensively both within and between families. The fatal perinatal neuromuscular subtype presents in utero with fetal akinesia deformation sequence, including decreased fetal movements, polyhydramnios, and fetal hydrops. Death usually occurs in the neonatal period. The congenital neuromuscular subtype presents in the newborn period with profound hypotonia, respiratory distress, and dilated cardiomyopathy. Death usually occurs in early infancy. Infants with the classic (progressive) hepatic subtype may appear normal at birth, but rapidly develop failure to thrive; hepatomegaly, liver dysfunction, and progressive liver cirrhosis; hypotonia; and cardiomyopathy. Without liver transplantation, death from liver failure usually occurs by age five years. Children with the non-progressive hepatic subtype tend to present with hepatomegaly, liver dysfunction, myopathy, and hypotonia; however, they are likely to survive without progression of the liver disease and may not show cardiac, skeletal muscle, or neurologic involvement. The childhood neuromuscular subtype is rare and the course is variable, ranging from onset in the second decade with a mild disease course to a more severe, progressive course resulting in death in the third decade.

Arylsulfatase A deficiency (also known as metachromatic leukodystrophy or MLD) is characterized by three clinical subtypes: late-infantile MLD, juvenile MLD, and adult MLD. Age of onset within a family is usually similar. The disease course may be from several years in the late-infantile-onset form to decades in the juvenile- and adult-onset forms. Late-infantile MLD. Onset is before age 30 months. Typical presenting findings include weakness, hypotonia, clumsiness, frequent falls, toe walking, and dysarthria. As the disease progresses, language, cognitive, and gross and fine motor skills regress. Later signs include spasticity, pain, seizures, and compromised vision and hearing. In the final stages, children have tonic spasms, decerebrate posturing, and general unawareness of their surroundings. Juvenile MLD. Onset is between age 30 months and 16 years. Initial manifestations include decline in school performance and emergence of behavioral problems, followed by gait disturbances. Progression is similar to but slower than in the late-infantile form. Adult MLD. Onset occurs after age 16 years, sometimes not until the fourth or fifth decade. Initial signs can include problems in school or job performance, personality changes, emotional lability, or psychosis; in others, neurologic symptoms (weakness and loss of coordination progressing to spasticity and incontinence) or seizures initially predominate. Peripheral neuropathy is common. Disease course is variable – with periods of stability interspersed with periods of decline – and may extend over two to three decades. The final stage is similar to earlier-onset forms.

Adult Refsum disease (ARD is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life.

Tangier disease is characterized by severe deficiency or absence of high-density lipoprotein (HDL) in the circulation resulting in tissue accumulation of cholesteryl esters throughout the body, particularly in the reticuloendothelial system. The major clinical signs of Tangier disease include hyperplastic yellow-orange tonsils, hepatosplenomegaly, and peripheral neuropathy, which may be either relapsing-remitting or chronic progressive in nature. Rarer complications may include corneal opacities that typically do not affect vision, premature atherosclerotic coronary artery disease occurring in the sixth and seventh decades of life (not usually before age 40 years), and mild hematologic manifestations, such as mild thrombocytopenia, reticulocytosis, stomatocytosis, or hemolytic anemia. The clinical expression of Tangier disease is variable, with some affected individuals only showing biochemical perturbations.

An abnormality of the pupillary light reaction characterized by a marked slowing of the light reaction of usually just one pupil. The pupil tends to be relatively dilated, and there is reduced accommodation.

Spinal muscular atrophy (SMA) is characterized by muscle weakness and atrophy resulting from progressive degeneration and irreversible loss of the anterior horn cells in the spinal cord (i.e., lower motor neurons) and the brain stem nuclei. The onset of weakness ranges from before birth to adulthood. The weakness is symmetric, proximal > distal, and progressive. Before the genetic basis of SMA was understood, it was classified into clinical subtypes based on maximum motor function achieved; however, it is now apparent that the phenotype of SMN1-associated SMA spans a continuum without clear delineation of subtypes. With supportive care only, poor weight gain with growth failure, restrictive lung disease, scoliosis, and joint contractures are common complications; however, newly available targeted treatment options are changing the natural history of this disease.

PLP1 disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease.

Roussy-Levy syndrome is an autosomal dominant disorder characterized by early onset of prominent ataxia followed by late onset of mild motor involvement. Symptoms progress very slowly, and affected individuals may remain ambulatory throughout life (Auer-Grumbach et al., 1998; Plante-Bordeneuve et al., 1999).

Sporadic inclusion body myositis (IBM) is the most common age-related muscle disease in the elderly that results in severe disability. Although traditionally considered an inflammatory myopathy, it is now considered to be more consistent with a myodegenerative disease (Sugarman et al., 2002; Askanas and Engel, 2006).

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

Pallister-Killian syndrome (PKS) is a dysmorphic condition involving most organ systems, but is also characterized by a tissue-limited mosaicism; most fibroblasts have 47 chromosomes with an extra small metacentric chromosome, whereas the karyotype of lymphocytes is normal. The extra metacentric chromosome is an isochromosome for part of the short arm of chromosome 12: i(12)(p10) (Peltomaki et al., 1987; Warburton et al., 1987).

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years).

The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). The most common presenting symptom in NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. Failure to thrive typically becomes evident by the second year of life. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system (CNS) manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some CNS manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B.

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\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 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\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).

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988).

Succinic semialdehyde dehydrogenase (SSADH) deficiency is characterized by infantile-onset hypotonia, developmental delay, cognitive impairment, expressive language deficit, and mild ataxia. Epilepsy is present in about half of affected individuals and is more common in adults. Hyperkinetic behavior, aggression, self-injurious behaviors, hallucinations, and sleep disturbances have been reported in nearly half of all affected individuals, more commonly in those who are older. Basal ganglia signs including choreoathetosis, dystonia, and myoclonus have been reported in a few individuals with earlier-onset, more severe disease. Involvement beyond the central nervous system has not been described. Individuals with SSADH deficiency typically have 4-hydroxybutyric aciduria present on urine organic acid analysis. Head MRI reveals T2 hyperintensities in multiple regions, involving the globus pallidi, cerebellar dentate nuclei, subthalamic nuclei, subcortical white matter, and brain stem, as well as cerebral and sometimes cerebellar atrophy. EEG findings include background slowing and spike discharges that are usually generalized.

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).

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.

Sudden, repetitive, nonrhythmic motor movements (spasms), involving the eyes and muscles of the face.

PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three clinical stages: infantile multisystem, late-infantile and childhood ataxia–intellectual disability, and adult stable disability. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. Clinical findings tend to be similar in sibs. In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, faltering growth, and developmental delay are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical courses are observed: (1) a nonfatal neurologic course with faltering growth, strabismus, developmental delay, cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade; and (2) a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen, thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed; females may lack secondary sexual development and males may exhibit decreased testicular volume. Hypogonadotropic hypogonadism and coagulopathy may occur. The risk for deep venous thrombosis is increased.

Chorea-acanthocytosis (ChAc) is characterized by a progressive movement disorder, cognitive and behavior changes, a myopathy that can be subclinical, and chronic hyperCKemia in serum. Although the disorder is named for acanthocytosis of the red blood cells, this feature is variable. The movement disorder is mostly limb chorea, but some individuals present with parkinsonism. Dystonia is common and affects the oral region and especially the tongue, causing dysarthria and serious dysphagia with resultant weight loss. Habitual tongue and lip biting are characteristic, as well as tongue protrusion dystonia. Progressive cognitive and behavioral changes resemble those in a frontal lobe syndrome. Seizures are observed in almost half of affected individuals and can be the initial manifestation. Myopathy results in progressive distal muscle wasting and weakness. Mean age of onset in ChAc is about 30 years, although ChAc can develop as early as the first decade or as late as the seventh decade. It runs a chronic progressive course and may lead to major disability within a few years. Life expectancy is reduced, with age of death ranging from 28 to 61 years.

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.

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.

Monosomy 18q is a partial deletion of the long arm of chromosome 18 characterized by highly variable phenotype, most commonly including hypotonia, developmental delay, short stature, growth hormone deficiency, hearing loss and external ear anomalies, intellectual disability, palatal defects, dysmorphic facial features, skeletal anomalies (foot deformities, tapering fingers, scoliosis) and mood disorders.

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.

Congenital myopathy-1A (CMYO1A) with susceptibility to malignant hyperthermia is an autosomal dominant disorder of skeletal muscle characterized by muscle weakness primarily affecting the proximal muscles of the lower limbs beginning in infancy or early childhood, although later onset of symptoms has been reported. There is significant phenotypic variability, even within families, and the wide clinical diversity most likely depends on the severity of the RYR1 mutation. The disorder is static or slowly progressive; affected individuals typically show delayed motor development and usually achieve independent walking, although many have difficulty running or climbing stairs. Additional features often include mild facial weakness, joint laxity, shoulder girdle weakness, and skeletal manifestations, such as dislocation of the hips, foot deformities, scoliosis, and Achilles tendon contractures. Some patients present with orthopedic deformities. Serum creatine kinase is usually not elevated. Respiratory involvement is rare and there is no central nervous system or cardiac involvement. Patients with dominant mutations in the RYR1 gene are at risk for malignant hyperthermia and both disorders may segregate in the same family. Historically, patients with congenital myopathy due to RYR1 mutations were diagnosed based on the finding of pathologic central cores (central core disease; CCD) on muscle biopsy, which represent areas that lack oxidative enzymes and mitochondrial activity in type 1 muscle fibers. However, additional pathologic findings may also be observed, including cores and rods, central nuclei, fiber type disproportion, multiminicores, and uniform type 1 fibers. These histopathologic features are not always specific to RYR1 myopathy and often change over time (Quinlivan et al., 2003; Jungbluth et al., 2007; Klein et al., 2012; Ogasawara and Nishino, 2021). Some patients with RYR1 mutations have pathologic findings on muscle biopsy, but are clinically asymptomatic (Shuaib et al., 1987; Quane et al., 1993). Rare patients with a more severe phenotype have been found to carry a heterozygous mutation in the RYR1 gene inherited from an unaffected parent. However, in these cases, there is a possibility of recessive inheritance (CMYO1B; 255320) with either a missed second RYR1 mutation in trans or a genomic rearrangement on the other allele that is undetectable on routine genomic sequencing, since the RYR1 gene is very large and genetic analysis may be difficult (Klein et al., 2012). Genetic Heterogeneity of Congenital Myopathy See also CMYO1B (255320), caused by mutation in the RYR1 gene (180901) on chromosome 19q13; CMYO2A (161800), CMYO2B (620265), and CMYO2C (620278), caused by mutation in the ACTA1 gene (102610) on chromosome 1q42; CMYO3 (602771), caused by mutation in the SELENON gene (606210) on chromosome 1p36; CMYO4A (255310) and CMYO4B (609284), caused by mutation in the TPM3 gene (191030) on chromosome 1q21; CMYO5 (611705), caused by mutation in the TTN gene (188840) on chromosome 2q31; CMYO6 (605637), caused by mutation in the MYH2 gene (160740) on chromosome 17p13; CMYO7A (608358) and CMYO7B (255160), caused by mutation in the MYH7 gene (160760) on chromosome 14q11; CMYO8 (618654), caused by mutation in the ACTN2 gene (102573) on chromosome 1q43; CMYO9A (618822) and CMYO9B (618823), caused by mutation in the FXR1 gene (600819) on chromosome 3q28; CMYO10A (614399) and CMYO10B (620249), caused by mutation in the MEGF10 gene (612453) on chromosome 5q23; CMYO11 (619967), caused by mutation in the HACD1 gene (610467) on chromosome 10p12; CMYO12 (612540), caused by mutation in the CNTN1 gene (600016) on chromosome 12q12; CMYO13 (255995), caused by mutation in the STAC3 gene (615521) on chromosome 12q13; CMYO14 (618414), caused by mutation in the MYL1 gene (160780) on chromosome 2q34; CMYO15 (620161), caused by mutation in the TNNC2 gene (191039) on chromosome 20q13; CMYO16 (618524), caused by mutation in the MYBPC1 gene (160794) on chromosome 12q23; CMYO17 (618975), caused by mutation in the MYOD1 gene (159970) on chromosome 11p15; CMYO18 (620246), caused by mutation in the CACNA1S gene (114208) on chromosome 1q32; CMYO19 (618578), caused by mutation in the PAX7 gene (167410) on chromosome 1p36; CMYO20 (620310), caused by mutation in the RYR3 gene (180903) on chromosome 15q13; CMYO21 (620326), caused by mutation in the DNAJB4 gene (611327) on chromosome 1p31; CMYO22A (620351) and CMYO22B (620369), both caused by mutation in the SCN4A gene (603967) on chromosome 17q23; CMYO23 (609285), caused by mutation in the TPM2 gene (190990) on chromosome 9p13; and CMYO24 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21.

Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration.

Spinocerebellar ataxia-4 (SCA4) is an autosomal dominant neurologic disorder characterized by the onset of balance disturbances and gait and limb ataxia usually in the fourth decade, although earlier onset in the teens or twenties has been reported. There is evidence of genetic anticipation within families. The disorder is slowly progressive, and most patients eventually become wheelchair-bound. Additional features include hypometric or slow saccades, sensory or sensorimotor axonal peripheral neuropathy, dysarthria, and autonomic dysfunction, including orthostatic hypotension and problems with bowel or bladder control. More severely affected individuals have dysphagia and significant unintended weight loss, which may contribute to premature death. Brain imaging shows cerebellar atrophy (Wallenius et al., 2024). For a discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

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.

TBC1D24-related disorders comprise a continuum of features that were originally described as distinct, recognized phenotypes: DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures). Profound sensorineural hearing loss, onychodystrophy, osteodystrophy, intellectual disability / developmental delay, and seizures. Familial infantile myoclonic epilepsy (FIME). Early-onset myoclonic seizures, focal epilepsy, dysarthria, and mild-to-moderate intellectual disability. Progressive myoclonus epilepsy (PME). Action myoclonus, tonic-clonic seizures, progressive neurologic decline, and ataxia. Early-infantile epileptic encephalopathy 16 (EIEE16). Epileptiform EEG abnormalities which themselves are believed to contribute to progressive disturbance in cerebral function. Autosomal recessive nonsyndromic hearing loss, DFNB86. Profound prelingual deafness. Autosomal dominant nonsyndromic hearing loss, DFNA65. Slowly progressive deafness with onset in the third decade, initially affecting the high frequencies.

The dystrophinopathies cover a spectrum of X-linked muscle disease ranging from mild to severe that includes Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy (DCM). The mild end of the spectrum includes the phenotypes of asymptomatic increase in serum concentration of creatine phosphokinase (CK) and muscle cramps with myoglobinuria. The severe end of the spectrum includes progressive muscle diseases that are classified as Duchenne/Becker muscular dystrophy when skeletal muscle is primarily affected and as DMD-associated DCM when the heart is primarily affected. Duchenne muscular dystrophy (DMD) usually presents in early childhood with delayed motor milestones including delays in walking independently and standing up from a supine position. Proximal weakness causes a waddling gait and difficulty climbing stairs, running, jumping, and standing up from a squatting position. DMD is rapidly progressive, with affected children being wheelchair dependent by age 12 years. Cardiomyopathy occurs in almost all individuals with DMD after age 18 years. Few survive beyond the third decade, with respiratory complications and progressive cardiomyopathy being common causes of death. Becker muscular dystrophy (BMD) is characterized by later-onset skeletal muscle weakness. With improved diagnostic techniques, it has been recognized that the mild end of the spectrum includes men with onset of symptoms after age 30 years who remain ambulatory even into their 60s. Despite the milder skeletal muscle involvement, heart failure from DCM is a common cause of morbidity and the most common cause of death in BMD. Mean age of death is in the mid-40s. DMD-associated DCM is characterized by left ventricular dilation and congestive heart failure. Females heterozygous for a DMD pathogenic variant are at increased risk for DCM.

Carnitine palmitoyltransferase 1A (CPT1A) deficiency is a disorder of long-chain fatty acid oxidation. Clinical manifestations usually occur in an individual with a concurrent febrile or gastrointestinal illness when energy demands are increased; onset of symptoms is usually rapid. The recognized phenotypes are: acute fatty liver of pregnancy, in which the fetus has biallelic pathogenic variants in CPT1A that causes CPT1A deficiency; and hepatic encephalopathy, in which individuals (typically children) present with hypoketotic hypoglycemia and sudden onset of liver failure. Individuals with hepatic encephalopathy typically present with hypoglycemia, absent or low levels of ketones, and elevated serum concentrations of liver transaminases, ammonia, and total carnitine. Between episodes of hepatic encephalopathy, individuals appear developmentally and cognitively normal unless previous metabolic decompensation has resulted in neurologic damage.

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.

Charcot-Marie-Tooth disease type 4D (CMT4D) is an autosomal recessive disorder of the peripheral nervous system characterized by early-onset distal muscle weakness and atrophy, foot deformities, and sensory loss affecting all modalities. Affected individuals develop deafness by the third decade of life (summary by Okamoto et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive Charcot-Marie-Tooth disease, see CMT4A (214400).

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).

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

Charcot-Marie-Tooth disease, type 4H (CMT4H) is a demyelinating CMT peripheral sensorimotor polyneuropathy. It has been described in 10 individuals from two large consanguineous families from Lebanon and Algeria. Onset occurs within the first two years of life with slowly progressive muscle weakness in the distal extremities. Other common features include delayed walking, an abnormal gait, scoliosis and pes equines with toe retraction. CMT4H is caused by mutations in the FGD4 gene (12p11.1). Transmitted in an autosomal recessive manner.

Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by Fratter et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). PEO caused by mutations in the POLG gene (174763) is associated with more complicated phenotypes than PEO caused by mutations in the SLC25A4 (103220) or C10ORF2 genes (Lamantea et al., 2002).

Nemaline myopathy is divided into six types. In order of decreasing severity, the types are: severe congenital, Amish, intermediate congenital, typical congenital, childhood-onset, and adult-onset. The types are distinguished by the age when symptoms first appear and the severity of symptoms; however, there is overlap among the various types. The severe congenital type is the most life-threatening. Most individuals with this type do not survive past early childhood due to respiratory failure. The Amish type solely affects the Old Order Amish population of Pennsylvania and is typically fatal in early childhood. The most common type of nemaline myopathy is the typical congenital type, which is characterized by muscle weakness and feeding problems beginning in infancy. Most of these individuals do not have severe breathing problems and can walk unassisted. People with the childhood-onset type usually develop muscle weakness in adolescence. The adult-onset type is the mildest of all the various types. People with this type usually develop muscle weakness between ages 20 and 50.\n\nNemaline myopathy is a disorder that primarily affects skeletal muscles, which are muscles that the body uses for movement. People with nemaline myopathy have muscle weakness (myopathy) throughout the body, but it is typically most severe in the muscles of the face; neck; trunk; and other muscles close to the center of the body (proximal muscles), such as those of the upper arms and legs. This weakness can worsen over time. Affected individuals may have feeding and swallowing difficulties, foot deformities, abnormal curvature of the spine (scoliosis), and joint deformities (contractures). Most people with nemaline myopathy are able to walk, although some affected children may begin walking later than usual. As the condition progresses, some people may require wheelchair assistance. In severe cases, the muscles used for breathing are affected and life-threatening breathing difficulties can occur.

SPG26 is an autosomal recessive form of complicated spastic paraplegia characterized by onset in the first 2 decades of life of gait abnormalities due to lower limb spasticity and muscle weakness. Some patients have upper limb involvement. Additional features include intellectual disability, peripheral neuropathy, dysarthria, cerebellar signs, extrapyramidal signs, and cortical atrophy. The disorder is slowly progressive (summary by Boukhris et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive SPG, see SPG5A (270800).

PCWH syndrome is a complex neurocristopathy that includes features of 4 distinct syndromes: peripheral demyelinating neuropathy (see 118200), central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (see 142623) (Inoue et al., 2004). Inoue et al. (2004) proposed the acronym PCWH for this disorder.

Autosomal dominant limb-girdle muscular dystrophy-3 (LGMDD3) is characterized by slowly progressive proximal muscle weakness affecting the upper and lower limbs. Onset is usually in adulthood, but can occur during the teenage years. Affected individuals may also develop cataracts before age 50 (summary by Vieira et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).

Permanent neonatal diabetes mellitus-pancreatic and cerebellar agenesis syndrome is characterized by neonatal diabetes mellitus associated with cerebellar and/or pancreatic agenesis.

Pierson syndrome (PIERS) is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss (summary by Zenker et al., 2004). Mutations in the LAMB2 gene also cause nephrotic syndrome type 5 with or without mild ocular anomalies (NPHS5; 614199).

Autosomal dominant sensory ataxia-1 (SNAX1) is a peripheral neuropathy resulting from the degeneration of dorsal root ganglia that affects both central and peripheral neurites of sensory neurons. Affected individuals show adult onset of slowly progressive clumsiness, gait ataxia, walking difficulties, and distal sensory loss which may be associated with abnormal sensory nerve conduction values. Some patients have vestibular ocular dysfunction. Muscle weakness and atrophy are not observed, and brain imaging is normal (summary by Cortese et al., 2020).

A form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy. In the single family reported to date, CMT2L onset is between 15 and 33 years. Patients present with a symmetric distal weakness of legs and occasionally of the hands, absent or reduced tendon reflexes, distal legs sensory loss and frequently a pes cavus. Progression is slow.

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.

Isolated complex I deficiency is a rare inborn error of metabolism due to mutations in nuclear or mitochondrial genes encoding subunits or assembly factors of the human mitochondrial complex I (NADH: ubiquinone oxidoreductase) and is characterized by a wide range of manifestations including marked and often fatal lactic acidosis, cardiomyopathy, leukoencephalopathy, pure myopathy and hepatopathy with tubulopathy. Among the numerous clinical phenotypes observed are Leigh syndrome, Leber hereditary optic neuropathy and MELAS syndrome (see these terms).

A rare, genetic, mitochondrial DNA-related mitochondrial myopathy disorder characterized by slowly progressive muscular weakness (proximal greater than distal), predominantly involving the facial muscles and scapular girdle, associated with insulin-dependent diabetes mellitus. Neurological involvement and congenital myopathy may be variably observed.

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.

A rare hereditary motor and sensory neuropathy with characteristics of intermediate motor median nerve conduction velocities (usually between 25 and 45 m/s) and signs of both axonal degeneration and demyelination without onion bulbs in nerve biopsies. It presents with usual Charcot-Marie-Tooth disease clinical features of variable severity (progressive muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, and feet deformities). Other findings in some of the families include debilitating neuropathic pain and mild postural/kinetic upper limb tremor.

For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

A form of Charcot-Marie-Tooth disease type 1, with a variable clinical presentation that can range from severe impairment with onset in childhood to mild impairment appearing during adulthood. The disease has characteristics of progressive peripheral motor and sensory neuropathy with distal paresis in the lower limbs that varies from mild weakness to complete paralysis of the distal muscle groups, absent tendon reflexes and reduced nerve conduction. Caused by mutations in the NEFL gene (8p21.2).

A form of axonal Charcot-Marie-Tooth disease a peripheral sensorimotor neuropathy. Onset is in the first to sixth decade with a gait anomaly and a leg weakness that reaches the arms secondarily. Tendon reflexes are reduced or absent and after years all patients have a pes cavus. Other signs may be present including hearing loss and postural tremor.

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

Disease with characteristics of sensory neuropathy and cerebellar ataxia. Prevalence is unknown. Only 26 cases in a 5-generation American family of Irish ancestry have been reported to date. Onset is in the second and third decades of life with symptomatic onset ranging from 13 to 27 years. Patients initially present with axonal sensory neuropathy, while cerebellar ataxia and motor neuron dysfunction develop later. Linked to chromosome 7q22-q23 but the responsible gene mutation has not yet been identified.

Spinocerebellar ataxia-21 (SCA21) is an autosomal dominant neurologic disorder characterized by onset in the first decades of life of slowly progressive cerebellar ataxia, which is associated with cognitive impairment in most patients (summary by Delplanque et al., 2014). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

A rare distal hereditary motor neuropathy with characteristics of slowly progressive atrophy and weakness of distal muscles of hands and feet with normal deep tendon reflexes or absent ankle reflexes and minimal or no sensory loss, sometimes mild proximal weakness in the legs and feet and hand deformities in males.

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

A rare chromosomal anomaly, partial deletion of the long arm of chromosome X, with characteristics of a combination of clinical manifestations of X-linked myotubular myopathy and a 46,XY disorder of sex development. Patients present with a severe form of congenital myopathy and abnormal male genitalia.

Spinocerebellar ataxia-19 (SCA19) is an autosomal dominant disorder characterized by progressive cerebellar ataxia with a variable age of onset (age 2 years to late adulthood). Other neurologic manifestations include developmental delay and cognitive impairment; movement disorders including myoclonus, dystonia, rigidity, and bradykinesia; and seizures. For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Charcot-Marie-Tooth disease, dominant intermediate-A (CMTDIA) is an autosomal dominant peripheral neuropathy characterized by onset of symptoms in the first or second decades of life. Affected individuals have difficulty walking with muscle cramps of the lower limbs; the motor symptoms may be worsened by cold. The disorder is slowly progressive, eventually involving all 4 limbs, but patients remain ambulatory. After age 40, patients develop more severe features, including distal muscle weakness and atrophy, pes cavus, areflexia, and distal sensory loss. Electrophysiologic studies yield nerve conduction velocities with 'intermediate' values between demyelinating and axonal neuropathy (see below). One such family has been reported (Rossi et al., 1985).

Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Classification CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see 118210) types on the basis of electrophysiologic and neuropathologic criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Families of this type were reported by Salisachs (1974) and Davis et al. (1978). Davis et al. (1978) proposed that this form be designated 'intermediate' CMT. Claeys et al. (2009) stated that some CMT families may have an even broader range of NCV than 25 to 45 m/s, with the lowest levels around 25 and the highest levels within the normal range (50+ m/s). They also suggested that the term 'intermediate' should not be used to describe a single NCV value, but rather the CMT subtype at the level of the family (e.g., in families with a range or combinations of NCV values). Berciano et al. (2017) provided a detailed review of the different forms of intermediate CMT, noting that diagnoses may be controversial because of variable classification issues. The authors presented an algorithm for the interpretation of electrophysiologic studies in CMT, and suggested that nerve conduction studies should be conducted on the upper arm (axilla to elbow). They noted that distal axonal degeneration can result in secondary myelination defects, which may cause significantly decreased motor NCV and CMAP values that may be misinterpreted. Genetic Heterogeneity of Autosomal Dominant Intermediate CMT In addition to CMTDIB, which is caused by mutation in the DNM2 gene, other forms of dominant intermediate CMT include CMTDIA (620378), mapped to chromosome 10q24-q25; CMTDIC (608323), caused by mutation in the YARS gene (603623) on chromosome 1p35; CMTDID (607791), caused by mutation in the MPZ gene (159440) on chromosome 1q22; CMTDIE with focal segmental glomerulosclerosis (CMTDIE; 614455), caused by mutation in the INF2 gene (610982) on chromosome 14q32; CMTDIF (615185), caused by mutation in the GNB4 gene (610863) on chromosome 3q26; and CMTDIG (617882), caused by mutation in the NEFL gene (162280) on chromosome 8p21.

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).

Recurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis associated with muscle pain and weakness and followed by excretion of myoglobin in the urine. Renal failure may occasionally occur. Onset is usually in early childhood under the age of 5 years. Unlike the exercise-induced rhabdomyolyses such as McArdle syndrome (232600), carnitine palmitoyltransferase deficiency (see 255110), and the Creteil variety of phosphoglycerate kinase deficiency (311800), the attacks in recurrent myoglobinuria no relation to exercise, but are triggered by intercurrent illnesses, commonly upper respiratory tract infections (Ramesh and Gardner-Medwin, 1992). See 160010 for discussion of a possible autosomal dominant form of myoglobinuria. Severe rhabdomyolysis is a major clinical feature of anesthetic-induced malignant hyperthermia (145600), an autosomal dominant disorder.

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.

Nemaline myopathy-2 (NEM2) is an autosomal recessive skeletal muscle disorder with a wide range of severity. The most common clinical presentation is early-onset (in infancy or childhood) muscle weakness predominantly affecting proximal limb muscles. Muscle biopsy shows accumulation of Z-disc and thin filament proteins into aggregates named 'nemaline bodies' or 'nemaline rods,' usually accompanied by disorganization of the muscle Z discs. The clinical and histologic spectrum of entities caused by variants in the NEB gene is a continuum, ranging in severity. The distribution of weakness can vary from generalized muscle weakness, more pronounced in proximal limb muscles, to distal-only involvement, although neck flexor weakness appears to be rather consistent. Histologic patterns range from a severe usually nondystrophic disturbance of the myofibrillar pattern to an almost normal pattern, with or without nemaline bodies, sometimes combined with cores (summary by Lehtokari et al., 2014). Genetic Heterogeneity of Nemaline Myopathy See also NEM1 (255310), caused by mutation in the tropomyosin-3 gene (TPM3; 191030) on chromosome 1q22; NEM3 (161800), caused by mutation in the alpha-actin-1 gene (ACTA1; 102610) on chromosome 1q42; NEM4 (609285), caused by mutation in the beta-tropomyosin gene (TPM2; 190990) on chromosome 9p13; NEM5A (605355), also known as Amish nemaline myopathy, NEM5B (620386), and NEM5C (620389), all caused by mutation in the troponin T1 gene (TNNT1; 191041) on chromosome 19q13; NEM6 (609273), caused by mutation in the KBTBD13 gene (613727) on chromosome 15q22; NEM7 (610687), caused by mutation in the cofilin-2 gene (CFL2; 601443) on chromosome 14q13; NEM8 (615348), caused by mutation in the KLHL40 gene (615340), on chromosome 3p22; NEM9 (615731), caused by mutation in the KLHL41 gene (607701) on chromosome 2q31; NEM10 (616165), caused by mutation in the LMOD3 gene (616112) on chromosome 3p14; and NEM11 (617336), caused by mutation in the MYPN gene (608517) on chromosome 10q21. Several of the genes encode components of skeletal muscle sarcomeric thin filaments (Sanoudou and Beggs, 2001). Mutations in the NEB gene are the most common cause of nemaline myopathy (Lehtokari et al., 2006).

STAC3 disorder is characterized by congenital myopathy, musculoskeletal involvement of the trunk and extremities, feeding difficulties, and delayed motor milestones. Most affected individuals have weakness with myopathic facies, scoliosis, kyphosis or kyphoscoliosis, and contractures. Other common findings are ptosis, abnormalities of the palate (including cleft palate), and short stature. Risk for malignant hyperthermia susceptibility and restrictive lung disease are increased. Intellect is typically normal. Originally described in individuals from the Lumbee Native American tribe (an admixture of Cheraw Indian, English, and African American ancestry) in the state of North Carolina and reported as Native American myopathy, STAC3 disorder has now been identified in numerous other populations worldwide.

Spinocerebellar ataxia-34 (SCA34) is an autosomal dominant disorder characterized by slowly progressive cerebellar ataxia. Onset usually occurs during the young adult years, and most patients remain ambulatory until late in life. One family with SCA34 also had onset of erythema and hyperkeratosis in early childhood (Cadieux-Dion et al., 2014), whereas other families have additional neurologic signs, including ocular movement disturbances and pyramidal tract signs (Ozaki et al., 2015). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Phelan-McDermid syndrome is characterized by neonatal hypotonia, absent to severely delayed speech, developmental delay, and minor dysmorphic facial features. Most affected individuals have moderate to profound intellectual disability. Other features include large fleshy hands, dysplastic toenails, and decreased perspiration that results in a tendency to overheat. Normal stature and normal head size distinguishes Phelan-McDermid syndrome from other autosomal chromosome disorders. Behavior characteristics include mouthing or chewing non-food items, decreased perception of pain, and autism spectrum disorder or autistic-like affect and behavior.

The autosomal dominant TRPV4 disorders (previously considered to be clinically distinct phenotypes before their molecular basis was discovered) are now grouped into neuromuscular disorders and skeletal dysplasias; however, the overlap within each group is considerable. Affected individuals typically have either neuromuscular or skeletal manifestations alone, and in only rare instances an overlap syndrome has been reported. The three autosomal dominant neuromuscular disorders (mildest to most severe) are: Charcot-Marie-Tooth disease type 2C. Scapuloperoneal spinal muscular atrophy. Congenital distal spinal muscular atrophy. The autosomal dominant neuromuscular disorders are characterized by a congenital-onset, static, or later-onset progressive peripheral neuropathy with variable combinations of laryngeal dysfunction (i.e., vocal fold paresis), respiratory dysfunction, and joint contractures. The six autosomal dominant skeletal dysplasias (mildest to most severe) are: Familial digital arthropathy-brachydactyly. Autosomal dominant brachyolmia. Spondylometaphyseal dysplasia, Kozlowski type. Spondyloepiphyseal dysplasia, Maroteaux type. Parastremmatic dysplasia. Metatropic dysplasia. The skeletal dysplasia is characterized by brachydactyly (in all 6); the five that are more severe have short stature that varies from mild to severe with progressive spinal deformity and involvement of the long bones and pelvis. In the mildest of the autosomal dominant TRPV4 disorders life span is normal; in the most severe it is shortened. Bilateral progressive sensorineural hearing loss (SNHL) can occur with both autosomal dominant neuromuscular disorders and skeletal dysplasias.

Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset of ataxia between age three and 30 years after initial normal development, axonal sensorimotor neuropathy, oculomotor apraxia, cerebellar atrophy, and elevated serum concentration of alpha-fetoprotein (AFP).

Spinal muscular atrophy is characterized by degeneration of the anterior horn cells in the spinal cord, leading to symmetric muscle weakness and wasting. See also autosomal recessive adult-onset proximal spinal muscular atrophy (SMA4; 271150), caused by defect in the SMN1 gene (600354), and autosomal dominant childhood-onset proximal SMA (158600).

Charcot-Marie-Tooth disease type 2B2 (CMT2B2) is an autosomal recessive sensorineural axonal peripheral neuropathy manifest as distal muscle weakness and atrophy and distal sensory impairment. The disorder predominantly affects the lower limbs, resulting in gait impairment, although upper limb and hand involvement also occurs. The age at onset and severity is variable: most have onset in the third decade, although earlier onset has been reported. The disorder is slowly progressive, and some patients may lose independent ambulation later in life. More variable features may include ataxia, dysarthria, cerebellar atrophy, and eye movement abnormalities (summary by Leal et al., 2018). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A1 (118210).

Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. On the basis of electrophysiologic criteria, CMT is divided into 2 major types: type 1, the demyelinating form, characterized by a motor median nerve conduction velocity less than 38 m/s (see CMT1B; 118200); and type 2, the axonal form, with a normal or slightly reduced nerve conduction velocity. For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A1 (118210).

The Russe type of hereditary motor and sensory neuropathy (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).

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.

Autosomal recessive Charcot-Marie-Tooth disease type 4B2 (CMT4B2) is a demyelinating hereditary motor and sensory neuropathy characterized by abnormal folding of myelin sheaths. CMT4B1 (601382) is a clinically similar disorder caused by mutation in the MTMR2 gene (603557) on 11q22. For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating CMT, see CMT4A (214400).

Autosomal recessive distal hereditary motor neuronopathy-1 (HMNR1) is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, most infants with the severe form of the disease die before 2 years of age. Affected individuals present in infancy with inspiratory stridor, weak cry, recurrent bronchopneumonia, and swallowing difficulties. The disorder is caused by distal and progressive motor neuronopathy resulting in muscle weakness (summary by Perego et al., 2020). Genetic Heterogeneity of Autosomal Recessive Distal Hereditary Motor Neuronopathy See also HMNR2 (605726), caused by mutation in the SIGMAR1 gene (601978); HMNR3 (607088) (encompassing Harding HMN types III and IV), which maps to chromosome 11q13; HMNR4 (611067), caused by mutation in the PLEKHG5 gene (611101); HMNR5 (614881), caused by mutation in the DNAJB2 gene (604139); HMNR6 (620011), caused by mutation in the REEP1 gene (609139); HMNR7 (619216), caused by mutation in the VWA1 gene (611901); HMNR8 (618912), caused by mutation in the SORD gene (182500); HMNR9 (620402), caused by mutation in the COQ7 gene (601683); HMNR10 (620542), caused by mutation in the VRK1 gene (602168); and HMNR11 (620854), caused by mutation in the RTN2 gene (603183).

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).

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.

Autosomal recessive spinocerebellar ataxia-2 (SCAR2) is a neurologic disorder characterized by onset of impaired motor development and ataxic gait in early childhood. Additional features often include loss of fine motor skills, dysarthria, nystagmus, cerebellar signs, and delayed cognitive development with intellectual disability. Brain imaging shows cerebellar atrophy. Overall, the disorder is non- or slowly progressive, with survival into adulthood (summary by Jobling et al., 2015).

Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed.

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).

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.

Distal arthrogryposis type 5 is distinguished from other forms of DA by the presence of ocular abnormalities, typically ptosis, ophthalmoplegia, and/or strabismus, in addition to contractures of the skeletal muscles. Some cases have been reported to have pulmonary hypertension as a result of restrictive lung disease (summary by Bamshad et al., 2009). There are 2 syndromes with features overlapping those of DA5 that are also caused by heterozygous mutation in PIEZO2: distal arthrogryposis type 3 (DA3, or Gordon syndrome; 114300) and Marden-Walker syndrome (MWKS; 248700), which are distinguished by the presence of cleft palate and mental retardation, respectively. McMillin et al. (2014) suggested that the 3 disorders might represent variable expressivity of the same condition. For a general phenotypic description and a discussion of genetic heterogeneity of distal arthrogryposis, see DA1A (108120). Genetic Heterogeneity of Distal Arthrogryposis 5 A subtype of DA5 due to mutation in the ECEL1 gene (605896) on chromosome 2q36 has been designated DA5D (615065). See NOMENCLATURE.

Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant, slowly progressive neurodegenerative disorder characterized by a wide range of clinical manifestations, including pyramidal and extrapyramidal symptoms, cerebellar ataxia, cognitive decline and dementia, peripheral neuropathy, and autonomic dysfunction. The age at onset varies, but most individuals present as adults between about 30 and 70 years of age. Pathologic investigation shows eosinophilic intranuclear inclusions in almost all cell types, including neurons, skin cells, fibroblasts, and skeletal muscle. Brain imaging shows a characteristic leukoencephalopathy with high intensity signals in the corticomedullary junction on diffusion-weighted imaging (DWI), as well as white matter abnormalities in subcortical and brainstem regions. Skin biopsy combined with brain imaging is useful for diagnosis (summary by Sone et al., 2016). The phenotype in some cases is suggestive of Parkinson disease (see 168600) and/or Alzheimer disease (see 104300), consistent with an evolving phenotypic spectrum of adult-onset NIID (summary by Tian et al., 2019).

Giant axonal neuropathy-2 is an autosomal dominant peripheral axonal neuropathy characterized by onset of distal sensory impairment and lower extremity muscle weakness and atrophy after the second decade. Foot deformities may be present in childhood. More severely affected individuals may develop cardiomyopathy. Sural nerve biopsy shows giant axonal swelling with neurofilament accumulation (summary by Klein et al., 2014).

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 (or neonatal) 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.

MDDGC4 is an autosomal recessive muscular dystrophy with onset in infancy or early childhood. Cognition and brain structure are usually normal (Godfrey et al., 2006). It is part of a group of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Mercuri et al., 2009).

Charcot-Marie-Tooth disease type 4J (CMT4J) is an autosomal recessive progressive neurologic disorder with a highly variable phenotype and onset ranging from early childhood to adulthood. Most patients have both proximal and distal asymmetric muscle weakness of the upper and lower limbs. There is significant motor dysfunction, followed by variably progressive sensory loss, which may be mild. Nerve conduction studies and nerve biopsies indicate demyelination as well as axonal loss (summary by Nicholson et al., 2011). For a phenotypic description and a discussion of genetic heterogeneity of autosomal recessive demyelinating Charcot-Marie-Tooth disease, see CMT4A (214400).

Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation (LBSL) is characterized by slowly progressive cerebellar ataxia and spasticity with dorsal column dysfunction (decreased position and vibration sense) in most individuals. The neurologic dysfunction involves the legs more than the arms. The tendon reflexes are retained. Deterioration of motor skills usually starts in childhood or adolescence, but occasionally not until adulthood. Dysarthria develops over time. Occasional findings include epilepsy; learning problems; cognitive decline; and reduced consciousness, neurologic deterioration, and fever following minor head trauma. Individuals with neonatal or early-infantile onset have a severe disease course often associated with early death. Those with childhood onset have slow progression with wheelchair dependence in the teens or twenties. Adult onset is associated with slow progression and mild impairment.

An extremely rare form of carbohydrate deficient glycoprotein syndrome characterized clinically in the single reported case by repeated hemorrhagic incidents, including severe pulmonary hemorrhage.

Disease caused by homozygous mutation in the prosaposin gene (PSAP) on chromosome 10q22. The disease is genetically distinct from Krabbe disease. Clinical features include onset in infancy with respiratory and neurologic involvement.

GNPTAB-related disorders comprise the phenotypes mucolipidosis II (ML II) and mucolipidosis IIIa/ß (ML IIIa/ß), and phenotypes intermediate between ML II and ML IIIa/ß. ML II is evident at birth and slowly progressive; death most often occurs in early childhood. Orthopedic abnormalities present at birth may include thoracic deformity, kyphosis, clubfeet, deformed long bones, and/or dislocation of the hip(s). Growth often ceases in the second year of life; contractures develop in all large joints. The skin is thickened, facial features are coarse, and gingiva are hypertrophic. All children have cardiac involvement, most commonly thickening and insufficiency of the mitral valve and, less frequently, the aortic valve. Progressive mucosal thickening narrows the airways, and gradual stiffening of the thoracic cage contributes to respiratory insufficiency, the most common cause of death. ML IIIa/ß becomes evident at about age three years with slow growth rate and short stature; joint stiffness and pain initially in the shoulders, hips, and fingers; gradual mild coarsening of facial features; and normal to mildly impaired cognitive development. Pain from osteoporosis becomes more severe during adolescence. Cardiorespiratory complications (restrictive lung disease, thickening and insufficiency of the mitral and aortic valves, left and/or right ventricular hypertrophy) are common causes of death, typically in early to middle adulthood. Phenotypes intermediate between ML II and ML IIIa/ß are characterized by physical growth in infancy that resembles that of ML II and neuromotor and speech development that resemble that of ML IIIa/ß.

Fiskerstrand type peripheral neuropathy is a slowly-progressive Refsum-like disorder associating signs of peripheral neuropathy with late-onset hearing loss, cataract and pigmentary retinopathy that become evident during the third decade of life.

A syndromic X-linked intellectual disability characterized by moderate intellectual disability with variable occurrence of asthenic body habitus, dysmorphic features, autistic features, macrocephaly, seizures, myoclonic jerks, and hyporeflexia that has material basis in mutation in the GRIA3 gene on chromosome Xq25.

A rare, genetic, muscular dystrophy disease characterized by the co-occurrence of late onset scapular and peroneal muscle weakness, principally manifesting with distal lower limb and proximal upper limb weakness and scapular winging.

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.

A mild form of axonal Charcot-Marie-Tooth disease, a peripheral sensorimotor neuropathy, with characteristics of distal legs sensory loss and weakness that can be asymmetric. Tendon reflexes are reduced in the knees and absent in ankles. Progression is slow.

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

Pitt-Hopkins-like syndrome-1 (PTHSL1) is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (summary by Smogavec et al., 2016).

Any thyrotoxic periodic paralysis in which the cause of the disease is a mutation in the KCNJ18 gene.

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.

Four phenotypes comprise the RRM2B mitochondrial DNA maintenance defects (RRM2B-MDMDs): RRM2B encephalomyopathic MDMD, the most severe phenotype, usually manifesting shortly after birth as hypotonia, poor feeding, and faltering growth requiring hospitalization. Subsequent assessments are likely to reveal multisystem involvement including sensorineural hearing loss, renal tubulopathy, and respiratory failure. Autosomal dominant progressive external ophthalmoplegia (adPEO), typically adult onset; other manifestations can include ptosis, bulbar dysfunction, fatigue, and muscle weakness. RRM2B autosomal recessive progressive external ophthalmoplegia (arPEO), a typically childhood-onset predominantly myopathic phenotype of PEO, ptosis, proximal muscle weakness, and bulbar dysfunction. RRM2B mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like, characterized by progressive ptosis, ophthalmoplegia, gastrointestinal dysmotility, cachexia, and peripheral neuropathy. To date, 78 individuals from 52 families with a molecularly confirmed RRM2B-MDMD have been reported.

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.

Myofibrillar myopathy-6 is an autosomal dominant severe neuromuscular disorder characterized by onset in the first decade of rapidly progressive generalized and proximal muscle weakness, respiratory insufficiency, cardiomyopathy, and skeletal deformities related to muscle weakness. Muscle biopsy shows fiber-type grouping, disruption of the Z lines, and filamentous inclusions, and sural nerve biopsy shows a neuropathy, often with giant axonal neurons. Most patients are severely affected by the second decade and need cardiac transplant, ventilation, and/or a wheelchair (summary by Jaffer et al., 2012). For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy (MFM), see MFM1 (601419).

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.

CDG IIe is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways. For a general discussion of CDGs, see CDG1A (212065).

Myotonic dystrophy type 2 (DM2) is characterized by myotonia and muscle dysfunction (proximal and axial weakness, myalgia, and stiffness), and less commonly by posterior subcapsular cataracts, cardiac conduction defects, insulin-insensitive type 2 diabetes mellitus, and other endocrine abnormalities. While myotonia (involuntary muscle contraction with delayed relaxation) has been reported during the first decade, onset is typically in the third to fourth decade, most commonly with fluctuating or episodic muscle pain that can be debilitating and proximal and axial weakness of the neck flexors and the hip flexors. Subsequently, weakness occurs in the elbow extensors and finger flexors. Facial weakness and weakness of the ankle dorsiflexors are less common. Myotonia rarely causes severe symptoms. In a subset of individuals, calf hypertrophy in combination with brisk reflexes is notable.

A neurodegenerative disease with characteristics of progressive muscular paralysis reflecting degeneration of motor neurons in the primary motor cortex, corticospinal tracts, brainstem and spinal cord. Caused by heterozygous mutation in the FUS gene on chromosome 16p11.

Patients with chromosome 2q37 deletion syndrome show highly variable clinical manifestations likely resulting from different deletion sizes and deletions of different genes. Variable clinical features included brachydactyly type E (BDE), affecting the metacarpals and metatarsals (in about 50% of patients), short stature, mild to moderate intellectual disability, behavioral abnormalities, and dysmorphic facial features. However, many individuals with deletions do not show cognitive deficits (summary by Villavicencio-Lorini et al., 2013, Wheeler et al., 2014, Jean-Marcais et al., 2015).

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Beltran-Valero de Bernabe et al., 2004). For a general phenotypic description and a discussion of genetic heterogeneity of muscular dystrophy-dystroglycanopathy type A, see MDDGA1 (236670).

MDDGB2 is an autosomal recessive congenital muscular dystrophy associated with impaired intellectual development and mild structural brain abnormalities (Yanagisawa et al., 2007). It is part of a group of similar disorders, collectively known as 'dystroglycanopathies,' resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239) (Godfrey et al., 2007). For a discussion of genetic heterogeneity of congenital muscular dystrophy-dystroglycanopathy type B, see MDDGB1 (613155).

Microcephaly, seizures, and developmental delay (MCSZ) is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients develop refractory seizures in infancy, consistent with a developmental and epileptic encephalopathy (DEE), whereas others have more well-controlled seizures and a more protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Limb-girdle muscular dystrophy type 1H (LGMD1H) is an autosomal dominant disorder characterized by adult onset of progressive proximal muscle weakness affecting both the upper and lower limbs (Bisceglia et al., 2010). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant limb-girdle muscular dystrophy, see LGMDD1 (603511).

An extremely rare subtype of autosomal recessive intermediate Charcot-Marie-Tooth (CMT) disease characterized by a CMT neuropathy associated with developmental delay, self-abusive behavior, dysmorphic features and vestibular Schwannoma. Motor nerve conduction velocities demonstrate features of both demyelinating and axonal pathology.

Thiamine metabolism dysfunction syndrome-4 (THMD4) is an autosomal recessive metabolic disorder characterized by childhood onset of episodic encephalopathy, often associated with a febrile illness, and causing transient neurologic dysfunction. Most patients recover fully, but some may have mild residual weakness. Affected individuals also develop a slowly progressive axonal polyneuropathy beginning in childhood. Brain imaging during the acute episodes shows lesions consistent with bilateral striatal degeneration or necrosis (summary by Spiegel et al., 2009). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).

Combined oxidative phosphorylation deficiency-6 (COXPD6) is an X-linked recessive severe encephalomyopathic disorder with onset in utero or in infancy. Affected patients have hypotonia and severely impaired psychomotor development associated with variably decreased enzymatic activity of mitochondrial respiratory complexes in skeletal muscle or fibroblasts. More variable features may include sensorimotor neuropathy, seizures, severe muscle weakness, abnormal signals in the basal ganglia, hypertrophic cardiomyopathy, deafness, swallowing difficulties, and respiratory insufficiency. Death in childhood may occur (summary by Berger et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Infantile mitochondrial myopathy due to reversible COX deficiency is a rare mitochondrial disorder characterized by onset in infancy of severe hypotonia and generalized muscle weakness associated with lactic acidosis, but is distinguished from other mitochondrial disorders in that affected individuals recover spontaneously after 1 year of age (summary by Mimaki et al., 2010). See also transient infantile liver failure (LFIT; 613070), which is a similar disorder.

Williams distal myopathy is an autosomal dominant slowly progressive muscular disorder characterized by distal muscle weakness and atrophy affecting the upper and lower limbs. Onset occurs around the third to fourth decades of life, and patients remain ambulatory even after long disease duration. Muscle biopsy shows nonspecific changes with no evidence of rods, necrosis, or inflammation (summary by Duff et al., 2011). Mutation in the FLNC gene can also cause myofibrillar myopathy-5 (MFM5; 609524), which shows a different pattern of muscle involvement and different histologic changes.

Multiple congenital anomalies-hypotonia-seizures syndrome is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (summary by Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis; see GPIBD1 (610293). Genetic Heterogeneity of Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome MCAHS2 (300868) is caused by mutation in the PIGA gene (311770) on chromosome Xp22, MCAHS3 (615398) is caused by mutation in the PIGT gene (610272) on chromosome 20q13, and MCAHS4 (618548) is caused by mutation in the PIGQ gene (605754) on chromosome 16p13. Knaus et al. (2018) provided a review of the main clinical features of the different types of MCAHS, noting that patients with mutations in the PIGN, PIGA, and PIGT genes have distinct patterns of facial anomalies that can be detected by computer-assisted comparison. Some individuals with MCAHS may have variable increases in alkaline phosphatase (AP) as well as variable decreases in GPI-linked proteins that can be detected by flow cytometry. However, there was no clear correlation between AP levels or GPI-linked protein abnormalities and degree of neurologic involvement, mutation class, or gene involved. Knaus et al. (2018) concluded that a distinction between MCAHS and HPMRS1 (239300), which is also caused by mutation in genes involved in GPI biosynthesis, may be artificial and even inaccurate, and that all these disorders should be considered and classified together under the more encompassing term of 'GPI biosynthesis defects' (GPIBD).

Patients with pyruvate dehydrogenase E1-beta deficiency (PDHBD) present with typical clinical, biochemical and neuroradiological features: encephalopathy, hypotonia, respiratory difficulties, seizures, and lactic acidosis. Agenesis of the corpus callosum is often present. Patients with a severe clinical course die in infancy (summary by Quintana et al., 2009). For a general phenotypic description and a discussion of genetic heterogeneity of pyruvate dehydrogenase deficiency, see 312170.

DNMT1-related disorder is a degenerative disorder of the central and peripheral nervous systems comprising a phenotypic spectrum that includes hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). DNMT1 disorder is often characterized by moderate-to-severe sensorineural hearing loss beginning in the teens or early 20s, sensory impairment, sudomotor dysfunction (loss of sweating), and dementia usually beginning in the mid-40s. In some affected individuals, narcolepsy/cataplexy syndrome and ataxia are predominant findings.

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.

Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.

Autosomal recessive spinocerebellar ataxia-12 is a neurologic disorder characterized by onset of generalized seizures in infancy, delayed psychomotor development with mental retardation, and cerebellar ataxia. Some patients may also show spasticity (summary by Mallaret et al., 2014).

Congenital myopathy-10A (CMYO10A) is a severe autosomal recessive skeletal muscle disorder characterized by generalized hypotonia, respiratory insufficiency, and poor feeding apparent from birth. Decreased fetal movements may be observed. More variable features include high-arched palate, distal joint contractures, foot deformities, scoliosis, areflexia, and dysphagia. Many patients show eventration of the diaphragm. Affected individuals become ventilator-dependent in the first months or years of life and never achieve walking; many die in childhood (Logan et al., 2011). Patients with more damaging mutations in the MEGF10 gene, including nonsense or frameshift null mutations, show the more severe phenotype (CMYO10A), whereas those with missense mutations affecting conserved cysteine residues in the EGF-like domain show the less severe phenotype with later onset of respiratory failure and minicores on muscle biopsy (CMYO10B) (Croci et al., 2022). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

A rare genetic axonal hereditary motor and sensory neuropathy disorder with characteristics of adulthood-onset of slowly progressive, occasionally asymmetrical, distal muscle weakness and atrophy (predominantly in the lower limbs), pan-modal sensory loss, muscle cramping in extremities and/or trunk, pes cavus and absent or reduced deep tendon reflexes. Gait anomalies and variable autonomic disturbances, such as erectile dysfunction and urinary urgency, may be associated. The disease can be caused by homozygous or heterozygous mutation in the LRSAM1 gene on chromosome 9q33.

Neurodevelopmental disorder with hypotonia, craniofacial abnormalities, and seizures (NEDHCS) is an autosomal recessive syndrome characterized primarily by hypotonia and poor feeding apparent in early infancy. Affected individuals have severe global developmental delay, early-onset intractable seizures, and recognizable craniofacial dysmorphism with skull abnormalities. The disorder is believed to be unique to the Amish population, where it exhibits a founder effect (summary by Ammous et al., 2021).

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

Complex cortical dysplasia with other brain malformations-13 (CDCBM13) is an autosomal dominant neurodevelopmental disorder characterized by global developmental delay with impaired intellectual development. Brain imaging shows variable neuronal migration defects resulting in cortical malformations, including pachygyria. More variable features include early-onset seizures and dysmorphic features. Some patients may also show signs of peripheral neuropathy, such as abnormal gait, hyporeflexia, and foot deformities (summary by Willemsen et al., 2012 and Poirier et al., 2013). For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).

Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) is an autosomal recessive slowly progressive neurologic disorder characterized by imbalance due to cerebellar gait and limb ataxia with cerebellar atrophy on brain imaging, nystagmus, dysarthria, and peripheral sensory neuropathy with decreased or absent deep tendon reflexes. More variable features include vestibular dysfunction, chronic cough, autonomic dysfunction, saccadic pursuit, and pyramidal signs (extensor plantar responses). Most patients have onset in late adulthood, although earlier onset has been reported. Rare patients have features suggestive of lower motor neuron involvement (Szmulewicz et al., 2011, Miyatake et al., 2022).

A rare subtype of CMT1 characterized by a variable clinical presentation. Onset within the first two years of life with a delay in walking is not uncommon; however, onset may occur later. CMT1E is caused by point mutations in the <i>PMP22</i> (17p12) gene. The disease severity depends on the particular <i>PMP22</i> mutation, with some cases being very mild and even resembling hereditary neuropathy with liability to pressure palsies, while others having an earlier onset with a more severe phenotype (reminiscent of Dejerine-Sottas syndrome) than that seen in CMT1A, caused by gene duplication. These severe cases may also report deafness and much slower motor nerve conduction velocities compared to CMT1A patients.

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 PEX2 gene have cells of complementation group 5 (CG5, equivalent to CG10 and CGF). For information on the history of PBD complementation groups, see 214100.

Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.

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. Some patients with PEX10 mutations have a milder disorder characterized by childhood-onset cerebellar ataxia and neuropathy without mental retardation (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 PEX10 gene have cells of complementation group 7 (CG7, equivalent to CGB). For information on the history of PBD complementation groups, see 214100.

A rare subtype of autosomal dominant Charcot-Marie-Tooth disease type 2 with characteristics of adolescent to adulthood-onset of symmetrical, slowly progressive distal muscle weakness and atrophy (with a predominant weakness of the distal lower limbs) associated with reduced or absent deep tendon reflexes, pes cavus and mild to moderated deep sensory impairment. There is evidence this disease is caused by a heterozygous loss-of-function mutation in the DHTKD1 gene on chromosome 10p14.

CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic phenotypes that can include: Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance. Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons. Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs. Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia. Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities. Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder. Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.

Mitochondrial DNA depletion syndrome-11 is an autosomal recessive mitochondrial disorder characterized by onset in childhood or adulthood of progressive external ophthalmoplegia (PEO), muscle weakness and atrophy, exercise intolerance, and respiratory insufficiency due to muscle weakness. More variable features include spinal deformity, emaciation, and cardiac abnormalities. Skeletal muscle biopsies show deletion and depletion of mitochondrial DNA (mtDNA) with variable defects in respiratory chain enzyme activities (summary by Kornblum et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

Osteosclerotic metaphyseal dysplasia (OSMD) is a rare condition characterized by distinctive radiographic changes, including osteosclerosis localized predominantly to the metaphyses of the long bones. The shafts of the long bones are osteopenic. Laboratory abnormalities include elevated alkaline phosphatase levels in some, but not all, patients. Elevated urinary pyridinoline and deoxypyridinoline levels, markers of osteoclastic activity, have also been reported (Nishimura and Kozlowski, 1993; Kasapkara et al., 2013; Guo et al., 2017). Patients with OSMD have been described who also show hypotonia, developmental delay, seizures, and later-onset spastic paraplegia; however, OSMD resulting from mutation in the LRRK1 gene does not appear to include these neurologic features (Nishimura and Kozlowski, 1993; Kasapkara et al., 2013; Guo et al., 2017). Reviews Howaldt et al. (2020) reviewed published reports of LRRK1-associated OSMD, and noted that patients typically present with recurrent pathologic fractures and osteosclerosis at multiple skeletal sites, predominantly at the metaphyses and vertebral bodies. Variable degrees of osteosclerosis of ribs and skull and of Erlenmeyer flask deformity of the femurs have been observed.

AOA3 is an autosomal recessive progressive neurologic disorder with onset in the second decade of life (Al Tassan et al., 2012). For a discussion of genetic heterogeneity of ataxia-oculomotor apraxia, see AOA1 (208920).

Congenital myopathy-2A (CMYO2A) is an autosomal dominant disorder of the skeletal muscle characterized by infantile- or childhood-onset myopathy with delayed motor milestones and nonprogressive muscle weakness. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype (CMYO2C; 620278). Some patients with de novo mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation. Less frequently, autosomal dominant transmission of the disorder within a family may occur when the ACTA1 mutation produces a phenotype compatible with adult life. Of note, intrafamilial variability has also been reported: a severely affected proband may be identified and then mildly affected or even asymptomatic relatives are found to carry the same mutation. The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (Ryan et al., 2001; Laing et al., 2009; Sanoudou and Beggs, 2001; Agrawal et al., 2004; Nowak et al., 2013; Sewry et al., 2019; Laitila and Wallgren-Pettersson, 2021). The most common histologic finding on muscle biopsy in patients with ACTA1 mutations is the presence of 'nemaline rods,' which represent abnormal thread- or rod-like structures ('nema' is Greek for 'thread'). However, skeletal muscle biopsy from patients with mutations in the ACTA1 gene can show a range of pathologic phenotypes. These include classic rods, intranuclear rods, clumped filaments, cores, or fiber-type disproportion, all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. Most patients have clinically severe disease, regardless of the histopathologic phenotype (Nowak et al., 2007; Sewry et al., 2019). ACTA1 mutations are the second most common cause of congenital myopathies classified histologically as 'nemaline myopathy' after mutations in the NEB gene (161650). ACTA1 mutations are overrepresented in the severe phenotype with early death (Laing et al., 2009). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).

Developmental and epileptic encephalopathy-18 (DEE18) is a severe autosomal recessive neurologic disorder characterized by lack of psychomotor development apparent from birth, dysmorphic facial features, and early onset of refractory seizures. Brain imaging shows a thick corpus callosum and persistent cavum septum pellucidum on brain imaging (summary by Basel-Vanagaite et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

A form of axonal Charcot-Marie-Tooth disease a peripheral sensorimotor neuropathy. A late onset with severe sensory loss associated with distal weakness mainly of the legs and absent or reduced deep tendon reflexes.

Ataxia-telangiectasia-like disorder-1 is an autosomal recessive disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia. Laboratory studies of patient cells showed increased susceptibility to radiation, consistent with a defect in DNA repair. The disorder shares some phenotypic features of ataxia-telangiectasia (AT; 208900), but telangiectases and immune deficiency are not present in ATLD1 (summary by Hernandez et al., 1993 and Stewart et al., 1999). Genetic Heterogeneity of Ataxia-Telangiectasia-Like Disorder See also ATLD2 (615919), caused by mutation in the PCNA gene (176740) on chromosome 20p12.

IMD23 is an autosomal recessive primary immunodeficiency syndrome characterized by onset of recurrent infections, usually respiratory or cutaneous, in early childhood. Immune workup usually shows neutropenia, lymphopenia, eosinophilia, and increased serum IgE or IgA. Neutrophil chemotactic defects have also been reported. Infectious agents include bacteria, viruses, and fungi. Many patients develop atopic dermatitis, eczema, and other signs of autoinflammation. Affected individuals may also show developmental delay or cognitive impairment of varying severity (summary by Bjorksten and Lundmark, 1976 and Zhang et al., 2014).

CHCHD10-related disorders are characterized by a spectrum of adult-onset neurologic phenotypes that can include: Mitochondrial myopathy (may also be early onset): weakness, amyotrophy, exercise intolerance. Amyotrophic lateral sclerosis (ALS): progressive degeneration of upper motor neurons and lower motor neurons. Frontotemporal dementia (FTD): slowly progressive behavioral changes, language disturbances, cognitive decline, extrapyramidal signs. Late-onset spinal motor neuronopathy (SMA, Jokela type): weakness, cramps, and/or fasciculations; areflexia. Axonal Charcot-Marie-Tooth neuropathy: slowly progressive lower-leg muscle weakness and atrophy, small hand muscle weakness, loss of tendon reflexes, sensory abnormalities. Cerebellar ataxia: gait ataxia, kinetic ataxia (progressive loss of coordination of lower- and upper-limb movements), dysarthria/dysphagia, nystagmus, cerebellar oculomotor disorder. Because of the recent discovery of CHCHD10-related disorders and the limited number of affected individuals reported to date, the natural history of these disorders (except for SMAJ caused by the p.Gly66Val pathogenic variant) is largely unknown.

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).

Presynaptic congenital myasthenic syndrome-7A with distal motor neuropathy (CMS7A) is an autosomal dominant neuromuscular disorder characterized by onset of foot deformities, delayed motor development, and slowly progressive distal muscle weakness resulting in gait difficulties in early childhood. Other features may include hyporeflexia, muscle atrophy, and upper limb involvement. Electrophysiologic studies show low compound muscle action potentials (CMAPs), consistent with a distal hereditary motor neuropathy (dHMN), as well as a decremental response to repetitive stimulation, indicating presynaptic defects at the neuromuscular junction (NMJ), consistent with myasthenic syndrome (summary by Fionda et al., 2021). The complex phenotype of patients with dominant SYT2 mutations likely results from impairment of 2 fundamental functions of SYT2: (1) disturbance of calcium-dependent synchronous presynaptic neurotransmitter release, resulting in a myasthenic disorder, and (2) disruption of exocytosis and endocytosis, causing a degenerative process affecting peripheral motor nerve terminals and resulting in a motor neuropathy (Maselli et al., 2021). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462). For a discussion of genetic heterogeneity of dHMN, see 182960.

A form of limb-girdle muscular dystrophy presenting in infancy with muscle weakness and delayed motor development (eventually learning to walk at 18 months of age) followed by progressive proximal weakness, pseudohypertrophy of calf muscles, mild facial weakness and borderline intelligence.

Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.

Charcot-Marie-Tooth disease type 2S is a relatively pure form of autosomal recessive axonal neuropathy characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy affecting the lower and upper limbs. Patients have decreased reflexes and variable distal sensory impairment (summary by Cottenie et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Charcot-Marie-Tooth disease type 2T (CMT2T) is a slowly progressive autosomal recessive sensorimotor peripheral neuropathy with onset in middle age (Higuchi et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Combined oxidative phosphorylation deficiency-24 (COXPD24) is an autosomal recessive mitochondrial disorder with wide phenotypic variability. Most patients present in infancy with delayed neurodevelopment, refractory seizures, hypotonia, and hearing impairment due to auditory neuropathy. Less common features may include cortical blindness, renal dysfunction, and/or liver involvement, suggestive of Alpers syndrome (MTDPS4A; 203700). Patients with the severe phenotype tend to have brain abnormalities on imaging, including cerebral atrophy and hyperintensities in the basal ganglia and brainstem, consistent with Leigh syndrome. Laboratory values may be normal or show increased lactate and evidence of mitochondrial respiratory chain defects, particularly in muscle. Some patients achieve little developmental milestones and may die in infancy or early childhood. However, some patients have a less severe phenotype manifest only by myopathy (summary by Sofou et al., 2015, Vanlander et al., 2015, and Mizuguchi et al., 2017). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Infantile-onset multisystem neurologic, endocrine, and pancreatic disease-1 (IMNEPD1) is an autosomal recessive multisystemic disorder with variable expressivity. The core features usually include global developmental delay with impaired intellectual development and speech delay, ataxia, sensorineural hearing loss, and pancreatic insufficiency. Additional features may include peripheral neuropathy, postnatal microcephaly, dysmorphic facial features, and cerebellar atrophy. However, some patients may not display all features (summary by Picker-Minh et al., 2016, Sharkia et al., 2017). Genetic Heterogeneity of Infantile-Onset Multisystem Neurologic, Endocrine, and Pancreatic Disease See also IMNEPD2 (619418), caused by mutation in the YARS1 gene (603623) on chromosome 1p35.

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

Reducing-body myopathy (RBM) is a rare myopathy characterized pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase (MAG) in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium (NBT) in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. The clinical features of RBM are variable; a severe form has onset in infancy or early childhood and results in severe disability or early death (RBMX1A; 300717), and a less severe form has onset in late childhood or adulthood (RBMX1B) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).

Scapulohumeroperoneal myopathy is an autosomal dominant muscle disorder characterized by slowly progressive muscle weakness and atrophy affecting both proximal and distal muscles of the upper and lower limbs. Onset is usually in the first decade and can be as early as infancy, although some patients do not notice symptoms until young adulthood. There is marked variability in severity (summary by Zukosky et al., 2015).

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.

Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (summary by Huber and Cormier-Daire, 2012 and Schmidts et al., 2013). There is phenotypic overlap with the cranioectodermal dysplasias (Sensenbrenner syndrome; see CED1, 218330). For a discussion of genetic heterogeneity of short-rib thoracic dysplasia with or without polydactyly, see SRTD1 (208500).

Hereditary motor and sensory neuropathy type VIB is an autosomal recessive complex progressive neurologic disorder characterized mainly by early-onset optic atrophy resulting in progressive visual loss and peripheral axonal sensorimotor neuropathy with highly variable age at onset and severity. Affected individuals may also have cerebellar or pontocerebellar atrophy on brain imaging, and they may show abnormal movements such as ataxia, dysmetria, and myoclonus (summary by Abrams et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152).

Hereditary sensory and autonomic neuropathy type VIII (HSAN8) is an autosomal recessive neurologic disorder characterized by congenital insensitivity to pain resulting in ulceration to the fingers, tongue, lips, and other distal appendages. Affected individuals may also have decreased sweating and tear production (summary by Chen et al., 2015). For a discussion of genetic heterogeneity of hereditary sensory and autonomic neuropathy, see HSAN1A (162400).

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).

Frontotemporal dementia and/or amyotrophic lateral sclerosis-4 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. The phenotype is highly variable (summary by Freischmidt et al., 2015). For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).

Frontotemporal dementia and/or amyotrophic lateral sclerosis-3 is an autosomal dominant neurodegenerative disorder characterized by adult or late adult onset of cognitive impairment, behavioral abnormalities, and speech apraxia and/or upper and lower motor neuron signs. Some patients may also develop Paget disease of bone. The phenotype is highly variable, even within families (summary by Rea et al., 2014). For a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).

Any congenital myasthenic syndrome in which the cause of the disease is a mutation in the LRP4 gene.

Reducing-body myopathy (RBM) is a rare myopathy characterized pathologically by the presence of intracytoplasmic inclusion bodies strongly stained by menadione-linked alpha-glycerophosphate dehydrogenase (MAG) in the absence of substrate, alpha-glycerophosphate. The term 'reducing body' refers to the reducing activity of the inclusions to nitroblue tetrazolium (NBT) in the absence of substrate. This condition is also commonly associated with rimmed vacuoles and cytoplasmic bodies. The clinical features of RBM are variable; a severe form has onset in infancy or early childhood and results in severe disability or early death, and a less severe form has onset in late childhood or adulthood (RBMX1B; 300718) (summary by Liewluck et al., 2007 and Shalaby et al., 2009).

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.

MPSPS is an autosomal recessive inborn error of metabolism resulting in a multisystem disorder with features of the mucopolysaccharidosis lysosomal storage diseases (see, e.g., 607016). Patients present in infancy or early childhood with respiratory difficulties, cardiac problems, anemia, dysostosis multiplex, renal involvement, coarse facies, and delayed psychomotor development. Most patients die of cardiorespiratory failure in the first years of life (summary by Kondo et al., 2017).

Developmental and epileptic encephalopathy-48 (DEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech; poor, if any, motor development; and onset of seizures usually in the first year of life, although later onset has been reported. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (summary by Assoum et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Myofibrillar myopathy-8 (MFM8) is an autosomal recessive myopathy characterized by slowly progressive proximal muscle weakness and atrophy affecting the upper and lower limbs, resulting in increased falls, gait problems, difficulty running or climbing stairs, and upper limb weakness or scapular winging. Some patients develop distal muscle weakness and atrophy. The phenotype may also be consistent with a clinical diagnosis of limb-girdle muscular dystrophy (LGMD). Age at symptom onset ranges from infancy to adulthood. Ambulation is generally preserved and cardiac involvement is rare, but respiratory compromise with decreased forced vital capacity often occurs. Muscle biopsy shows a mix of myopathic features, including myofibrillar inclusions and sarcomeric disorganization; some patients have been reported to have dystrophic changes on muscle biopsy (O'Grady et al., 2016; Daimaguler et al., 2021). There is significant phenotypic variation, even in patients with the same mutation, which must be taken into account when counseling affecting individuals (Woods et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

MTDPS12A is characterized by severe hypotonia due to mitochondrial dysfunction apparent at birth. Affected infants have respiratory insufficiency requiring mechanical ventilation and have poor or no motor development. Many die in infancy, and those that survive have profound hypotonia with significant muscle weakness and inability to walk independently. Some patients develop hypertrophic cardiomyopathy. Muscle samples show mtDNA depletion and severe combined mitochondrial respiratory chain deficiencies (summary by Thompson et al., 2016). For a discussion of genetic heterogeneity of mtDNA depletion syndromes, see MTDPS1 (603041).

Myofibrillar myopathy-7 (MFM7) is an autosomal recessive muscle disorder characterized by early childhood onset of slowly progressive muscle weakness that primarily affects the lower limbs and is associated with joint contractures (summary by Straussberg et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

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.

Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4) is characterized by adult onset of eye muscle weakness and proximal limb muscle weakness associated with deletions of mtDNA on skeletal muscle biopsy, which results from defective mtDNA replication in post-mitotic muscle tissue. Additional features are more variable (summary by Ronchi et al., 2012). For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).

Pontocerebellar hypoplasia type 2F (PCH2F) is an autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly and variable neurologic signs and symptoms, including cognitive and motor delay, poor or absent speech, seizures, and spasticity (summary by Breuss et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of pontocerebellar hypoplasia type 2, see PCH2A (277470).

Spinocerebellar ataxia-43 (SCA43) is an autosomal dominant, slowly progressive neurologic disorder characterized by adult-onset gait and limb ataxia and often associated with peripheral neuropathy mainly affecting the motor system, although some patients may have distal sensory impairment (summary by Depondt et al., 2016). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Axonal Charcot-Marie-Tooth disease type 2CC is an autosomal dominant peripheral neuropathy that predominantly affects the lower limbs, resulting in muscle weakness and atrophy and gait impairment. Other features include distal sensory impairment and less severe involvement of the upper limbs. The age at onset and severity are variable (summary by Rebelo et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).

Neurodevelopmental disorder with or without hypotonia, seizures, and cerebellar atrophy (NEDHSCA) is an autosomal recessive disorder characterized by severely delayed psychomotor development, hypotonia apparent since infancy, and early-onset seizures in most patients. Some patients may have additional features, such as cerebellar atrophy, ataxia, and nonspecific dysmorphic features. NEDHSCA is one of a group of similar neurologic disorders resulting from biochemical defects in the glycosylphosphatidylinositol (GPI) biosynthetic pathway. Some patients with NEDHSCA may have the Emm-null blood group phenotype (see 619812) (summary by Makrythanasis et al., 2016; Duval et al., 2021). For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

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 (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) 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 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.

Developmental and epileptic encephalopathy-51 (DEE51) is an autosomal recessive severe neurodevelopmental disorder characterized by onset of intractable seizures and hypotonia in the first days or weeks of life. Affected individuals have severely delayed psychomotor development and may show abnormal movements. Brain imaging shows nonspecific abnormalities, such as cerebral atrophy, cerebellar atrophy, and delayed myelination. Laboratory studies showed increased lactate, suggesting mitochondrial dysfunction (summary by Ait-El-Mkadem et al., 2017). For a discussion of genetic heterogeneity of DEE, see 308350.

Neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM) is an autosomal recessive disorder comprising impaired intellectual development, speech delay, mild microcephaly, and midbrain-hindbrain malformation (Ravindran et al., 2017).

Neurodegeneration with brain iron accumulation refers to a group of neurodegenerative disorders characterized by progressive motor and cognitive dysfunction beginning in childhood or young adulthood. Patients show extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism. Brain imaging shows iron accumulation in the basal ganglia (summary by Dusi et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).

Combined oxidative phosphorylation deficiency-8 (COXPD8) is an autosomal recessive disorder caused by dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (summary by Gotz et al., 2011). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Mitochondrial myopathy and ataxia (MMYAT) is an autosomal recessive mtDNA depletion disorder characterized by cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic, and pigmentary retinopathy (summary by Donkervoort et al., 2019).

Pontocerebellar hypoplasia type 11 (PCH11) is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development with impaired intellectual development and poor speech, microcephaly, dysmorphic features, and pontocerebellar hypoplasia on brain imaging. Additional features are more variable (summary by Marin-Valencia et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1 (607596).

HMND9 is an autosomal dominant neurologic disorder characterized by juvenile onset of slowly progressive distal muscle weakness and atrophy affecting both the lower and upper limbs (summary by Tsai et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).

NEDMIAL is a neurodevelopmental disorder characterized by delayed psychomotor development and hypotonia apparent from early infancy, resulting in feeding difficulties, ataxic gait or inability to walk, delayed or absent speech development, and impaired intellectual development, sometimes with behavioral abnormalities, such as hand-flapping. Additional common features may include sleep disorder, nonspecific dysmorphic facial features, and joint hyperlaxity (summary by Lessel et al., 2017 and Mannucci et al., 2021).

Schwartz-Jampel syndrome type 1 (SJS1) is a rare autosomal recessive disorder characterized by muscle stiffness (myotonia) and chondrodysplasia. Affected individuals usually present in childhood with permanent muscle stiffness or bone deformities. Common clinical features include mask-like facies (narrow palpebral fissures, blepharospasm, and pursed lips); permanent muscle stiffness with continuous skeletal muscle activity recorded on electromyography; dwarfism; pectus carinatum; kyphoscoliosis; bowing of long bones; and epiphyseal, metaphyseal, and hip dysplasia. The disorder is slowly progressive but does not appear to alter life span (summary by Stum et al., 2006).

Perrault syndrome is characterized by sensorineural hearing loss (SNHL) in males and females and ovarian dysfunction in females. SNHL is bilateral and ranges from profound with prelingual (congenital) onset to moderate with early-childhood onset. When onset is in early childhood, hearing loss can be progressive. Ovarian dysfunction ranges from gonadal dysgenesis (absent or streak gonads) manifesting as primary amenorrhea to primary ovarian insufficiency (POI) defined as cessation of menses before age 40 years. Fertility in affected males is reported as normal (although the number of reported males is limited). Neurologic features described in some individuals with Perrault syndrome include learning difficulties and developmental delay, cerebellar ataxia, and motor and sensory peripheral neuropathy.

Laing distal myopathy is characterized by early-onset weakness (usually before age 5 years) that initially involves the dorsiflexors of the ankles and great toes and then the finger extensors, especially those of the third and fourth fingers. Weakness of the neck flexors is seen in most affected individuals and mild facial weakness is often present. After distal weakness has been present for more than ten years, mild proximal weakness may be observed. Life expectancy is normal.

Neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features (NEDMAGA) is characterized by infantile-onset global developmental delay with severe to profound intellectual disability, mildly delayed walking with broad-based and unsteady gait, and absence of meaningful language. Patients have features of autism, with repetitive behaviors and poor communication, but usually are socially reactive and have a happy demeanor. More variable neurologic features include mild seizures, spasticity, and peripheral neuropathy (summary by Palmer et al., 2017).

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.

Ververi-Brady syndrome (VEBRAS) is characterized by mild developmental delay, mildly impaired intellectual development and speech delay, and mild dysmorphic facial features. Affected individuals can usually attend mainstream schools with support, and may also show autistic features (summary by Ververi et al., 2018).

Combined oxidative phosphorylation deficiency-13 (COXPD13) is an autosomal recessive multisystem disorder resulting from mitochondrial dysfunction. Affected individuals develop severe neurologic impairment in the first months of life, including hypotonia, abnormal dystonic movements, hearing loss, poor feeding, global developmental delay, and abnormal eye movements. Brain imaging shows signal abnormalities in putamen, basal ganglia, caudate nuclei, or corpus callosum, as well as delayed myelination. Analysis of patient tissues shows multiple defects in enzymatic activities of the mitochondrial respiratory chain, although some tissues may show normal values since tissue expression of the mitochondrial defect and metabolic needs of specific tissues are variable (summary by Vedrenne et al., 2012). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

Zellweger spectrum disorder (ZSD) is a phenotypic continuum ranging from severe to mild. While individual phenotypes (e.g., Zellweger syndrome [ZS], neonatal adrenoleukodystrophy [NALD], and infantile Refsum disease [IRD]) were described in the past before the biochemical and molecular bases of this spectrum were fully determined, the term "ZSD" is now used to refer to all individuals with a defect in one of the ZSD-PEX genes regardless of phenotype. Individuals with ZSD usually come to clinical attention in the newborn period or later in childhood. Affected newborns are hypotonic and feed poorly. They have distinctive facies, congenital malformations (neuronal migration defects associated with neonatal-onset seizures, renal cysts, and bony stippling [chondrodysplasia punctata] of the patella[e] and the long bones), and liver disease that can be severe. Infants with severe ZSD are significantly impaired and typically die during the first year of life, usually having made no developmental progress. Individuals with intermediate/milder ZSD do not have congenital malformations, but rather progressive peroxisome dysfunction variably manifest as sensory loss (secondary to retinal dystrophy and sensorineural hearing loss), neurologic involvement (ataxia, polyneuropathy, and leukodystrophy), liver dysfunction, adrenal insufficiency, and renal oxalate stones. While hypotonia and developmental delays are typical, intellect can be normal. Some have osteopenia; almost all have ameleogenesis imperfecta in the secondary teeth.

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.

Congenital hypomyelinating neuropathy-2 is an autosomal dominant neurologic disorder characterized by early-onset hypotonia, severely delayed motor development, muscle weakness with areflexia, and severely decreased nerve conduction velocities (NCV) resulting from improper myelination of axons. The severity is variable: some patients may present at birth with contractures and respiratory insufficiency, whereas others may achieve walking (summary by Warner et al., 1996). CHN shows significant phenotypic overlap with Dejerine-Sottas syndrome (DSS; 145900), which is also a neuropathy with early onset. Some classify the disorders differently, noting that CHN is characterized by hypo- or amyelination resulting from a congenital defect in myelin formation, whereas DSS has features of continuous myelin breakdown, with demyelination and remyelination (summary by Smit et al., 2008). For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).

Dopamine beta-hydroxylase (DBH) deficiency is characterized by lack of sympathetic noradrenergic function but normal parasympathetic and sympathetic cholinergic function. Affected individuals exhibit profound deficits in autonomic regulation of cardiovascular function that predispose to orthostatic hypotension. Although DBH deficiency appears to be present from birth, the diagnosis is not generally recognized until late childhood. The combination of ptosis of the eyelids in infants and children, together with hypotension, is suggestive of the disease. In the perinatal period, DBH deficiency has been complicated by vomiting, dehydration, hypotension, hypothermia, and hypoglycemia requiring repeated hospitalization; children have reduced exercise capacity. By early adulthood, individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis of the eyelids, and nasal stuffiness. Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain; symptoms may worsen in hot environments or after heavy meals or alcohol ingestion. Life expectancy is unknown, but some affected individuals have lived beyond age 60 years.

Charcot-Marie-Tooth disease type 2DD is an autosomal dominant peripheral sensorimotor neuropathy mainly affecting the lower limbs. Affected individuals have gait impairment due to distal muscle weakness and atrophy. Some patients may also have involvement of the distal upper limbs, resulting in atrophy of the intrinsic hand muscles. The age at onset and severity of the disorder is highly variable, even within families, and those with earlier onset in late childhood or the teenage years tend to have a more severe disease course. Patients remain ambulatory even late in the disease, although some may require orthotic devices (summary by Lassuthova et al., 2018). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).

Pontocerebellar hypoplasia type 1D (PCH1D) is a severe autosomal recessive neurologic disorder characterized by severe hypotonia and a motor neuronopathy apparent at birth or in infancy. Patients have respiratory insufficiency, feeding difficulties, and severely delayed or minimal gross motor development. Other features may include eye movement abnormalities, poor overall growth, contractures. Brain imaging shows progressive cerebellar atrophy with relative sparing of the brainstem (summary by Burns et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).

Autosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (summary by Ylikallio et al., 2017).

Congenital hypomyelinating neuropathy-3 is an autosomal recessive neurologic disorder characterized by onset of neurogenic muscle impairment in utero. Affected individuals present at birth with severe hypotonia, often causing respiratory insufficiency or failure and inability to swallow or feed properly. They have profoundly impaired psychomotor development and may die in infancy or early childhood. Those that survive are unable to sit or walk. Sural nerve biopsy shows hypomyelination of the nerve fibers, and brain imaging often shows impaired myelination and cerebral and cerebellar atrophy. Nerve conduction velocities are severely decreased (about 10 m/s) or absent due to improper myelination (summary by Vallat et al., 2016 and Low et al., 2018). For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).

Trichohepatoneurodevelopmental syndrome is a complex multisystem disorder characterized by woolly or coarse hair, liver dysfunction, pruritus, dysmorphic features, hypotonia, and severe global developmental delay (Morimoto et al., 2018).

CMTDIF is an autosomal dominant neurologic disorder characterized by onset around adolescence of slowly progressive distal muscle atrophy and weakness affecting the upper and lower limbs and resulting in steppage gait. There is distal sensory impairment with decreased reflexes. Nerve conduction velocities are variable, ranging from the demyelinating to the axonal range (summary by Soong et al., 2013). For a discussion of genetic heterogeneity of CMTDI, see 606482.

Autosomal recessive spinocerebellar ataxia-20 is a neurodevelopmental disorder characterized by severely delayed psychomotor development with poor or absent speech, wide-based or absent gait, coarse facies, and cerebellar atrophy (summary by Thomas et al., 2014).

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).

Neurodevelopmental disorder with central and peripheral motor dysfunction (NEDCPMD) is an autosomal recessive neurologic disorder with a highly variable phenotype. At the severe end of the spectrum, patients may have hypotonia apparent from birth, necessitating mechanical respiration and tube-feeding, and global developmental delay with absence of reaction to touch and no eye contact. At the mild end of the spectrum, patients may present with infantile-onset progressive ataxia and demyelinating peripheral neuropathy. The disorder is caused by mutation in the NFASC gene, which has several neuronal- and glial-specific transcripts. The variable clinical phenotype may be caused by several factors, including the severity of the mutation, the selective involvement of distinct isoforms by pathogenic variants, and the presence of genetic modifiers (summary by Monfrini et al., 2019).

Spinocerebellar ataxia with axonal neuropathy-3 (SCAN3) is an autosomal recessive neuromuscular disorder characterized by onset in the first decade of slowly progressive distal muscle weakness and atrophy and distal sensory impairment due to an axonal peripheral neuropathy. Affected individuals have gait disturbances and sometimes manual dexterity difficulties, as well as cerebellar ataxia associated with cerebellar atrophy on brain imaging. Additional features usually include dysarthria, hyporeflexia, and increased serum creatine kinase. Some patients may have impaired intellectual development (summary by Higuchi et al., 2018). For a discussion of genetic heterogeneity of SCAN, see SCAN1 (607250).

Charcot-Marie-Tooth disease type 2EE (CMT2EE) is an autosomal recessive sensorimotor peripheral axonal neuropathy with onset in the first or second decades of life. The disorder primarily affects the lower limbs and is slowly progressive, sometimes resulting in loss of ambulation, with later onset of upper limb involvement. There is significant distal muscle weakness and atrophy, usually with foot or hand deformities. Skeletal muscle biopsy shows findings of disturbed mitochondrial maintenance. Cognition is unaffected, and chronic liver disease is absent (summary by Baumann et al., 2019). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT type 2, see CMT2A (118210).

Myogenic-type arthrogryposis multiplex congenita-3 (AMC3) is an autosomal recessive disorder characterized by decreased fetal movements, hypotonia, variable skeletal defects, including clubfoot and scoliosis, and delayed motor milestones with difficulty walking (summary by Baumann et al., 2017).

Episodic mitochondrial myopathy with or without optic atrophy and reversible leukoencephalopathy (MEOAL) is an autosomal recessive neuromuscular disorder characterized mainly by childhood onset of progressive muscle weakness and exercise intolerance. Patients have episodic exacerbation, which may be associated with increased serum creatine kinase or lactic acid. Additional more variable features may include optic atrophy, reversible leukoencephalopathy, and later onset of a sensorimotor polyneuropathy. The disorder results from impaired formation of Fe-S clusters, which are essential cofactors for proper mitochondrial function (summary by Gurgel-Giannetti et al., 2018)

Developmental and epileptic encephalopathy-80 (DEE80) is an autosomal recessive neurologic disorder characterized by the onset of refractory seizures in the first year of life. Patients have severe global developmental delay and may have additional variable features, including dysmorphic or coarse facial features, distal skeletal abnormalities, and impaired hearing or vision. At the cellular level, the disorder is caused by a defect in the synthesis of glycosylphosphatidylinositol (GPI), and thus affects the expression of GPI-anchored proteins at the cell surface (summary by Murakami et al., 2019). For a discussion of genetic heterogeneity of DEE, see 308350. For a discussion of genetic heterogeneity of GPI biosynthesis defects, see GPIBD1 (610293).

SPTLC1-related hereditary sensory neuropathy (HSN) is an axonal form of hereditary motor and sensory neuropathy distinguished by prominent early sensory loss and later positive sensory phenomena including dysesthesia and characteristic "lightning" or "shooting" pains. Loss of sensation can lead to painless injuries, which, if unrecognized, result in slow wound healing and subsequent osteomyelitis requiring distal amputations. Motor involvement is present in all advanced cases and can be severe. After age 20 years, the distal wasting and weakness may involve proximal muscles, possibly leading to wheelchair dependency by the seventh or eighth decade. Sensorineural hearing loss is variable.

Mitochondrial form of axonal Charcot-Marie-Tooth disease-1 (CMTMA1) is inherited only through the maternal line. The disorder is characterized by onset of distal muscle weakness and atrophy mainly affecting the lower limbs and resulting in difficulty walking in the second decade of life, although both earlier and later onset can occur. Upper limb involvement often develops with time, and affected individuals have weakness and atrophy of the intrinsic hand muscles. Other features may include distal sensory impairment, foot deformities, scoliosis, hypo- or hyperreflexia, spastic paraparesis, and neurogenic bladder. Electrophysiologic studies are compatible with an axonal sensorimotor peripheral neuropathy, and muscle and nerve biopsy show evidence of mitochondrial dysfunction with decreased activities of respiratory complexes, mtDNA deletions, and mitochondrial hyperplasia (summary by Fay et al., 2020).

46,XY gonadal dysgenesis-motor and sensory neuropathy syndrome is a rare, genetic, developmental defect during embryogenesis disorder characterized by partial (unilateral testis, persistence of Müllerian duct structures) or complete (streak gonads only) gonadal dysgenesis, usually manifesting with primary amenorrhea in individuals with female phenotype but 46,XY karyotype, and sensorimotor dysmyelinating minifascicular polyneuropathy, which presents with numbness, weakness, exercise-induced muscle cramps, sensory disturbances and reduced/absent deep tendon reflexes. Germ cell tumors (seminoma, dysgerminoma, gonadoblastoma) may develop from the gonadal tissue.

Mitochondrial complex IV deficiency nuclear type 15 (MC4DN15) is an autosomal recessive multisystem metabolic disorder characterized by the onset of symptoms in infancy. Affected individuals show global developmental delay, poor feeding, short stature with microcephaly, proximal muscle weakness, and distal spasticity. Other manifestations include scoliosis, primary pulmonary hypertension, childhood-onset refractory seizures, and inability to walk. Brain imaging shows features consistent with Leigh syndrome (see 256000) and enlarged ventricles. Laboratory studies show increased serum and CSF lactate, as well as decreased levels and activity of mitochondrial respiratory complex IV (summary by Hallmann et al., 2016). For a discussion of genetic heterogeneity of mitochondrial complex IV (cytochrome c oxidase) deficiency, see 220110.

Developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy (DIGFAN) is a complex neurologic disorder characterized by impaired motor and intellectual development, hypotonia, poor overall growth, usually with short stature and microcephaly, and subtly dysmorphic facial features. Affected individuals have distal muscle weakness and muscle atrophy resulting in delayed acquisition of motor skills and persistent gait abnormalities. Although many patients have clinical and/or electrophysiologic features consistent with an axonal sensorimotor peripheral neuropathy, such as hyporeflexia, impaired sensation, foot drop, and pes cavus, the signs and severity are highly variable. Additional features may include hearing loss, pigmentary retinopathy, and abnormalities on brain imaging, including cerebral or cerebellar atrophy, hypomyelination, and lesions in the basal ganglia or brainstem. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN syndrome), which highlights the expanding clinical spectrum associated with MORC2 mutations and may render classification of patients into one or the other disorder challenging (summary by Guillen Sacoto et al., 2020).

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).

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).

Pontocerebellar hypoplasia type 1F (PCH1F) is an autosomal recessive neurologic disorder characterized by hypotonia, global developmental delay, poor overall growth, and dysmorphic facial features. Brain imaging shows pontocerebellar hypoplasia, thin corpus callosum, cerebral atrophy, and delayed myelination (summary by Somashekar et al., 2021). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).

Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) is an autosomal recessive neurologic syndrome characterized by global developmental delay with severely impaired intellectual development, hypotonia and muscle weakness, often resulting in the inability to walk or sit, and characteristic coarse facial features. Additional features include feeding difficulties, respiratory distress, scoliosis, poor visual function, and rotary nystagmus. Brain imaging shows variable abnormalities, including enlarged ventricles, decreased white matter volume, white matter changes, thin corpus callosum, and cerebellar hypoplasia (summary by Loddo et al., 2020).

Charcot-Marie-Tooth disease type 2GG (CMT2GG) is an autosomal dominant axonal peripheral neuropathy characterized by slowly progressive distal muscle weakness and atrophy primarily affecting the lower limbs and causing difficulty walking. The onset is usually in adulthood, although rare patients may have mild symptoms from childhood. Some individuals may also have involvement of the hands. Although most patients have hypo- or areflexia at the ankles, distal sensory impairment is not always present, indicating a spectrum of disease encompassing both distal hereditary neuropathy and axonal CMT. Electrophysiologic studies are consistent with a axonal process (summary by Mendoza-Ferreira et al., 2020). For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Focal segmental glomerulosclerosis and neurodevelopmental syndrome (FSGSNEDS) is characterized by global developmental delay and renal dysfunction manifest as proteinuria and nephrotic syndrome apparent from infancy or early childhood. Some patients present with renal disease, whereas others present with developmental delay and develop renal disease later in childhood. Renal biopsy shows focal segmental glomerulosclerosis (FSGS), but the course of the disease is variable: some patients have transient proteinuria and others require renal transplant. Neurodevelopmental features are also variable, with some patients having only mildly impaired intellectual development, and others having a severe developmental disorder associated with early-onset refractory seizures or epileptic encephalopathy. Additional features, including feeding difficulties, poor overall growth, and nonspecific dysmorphic facial features, are commonly observed (summary by Assoum et al., 2018 and Weng et al., 2021).

Oculopharyngodistal myopathy-3 (OPDM3) is a neuromyodegenerative disease characterized by progressive muscle weakness with ocular, facial, pharyngeal, and distal limb involvement, resulting in dysarthria and gait difficulties. The onset of the disorder is usually in adulthood, although childhood onset has rarely been reported. Additional features include hyporeflexia, proximal muscle weakness, neck muscle weakness, dysarthria, dysphagia, and ptosis. Some patients may develop pigmentary retinopathy, peripheral neuropathy, or hearing loss. Cognition is usually not affected, but there may be deficits or psychiatric manifestations. Brain imaging tends to show a leukoencephalopathy, often with a characteristic linear signal along the corticomedullary junction on brain imaging. Skin and muscle biopsy show intranuclear inclusions and rimmed vacuoles. Many of the clinical features are reminiscent of NIID, suggesting that these disorders likely fall within a broad phenotypic spectrum of diseases with neuromyodegenerative features associated with abnormal repeat expansions in this gene (summary by Ogasawara et al., 2020 and Yu et al., 2021). For a discussion of genetic heterogeneity of OPDM, see OPDM1 (164310).

Developmental delay with or without intellectual impairment or behavioral abnormalities (DDIB) is an autosomal dominant disorder with a nonspecific phenotype of developmental delay. Additional features may include neonatal feeding problems, hypotonia, and dysmorphic facial features (Dulovic-Mahlow et al., 2019; van Woerden et al., 2021).

Infantile hypotonia with psychomotor retardation and characteristic facies-3 is a severe autosomal recessive neurodevelopmental disorder with onset at birth or in early infancy. Most affected individuals show very poor, if any, normal psychomotor development, poor speech, and inability to walk independently (summary by Bhoj et al., 2016). For a general phenotypic description and a discussion of genetic heterogeneity of infantile hypotonia with psychomotor retardation and characteristic facies, see IHPRF1 (615419).

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).

Charcot-Marie-Tooth disease type 2Z (CMT2Z) is an autosomal dominant axonal peripheral neuropathy characterized by onset, usually in the first decade, of distal lower limb muscle weakness and sensory impairment. The disorder is progressive, and affected individuals tend to develop upper limb and proximal muscle involvement in an asymmetric pattern, resulting in severe disability late in adulthood. Rare occurrence of global developmental delay with impaired intellectual development or learning difficulties has been observed. In some instances, the same mutation may result in different phenotypic manifestations (CMT2Z or DIGFAN), which highlights the clinical spectrum associated with MORC2 mutations and may render the classification of patients into one or the other disorder challenging (summary by Sevilla et al., 2016, Ando et al., 2017, Guillen Sacoto et al., 2020). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

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 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).

Inclusion body myopathy and brain white matter abnormalities (IBMWMA) is an autosomal dominant adult-onset disorder characterized predominantly by proximal limb girdle muscle weakness affecting the lower and upper limbs and resulting in gait difficulties and scapular winging. Additional features may include dysarthria, dysphagia, low back pain, and hyporeflexia. EMG is consistent with a myopathic process, although neuropathic findings have also been shown. Muscle biopsy shows fiber type variation, internal nuclei, rimmed vacuoles, and cytoplasmic protein aggregates or inclusions. Serum creatine kinase is usually elevated. Cognitive impairment or frontotemporal dementia occurs in some patients. The disorder is slowly progressive; some patients become wheelchair-bound after many years. Rare patients with this mutation develop ALS; some have both myopathy and ALS. Brain imaging shows white matter abnormalities using diffusion tensor imaging. The disorder is classified as multisystem proteinopathy-6 (MSP6) due to the characteristic disease mechanism of protein misfolding and abnormal tissue deposition (summary by Leoni et al., 2021).

Demyelinating Charcot-Marie-Tooth disease type 1I (CMT1I) is a neurologic disorder characterized predominantly by delayed motor development in the first years of life associated with gait abnormalities, sensory ataxia, hyporeflexia, and distal sensory impairment due to a sensorimotor peripheral neuropathy that mainly affects the lower limbs. The disorder is progressive, and some may have upper limb involvement. A subset of patients has central nervous system involvement that manifests as global developmental delay with impaired intellectual development and speech difficulties. Other features may include spasticity, hyperreflexia, tremor, dysmetria, seizures, or cerebellar findings. Brain imaging may be normal or show nonspecific abnormalities, such as white matter signal changes and delayed myelination (summary by Djordjevic et al., 2021). For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

Cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism (CDIDHH) is characterized by delayed motor development, ataxia, severe progressive scoliosis, moderate to severe intellectual disability, and delayed sexual development. Cerebellar hypoplasia has been observed in some patients (Whittaker et al., 2021).

Developmental and epileptic encephalopathy-100 (DEE100) is a severe neurologic disorder characterized by global developmental delay and onset of variable types of seizures in the first months or years of life. Most patients have refractory seizures and show developmental regression after seizure onset. Affected individuals have ataxic gait or inability to walk and severe to profoundly impaired intellectual development, often with absent speech. Additional more variable features may include axial hypotonia, hyperkinetic movements, dysmorphic facial features, and brain imaging abnormalities (summary by Schneider et al., 2021). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Pontocerebellar hypoplasia type 17 (PCH17) is a severe autosomal recessive developmental disorder characterized by neonatal hypotonia, severe feeding difficulties, and respiratory insufficiency. Brain imaging shows cerebellar and brainstem hypoplasia. Most affected individuals die in infancy. Those who survive show variable developmental delay. Other features of the disorder include distal hypertonia, poor overall growth, visual defects, autonomic problems, dysmorphic features, and seizures (Coolen et al., 2022). For a phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).

Craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome-1 (CFSMR1) is characterized by cranial involvement with macrocrania at birth, brachycephaly, anomalies of middle fossa structures including hypoplasia of corpus callosum, enlargement of septum pellucidum, and dilated lateral ventricles, as well as cortical atrophy and hypodensity of the gray matter. Facial dysmorphisms include flat face, hypertelorism, epicanthal folds, synophrys, broad nasal bridge, cleft lip and cleft palate, and low-set posteriorly rotated ears. Patients also exhibit short neck and multiple costal and vertebral anomalies. The face is rather characteristic, and various authors have consistently reported affable/friendly personality, despite intellectual delay (summary by Alanay et al., 2014). Genetic Heterogeneity of Craniofacial Dysmorphism, Skeletal Anomalies, and Impaired Intellectual Development Syndrome CFSMR2 (616994) is caused by mutation in the RAB5IF gene (619960) on chromosome 20q11.

Intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects (IDDMDS) is an autosomal recessive disorder characterized by global developmental delay apparent in infancy manifest as speech delay and late walking by a few years. Affected individuals have hypertonia or, more rarely, hypotonia; a notable common feature is facial myokymia with corresponding EMG findings. Additional features include distal skeletal defects such as joint contractures, hypo- or areflexia, and hernia (Marafi et al., 2022).

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).

Developmental and epileptic encephalopathy-109 (DEE109) is characterized by the onset of various types of seizures in the first months or years of life. Affected individuals show developmental delay before and concurrent with the onset of seizures. Features include impaired intellectual development with poor speech, ataxic gait, coordination problems, and behavioral abnormalities (Manivannan et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Juvenile amyotrophic lateral sclerosis-27 (ALS27) is an autosomal dominant disorder characterized by early childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities, followed by progressive lower motor neuron-mediated weakness without sensory signs or symptoms (Mohassel et al., 2021). For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

Autosomal recessive limb-girdle muscular dystrophy-28 (LGMDR28) is characterized by progressive muscle weakness affecting the proximal and axial muscles of the upper and lower limbs. The age at onset is highly variable, usually in the first decade, although onset in the fourth decade has also been reported. The disorder can be rapidly progressive or show a slower course. Most patients have limited ambulation or become wheelchair-bound within a few decades, and respiratory insufficiency commonly occurs. Laboratory studies show increased serum creatine kinase and elevated fasting blood glucose levels, although cholesterol is normal. EMG shows a myopathic pattern; muscle biopsy is generally unremarkable, but can show nonspecific myopathic or dystrophic features (Yogev et al., 2023; Morales-Rosado et al., 2023). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

Neurodevelopmental disorder with impaired language, behavioral abnormalities, and dysmorphic facies (NEDLBF) is characterized by global developmental delay, speech delay, variably impaired intellectual development, behavioral abnormalities, and dysmorphic facial features. The phenotype and severity of the disorder is heterogeneous, ranging from borderline to severe. Brain imaging is usually normal. More variable additional features include early feeding difficulties, failure to thrive, short stature, mild visual impairment, hypotonia, seizures (particularly febrile), and distal skeletal defects of the hands and feet (Jia et al., 2022).

Autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10) is a slowly progressive disorder characterized by distal muscle weakness and atrophy predominantly affecting the lower limbs and resulting in gait abnormalities; upper limb involvement often occurs. Most individuals have juvenile or adult onset, but some may show earlier onset in infancy or childhood. Although most affected individuals have a pure distal motor neuropathy, some may also have signs of upper motor neuron disease, including pyramidal signs and hyperreflexia, and some may show mild sensory involvement or mild respiratory insufficiency. Foot deformities and calf atrophy are commonly observed. Intellectual development, cognitive function, and brain imaging are typically normal. Electrophysiologic studies are consistent with an axonal motor (sometimes sensorimotor) neuropathy. In general, patients with earlier onset have a more severe disorder with faster progression (summary by El-Bazzal et al., 2019; Demaegd et al., 2022). El-Bazzal et al. (2019) and Lazo and Morejon-Garcia (2023) noted that VRK1-related motor neuron disease is clinically heterogeneous and has been described by various clinical terms, including spinal muscular atrophy, distal spinal muscular atrophy, amyotrophic lateral sclerosis (ALS), juvenile-onset ALS, hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease, and pure distal motor neuropathy. VRK1 mutations result in functional insufficiency. For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).

Alfadhel syndrome (AFDL) is an autosomal recessive neurodevelopmental disorder with features of global developmental delay, hypotonia, and facial dysmorphism (Asiri et al., 2020, Bertoli-Avella et al., 2021).

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.