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).

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).

Emery-Dreifuss muscular dystrophy (EDMD) is characterized by the clinical triad of: joint contractures that begin in early childhood; slowly progressive muscle weakness and wasting initially in a humero-peroneal distribution that later extends to the scapular and pelvic girdle muscles; and cardiac involvement that may manifest as palpitations, presyncope and syncope, poor exercise tolerance, and congestive heart failure along with variable cardiac rhythm disturbances. Age of onset, severity, and progression of muscle and cardiac involvement demonstrate both inter- and intrafamilial variability. Clinical variability ranges from early onset with severe presentation in childhood to late onset with slow progression in adulthood. In general, joint contractures appear during the first two decades, followed by muscle weakness and wasting. Cardiac involvement usually occurs after the second decade and respiratory function may be impaired in some individuals.

X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4) is a mitochondrial disorder manifest as progressive neurologic dysfunction with highly variable features. The age at onset ranges from infancy to young adulthood, and patients can present with different features, including hearing loss, delayed motor development, or difficulty walking due to peripheral neuropathy and/or cerebellar ataxia. Most patients develop all features, including a progressive sensorimotor axonal neuropathy and deafness due to auditory neuropathy. Additional more variable features can include cognitive impairment, cerebellar atrophy on brain imaging, cerebellar signs, such as dysarthria, abnormal extraocular movements, tremor, and dysmetria, as well as spasticity. There is significant intrafamilial variability: the variable features are consistent with mitochondrial dysfunction. Prolonged treatment with riboflavin may result in some mild improvement in the ataxia (summary by Rinaldi et al., 2012, Heimer et al., 2018, Bogdanova-Mihaylova et al., 2019).

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.

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

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.

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.

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.

Autosomal recessive distal hereditary motor neuronopathy-3 (HMNR3), also known as distal spinal muscular atrophy (DSMA) and distal hereditary motor neuronopathy (dHMN or HMN), is characterized by distal muscle weakness and wasting without significant sensory involvement. For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320). Harding (1993) classified autosomal recessive distal hereditary motor neuronopathy as dHMN IV (HMN4) and dHMN III (HMN3). Both have juvenile onset and differ only by less severe involvement in HMN3. However, Viollet et al. (2004) reported an extended Lebanese kindred in which both HMN III and HMN IV occurred, suggesting that the same gene was involved in both phenotypes (see Irobi et al., 2006).

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.

GNE myopathy is a slowly progressive muscle disease that typically presents between age 20 and 40 years with bilateral foot drop caused by anterior tibialis weakness. Lower-extremity muscle involvement progresses from the anterior to the posterior compartment of the lower leg, followed by hamstrings, then hip girdle muscles, with relative sparing of the quadriceps. A wheelchair may be needed about ten to 20 years after the onset of manifestations. The upper extremities, which may be affected within five to ten years of disease onset, do not necessarily follow a distal-to-proximal progression. In advanced stages, neck and core muscles can become affected.

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).

Autosomal recessive limb-girdle muscular dystrophy-7 (LGMDR7), also known as LGMDR7, is a skeletal muscle disorder with age of onset in the first or second decade of life. Weakness of proximal and some distal muscles progresses to inability to walk by the third or fourth decade, although some individuals retain the ability to walk without support later. Heart involvement may be present. Creatine kinase levels are increased as much as 30-fold (summary by Moreira et al., 2000). For a general description and a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

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

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).

The spectrum of ANO5 muscle disease is a continuum that ranges from asymptomatic hyperCKemia and exercise-induced myalgia to proximal and/or distal muscle weakness. The most typical presentation is limb-girdle muscular dystrophy type 2L (LGMD2L) with late-onset proximal lower-limb weakness in the fourth or fifth decade (range 15-70 years). Less common is Miyoshi-like disease (Miyoshi muscular dystrophy 3) with early-adult-onset calf distal myopathy (around age 20 years). Incidental hyperCKemia may be present even earlier. Initial symptoms are walking difficulties, reduced sports performance, and difficulties in standing on toes as well as nonspecific exercise myalgia and/or burning sensation in the calf muscles. Muscle weakness and atrophy are frequently asymmetric. Cardiac findings can include cardiomyopathy and arrhythmias and/or left ventricular dysfunction. Bulbar or respiratory symptoms have not been reported. Females have milder disease manifestations than males. Disease progression is slow in both the LGMD and distal forms; ambulation is preserved until very late in the disease course. Life span is normal.

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

Hereditary sensory and autonomic neuropathy type IC (HSAN1C) is an autosomal dominant neurologic disorder characterized by sensory neuropathy with variable autonomic and motor involvement. Most patients have adult onset of slowly progressive distal sensory impairment manifest as numbness, tingling, or pain, as well as distal muscle atrophy. Complications include ulceration and osteomyelitis. Some patients may have a more severe phenotype with onset in childhood. Electrophysiologic studies show a predominantly axonal neuropathy with some demyelinating features. Some patients may have evidence of central nervous system involvement, including macular telangiectasia type 2 and/or pyramidal signs. Affected individuals have increased levels of plasma 1-deoxysphingolipids (1-deoxySLs), which are thought to be neurotoxic. (summary by Rotthier et al., 2010, Gantner et al., 2019, and Triplett et al., 2019). Oral supplementation with serine decreases 1-deoxySL and may offer some clinical benefits (Fridman et al., 2019). For a discussion of genetic heterogeneity of HSAN, see HSAN1A (162400).

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.

Spastic paraplegia-54 (SPG54) is a complicated form of spastic paraplegia, a neurodegenerative disorder affecting fibers of the corticospinal tract. Affected individuals have delayed psychomotor development, intellectual disability, and early-onset spasticity of the lower limbs. Brain MRI shows a thin corpus callosum and periventricular white matter lesions. Brain magnetic resonance spectroscopy shows an abnormal lipid peak (summary by Schuurs-Hoeijmakers et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.

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.

A subtype of Charcot-Marie-Tooth type 4 with characteristics of childhood onset of slowly progressing, demyelinating sensorimotor neuropathy, focally folded myelin sheaths in nerve biopsy, reduced nerve conduction velocities and the typical Charcot-Marie-Tooth phenotype (i.e. distal muscle weakness and atrophy, and sensory loss). There is evidence this disease is caused by homozygous or compound heterozygous mutation in the SBF1 gene on chromosome 22q.

Amyotrophic lateral sclerosis-21 (ALS21) is an autosomal dominant neurodegenerative disorder affecting upper and lower motor neurons, resulting in muscle weakness and respiratory failure. Some patients may develop myopathic features or dementia (summary by Johnson et al., 2014). For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

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).

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).

Centronuclear myopathy-1 (CNM1) is an autosomal dominant congenital myopathy characterized by slowly progressive muscular weakness and wasting. The disorder involves mainly limb girdle, trunk, and neck muscles but may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life, and some affected individuals become wheelchair-bound in their fifties. Ptosis and limitation of eye movements occur frequently. The most prominent histopathologic features include high frequency of centrally located nuclei in a large number of extrafusal muscle fibers (which is the basis of the name of the disorder), radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers (summary by Bitoun et al., 2005). Genetic Heterogeneity of Centronuclear Myopathy Centronuclear myopathy is a genetically heterogeneous disorder. See also X-linked CNM (CNMX; 310400), caused by mutation in the MTM1 gene (300415) on chromosome Xq28; CNM2 (255200), caused by mutation in the BIN1 gene (601248) on chromosome 2q14; CNM4 (614807), caused by mutation in the CCDC78 gene (614666) on chromosome 16p13; CNM5 (615959), caused by mutation in the SPEG gene (615950) on chromosome 2q35; and CNM6 (617760), caused by mutation in the ZAK gene (609479) on chromosome 2q31. The mutation in the MYF6 gene that was reported to cause a form of CNM, formerly designated CNM3, has been reclassified as a variant of unknown significance; see 159991.0001. Some patients with mutation in the RYR1 gene (180901) have findings of centronuclear myopathy on skeletal muscle biopsy (see 255320).

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.

SMALED2A is an autosomal dominant form of spinal muscular atrophy characterized by early childhood onset of muscle weakness and atrophy predominantly affecting the proximal and distal muscles of the lower extremity, although some patients may show upper extremity involvement. The disorder results in delayed walking, waddling gait, difficulty walking, and loss of distal reflexes. Some patients may have foot deformities or hyperlordosis, and some show mild upper motor signs, such as spasticity. Sensation, bulbar function, and cognitive function are preserved. The disorder shows very slow progression throughout life (summary by Oates et al., 2013). For discussion of genetic heterogeneity of lower extremity-predominant spinal muscular atrophy, see SMALED1 (158600).

Charcot-Marie-Tooth disease type 1G is an autosomal dominant progressive peripheral sensorimotor neuropathy characterized by distal muscle weakness and atrophy with onset in the first or second decade. Affected individuals have difficulty walking, distal sensory impairment with decreased or absent reflexes, and often have foot deformities. Median motor nerve conduction velocities (NCV) are decreased (less than 38 m/s) and sural nerve biopsy shows myelin defects and onion bulb formation (summary by Hong et al., 2016 and Motley et al., 2016). For a phenotypic description and a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

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 distal hereditary motor neuronopathy-8 (HMNR8), or sorbitol dehydrogenase deficiency with peripheral neuropathy (SORDD), is characterized by onset of distal muscle weakness mainly affecting the lower limbs and resulting in difficulty walking. Onset of symptoms is usually in the first or second decades of life, although later adult onset has been reported; the disorder is slowly progressive. Nerve conduction velocities are most consistent with an axonal process. More variable features include distal sensory impairment, upper limb tremor, and scoliosis. Laboratory studies show increased serum sorbitol (summary by Cortese et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).

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).

Autosomal dominant distal hereditary motor neuronopathy-13 (HMND13) is a neurologic disorder characterized by distal muscle weakness and atrophy affecting both the upper and lower limbs, resulting in difficulty walking and poor fine hand motor skills. Some patients show spasticity and hyperreflexia, mainly of the lower limbs: these features overlap with those observed in Silver syndrome, an allelic disorder. In addition, some patients with BSCL2 mutations show features of Charcot-Marie-Tooth type 2 (CMT2) with distal sensory impairment. HMND13, Silver syndrome (SPG17), and features of axonal sensorimotor peripheral neuropathy (CMT2) thus represent a phenotypic spectrum associated with heterozygous mutations in the BSCL2 gene. Individuals with the same mutation may manifest features consistent with any of those disorders; variability is even observed within the same family (summary by Van de Warrenburg et al., 2006; Luigetti et al., 2010; Choi et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of distal HMN, see HMND1 (182960).

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).

Autosomal recessive limb-girdle muscular dystrophy-27 (LGMDR27) is characterized by progressive muscle weakness primarily affecting the lower limbs and resulting in walking difficulty or loss of ambulation. The age at onset is highly variable, from infancy to young adulthood. Patients with infantile onset may have a more severe disease course with rapid progression. Upper limb involvement and distal muscle weakness may also occur. Additional more variable features include neck muscle weakness, scoliosis, and joint contractures. Less common features include impaired intellectual development or speech delay, cardiomyopathy, and cardiac arrhythmia. Muscle biopsy shows nonspecific dystrophic changes (Coppens et al., 2021). For a discussion of genetic heterogeneity of autosomal recessive limb-girdle muscular dystrophy, see LGMDR1 (253600).

Distal myopathy-5 (MPD5) is an autosomal recessive, slowly progressive muscle disorder characterized by adolescent onset of distal muscle weakness and atrophy predominantly affecting the lower limbs. Other features include facial weakness and hyporeflexia. Patients remain ambulatory even after long disease duration (summary by Park et al., 2016).

Charcot-Marie-Tooth disease type 2X (CMT2X) is an autosomal recessive, slowly progressive, axonal peripheral sensorimotor neuropathy characterized by lower limb muscle weakness and atrophy associated with distal sensory impairment and gait difficulties. Some patients also have involvement of the upper limbs. Onset usually occurs in the first 2 decades of life, although later onset can also occur (summary by Montecchiani et al., 2016) For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

Charcot-Marie-Tooth disease type 2Y is an autosomal dominant peripheral neuropathy characterized by distal muscle weakness and atrophy associated with length-dependent sensory loss. Most patients have involvement of both the lower and upper limbs. The age at onset and the severity of the disorder are highly variable (summary by Gonzalez et al., 2014). For a phenotypic description and a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

X-linked adult-onset distal myopathy-7 (MPD7) is an X-linked recessive disorder that affects only males. It is characterized by onset of distal muscle weakness predominantly affecting the lower limbs between 20 and 60 years of age. The disorder is slowly progressive, with most affected individuals developing distal upper limb involvement and some developing proximal muscle involvement, although patients remain ambulatory. Muscle biopsy shows variable myopathic changes as well as sarcoplasmic inclusions that may represent abnormally aggregated proteins (summary by Johari et al., 2021).

Demyelinating Charcot-Marie-Tooth disease-1H (CMT1H) is an autosomal dominant peripheral sensorimotor neuropathy with onset usually in adulthood (third to fifth decades). Affected individuals present with foot deformities, upper or lower limb sensory disturbances, and motor deficits, mainly impaired gait. Of note, many patients complain of unpleasant sensory sensations in the upper extremities and hands. The disorder is slowly progressive and becomes more apparent with age, although patients usually remain ambulatory. Other features include hypo- or areflexia, limb muscle weakness, and impaired gait. Electrophysiologic studies are consistent with a demyelinating polyneuropathy. Rare patients may have hyperelastic skin or develop age-related macular degeneration (summary by Auer-Grumbach et al., 2011 and Safka Brozkova et al., 2020) For a discussion of genetic heterogeneity of autosomal dominant Charcot-Marie-Tooth disease type 1, see CMT1B (118200).

Childhood-onset biotin-responsive peripheral motor neuropathy (COMNB) is an autosomal recessive disorder characterized predominantly by the onset of distal muscle weakness and atrophy late in the first decade of life. The disorder predominantly affects the upper limbs and hands, resulting in difficulties with fine motor skills. Some patients may have lower limb involvement, resulting in gait difficulties. Electrophysiologic studies and muscle biopsy are consistent with chronic denervation with axonal and demyelinating features. Rare patients may have additional neurologic signs, including spasticity, ataxia, and cerebellar signs. Sensation is intact, and patients have normal cognitive development. Treatment with biotin, pantothenic acid, and lipoic acid may result in clinical improvement (Holling et al., 2022).

Axonal Charcot-Marie-Tooth disease type 2II (CMT2II) is an autosomal dominant neurologic disorder characterized by a slowly progressive sensorimotor peripheral neuropathy affecting mainly the lower limbs, resulting in distal muscle weakness and atrophy and subsequent walking difficulties. Some patients may have upper limb involvement with atrophy of the intrinsic hand muscles. The age at onset is highly variable, ranging from infancy to adulthood. Electrophysiologic studies are usually consistent with an axonal process, although some may show intermediate or even demyelinating values (Park et al., 2020; Ando et al., 2022). One family with possible autosomal recessive inheritance has been reported (Bogdanova-Mihaylova et al., 2021). For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).

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

Congenital myopathy-4B (CMYO4B) is an autosomal recessive disorder of the skeletal muscle characterized by the onset of muscle weakness in infancy or early childhood. The severity and pattern of muscle weakness varies, but most affected individuals show congenital contractures, delayed motor development, hypotonia, generalized muscle weakness, and weakness of the proximal limb muscles and neck muscles, resulting in difficulty walking or inability to walk. Affected individuals have respiratory insufficiency due to muscle weakness, which may be life-threatening. Other common features include myopathic facies, chest deformities, distal joint laxity, and scoliosis. Variable histologic findings on skeletal muscle biopsy are observed, including nemaline rods, type 1 fiber predomination, and centralized nuclei (Tan et al., 1999; Lehtokari et al., 2008). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

Autosomal recessive distal hereditary motor neuronopathy-9 (HMNR9) is a slowly progressive peripheral neuropathy characterized by juvenile onset of distal muscle weakness and atrophy, resulting in gait difficulties. Most affected individuals also have upper limb involvement with weakness and atrophy of the hand muscles. Foot deformities are often present. Some patients may have mild sensory abnormalities or pyramidal signs. Electrophysiologic studies are consistent with a length-dependent axonal motor neuropathy (summary by Jacquier et al., 2023). For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).

Autosomal dominant distal hereditary motor neuronopathy-11 (HMND11) is a peripheral axonal motor neuropathy characterized by juvenile or young-adult onset of distal limb muscle weakness and atrophy mainly affecting the lower limbs, resulting in gait instability and walking difficulties. Foot deformities may also be present. The disorder is usually slowly progressive, and patients remain ambulatory until late adulthood. Some affected individuals may have distal upper limb and hand involvement or mild distal sensory abnormalities, but motor symptoms dominate the clinical picture. Electrophysiologic studies are consistent with a length-dependent axonal motor or sensorimotor neuropathy. Seizures are not present and brain imaging is normal (Beijer et al., 2019). One reported affected individual had a marfanoid habitus and mild speech delay with learning disabilities, suggesting possible expansion of the phenotypic spectrum (Ylikallio et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).

Autosomal dominant spastic paraplegia-91 with or without cerebellar ataxia (SPG91) is a highly variable neurologic disorder characterized by early-onset gait abnormalities due to spastic paraplegia of the lower limbs, sometimes with cerebellar ataxia. The age at onset is highly variable (congenital to young adult), although most patients have symptom onset in the first decade. Some patients present with a spastic paraplegia-predominant phenotype with significant pyramidal signs, whereas others present with an ataxic-predominant phenotype. In addition, although most patients have a more 'pure' phenotype restricted to gait abnormalities without additional features, others have a more 'complicated' phenotype with additional features such as sensory abnormalities, peripheral neuropathy, optic neuropathy, developmental delay, variably impaired intellectual development, and seizures. Many have normal brain imaging, but cerebellar atrophy may be observed in those with prominent cerebellar ataxia (Van de Vondel et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).