Genetic prion disease generally manifests with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Although these phenotypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset typically ranges from 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome.

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.

X-linked adrenoleukodystrophy (X-ALD) affects the nervous system white matter and the adrenal cortex. Three main phenotypes are seen in affected males: The childhood cerebral form manifests most commonly between ages four and eight years. It initially resembles attention-deficit disorder or hyperactivity; progressive impairment of cognition, behavior, vision, hearing, and motor function follow the initial symptoms and often lead to total disability within six months to two years. Most individuals have impaired adrenocortical function at the time that neurologic disturbances are first noted. Adrenomyeloneuropathy (AMN) manifests most commonly in an individual in his twenties or middle age as progressive stiffness and weakness of the legs, sphincter disturbances, sexual dysfunction, and often, impaired adrenocortical function; all symptoms are progressive over decades. "Addison disease only" presents with primary adrenocortical insufficiency between age two years and adulthood and most commonly by age 7.5 years, without evidence of neurologic abnormality; however, some degree of neurologic disability (most commonly AMN) usually develops by middle age. More than 20% of female carriers develop mild-to-moderate spastic paraparesis in middle age or later. Adrenal function is usually normal.

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

Troyer syndrome is characterized by progressive spastic paraparesis, dysarthria, pseudobulbar palsy, distal amyotrophy, short stature, and subtle skeletal abnormalities. Most affected children exhibit delays in walking and speech and difficulty in managing oral secretions, followed by increased lower-limb spasticity and slow deterioration in both gait and speech. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis. Emotional lability / difficulty in controlling emotions and affective disorders, such as inappropriate euphoria and/or crying, are frequently described. Life expectancy is normal.

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

Spinal neurofibromatosis is an autosomal dominant disorder characterized by a high load of spinal tumors. These tumors may be asymptomatic or result in neurologic symptoms, including back pain, difficulty walking, and paresthesias. Spinal NF is considered to be a subtype of neurofibromatosis type I (NF1; 162200), which is an allelic disorder. Patients with spinal NF may or may not have the classic cutaneous cafe-au-lait pigmentary macules or ocular Lisch nodules typically observed in patients with classic NF1. Patients with spinal NF should be followed closely for spinal sequelae (summary by Burkitt Wright et al., 2013).

Spastic paraplegia-29 (SPG28) is an autosomal recessive neurodegenerative disorder characterized by early-onset, slowly progressive lower-limb spasticity resulting in walking difficulties. Some patients also have distal sensory impairment (summary by Tesson et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see 270800.

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).

Alpha-B crystallin-related myofibrillar myopathy is an autosomal dominant muscular disorder characterized by adult onset of progressive muscle weakness affecting both the proximal and distal muscles and associated with respiratory insufficiency, cardiomyopathy, and cataracts. There is phenotypic variability both within and between families (Fardeau et al., 1978; Selcen and Engel, 2003). A homozygous founder mutation in the CRYAB gene has been identified in Canadian aboriginal infants of Cree origin who have a severe fatal infantile hypertonic form of myofibrillar myopathy; see 613869. For a phenotypic description and a discussion of genetic heterogeneity of myofibrillar myopathy, see MFM1 (601419).

A form of hereditary spastic paraplegia which usually presents in late adolescence or early adulthood as a pure phenotype of lower limb spasticity with hyperreflexia and extensor plantar responses, as well as mild bladder disturbances and pes cavus. Rarely, it can present as a complex phenotype with additional manifestations including epilepsy, variable peripheral neuropathy and/or memory impairment. Caused by mutations in the NIPA1 gene (15q11.2) encoding the magnesium transporter NIPA1.

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.

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 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.

The spectrum of DCTN1-related neurodegeneration includes Perry syndrome, distal hereditary motor neuronopathy type 7B (dHMN7B), frontotemporal dementia (FTD), motor neuron disease / amyotrophic lateral sclerosis (ALS), and progressive supranuclear palsy. Some individuals present with overlapping phenotypes (e.g., FTD-ALS, Perry syndrome-dHMN7B). Perry syndrome (the most common of the phenotypes associated with DCTN1) is characterized by parkinsonism, neuropsychiatric symptoms, hypoventilation, and weight loss. The mean age of onset in those with Perry syndrome is 49 years (range: 35-70 years), and the mean disease duration is five years (range: 2-14 years). In most affected persons, the reported cause/circumstance of death relates to sudden death/hypoventilation or suicide.

Phosphorylase kinase (PhK) deficiency causing glycogen storage disease type IX (GSD IX) results from deficiency of the enzyme phosphorylase b kinase, which has a major regulatory role in the breakdown of glycogen. The two types of PhK deficiency are liver PhK deficiency (characterized by early childhood onset of hepatomegaly and growth restriction, and often, but not always, fasting ketosis and hypoglycemia) and muscle PhK deficiency, which is considerably rarer (characterized by any of the following: exercise intolerance, myalgia, muscle cramps, myoglobinuria, and progressive muscle weakness). While symptoms and biochemical abnormalities of liver PhK deficiency were thought to improve with age, it is becoming evident that affected individuals need to be monitored for long-term complications such as liver fibrosis and cirrhosis.

Spastic paraplegias (SPGs) are a genetically heterogeneous group of neurologic disorders characterized by progressive weakness and spasticity of the legs. Complicated SPGs are accompanied by additional neurologic symptoms such as cerebellar ataxia, sensory loss, mental retardation, nystagmus, and optic atrophy (summary by Steinmuller et al., 1997). A locus for spastic paraplegia-16 has been mapped to Xq11.2-q23 (Steinmuller et al., 1997). For a discussion of genetic heterogeneity of X-linked spastic paraplegia, see 303350.

VPS13D movement disorder is a hyperkinetic movement disorder (dystonia, chorea, and/or ataxia) of variable age of onset that can be associated with developmental delay. Onset ranges from birth to adulthood. Individuals can present in childhood with motor delays and gait instability. Cognitive impairment ranging from mild intellectual disability to developmental delay has been reported, and several individuals have normal cognitive function. Individuals have also presented as young adults with gait difficulties caused by spastic ataxia or ataxia. In addition to gait ataxia, affected individuals had limb ataxia, dysarthria, and eye movement abnormalities (macro-saccadic oscillations, nystagmus, and saccadic pursuit). Additional features reported in some individuals include peripheral neuropathy and/or seizures. The disorder progresses to spastic ataxia or generalized dystonia, which can lead to loss of independent ambulation.

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

A pure form of hereditary spastic paraplegia with characteristics of a slowly progressive and relatively benign spastic paraplegia presenting in adulthood with spastic gait, lower limb hyperreflexia, extensor plantar responses, bladder dysfunction (urinary urgency and/or incontinence), and mild sensory and motor peripheral neuropathy.

Amyotrophic lateral sclerosis-3 (ALS3) is a neurodegenerative disorder characterized by the death of motor neurons in the cortex, brainstem, and spinal cord, resulting in progressive muscle weakness and atrophy and death from respiratory failure, usually within 3 to 5 years of symptom onset (Brown, 1995). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

Spastic paraplegia-5A (SPG5A) is an autosomal recessive neurologic disorder with a wide phenotypic spectrum. Some patients have pure spastic paraplegia affecting only gait, whereas others may have a complicated phenotype with additional manifestations, including optic atrophy or cerebellar ataxia (summary by Arnoldi et al., 2012). The hereditary spastic paraplegias (SPG) are a group of clinically and genetically diverse disorders characterized by progressive, usually severe, lower extremity spasticity; see reviews of Fink et al. (1996) and Fink (1997). Inheritance is most often autosomal dominant (see 182600), but X-linked (see 303350) and autosomal recessive forms also occur. Genetic Heterogeneity of Autosomal Recessive Spastic Paraplegia Autosomal recessive forms of SPG include SPG7 (607259), caused by mutation in the paraplegin gene (602783) on chromosome 16q24; SPG9B (616586), caused by mutation in the ALDH18A1 gene (138250) on 10q24; SPG11 (604360), caused by mutation in the spatacsin gene (610844) on 15q21; SPG15 (270700), caused by mutation in the ZFYVE26 gene (612012) on 14q24; SPG18 (611225), caused by mutation in the ERLIN2 gene (611605) on 8p11; SPG20 (275900), caused by mutation in the spartin gene (607111) on 13q12; SPG21 (248900), caused by mutation in the maspardin gene (608181) on 15q21; SPG26 (609195), caused by mutation in the B4GALNT1 gene (601873) on 12q13; SPG28 (609340), caused by mutation in the DDHD1 gene (614603) on 14q22; SPG30 (610357), caused by mutation in the KIF1A gene (601255) on 2q37; SPG35 (612319), caused by mutation in the FA2H gene (611026) on 16q23; SPG39 (612020), caused by mutation in the PNPLA6 gene (603197) on 19p13; SPG43 (615043), caused by mutation in the C19ORF12 gene (614297) on 19q12; SPG44 (613206), caused by mutation in the GJC2 gene (608803) on 1q42; SPG45 (613162), caused by mutation in the NT5C2 gene (600417) on 10q24; SPG46 (614409), caused by mutation in the GBA2 gene (609471) on 9p13; SPG48 (613647), caused by mutation in the KIAA0415 gene (613653) on 7p22; SPG50 (612936), caused by mutation in the AP4M1 gene (602296) on 7q22; SPG51 (613744), caused by mutation in the AP4E1 gene (607244) on 15q21; SPG52 (614067), caused by mutation in the AP4S1 gene (607243) on 14q12; SPG53 (614898), caused by mutation in the VPS37A gene (609927) on 8p22; SPG54 (615033), caused by mutation in the DDHD2 gene (615003) on 8p11; SPG55 (615035), caused by mutation in the MTRFR gene on 12q24; SPG56 (615030), caused by mutation in the CYP2U1 gene (610670) on 4q25; SPG57 (615658), caused by mutation in the TFG gene (602498) on 3q12; SPG61 (615685), caused by mutation in the ARL6IP1 gene (607669) on 1p12; SPG62 (615681), caused by mutation in the ERLIN1 gene on 10q24; SPG63 (615686), caused by mutation in the AMPD2 gene (102771) on 1p13; SPG64 (615683), caused by mutation in the ENTPD1 gene (601752) on 10q24; SPG72 (615625), caused by mutation in the REEP2 gene (609347) on 5q31; SPG74 (616451), caused by mutation in the IBA57 gene (615316) on 1q42; SPG75 (616680), caused by mutation in the MAG gene (159460) on 19q13; SPG76 (616907), caused by mutation in the CAPN1 gene (114220) on 11q13; SPG77 (617046), caused by mutation in the FARS2 gene (611592) on 6p25; SPG78 (617225), caused by mutation in the ATP13A2 gene (610513) on 1p36; SPG79 (615491), caused by mutation in the UCHL1 gene (191342) on 4p13; SPG81 (618768), caused by mutation in the SELENOI gene (607915) on 2p23; SPG82 (618770), caused by mutation in the PCYT2 gene (602679) on 17q25; SPG83 (619027), caused by mutation in the HPDL gene (618994) on 1p34; SPG84 (619621), caused by mutation in the PI4KA gene (600286) on 22q11; SPG85 (619686), caused by mutation in the RNF170 gene (614649) on 8p11; SPG86 (619735), caused by mutation in the ABHD16A gene (142620) on 6p21; SPG87 (619966), caused by mutation in the TMEM63C gene (619953) on 14q24; SPG89 (620379), caused by mutation in the AMFR gene (603243) on 16q13; SPG90B (620417), caused by mutation in the SPTSSA gene (613540) on 14q13; SPG92 (620911), caused by mutation in the FICD gene (620875) on chromosome 12q23; and SPG93 (620938), caused by mutation in the NFU1 gene (608100) on chromosome 2p13. Additional autosomal recessive forms of SPG have been mapped to chromosomes 3q (SPG14; 605229), 13q14 (SPG24; 607584), 6q (SPG25; 608220), and 10q22 (SPG27; 609041). A disorder that was formerly designated SPG49 has been reclassified as hereditary sensory and autonomic neuropathy-9 with developmental delay (HSAN9; 615031).

Spastic paraplegia 15 (SPG15), typically an early-onset complex hereditary spastic paraplegia, is characterized by progressive spasticity that begins in the lower extremities and is associated with several manifestations resulting from central and peripheral nervous system dysfunction. While onset of spasticity is typically in mid- to late childhood or adolescence (i.e., between ages 5 and 18 years), other manifestations, such as developmental delay or learning disability, may be present earlier, often preceding motor involvement. Individuals with adult onset have also been reported.

Nemaline myopathy-7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (summary by Ockeloen et al., 2012). For a discussion of genetic heterogeneity of nemaline myopathy, see 161800.

Spastic paraplegia-31 (SPG31) is an autosomal dominant neurologic disorder characterized primarily by spasticity of the lower limbs, resulting in gait abnormalities and muscle weakness. There is a bimodal age at onset with a peak in the second and fourth decades of life. Most affected individuals have a 'pure' form of the disorder with gait difficulties and hyperreflexia of the lower limbs. However, there is phenotypic heterogeneity, and some patients have a 'complex' form of the disorder with additional signs and symptoms, such as peripheral neuropathy, cerebellar ataxia, postural tremor, or urinary symptoms. The disorder is slowly progressive, and there is intrafamilial variability and incomplete penetrance (summary by Goizet et al., 2011 and Toft et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Any hereditary spastic paraplegia in which the cause of the disease is a mutation in the ZFYVE27 gene.

A rare hereditary spastic paraplegia with characteristics of progressive spastic paraplegia with pyramidal signs in the lower limbs, decreased vibration sense, and increased reflexes in the upper limbs. Caused by heterozygous mutation in the HSPD1 on chromosome 2q33.

A rare complex hereditary spastic paraplegia with characteristics of adulthood onset of slowly progressive spastic paraplegia of lower limbs presenting with spastic gait, hyperreflexia and mild lower limb hypertonicity associated with mild intellectual disability, visual agnosia, short and long-term memory deficiency and mild distal motor neuropathy. Bilateral pes cavus and extensor plantar responses are also associated.

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

Spastic paraplegia-12 (SPG12) is an autosomal dominant neurodegenerative disorder characterized by lower limb spasticity and hyperreflexia, resulting in walking difficulties. Some patients may have urinary symptoms and distal sensory impairment. Age at onset ranges from childhood to adulthood (summary by Montenegro et al., 2012). For a general description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Spastic paraplegia 11 (SPG11) is characterized by progressive spasticity and weakness of the lower limbs frequently associated with the following: mild intellectual disability with learning difficulties in childhood and/or progressive cognitive decline; peripheral neuropathy; pseudobulbar involvement; and increased reflexes in the upper limbs. Less frequent findings include: cerebellar signs (ataxia, nystagmus, saccadic pursuit); retinal degeneration; pes cavus; scoliosis; and parkinsonism with characteristic brain MRI features that include thinning of the corpus callosum. Onset occurs mainly during infancy or adolescence (range: age 1-31 years) and in rare cases as late as age 60 years. Most affected individuals become wheelchair bound one or two decades after disease onset.

Spastic paraplegia-10 (SPG10) is an autosomal dominant neurologic disorder with variable manifestations. Some patients have onset of a 'pure' spastic paraplegia, with lower limb spasticity, hyperreflexia, extensor plantar responses, and variable involvement of the upper limbs beginning in childhood or young adulthood. Some patients show distal sensory impairment, which can be part of the 'pure' phenotype. However, some patients also show an axonal sensorimotor peripheral neuropathy with distal sensory impairment and distal muscle atrophy reminiscent of Charcot-Marie-Tooth disease type 2 (see, e.g., CMT2A, 118210). Rarely, patients with KIF5A mutations may have additional neurologic features, including parkinsonism or cognitive decline, consistent with a 'complicated' phenotype. Spastic paraplegia and peripheral neuropathy in isolation may represent extreme ends of the phenotypic spectrum of KIF5A mutations (summary by Goizet et al., 2009 and Crimella et al., 2012). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Spinocerebellar ataxia-29 (SCA29) is an autosomal dominant neurologic disorder characterized by onset in infancy of delayed motor development and mild cognitive delay. Affected individuals develop a very slowly progressive or nonprogressive gait and limb ataxia associated with cerebellar atrophy on brain imaging. Additional variable features include nystagmus, dysarthria, and tremor (summary by Huang et al., 2012). For a general discussion of autosomal dominant spinocerebellar ataxia, see SCA1 (164400).

Hereditary spastic paraplegia 8 (SPG8) is a slowly progressive pure spastic paraplegia of the lower limbs (i.e., pyramidal signs including hyperreflexia, spasticity, and occasionally clonus without other neurologic findings). Some affected individuals have urinary urgency that usually becomes apparent at the same time as the spasticity. Onset is between ages ten and 59 years. Affected individuals often become wheelchair dependent. While intra- and interfamilial phenotypic variability is high, SPG8 is typically more severe than other types of hereditary spastic paraplegia.

Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life, followed by slowly progressive neurologic impairment manifest as ataxia, spasticity (brisk tendon reflexes and bilateral extensor plantar responses), and mild-to-moderate cognitive impairment. Dysarthria and truncal hypotonia are observed. Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur. Cataracts may be absent in some individuals.

Spastic paraplegia 4 (SPG4; also known as SPAST-HSP) is characterized by insidiously progressive bilateral lower-limb gait spasticity. More than 50% of affected individuals have some weakness in the legs and impaired vibration sense at the ankles. Sphincter disturbances are very common. Onset is insidious, mostly in young adulthood, although symptoms may start as early as age one year and as late as age 76 years. Intrafamilial variation is considerable.

Calpainopathy is characterized by symmetric and progressive weakness of proximal limb-girdle muscles. The age at onset of muscle weakness ranges from two to 40 years. The phenotype shows intra- and interfamilial variability ranging from severe to mild. Three autosomal recessive calpainopathy phenotypes have been identified based on the distribution of muscle weakness and age at onset: Pelvifemoral limb-girdle muscular dystrophy (LGMD) (Leyden-Möbius LGMD) phenotype, the most frequently observed calpainopathy phenotype, in which muscle weakness is first evident in the pelvic girdle and later in the shoulder girdle, with onset that may occur as early as before age 12 years or as late as after age 30 years. Scapulohumeral LGMD (Erb LGMD) phenotype, usually a milder phenotype with infrequent early onset, in which muscle weakness is first evident in the shoulder girdle and later in the pelvic girdle. HyperCKemia, usually observed in children or young individuals, in which individuals are asymptomatic and have high serum creatine kinase (CK) concentrations. The autosomal dominant form of calpainopathy shows a variability of clinical phenotype, ranging from almost asymptomatic to wheelchair dependence after age 60 years in few cases with a generally milder phenotype than the recessive form. Clinical findings of calpainopathy include the tendency to walk on tiptoe, difficulty in running, scapular winging, waddling gait, and slight hyperlordosis. Other findings include symmetric weakness of proximal more than distal muscles in the limbs, trunk, and periscapular area; laxity of the abdominal muscles; Achilles tendon shortening; scoliosis; and joint contractures. Affected individuals typically do not have cardiac involvement or intellectual disability.

A rare complex type of hereditary spastic paraplegia with characteristics of slowly progressive spastic paraplegia (with walking difficulties appearing at onset at 6-7 years of age) associated with mild intellectual disability. Brain imaging reveals thin corpus callosum, cortical and cerebellar atrophy, and pontine dysraphia. The SPG32 phenotype has been mapped to a locus on chromosome 14q12-q21.

A complex hereditary spastic paraplegia with characteristics of mild to severe lower limbs spasticity, hyperreflexia, extensor plantar responses, pes cavus and significant wasting and weakness of the small hand muscles. Impaired vibration sensation, temporal lobe epilepsy and cognitive dysfunction were also reported.

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-18B (SPG18B) is a severe autosomal recessive neurologic disorder characterized by onset in early childhood of progressive spastic paraplegia resulting in motor disability. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures (summary by Alazami et al., 2011 and Yildirim et al., 2011).

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.

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.

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).

Autosomal recessive spastic paraplegia-46 (SPG46) is a neurodegenerative disorder characterized by onset in childhood of slowly progressive spastic paraplegia and cerebellar signs. Some patients have cognitive impairment, cataracts, and cerebral, cerebellar, and corpus callosum atrophy on brain imaging (summary by Boukhris et al., 2010 and Martin et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) (summary by Engel et al., 2003; Engel et al., 2015). Approximately 10% of CMS cases are presynaptic, 15% are synaptic, and 75% are postsynaptic, the majority of which are caused by AChR deficiency (Engel et al., 2003). Slow-channel congenital myasthenic syndrome (SCCMS) is a disorder of the postsynaptic NMJ characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically prolonged opening and activity of the channel, which causes prolonged synaptic currents resulting in a depolarization block. This is associated with calcium overload, which may contribute to subsequent degeneration of the endplate and postsynaptic membrane. Treatment with quinine, quinidine, or fluoxetine may be helpful; acetylcholinesterase inhibitors and amifampridine should be avoided (summary by Engel et al., 2015). Genetic Heterogeneity of Congenital Myasthenic Syndromes Recessive mutations in subunits of the acetylcholine receptor are the most common cause of CMS (Harper, 2004). CMS1A and CMS1B (608930) are caused by mutation in the CHRNA1 gene (100690); CMS2A (616313) and CMS2C (616314) are caused by mutation in the CHRNB1 gene (100710) on 17p12; CMS3A (616321), CMS3B (616322), and CMS3C (616323) are caused by mutation in the CHRND gene (100720) on 2q33; and CMS4A (605809), CMS4B (616324), and CMS4C (608931) are caused by mutation in the CHRNE gene (100725) on 17p13. CMS5 (603034) is caused by mutation in the COLQ gene (603033) on 3p25; CMS6 (254210) is caused by mutation in the CHAT gene (118490) on 10q; CMS7 (616040) is caused by mutation in the SYT2 gene (600104) on 1q32; CMS8 (615120) is caused by mutation in the AGRN gene (103320) on 1p; CMS9 (616325) is caused by mutation in the MUSK gene (601296) on 9q31; CMS10 (254300) is caused by mutation in the DOK7 gene (610285) on 4p; CMS11 (616326) is caused by mutation in the RAPSN gene (601592) on 11p11; CMS12 (610542) is caused by mutation in the GFPT1 gene (138292) on 2p14; CMS13 (614750) is caused by mutation in the DPAGT1 gene (191350) on 11q23; CMS14 (616228) is caused by mutation in the ALG2 gene (607905) on 9q22; CMS15 (616227) is caused by mutation in the ALG14 gene (612866) on 1p21; CMS16 (614198) is caused by mutation in the SCN4A gene (603967) on 17q; CMS17 (616304) is caused by mutation in the LRP4 gene (604270) on 11p12; CMS18 (616330) is caused by mutation in the SNAP25 gene (600322) on 20p11; CMS19 (616720) is caused by mutation in the COL13A1 gene (120350) on 10q22; CMS20 (617143) is caused by mutation in the SLC5A7 gene (608761) on 2q12; CMS21 (617239) is caused by mutation in the SLC18A3 gene (600336) on 10q11; CMS22 (616224) is caused by mutation in the PREPL gene (609557) on 2p21; CMS23 (618197) is caused by mutation in the SLC25A1 gene (190315) on 22q11; CMS24 (618198) is caused by mutation in the MYO9A gene (604875) on 15q22; and CMS25 (618323) is caused by mutation in the VAMP1 gene (185880) on 12p13.

The spectrum of BSCL2-related neurologic disorders includes Silver syndrome and variants of Charcot-Marie-Tooth neuropathy type 2, distal hereditary motor neuropathy (dHMN) type V, and spastic paraplegia 17. Features of these disorders include onset of symptoms ranging from the first to the seventh decade, slow disease progression, upper motor neuron involvement (gait disturbance with pyramidal signs ranging from mild to severe spasticity with hyperreflexia in the lower limbs and variable extensor plantar responses), lower motor neuron involvement (amyotrophy of the peroneal muscles and small muscles of the hand), and pes cavus and other foot deformities. Disease severity is variable among and within families.

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

A complex form of hereditary spastic paraplegia, with onset in childhood or adulthood of progressive spastic paraplegia (with spastic gait, spasticity, lower limb weakness, pes cavus and urinary urgency) associated with the additional manifestation of peripheral sensorimotor neuropathy. The SPG36 phenotype has been mapped to a locus on chromosome 12q23-q24.

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

Any amyotrophic lateral sclerosis in which the cause of the disease is a mutation in the SIGMAR1 gene.

Spastic ataxia-5 (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (summary by Pierson et al., 2011). For a discussion of genetic heterogeneity of spastic ataxia, see SPAX1 (108600).

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 complex type of hereditary spastic paraplegia with characteristics of childhood onset of progressive spastic paraplegia associated with optic atrophy (with reduced visual acuity and central scotoma), ophthalmoplegia, reduced upper-extremity strength and dexterity, muscular atrophy in the lower extremities and sensorimotor neuropathy. Caused by mutations in the C12ORF65 gene (12q24.31) encoding probable peptide chain release factor C12ORF65, mitochondrial.

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.

Lipodystrophies are rare disorders characterized by loss of body fat from various regions and predisposition to metabolic complications of insulin resistance and lipid abnormalities. FPLD7 is an autosomal dominant disorder with a highly variable phenotype. Additional features, including early-onset cataracts and later onset of spasticity of the lower limbs, have been noted in some patients (summary by Garg et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

A pure form of hereditary spastic paraplegia with onset in adolescence or early adulthood of slowly progressive spastic paraplegia, proximal muscle weakness of the lower extremities and small hand muscles, hyperreflexia, spastic gait and mild urinary compromise.

Autosomal dominant distal hereditary motor neuronopathy-6 (HMND6) is a neurologic disorder characterized by onset of slowly progressive distal lower limb weakness and atrophy between the second and fourth decades of life. Weakness usually begins in the calf muscles and later involves more proximal muscles. The severity is variable, and some patients have difficulty walking or running. Most also have upper limb involvement, particularly of the triceps and intrinsic hand muscles. Some patients may lose independent ambulation later in the disease course. Sensory impairment is typically not present, and cognition and bulbar function are normal (summary by Sumner et al., 2013). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant distal HMN (dHMN), see HMND1 (182960).

Familial partial lipodystrophy type 6 (FPLD6) is characterized by abnormal subcutaneous fat distribution, with variable excess accumulation of fat in the face, neck, shoulders, axillae, back, abdomen, and pubic region, and reduction in subcutaneous fat of the lower extremities. Progressive adult-onset myopathy is seen in some patients, and there is variable association with diabetes, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and hepatic steatosis (Zolotov et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of familial partial lipodystrophy (FPLD), see 151660.

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).

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).

Distal arthrogryposis with impaired proprioception and touch is an autosomal recessive neurologic disorder characterized by loss of certain mechanosensation modalities resulting in ataxia, difficulty walking, dysmetria, muscle weakness and atrophy, and progressive skeletal contractures. Patients have onset of symptoms in early childhood (summary by Chesler et al., 2016 and Delle Vedove et al., 2016).

GNB1 encephalopathy (GNB1-E) is characterized by moderate-to-severe developmental delay / intellectual disability, structural brain abnormalities, and often infantile hypotonia and seizures. Other less common findings include dystonia, reduced vision, behavior issues, growth delay, gastrointestinal (GI) problems, genitourinary (GU) abnormalities in males, and cutaneous mastocytosis.

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).

Dysferlinopathy includes a spectrum of muscle disease characterized by two major phenotypes: Miyoshi muscular dystrophy (MMD) and limb-girdle muscular dystrophy type 2B (LGMD2B); and two minor phenotypes: asymptomatic hyperCKemia and distal myopathy with anterior tibial onset (DMAT). MMD (median age of onset 19 years) is characterized by muscle weakness and atrophy, most marked in the distal parts of the legs, especially the gastrocnemius and soleus muscles. Over a period of years, the weakness and atrophy spread to the thighs and gluteal muscles. The forearms may become mildly atrophic with decrease in grip strength; the small muscles of the hands are spared. LGMD2B is characterized by early weakness and atrophy of the pelvic and shoulder girdle muscles in adolescence or young adulthood, with slow progression. Other phenotypes in this spectrum are scapuloperoneal syndrome and congenital muscular dystrophy. Asymptomatic hyperCKemia is characterized by marked elevation of serum CK concentration only. DMAT is characterized by early and predominant distal muscle weakness, particularly of the muscles of the anterior compartment of the legs.

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.

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).

A rare subtype of autosomal recessive limb-girdle muscular dystrophy disorder with characteristics of infantile to childhood-onset of slowly progressive, principally proximal shoulder and/or pelvic-girdle muscular weakness that typically presents with positive Gowers'' sign and is associated with elevated creatine kinase levels, hyporeflexia, joint and achilles tendon contractures and muscle hypertrophy usually of the thighs, calves and/or tongue. Other highly variable features include cerebellar, cardiac and ocular abnormalities.

Hereditary motor and sensory neuropathy type VIC with optic atrophy (HMSN6C) is an autosomal recessive axonal sensorimotor peripheral neuropathy characterized by progressive distal muscle weakness and atrophy primarily affecting the lower limbs. Onset of neuropathy is in the first decade, manifest by difficulty walking and running and followed by similar involvement of the upper limbs and hands. The disorder is associated with distal sensory impairment, particularly of position and vibration sense, as well as areflexia; individuals usually have pes cavus, hammertoes, and atrophy of the intrinsic hand muscles. In addition, progressive optic atrophy and visual impairment occur during adulthood. Treatment with pyridoxal 5-prime phosphate supplementation (vitamin B6) may result in amelioration of symptoms and slow progression of the disease (summary by Chelban et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of HMSN6, see HMSN6A (601152).

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)

Spastic paraplegia-30A (SPG30A) is a neurologic disorder characterized by onset of slowly progressive spastic paraplegia in the first or second decades of life. Affected individuals have unsteady spastic gait and hyperreflexia of the lower limbs. Most patients have a 'pure' form of the disorder, limited to spastic paraplegia, whereas some may have a 'complicated' form that includes mild cognitive dysfunction, learning disabilities, or behavioral abnormalities, peripheral axonal sensorimotor neuropathy, and urinary sphincter problems. The phenotypic features represent a spectrum of abnormalities of the central, peripheral, and autonomic nervous system (summary by Pennings et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

Frontotemporal dementia and/or amyotrophic lateral sclerosis-6 (FTDALS6) is an autosomal dominant neurodegenerative disorder with highly variable manifestations. Some patients present in adulthood with progressive FTD, often classified as the 'behavioral variant,' which is characterized by reduced empathy, impulsive behavior, personality changes, and reduced verbal output. Other patients present with features of amyotrophic lateral sclerosis (ALS), which is a fatal neurodegenerative disease characterized by upper and lower motor neuron dysfunction resulting in rapidly progressive paralysis and death from respiratory failure. The pathologic hallmarks of this disease include pallor of the corticospinal tract due to loss of motor neurons (in ALS). In both ALS and FTD, there are ubiquitin-positive inclusions within surviving neurons as well as deposition of pathologic TDP43 (TARDBP; 605078) or p62 (SQSTM1; 601530) aggregates. Patients with a D395G mutation (601023.0014) have been shown to develop pathologic tau (MAPT; 157140) aggregates. Some patients with the disorder may have features of both diseases, and there is significant interfamilial and intrafamilial phenotypic variability (summary by Johnson et al., 2010; Wong et al., 2018; Al-Obeidi et al., 2018; Darwich et al., 2020). For a general phenotypic description and a discussion of genetic heterogeneity of FTDALS, see FTDALS1 (105550).

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.

PI4KA-related disorder is a clinically variable disorder characterized primarily by neurologic dysfunction (limb spasticity, developmental delay, intellectual disability, seizures, ataxia, nystagmus), gastrointestinal manifestations (multiple intestinal atresia, inflammatory bowel disease), and combined immunodeficiency (leukopenia, variable immunoglobulin defects). Age of onset is typically antenatal or in early childhood; individuals can present with any combination of these features. Rare individuals present with later-onset hereditary spastic paraplegia. Brain MRI findings can include hypomyelinating leukodystrophy, cerebellar hypoplasia/atrophy, thin or dysplastic corpus callosum, and/or perisylvian polymicrogyria.

Early-onset dystonia and/or spastic paraplegia (DYTSPG) is an autosomal dominant neurologic movement disorder characterized by phenotypic variability, even within the same family. Some patients have onset of progressive focal and generalized dystonia in the first decade, as young as infancy, whereas others develop progressive spastic paraplegia as adults, suggesting that age affects the phenotype. Some patients have manifestations of both disorders. Most patients have ambulation difficulties (Gilbert et al., 2009). Rare patients may show hypotonia and neurodevelopmental delay (Zech et al., 2022).

Autosomal recessive spastic paraplegia-85 (SPG85) is a neurologic disorder characterized by the onset of motor symptoms in the first few years of life. Affected individuals have spasticity and hyperreflexia of the lower limbs resulting in gait abnormalities. Older patients may have upper limb involvement and demonstrate axonal polyneuropathy. Additional features include optic atrophy, dysarthria, dysphagia, ataxia, and urinary incontinence. Brain imaging may show cerebellar atrophy (summary by Wagner et al., 2019). For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

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

The spectrum of FARS2 deficiency ranges from the infantile-onset phenotype, characterized by epileptic encephalopathy with lactic acidosis and poor prognosis (70% of affected individuals), to the later-onset phenotype, characterized by spastic paraplegia, less severe neurologic manifestations, and longer survival (30% of affected individuals). To date FARS2 deficiency has been reported in 37 individuals from 25 families. Infantile-onset phenotype. Seizures are difficult to control and may progress quickly at an early age to intractable seizures with frequent status epilepticus; some children have hypsarrhythmia on EEG. All have developmental delay; most are nonverbal and unable to walk. Feeding difficulties are common. More than half of affected children die in early childhood. Later-onset phenotype. All affected individuals have spastic paraplegia manifested by weakness, spasticity, and exaggerated reflexes of the lower extremities associated with walking difficulties; some have developmental delay/intellectual disability; some have brief seizures that resolve over time.

Combined oxidative phosphorylation deficiency-54 (COXPD54) is an autosomal recessive disorder with pleiotropic multisystem presentations resulting from a disruption in mitochondrial transcription and translation. The phenotype is highly variable. Many patients have early-onset sensorineural hearing loss, sometimes in isolation, and sometimes associated with global developmental delay or primary ovarian failure. Other features may include peripheral hypertonia, seizures, muscle weakness, behavioral abnormalities, and leukoencephalopathy on brain imaging. Serum lactate may or may not be elevated (summary by Hochberg et al., 2021). For a discussion of genetic heterogeneity of combined oxidative phosphorylation deficiency, see COXPD1 (609060).

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 spastic paraplegia-88 (SPG88) is characterized by onset of symptoms in the first year of life. Affected individuals show delayed motor development with walking difficulties due to spasticity of the lower limbs. The disorder is slowly progressive, but variable in severity; some patients are unable to ambulate independently. Most patients have a pure form of the disorder, although rare patients have been reported to have additional features, including peripheral neuropathy, speech delay, ADHD, and nonspecific brain imaging abnormalities (Schob et al., 2021, Estiar et al., 2022, De Winter et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).

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).

Leukoencephalopathy with vanishing white matter-2 (VWM2) is a chronic and progressive autosomal recessive leukoencephalopathy characterized by neurologic deterioration with cerebellar ataxia, spasticity, and relatively mild mental decline. Severity ranges from onset at birth with death in infancy to mild cases with later and even adult onset. Initial development may be normal. Episodes of rapid deterioration occur following febrile infection or minor head trauma. Death occurs after a variable period usually of a few years to a few decades, usually following an episode of fever and coma. Affected females may have ovarian failure manifest as primary or secondary amenorrhea. Magnetic resonance imaging (MRI) and magnetic resonance spectroscopy are diagnostic and show a diffuse abnormality of the cerebral white matter beginning in the presymptomatic stage, with increasing amounts of the abnormal white matter vanishing and being replaced by cerebrospinal fluid; autopsy confirms these findings (summary by Leegwater et al., 2001, van der Knaap et al., 2003). For a discussion of genetic heterogeneity of VWM, see 603896.

Leukoencephalopathy with vanishing white matter-3 (VWM3) is an autosomal recessive leukoencephalopathy characterized by progressive cerebellar ataxia, spasticity, and mental decline. The course is chronic and progressive, with episodes of rapid deterioration following minor head trauma. Affected females may have amenorrhea. Magnetic resonance imaging (MRI) reveals diffuse leukoencephalopathy with lesions having cerebrospinal fluid (CSF)-like signals (summary by Matsukawa et al., 2011). For a discussion of genetic heterogeneity of VWM, see 603896.

Autosomal dominant nemaline myopathy-5C (NEM5C) is a relatively mild skeletal muscle disorder with wide clinical variability, even within families. Affected individuals develop symptoms of muscle weakness in the first or second decades; those with earlier onset tend to have a more severe disease course. Features include difficulty walking on the heels, waddling gait, proximal muscle weakness affecting the upper and lower limbs, and Gowers sign. Additional features may include myopathic facies, high-arched palate, scoliosis or kyphosis, and ankle weakness. Patients remain ambulatory into late adulthood. Skeletal muscle biopsy shows hypotrophy of type 1 fibers, hypertrophy of type 2 fibers, fiber size variation, and myofibrillar disorganization. Nemaline rods in type 1 fibers are often observed, but are not always present (Konersman et al., 2017; Holling et al., 2022). For a discussion of genetic heterogeneity of nemaline myopathy, see NEM2 (256030).

Amyotrophic lateral sclerosis-28 (ALS28) is an autosomal dominant neurodegenerative disorder characterized by adult onset of slowly progressive limb muscle weakness and atrophy resulting in gait difficulties, loss of ambulation, and distal upper limb weakness. Facial involvement is rare, but some patients may have respiratory insufficiency. EMG and muscle biopsy show active and chronic denervation. Patient-derived motor neurons show accumulation of TDP43 (605078) and toxic intranuclear RNA accumulation (Kume et al., 2023). For discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

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

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).

Developmental delay with or without epilepsy (DEVEP) is a clinically heterogeneous neurodevelopmental disorder characterized by motor delay, speech delay, and variably impaired intellectual development apparent from infancy or early childhood. Hypotonia and behavioral abnormalities are common. About half of affected individuals develop various types of seizures that are not as severe as observed in the allelic disorder DEE5. In general, the phenotype is similar to but milder than DEE5. Some individuals with DEVEP have ataxia or nystagmus associated with cerebellar atrophy on brain imaging, indicating phenotypic overlap with the allelic disorder SPG91 (Morsy et al., 2023). In a study of 31 individuals with SPTAN1 mutations, Morsy et al. (2023) delineated 3 distinct phenotypic subgroups: DEE5; a milder phenotype of developmental delay with or without seizures (DEVEP); and pure or complicated spastic paraplegia/ataxia (SPG91). Syrbe et al. (2017) similarly emphasized the remarkably broad phenotypic spectrum of neurologic disorders associated with heterozygous SPTAN1 mutations in their cohort study.

Immunodeficiency-115 with autoinflammation (IMD115) is an autosomal recessive disorder characterized by the onset of symptoms of immune dysregulation in early infancy. Affected individuals have immunodeficiency with recurrent bacterial, viral, and fungal infections, as well as autoinflammatory features, including arthritis and dermatitis. Some patients may have more systemic involvement, such as myopathy, gastrointestinal abnormalities, and anemia. Laboratory studies show variable B-cell and T-cell defects, sometimes with defective antibody responses and hypogammaglobulinemia (Boisson et al., 2015; Oda et al., 2019).