MedGen

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. [from GeneReviews]

SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by severe spine deformities (scoliosis or kyphoscoliosis) and foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence. Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems. [from GeneReviews]

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. [from GeneReviews]

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. [from GeneReviews]

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. [from SNOMEDCT_US]

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. [from GeneReviews]

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

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; and SPG90B (620417), caused by mutation in the SPTSSA gene (613540) on 14q13. 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). [from OMIM]

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

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

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). [from OMIM]

LMNA-related congenital muscular dystrophy (L-CMD) is a condition that primarily affects muscles used for movement (skeletal muscles). It is part of a group of genetic conditions called congenital muscular dystrophies, which cause weak muscle tone (hypotonia) and muscle wasting (atrophy) beginning very early in life.

In people with L-CMD, muscle weakness becomes apparent in infancy or early childhood and can worsen quickly. The most severely affected infants develop few motor skills, and they are never able to hold up their heads, roll over, or sit. Less severely affected children may learn to sit, stand, and walk before muscle weakness becomes apparent. First the neck muscles weaken, causing the head to fall forward (dropped-head syndrome). As other skeletal muscles become weaker, these children may ultimately lose the ability to sit, stand, and walk unassisted.

Other features of L-CMD often include spinal rigidity and abnormal curvature of the spine (scoliosis and lordosis); joint deformities (contractures) that restrict movement, particularly in the hips and legs; and an inward-turning foot. People with L-CMD also have an increased risk of heart rhythm abnormalities (arrhythmias).

Over time, muscle weakness causes most infants and children with L-CMD to have trouble eating and breathing. The breathing problems result from restrictive respiratory insufficiency, which occurs when muscles in the chest are weakened and the ribcage becomes increasingly rigid. This problem can be life-threatening, and many affected children require support with a machine to help them breathe (mechanical ventilation). [from MedlinePlus Genetics]

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

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

A rare hereditary motor and sensory neuropathy characterized by intermediate motor median nerve conduction velocities (usually between 25 and 60 m/s). It presents with moderately severe, slowly progressive usual clinical features of Charcot-Marie-Tooth disease (muscle weakness and atrophy of the distal extremities, distal sensory loss, reduced or absent deep tendon reflexes, feet deformities, extensor digitorum brevis atrophy). Findings in nerve biopsies include age-dependent axonal degeneration, reduced number of large myelinated fibers, segmental remyelination, and no onion bulbs. [from SNOMEDCT_US]

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. [from GeneReviews]

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). [from OMIM]

A rare genetic peripheral sensorimotor neuropathy with an X-linked recessive inheritance pattern and the childhood to adolescent-onset of progressive, distal muscle weakness and atrophy (beginning in the lower extremities and then affecting the upper extremities), as well as distal, pan sensory loss in the upper and lower extremities, pes cavus, and absent or reduced distal tendon reflexes. Pain and paraesthesia are frequently the initial sensory symptoms. Spastic paraparesis (manifested by clasp-knife sign, hyperactive deep-tendon reflexes, and Babinski sign) has also been reported. [from SNOMEDCT_US]

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). [from OMIM]

Distal hereditary motor neuronopathy (dHMN or HMN) is a heterogeneous group of neuromuscular disorders caused by anterior horn cell degeneration and characterized by progressive distal motor weakness and muscular atrophy of the peripheral nervous system without sensory impairment. Distal HMN is also referred to as spinal Charcot-Marie-Tooth disease (spinal CMT). Distal HMN is often referred to as a 'neuronopathy' instead of a 'neuropathy' based on the hypothesis that the primary pathologic process resides in the neuron cell body and not in the axons (Irobi et al., 2006). Historically, Harding (1993) proposed a clinical classification of distal HMN into 7 phenotypic subtypes according to age at onset, mode of inheritance, and presence of additional features; see NOMENCLATURE. Genetic Heterogeneity of Autosomal Dominant Distal Hereditary Motor Neuronopathy Genetically distinct forms of autosomal dominant distal hereditary motor neuropathy include HMND1; HMND2 (158590), caused by mutation in the HSPB8 gene (608014); HMND3 (608634), caused by mutation in the HSPB1 gene (602195); HMND4 (613376), caused by mutation in the HSPB3 gene (604624); HMND5 (600794), caused by mutation in the GARS gene (600287); HMND6 (615575), caused by mutation in the FBXO38 gene (608533); HMND7 (158580), caused by mutation in the SLC5A7 gene (608761); HMND8 (600175), caused by mutation in the TRPV4 gene (605427); HMND9 (617721), caused by mutation in the WARS gene (191050); HMND10 (620080), caused by mutation in the EMILIN1 gene (130660); HMND11 (620528), caused by mutation in the SPTAN1 gene (182810); HMND12 (614751), caused by mutation in the REEP1 gene (609139); HMND13 (619112), caused by mutation in the BSCL2 gene (606158); and HMND14 (607641), caused by mutation in the DCTN1 gene (601143). See also X-linked HMN (HMNX; 300489), caused by mutation in the ATP7A gene (300011) on chromosome Xq21. Additional disorders with overlapping features include autosomal dominant ALS4 (602433), caused by mutation in the SETX gene (608465); and CMS7A (616040), caused by mutation in the SYT2 gene (600104). [from OMIM]