Alternative titles; symbols
SNOMEDCT: 763455008; ORPHA: 101075, 1175; DO: 0110209;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq13.1 | Charcot-Marie-Tooth neuropathy, X-linked dominant, 1 | 302800 | X-linked dominant | 3 | GJB1 | 304040 |
A number sign (#) is used with this entry because of evidence that X-linked dominant Charcot-Marie-Tooth disease-1 (CMTX1) is caused by hemizygous or heterozygous mutation in the GJB1 gene (304040) on chromosome Xq13.
Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1) and primary peripheral axonal (type 2) neuropathies. The demyelinating neuropathies classified as CMT type 1, also known as HMSN I, are characterized by severely reduced motor nerve conduction velocities (NCV) (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy (see CMT1B; 118200). The axonal neuropathies classified as CMT type 2, also known as HMSN II, are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (see CMT2A1; 118210). Distal hereditary motor neuropathy (dHMN) (see 158590) is a spinal type of CMT characterized by exclusive motor involvement and sparing of sensory nerves (Pareyson, 1999). There are X-linked, autosomal dominant (see 118200), and autosomal recessive (see 214400) forms of CMT.
The form of Charcot-Marie-Tooth neuropathy that maps to chromosome Xq13 (CMTX1) is X-linked dominant or X-linked intermediate; heterozygous females are more mildly affected than are hemizygous males.
Genetic Heterogeneity of X-linked Charcot-Marie-Tooth Disease
Ionasescu et al. (1991) presented data suggesting the existence of an X-linked recessive CMT disease on Xp22.2 (CMTX2; 302801). CMTX3 is caused by a genomic rearrangement between chromosomes 8q24.3 and Xq27.1. Cowchock syndrome (310490), which maps to chromosome Xq26, is also referred to as CMTX4. CMTX5 (311070) is caused by mutation in the PRPS1 gene (311850) on chromosome Xq22. CMTX6 (300905) is caused by mutation in the PDK3 gene (300906) on Xp22.
CMTX has both demyelinating and axonal features (Bergoffen et al., 1993, Hahn et al., 1990).
Phillips et al. (1985) described a large family with a pattern of X-linked dominant inheritance. Clinically and electrophysiologically, the phenotype was similar to HMSN of the 'intermediate' type, in accordance with the Allan rule (Allan, 1939). Men were more severely affected than women, with very slow nerve conduction velocities. NCVs were mildly slow or normal in women. Hypertrophic nerves were not found.
Hahn et al. (1990) reported clinical, neuropathologic, and electrophysiologic observations on a French Canadian family with HMSN transmitted as an X-linked dominant disorder over 6 generations. The disorder was characterized by onset in early childhood, pes cavus, atrophy and weakness of peroneal muscles and intrinsic hand muscles, and sensory abnormalities. Males were severely affected, whereas females had mild or subclinical disease. Electrophysiologic observations indicated a substantial loss of distal motor and sensory nerve fibers. Evoked muscle action potentials were absent or severely reduced and peroneal motor nerve conduction velocities were mildly reduced to a mean of 36.5 m/s. Nerve biopsies showed loss of myelinated and unmyelinated nerve fibers, regenerative sprouting, and secondary demyelination. The authors concluded that this form of HMSN is the result of primary axonal degeneration.
Fain et al. (1994) examined 52 affected individuals from 4 multigenerational kindreds. All affected males had distal muscle weakness, atrophy, depressed deep tendon reflexes, and motor NCV less than 38 m/s. All females who were considered affected had mild distal muscle weakness, hypoactive reflexes, and NCV less than 38 m/s, consistent with a demyelinating neuropathy. The majority of affected females showed significant weakness beyond the fourth decade. Variable pes cavus deformity and variable degree of sensory loss were present in both affected males and females.
Le Guern et al. (1994) reported a large family with X-linked dominant Charcot-Marie-Tooth disease. There were 7 affected males with NCV between 31 and 35 m/s in the median nerve and 12 affected females with NCV ranging from 31 to 52 m/s in the median nerve. Four of the women were asymptomatic but demonstrated electrophysiologic abnormalities. No male-to-male transmission was detected.
Birouk et al. (1998) examined 48 CMTX patients from 10 families with CMTX1, confirmed by mutation analysis. Males were more severely affected than females, although 6 females were severely disabled. Motor NCV ranged from 30 to 40 m/s in males. Sural nerve biopsies showed axonal neuropathy. The authors concluded that this was an axonal neuropathy rather than a demyelinating disease.
Yiu et al. (2011) provided a retrospective review of 17 children with X-linked CMT, 8 of whom (6 boys and 2 girls) had proven pathogenic mutations in the GJB1 gene. Most children with CMTX1 presented in infancy or early childhood with gait disturbances, although 3 presented with atypical features: a boy with hand tremor at age 12 years, a girl with sensorineural hearing loss at age 3 years, and a boy with transient CNS disturbance after hyperventilation at age 10 years, although in retrospect he had always walked flat-footed. Clinical features included toe walking (3 of 8), Achilles contractures (5), delayed motor development (3), frequent falls (4), hand weakness (2), hand tremor (3), and ankle sprains (2). Physical examination findings included pes cavus (5 of 8), distal lower limb wasting (4), distal upper limb wasting (5), difficulty walking on heels (6), distal lower limb weakness (6), distal upper limb weakness (3), absent ankle jerks (7), and distal sensory loss (3). Nerve conduction velocity studies in 3 boys ranged from 30 to 50 m/s and in 1 girl ranged from 41 to 46 m/s. The girl who presented with hearing loss had no other neurologic abnormalities. Two patients had sural nerve biopsies showing a reduction in myelinated nerve fiber density, thin myelin sheaths, and onion bulb formations. Muscle biopsy from 1 patient showed neurogenic changes with marked fiber size variation and type 1 fiber predominance. Five obligate carrier mothers had an abnormal neurologic examination, with distal upper and lower limb wasting and weakness with foot deformities. One girl and an unrelated carrier mother had recurrent pathologic fractures, an unusual feature.
Clinical Variability
Spira et al. (1979) reported a family originating from South Australia with X-linked recessive inheritance of spinocerebellar degeneration in 10 males. Age at onset of ataxia was in the first or second decade, with the 2 oldest patients becoming wheelchair-bound as young adults. Cerebellar features included gait and limb ataxia, intention tremor, dysmetria, dysdiadochokinesia, dysarthria, and nystagmus. Other features included pes cavus, scoliosis, hyperreflexia with absent ankle reflexes, extensor plantar responses, and muscle atrophy. Decreased distal position and vibration sense were noted only in the 2 oldest patients. Motor nerve conduction velocities were decreased and sensory nerve conduction studies showed increased latency and decreased amplitude. Sural nerve biopsy showed marked reduction in the density of large diameter fibers. Postmortem findings of 1 patient showed extensive loss of cerebellar Purkinje cells, loss of neurons and myelin from the inferior olives, and loss of myelin from the spinocerebellar tracts, posterior columns, and corticospinal tracts. Intelligence was unaffected. Caramins et al. (2013) reported follow-up of the family studied by Spira et al. (1979). Physical examination of 4 available affected males revealed a consistent phenotype with cerebellar signs, pyramidal features, and signs of a sensorimotor neuropathy, which was confirmed by electrophysiologic studies. Brain MRI of 1 patient showed cerebellar and spinal cord atrophy. A 67-year-old asymptomatic obligate female carrier who was examined showed minor heel-shin ataxia, gait impairment, and absent ankle jerks. Exome sequencing revealed a missense mutation in the GJB1 gene (P58S; 304040.0022) that segregated with the disorder in the family.
Central Nervous System Involvement
There are reports of CNS involvement in CMTX1 with (Panas et al., 1998; Marques et al., 1999) and without (Stojkovic et al., 1999; Nicholson et al., 1998) cerebral abnormalities on MRI. Schelhaas et al. (2002) presented a 14-year-old boy with CMTX1 who developed subacute respiratory distress and a pseudobulbar syndrome after an episode of fever. MRI of the brain showed confluent cerebral white matter lesions. The clinical features and cerebral white matter lesions in this patient resolved spontaneously.
Hanemann et al. (2003) reported a family in which 3 members were affected with X-linked CMT. In addition to classic CMT clinical findings, all 3 patients had transient CNS symptoms correlating with transient and reversible white matter lesions on MRI. CNS symptoms included paraparesis, monoparesis, tetraparesis, dysarthria, aphasia, and cranial nerve palsies.
Taylor et al. (2003) reported a 12-year-old boy with X-linked CMT who had 3 consecutive episodes of transient neurologic dysfunction over the course of 3 days, with complete recovery between each episode. Deficits included numbness of the face, paresis of the face and limbs, dysarthria, complete motor aphasia, and loss of gag reflex. MRI showed abnormal signals in the posterior frontal and parietal white matter, which improved 11 weeks later.
Herringham (1889) reported a family with 20 affected males in 4 generations. Erwin (1944) observed 7 cases of sex-linked recessive inheritance in 5 generations. Woratz (1964) (cited by Becker, 1966) studied a family in which X-linked dominant inheritance was present. A large number of persons in 6 generations were affected. Ten affected fathers had only affected daughters (15) and only normal sons (8), whereas 26 affected mothers had affected sons (23) and affected daughters (21) as well as unaffected offspring. Males were more severely affected than females.
The large kindred reported by Gal et al. (1985) was said to follow complete X-linked dominant inheritance, whereas the large family described by Goonewardena et al. (1988) showed X-linked incomplete dominant inheritance, with variable expression among daughters of affected males or carrier females. Bergoffen et al. (1993) noted that this form of CMT is an X-linked dominant condition with incomplete penetrance.
Montenegro et al. (2011) reported the use of exome sequencing to identify a mutation in the GJB1 gene (V95M; 304040.0011) in affected members of a large family with Charcot-Marie-Tooth disease and a questionable inheritance pattern. Affected individuals had classic features of the disease, with onset between ages 14 and 40 years of distal sensory impairment and muscle weakness and atrophy affecting the upper and lower limbs. Nerve conduction velocities were in the intermediate range.
De Weerdt et al. (1976) excluded close linkage of X-linked CMT to the Xg locus. A large pedigree was reported by Iselius and Grimby (1982). Close linkage to colorblindness was excluded. In a restudy of the original family reported by Woratz (1964), an exceptionally extensive pedigree, Gal et al. (1985) found a suggestion of close linkage with a polymorphic DNA probe, DXYS1 (pDp34), located on the proximal long arm of X (Xq13-q21). The lod score was 1.358 at 0.0 recombination. The regional assignment was confirmed through the work of Fischbeck et al. (1985, 1986), who referred to the disorder as X-linked neuropathy, and that of Beckett et al. (1985, 1986) linking it to DXYS1. Beckett et al. (1985, 1986) suggested that CMTX1 (and DXYS1) may be distal to PGK1 (311800) in band Xq13.
Using DNA markers, Fischbeck et al. (1986) performed linkage studies in 4 families with X-linked neuropathy. In each case, they confirmed X-linkage as opposed to sex-limited expression of an autosomal dominant disorder. Furthermore, although there was considerable clinical interfamilial variability, the neuropathy gene in each family was located in the same region, near DXYS1 and the centromere of the X chromosome, so that these presumably represent either identical or allelic disorders. One of their families was of Italian ancestry living in Bucks County, Pennsylvania. Onset in this family was very early and progression gradual. Several of those affected had associated deafness (Cowchock et al., 1985; Sladky and Brown, 1984); see 310490. Their family 2 was originally described by Allan (1939) and thus has great historical interest; the family had been restudied by Rozear et al. (1987). The third family was that described by Fryns and Van den Berghe (1980) in Belgium. The fourth family was previously unreported.
Kelly et al. (1987) presented data suggesting that Charcot-Marie-Tooth disease and Kennedy spinal muscular atrophy (313200), both of which are linked to DXYS1, lie on opposite sides of this marker. Goonewardena et al. (1987) found a peak lod score of 5.05 at theta = 0.0 for linkage between CMTX1 and DXYS1. Because Hodgson et al. (1987) found deletion of DXYS1 in a male with choroideremia (303100) and mental retardation but without CMTX, Goonewardena et al. (1987) concluded that the CMTX locus is proximal to DXYS1 and, presumably, to choroideremia. In a follow-up of the North Carolina family originally reported by Allan (1939), Rozear et al. (1987) presented data on 13 affected males and 25 obligate or probable heterozygous females, documenting the devastating nature of the disease in men and the highly variable degree of clinical involvement in female carriers. Studies of DNA markers were consistent with location of the gene in the area of DXYS1. The combination of their data with those from other families yielded a lod score of 3.614 at theta = 0.05 and of 5.753 at theta = 0.10. Goonewardena et al. (1988) added further data.
In a large Scottish kindred, Fairweather et al. (1988) found a lod score of 3.34 at zero recombination for linkage with PGK1 (311800). In a single Scottish family, Haites et al. (1989) found a lod score of 4.55 at a recombination fraction of 0.03 for linkage with DXYS1 and a lod score of 3.34 at zero recombination for linkage to PGK1. Mostacciuolo et al. (1991) presented data on a large Italian family which supported linkage in the pericentric region of the X chromosome. Using 4 variable short-sequence repeat markers, as well as RFLP markers, Bergoffen et al. (1993) localized the CMTX gene to the proximal Xq segment between PGKP1 (Xq11.2-q12) and DXS72 (Xq21.1), with a combined maximum multipoint lod score of 15.3 at DXS453 (theta = 0.0). Using 12 highly polymorphic short tandem repeat markers from the pericentric region of the X chromosome in the study of 4 multigenerational families with CMTX, Fain et al. (1994) refined the localization of CMTX between DXS337 and DXS441, PGK1 lying distal to DXS441. Le Guern et al. (1994) performed linkage analysis on a large family with X-linked dominant Charcot-Marie-Tooth disease. Multipoint linkage analysis mapped the responsible gene between the androgen receptor gene (313700) and DXYS1, with a maximum lod score of 4.60 at DXS453.
In affected persons from 8 CMTX families, Bergoffen et al. (1993) demonstrated point mutations in the connexin-32 gene (e.g., 304040.0001). The families in which mutations were identified included one studied by William Allan (1939), who had pointed out that this disorder is one of the entities that, like spastic paraplegia and retinitis pigmentosa, demonstrate autosomal dominant inheritance in some families, autosomal recessive inheritance in others, and X-linked inheritance in yet others.
Tabaraud et al. (1999) reported findings of prominent demyelination as the cause of X-linked Charcot-Marie-Tooth disease in a 71-year-old woman with late-onset disease. Electrophysiologic studies revealed a nonuniform slowing of motor conduction velocities and dispersion of compound action potentials indicative of a demyelinating process which was confirmed by nerve biopsy. Such electrophysiologic features are unusual in hereditary neuropathies and are more commonly found with acquired chronic demyelinating neuropathies. The patient was found to have a truncating mutation in the connexin-32 gene predicted to result in a protein of 102 codons rather than the normal 283 (304040.0013). The authors noted that the pathology of CMTX in other reported cases had variably been interpreted as axonal, demyelinating, or showing both features.
Casasnovas et al. (2006) identified 34 GJB1 mutations, including 6 novel mutations, in 59 patients from 34 CMT families of Spanish or Portuguese descent. The extracellular loop domains were affected in 64.6% of mutations.
Associations Pending Confirmation
For discussion of a possible association between an X-linked intermediate form of Charcot-Marie-Tooth disease and variation in the DRP2 gene, see 300052.0001.
Shy et al. (2007) evaluated 73 male patients with CMTX1, ranging from 9 to 76 years of age, who had a total of 28 distinct GJB1 mutations. Two patients had a complete deletion of the GJB1 gene, and all others had truncating or missense mutations affecting various regions of the protein. Disability was relatively mild in the first 2 decades but progressed to severe after age 60, regardless of the mutation. There was no correlation between disease severity and specific mutations, and there was considerable variability among many patients carrying the same mutation. Moreover, virtually all patients of a given age had similar severity scores regardless of the mutation, and similar phenotypes resulted from deletions, missense, and nonsense mutations. Electrophysiologic studies indicated that axonal loss progressed with age, whereas conduction slowing did not clearly correlate with age. Functional disability correlated with motor axonal loss. Shy et al. (2007) concluded that GJB1 mutations result in a loss of function.
Abe et al. (2011) identified GJB1 mutations in 19 (8.5%) of 227 Japanese patients with demyelinating CMT and in 6 (4.7%) of 127 Japanese patients with axonal CMT.
In 28 (5.3%) of 527 unrelated Korean families with CMT, Kim et al. (2012) identified 23 different mutations in the GJB1 gene (see, e.g., 304040.0005 and 304040.0011). Nine of the mutations were novel. Mutations affected the extracellular 2 (EC2) domain of the protein in 44% of families.
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