Unusual electrophysiological findings in X-linked dominant Charcot-Marie-Tooth disease

Abstract

X‐linked Charcot‐Marie‐Tooth disease (CMTX) is the second most common form of Charcot‐Marie‐Tooth disease. Variable histopathological and nerve conduction velocity (NCV) results have suggested either a primary demyelinating or axonal polyneuropathy. We identified five individuals across three generations in a family with CMTX associated with a mutation in the gene coding for connexin 32. All individuals were studied by clinical neurological examination, DNA analysis, and nerve conduction studies. The proband (1174/KD) also underwent a sural nerve biopsy. As expected, all the affected males were more clinically affected than the females. All affected males and obligate female carriers exhibited some electrophysiological characteristics of demyelination. However, striking heterogeneity of nerve conduction velocities was seen. This family shows that CMTX is a heterogeneous and distinctly nonuniform demyelinating polyneuropathy, the severity of which varies with sex and age. Such electrophysiological variability is unique among hereditary neuropathies. © 2000 John Wiley & Sons, Inc. Muscle Nerve 23: 182–188, 2000.

Gap junction beta 1 (GJB1) gene mutations in Italian patients with X-linked Charcot-Marie-Tooth disease

“…However, a significant intrafamiliar phenotypic variability, ranging from a severe, early onset neuropathy to a mild, late-onset peripheral nervous disease, was present. The clinical variability, particularly in female subjects, has already been reported and may be explained by the process of Lyonisation, which leads to a mosaic of wildtype and mutant myelin in heterozygous female subjects (Gutierrez et al 2000). The likelihood that a female patient with a severe neuropathy could be affected by CMT1X must be therefore taken into account.…”

“…Manifestations in female heterozygotes are variable, probably because of random X-chromosome inactivation (Lyonisation), as directly demonstrated in mice . In some cases, involvement of female hemizygotes is severe, but overall, they are affected to a degree that lies between normal and affected male subjects (Nicholson and Nash 1993;Gutierrez et al 2000;Lewis and Shy 1999;Lewis et al 2000).…”

The Role of Gap Junctions in Charcot-Marie-Tooth Disease

“…Typical features include agerelated loss of myelinated fibers and, in parallel, an increasing number of regenerated axon clusters (Rozear et al, 1987;Hahn et al, 1990Hahn et al, , 1999Nicholson and Nash, 1993;Birouk et al, 1998;Sander et al, 1998;Senderek et al, 1998Senderek et al, , 1999Tabaraud et al, 1999;Gutierrez et al, 2000;Vital et al, 2001;. Many myelin sheaths are inappropriately thin for the axonal diameter, suggesting chronic segmental demyelination and remyelination or remyelination after axonal regeneration (Sander et al, 1998;Hahn et al, 2001;Vital et al, 2001;Hattori et al, 2003;.…”

Diagnosis of hereditary neuropathies in adult patients

“…CMTX has a peculiar behaviour, as conduction slowing is greater in males than females; although NCV may vary between 18 and 60 m/s, conduction velocities are often intermediate between CMT1 and CMT2 in males (30-45 m/s in upper limbs), and in the lower range of CMT2 in females [32,45,62]. A certain degree of asymmetry in nerve conduction abnormalities has been reported in CMTX, as the median nerve is often more affected than the ulnar nerve, conduction slowing may be nonuniform along nerve trunks, and sometimes excessive temporal dispersion and even conduction blocks are found [32,44,62]. c) Molecular analyses.…”