Charcot–Marie–Tooth neuropathy: clinical phenotypes of four novel mutations in the MPZ and Cx 32 genes

SIMPLE mutation in demyelinating neuropathy and distribution in sciatic nerve

“…26 -28 The results of the NCV studies showed temporal dispersion in two of four affected individuals of pedigree K2900, representing 25% (3/12) of all motor nerves tested, a phenomenon not typically seen in patients with CMT1, with the exception of recently identified missense mutations of the MPZ gene. 29 In addition, upper limb MNCVs were significantly higher than those in the lower limbs, some even greater than 40m/sec. Other electrophysiological studies of patients with CMT1 have emphasized uniformity of conduction slowing and the absence of segmental amplitude reductions or temporal dispersion.…”

GJB1 gene mutations in suspected inflammatory demyelinating neuropathies not responding to treatment

“…Although some variability in females may relate to different lyonisation of the X chromosome in Schwann cell precursors,1 this cannot explain observations in the male population. It is interesting to note that conduction block has rarely been reported in other intermediate CMT neuropathies (eg, a man with a S140T mutation in the Myelin protein zero gene) 5. Furthermore, temporal dispersion has been reported in patients with CMT1C with missense mutations in the small integral membrane protein of lysosome/late endosome ( SIMPLE ) gene 6…”

Genotype-phenotype correlation in a family with late onset CMT and an MPZ lys236del mutation

“…It is uncertain how the MPZ lys236del mutation leads to a CMT phenotype, however a lys236 is conserved between species suggesting functional importance. 3 The intracytoplasmic domain of MPZ is felt to facilitate myelin compaction through involvement in an adhesion mediated signal transduction cascade. 2 3 The lys236del mutation may alter the phosphorylation state of serine residues located near the carboxy terminus of MPZ which have been suggested to be important in regulating the role of MPZ in myelin compaction.…”

“…2 An adult onset phenotype with mildly slowed or normal CV and more prominent axonal degeneration has been associated with mutations that are suggested to impair axon-schwann cell interactions. 3 While 109 MPZ gene mutations have been reported in association with CMT (http://www.molgen. ua.ac.be/CMTMutations/default.cfm), only three have been in frame, single codon deletions, most being due to point substitutions of a single nucleotide.…”

“…Recently Street et al described a single codon deletion of the intracellular domain of MPZ (MPZ lys236del) in two members of a family with mild late onset CMT. 3 The authors designated this codon deletion as a probable disease causing mutation, requiring further documentation, given the in frame nature of the deletion. 3 Here we provide additional evidence, in another family, that the MPZ lys236del mutation is associated with a mild late onset CMT phenotype with variable penetrance, and we describe detailed clinical, electrophysiological, and genotype correlations in three generations of this family.…”