Pathological findings in the x-linked form of Charcot-Marie-Tooth disease:a morphometric and ultrastructural analysis

Mutations in the connexin 32 gene (Cx 32) are associated with the x-linked form of Charcot-Marie-Tooth disease (CMTX) and segregate with a CMT 1 pheno type. The gap junction protein Cx 32 is expressed in myelinating Schwann ce lls and has been localized to regions of non-compacted cytoplasm in paranod es and in Schmidt-Lanterman incisures. Mutant Cx 32 myelin proteins are pre dicted to impair Schwann cell functions. We have studied the resulting path ology in motor and sensory nerves from the probands of 13 CMTX kindreds wit h precisely defined genotype. This report provides a detailed descriptive a nd morphometric analysis of 14 CMTX nerve biopsy samples, taken at various stages in the development of the neuropathy and studied by light and electr on microscopic examination. Findings indicated unusually prominent changes in paranodal myelin with resulting widened nodes of Ranvier, but with segme ntal demyelination being less common. In parallel early axonal cytoskeletal abnormalities were noted, which were followed later by axonal atrophy, deg eneration and loss of myelinated nerve fibers, occurring in a length-depend ent fashion. Regenerative sprouting was also unusually prominent. Ultrastru ctural abnormalities included a frequent dilatation of the adaxonal spaces, prominence of the adaxonal Schwann cell cytoplasm and widening of the Schm idt-Lanterman incisures. We conclude that mutations in Cx 32 gap junction p rotein lead to a compromise of Schwann cell functions and to impaired Schwa nn cell-axon interactions with subsequent pathology in both myelin and axon s.