Histopathological features of X-linked Charcot-Marie-Tooth disease in 8 patients from 6 families with different connexin32 mutations

There is still confusion as to whether X-linked Charcot-Marie-Tooth disease (CMTX) is primarily an axonal disorder or is primarily demyelinating. Eigh t symptomatic patients, 7 males and 1 female, from 6 families with identifi ed connexin32 mutations underwent a superficial peroneal nerve biopsy. Quan titative and ultrastructural studies were performed, and histopathological lesions in these 8 patients proved to be quite homogeneous. The myelinated fiber count was within normal values or only moderately decreased. In 7 cas es, the distribution of myelinated fibers was unimodal due to a loss of lar ge fibers, coexisting with numerous clusters of small regenerating fibers. At ultrastructural level, these clusters were often surrounded by flattened Schwann cell processes giving an aspect of "pseudo-onion bulb" formation. There was no "naked axon" tie, demyelinated axon), and real "onion bulb" fo rmations composed of flattened Schwann cell processes surrounding an isolat ed myelinated fiber were discrete and not numerous. Macrophages laden with myelin debris were scarce or absent in the endoneurium. Several fibers appe ared discretely hypomyelinated and the calculated g-ratio was scarcely high er than the mean control value. Lesions of unmyelinated fibers were absent in 7 cases and mild in one. Given that the primary defect concerns connexin 32, we think that the histopathological features observed in our patients c orrespond to primary hypomyelination rather than to ongoing demyelination. The associated axonal degeneration might be secondary to defective axon-Sch wann cell interactions.