Clinical phenotype in X-linked Charcot-Marie-Tooth disease with an entire deletion of the connexin 32 coding sequence

To clarify the clinical phenotype and molecular mechanism in X-linked Charc ot-Marie-Tooth disease (CMTX) patients with a deletion of the whole connexi n 32 (Cx32) coding sequence, we studied a family with this deletion by elec trophysiology, Southern blotting and quantitative PCR analyses. Two brother s with no copy of Cx32, 27 and 25 years old, showed steppage gait, moderate muscle atrophy and weakness, and mild sensory disturbance in the distal pa rts of the legs. The clinical phenotypes in these brothers were not differe nt from those in patients with other types of severe Cx32 mutations. Their mother, with one copy of Cx32, showed very mild muscle weakness and sensory disturbance. An electrophysiological study showed a nonuniform demyelinati ng neuropathy with some aspects of an axonal-loss neuropathy. Sural nerve b iopsy showed loss of myelinated fibers, many relatively thin myelin sheaths , clusters of small myelinated fibers, and some onion bulb formations. The present findings suggest that both a demyelinating process and an axonal in volvement were present in the patients with total defect of Cx32 probably d ue to loss of the function mechanism of Cx32 as the underlying molecular me chanism, because a dominant negative effect theory is not applicable in the se patients. (C) 2001 Elsevier Science B.V. All rights reserved.