Efficient neurophysiologic selection of X-linked Charcot-Marie-Tooth families: ten novel mutations

To devise a neurophysiologic strategy to select X-linked Charcot-Marie-Tooth neuropathy syndrome (CMTX) families for connexin 32 mutation screening.

Once the common chromosome 17 DNA duplication (CMT1A syndrome) has been excluded, clinical features are not sufficiently distinctive to select which of three genes (PMP22, Po, or connexin 32) should be screened for mutations.

The yield of connexin 32 mutations was compared in possible CMTX families with clinical and genetic features of CMTX and probable CMTX families, defined by additional characteristic neurophysiologic features of CMTX. Of 232 CMT families with median motor nerve conduction velocities below 50 m/second (s) in affected men, 50 were found to have no CMT1A duplication and a pattern of inheritance compatible with CMTX (no man-to-man inheritance of CMT). These families were divided into 23 probable CMTX families (defined as having electrophysiologic indicators of CMTX), 23 possible CMTX families (with no neurophysiologic features of CMTX), and five unlikely CMTX families (with normal brainstem evoked auditory potentials [BAEPs]).

The yield of mutations in the whole group was 25 mutations in 51 families (50%). Most probable CMTX families (21 of 23; 91%) had connexin 32 coding region mutations. Included in this group were 14 families with obligate female carriers; 11 of these had intermediate conduction velocities (>42 m/s) and nine (81%) had connexin 32 mutations. Only 3 of 23 (13%) possible CMTX families had connexin 32 mutations. One of five families with normal BAEPs in affected men had a connexin 32 mutation, and one had a Po Ala112Val mutation. Seventeen different mutations were found among 24 families, including 10 previously undescribed mutations (Leu9Trp, Ile28Thr, Ile30Thr, Ile127Met, Leu131Pro, Tyr154 stop, Pro158Ala, one base deletion of codon 158 causing stop at codon 195, Val192Phe, and Leu239Ile).

The yield of connexin 32 mutations can be increased from approximately 6% of all CMT type I families to 91% of nonduplicated nondominant families with characteristic electrophysiologic changes of CMTX.