Clinical, electrophysiological and molecular genetic characteristics of 93patients with X-linked Charcot-Marie-Tooth disease

X-linked dominant Charcot-Marie-Tooth (CMTX) disease is a motor and sensory neuropathy caused by mutations in the connexin 32 (CX32) gene. In this stu dy we report the clinical, electrophysiological and genetic features of 93 patients (41 males, 52 females) from 37 unrelated families with CMTX. Age a t onset was 15.4 +/- 9.6 years in males (range 1-40 years) and 18.7 +/- 13. 1 years in females (range 1-56 years) (P = 0.22) and the duration of diseas e at the time of examination was 18.3 +/- 14.6 years in males and 23.9 +/- 13.7 years in females (P = 0.11). Males were more severely affected than fe males, with significantly more frequent muscle weakness, amyotrophy, propri oception loss, upper limb areflexia and pes cavus. Females were more freque ntly asymptomatic, whereas high functional disability scores were more freq uently encountered in males. The electrophysiological studies showed that m otor nerve conduction velocities in CMTX females, but not males, were heter ogeneous between nerves compared with Charcot-Marie-Tooth type 1A (CMT1A) p atients and controls. The terminal latency index (TLI) for the median nerve was 0.37 +/- 0.08; it was similar in men and in women and a little higher than those observed in CMT1A and controls. The range of values for median T LI was wider in both male and female CMTX patients than in controls, but wa s similar to that of CMT1A patients, suggesting that motor conduction was r elatively homogeneous within a given nerve. Twenty-seven different CX32 mut ations, including missense (n = 23), nonsense (n = 2) and frameshift mutati ons (n = 1) and one entire deletion of the CX32 coding sequence, were obser ved in the 37 families. Four of these mutations are described for the first time. The phenotype of the patients, especially age at onset, is discussed in relation to the functional consequences of CX32 mutations, analysed in vitro in Xenopus oocytes and mammalian cells. CMTX patients with age at ons et in the first decade mostly presented nonfunctional mutations, suggesting that the physiological consequences of the mutations affect age at onset i n CMTX.