CMT1X phenotypes represent loss of GJB1 gene function

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Abstract
Objective: To investigate possible genotype–phenotype correlations and to evaluate the natural history of patients with Charcot–Marie–Tooth disease type 1X (CMT1X). Background: CMT1X is caused by over 260 distinct mutations in the gap junction beta 1 (GJB1) gene, located on the X chromosome, which encodes the gap junction protein connexin 32 (Cx32). The natural history of CMT1X is poorly understood, and it remains unknown whether particular mutations cause more severe neuropathies through abnormal gain-of-function mechanisms. Methods: We evaluated 73 male patients with CMT1X, who each have 1 of 28 different GJB1 mutations predicted to affect nearly all domains of Cx32. Disability was evaluated quantitatively by the CMT Neuropathy Score (CMTNS) as well as by the CMT Symptom Score (CMTSS) and the CMT Examination Score (CMTES), which are both based on the CMTNS. Patients were also evaluated by neurophysiology. Results: In all patients, disability increased with age, and the degree of disability was comparable with that observed in patients with a documented GJB1 deletion. Disability correlated with a loss of motor units as assessed by motor unit number estimates. Conclusions: Taken together, these data suggest that most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. Therefore, treatment of male patients with Charcot–Marie–Tooth disease type 1X may prove amenable to gene replacement strategies.