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CMT1X phenotypes represent loss of GJB1 gene function

From the Department of Neurology (M.E.S., C.S., E.R.S., K.M.K., D.R.F., R.A.L.) and Center for Molecular Medicine and Genetics (M.E.S., C.S., E.R.S., K.M.K.), Wayne State University, Detroit, MI; Departments of Clinical Neurological Sciences (T.D.), Rehabilitation Medicine (T.D.), and Molecular Genetics and Biochemistry (P.J.A.), Department of Clinical Neurological Sciences (A.F.H.), London Health Sciences Center, University of Western Ontario, Canada; and Department of Neurology (S.S.S.), University of Pennsylvania School of Medicine, Philadelphia.

Address correspondence and reprint requests to Dr Shy, Department of Neurology, Wayne State University, 421 E. Canfield, Detroit, MI 48201; e-mail: m.shy{at}wayne.edu

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.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the March 13 issue to find the title link for this article.

Supported by a grant from the NINDS (R01NS43168-01A1).

Disclosure: The authors report no conflicts of interest.

Received July 26, 2006. Accepted in final form November 13, 2006.

This article has been cited by other articles:

				E. R. Swan, D. R. Fuerst, and M. E. Shy Women and men are equally disabled by Charcot-Marie-Tooth disease type 1A Neurology, March 13, 2007; 68(11): 873 - 873. [Full Text] [PDF]