CMT1X phenotypes represent loss of GJB1 gene function

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Neurology. 2007 Mar 13;68(11):849-55.

CMT1X phenotypes represent loss of GJB1 gene function.

Shy ME, Siskind C, Swan ER, Krajewski KM, Doherty T, Fuerst DR,

Ainsworth PJ, RA, Scherer SS, Hahn AF.

Department of Neurology, Wayne State University, 421 E. Canfield,

Detroit, MI 48201, USA.

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.