Proof of genetic heterogeneity in X-linked CMT

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Neurology. 2006 Dec 12;67(11):2016-21.

Proof of genetic heterogeneity in X-linked Charcot-Marie-Tooth

disease.

Huttner IG, Kennerson ML, Reddel SW, Radovanovic D, Nicholson GA.

Molecular Medicine Laboratory, Concord Hospital, NSW 2139,

Australia.

OBJECTIVE: To characterize a large family with X-linked Charcot-

Marie-Tooth (CMT) neuropathy without mutations in the gap junction

protein B1 (GJB1) gene, which has an unusual phenotype that is

different in some aspects from classic CMTX1.

METHODS: We tested CMT families consistent with X-linked inheritance

for GJB1 mutations. We compared the largest family (CMT623) without

GJB1 mutation and with linkage excluding the CMTX1 locus to CMTX1

and normal individuals.

RESULTS: Only 51% of probable X-linked CMT families had mutations in

GJB1. Family CMT623 shows linkage to Xq26.3-q27.1 (lod score z =

6.58), a region within the previously identified locus for CMTX3,

Xq26-q28. Unlike CMTX1, affected males in family CMT623 report pain

and paraesthesia before the onset of sensory loss, and women are

usually asymptomatic. As in CMTX1, affected males have widely

ranging intermediate motor conduction velocities. The coding regions

of 14 positional candidate genes within the narrowed CMTX3 locus

have been excluded for a pathogenic role in the disease.

CONCLUSION: This study is the first to confirm the CMTX3 locus and

to refine the genetic interval to a 5.7-Mb region flanked by the

markers DXS1041 and DXS8106. GJB1 mutation-negative forms of X-

linked CMT, such as CMTX3, may account for a significant proportion

of X-linked CMT.