Six novel connexin32 (GJB 1) mutations in X-linked Charcot-Marie-Tooth disease. (Short Report).

X-linked Charcot-Marie-Tooth disease (CMTX) is a ciinicaliy heterogeneous

hereditary motor and sensory neuropathy with X-linked transmission. Common clinical manifestations of CMTX, as in other forms of Charcot-Marie-Tooth disease (CMT), are distal muscle wasting and weakness, hypore-flexia, distal sensory disturbance, and foot deformities. Motor nerve conduction velocity is reduced. In male patients it is often less than 38 m/s in the median nerve (a value often used to distinguish between "demyelinating" and "axonal" forms of CMT), but in female patients conduction velocity may be faster than this or normal. Mutations in the connexin32 (gap junction protein [beta] 1 (GJB1)) gene are responsible for the majority of CMTX cases. This report describes six British CMTX families with six novel mutations (four missense, one nonsense, and one frame shift) of the GJB1 gene. Affected members in these six families had typical signs of CMT but in some affected members of three families there was additional central nervous system involvement or deafness in the absence of any other explanation other than CMT.

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Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous hereditary motor and sensory neuropathy characterised by distal muscle wasting and weakness, sensory disturbance, hyporeflexia, and foot deformities. It is a common disorder with a population frequency of about 1:2500. (1) CMT is broadly classified into type 1 (demyelinating, median motor nerve conduction velocity (MCV) < 38 m/s) and type 2 (axonal, MCV > 38 m/s). (2) The most common mode of inheritance for both type 1 and type 2 is autosomal dominant but some CMT families have X-linked inheritance (CMTX). CMTX patients have features of both type 1 and type 2, although some have mild central nervous system (CNS) involvement. (3-4) Results of electrophysiological studies in patients with CMTX are variable with MCVs in affected males usually either in the demyelinating range or in the intermediate range. Females are usually more mildly affected with MCVs that can be either in the intermediate or in the axonal range, or can be normal. (5-9) Undue reliance on neurophysiological findings in female patients may lead to a delay in diagnosis, especially if they are in the axonal range and a family member has been given a misdiagnosis as probable autosomal dominant CMT type 2.

The connexin32 (gap junction protein [beta] 1, GJB1) gene is one of the genes responsible for CMTX. (10-12) To date 230 mutations of GJB1 gene have been reported to cause CMTX (the Inherited Peripheral Neuropathies Mutation Database is available at http://molgen-www.uia.ac.be/CMTMutations/). Mutations of the GJB1 gene …