Gene Mapping, Mutation Analysis Of Neurofilament-light Gene And Study Of Brainstem Auditory Evoked Potentials In Chinese Charcot-Marie-Tooth Disease Patients

Part I A new locus for autosomal dominant Charcot-Marie-Tooth Disease type2 (CMT2G) maps to chromosome 12q24Charcot-Marie-Tooth Disease (CMT) is one of the most common inherited neurological disorders with a prevalence estimated at 1/2500. On nerve biopsy and neurophysiology, CMT falls into two main subtypes, the demyelinating form, CMT1, and the axonal type, CMT2. CMT1 is characterized by reduced nerve conduction velocities (NCVs) with value <38m/s for the median motor nerve, segmental de- and remyelination, and onion bulb formation. These changes differentiate CMT1 from CMT2 in which NCVs are near normal and nerve pathology shows axonal loss and regenerative sprouting. Six loci .for autosomal dominant CMT2 have been mapped thus far (on lp36-35, 3ql3-q22, 7pl4, 8p21, 7qll-q21 and3q!3.1). Only four disease genes, kinesin family member IB gene (KIF1B) for CMT2A, RAS-related GTP-binding protein 7 gene (RAB7) for CMT2B, glycyl tRNA synthetase gene (GARS) for CMT2D and neurofilament-light gene (NEFL) for CMT2E were identified. A large Chinese family with CMT2 was found in the Hunan and Hubei province of China. Affected members have a typical CMT2 phenotype except for 2 patients have weakness and atrophy in both proximal and distal muscles of the lower limbs. LOD scores at the CMTIA, CMTIB, CMT2A, CMT2D, CMT2E and CMT2F loci were negative, making it very improbable that the disease in the investigated family belongs to any of these genetic entities. The results of a genome-widescreening demonstrated linkage to a locus on chromosome 12q24, over an 6.8-cM interval between markers D12S1720 and D12S1611. A maximal two-point LOD score of 6.35 for marker D12S76 at recombination fraction (0) of 0, and a multipoint LOD score of 8.48 for marker D12S76 at 0 = 0, strongly support linkage to this locus. Thus CMT2 neuropathy in this family represents a novel genetic entity designated as CMT2G. The most obvious candidate gene, HXJYJ, which belongs to the intermediate filament family, didn't show evidence responsible for the disease.