A large Russian family with CMT2 was found in the Mordovian Republic (Russia). Affected members had the typical CMT2 phenotype according to diagnostic criteria set forth by the European CMT Consortium (De Jonghe et al, 1998). In this family, CMT2 usually manifests itself between the second and third decades of life, with difficulty in walking and weakness of the leg muscles, followed by wasting of the lower limbs and a variable degree of deformity of the feet (all patients older than 20 years showed pes cavus, to a greater or lesser extent). EMG investigation revealed reduced muscle action potential amplitude. There was electromyographic evidence of denervation of the distal limb muscles. Six of 12 affected individuals showed spontaneous fasciculation in limb-girdle muscles. One affected individual, 68-years-old, showed significantly impaired balance, together with ptosis. Affected individuals did not exhibit palpably enlarged nerves, and there were no instances of ulcerated feet, hearing impairment, or paralysis of the vocal chords or diaphragm. Additionally, several patients suffered from hyperkeratosis, although the association, if any, between the two disorders is not clear.

There was a clear history of male-to-male transmission in the family, confirming the autosomal dominant nature of the disorder. Linkage with the CMT loci already known (CMT1A, CMT1B, CMT2A, CMT2B, CMT2D, and a number of other CMT-related loci) was excluded. Genome-wide screening pinpointed the disease locus in this family to chromosome 8p21, within a 16-cM interval between markers D8S136 and D8S1769. A maximum two-point LOD score of 5.93 was yielded by a microsatellite from the 50 region of the neurofilament-light gene (NF-L). A related neurofilament-medium gene (NF-M) is also located in the same region. Neurofilament proteins play an important role in axonal structure and are implicated in several neuronal disorders, thus NF-L and NF-M were considered as candidate genes. Screening of affected family members for mutations in the NF-L and NF-M genes revealed the only DNA alteration linked with the disease: a A998C transversion in the first exon of NF-L, which converts a Glutamine333 amino acid to proline. This mutation is located in a region of NF-L, which is conserved in mice, rats, pigs and cows, and shows high similarity in the quail and Xenopus. Glutamine is found in the same position in all available sequences of NF-L, or of corresponding proteins, even in such remote species as Xenopus laevis. This degree of conservation suggests the importance of this particular amino acid for the structure or function of the protein.

This alteration was not found in 180 normal chromosomes. Twenty unrelated CMT2 patients, as well as 26 others with an undetermined form of CMT from Russia, also were screened for mutations in NF-L, but no additional mutations were found. It is suggested that Gln333Pro represents a rare disease-causing mutation, which results in the CMT2 phenotype.