Walsh & Hoyt: Heriditary Polyneuropathies

In 1886, Charcot and Marie, as well as Tooth, collected 39 cases from personal observations and reports in the literature of a heredofamilial disorder characterized by progressive muscular weakness and atrophy that began during the first two decades of life. Subsequent classifications of Charcot-Marie-Tooth disease (CMT) have been by clinical syndrome, histopathology, and pattern of inheritance and, later, by genetic defect and affected gene products. This group of hereditary polyneuropathies accounts for 90% of all hereditary neuropathies, with the prevalence in the United States being about 40 per 100,000. Most forms of CMT begin between the ages of 2 and 15 years. The first signs are usually pes cavus, foot deformities, or scoliosis. There is slowly progressive weakness and wasting, first of the feet and legs and then of the hands. Motor symptoms predominate over sensory abnormalities. The most common form of CMT is type 1, a demyelinating neuropathy with autosomal-dominant inheritance, mapped most commonly to the short arm of chromosome 17 (17p11.2) (type 1A), although a few pedigrees with this phenotype are linked to the long arm of chromosome 1 (type 1B). CMT type 2 is clinically similar, but nerve conductions are of normal velocity, suggesting the process is neuronal rather than demyelinating. Type 2 can be inherited in an autosomal-dominant fashion (linked to the short arm of chromosome 1) or autosomal-recessively (linked to the long arm of chromosome 8). Type 3 is the most severe form. When type 3 is inherited in an autosomal-dominant pattern, the linkage is to the same region on chromosome 1 associated with type 1B; when it is autosomal recessive, the linkage is to the same region on chromosome 17 associated with type 1A. There are also X-linked forms of CMT, both X-linked dominant (linked to defects on the long arm) and X-linked recessive (linked to regions on either the long arm or the short arm). As of 2002, causative mutations for the hereditary peripheral neuropathies had been identified in 17 different genes.