CLINICAL AND PATHOLOGICAL PHENOTYPE OF THE ORIGINAL FAMILY WITH CHARCOT-MARIE-TOOTH TYPE 1B - A 20-YEAR STUDY

Charcot-Marie-Tooth type 1B is an uncommon form of hereditary motor an d sensory neuropathy caused by mutations in the P-0 myelin protein gen e on chromosome 1. We report here a 20-year observation of 13 members of the first family with Charcot-Marie-Tooth disease to demonstrate li nkage to chromosome 1 and now known to have a C270A mutation in the P- 0 gene altering the extracellular domain of the protein. Affected indi viduals generally show an early age at onset, often indicated by delay ed ability to walk. Proximal muscle weakness of the lower extremities is common and often marked, but the individuals remain ambulatory and there is no decrease in life span. Motor nerve conduction velocities o f the fastest fibers are severely slowed (mean, 9-11 m/sec), even when compared with 3 families having Charcot-Marie Tooth type 1A (mean, 19 -21 m/sec). Variability of disability between family members suggests that genetic and environmental factors in addition to the P-0 mutation play a role in the final phenotype. Nerve biopsy specimens demonstrat e hypertrophy, onion bulb formation, loss of myelinated fibers, and oc casional myelin thickening similar to that described in P-0 myelin kno ckout mice. Autopsy of the 92-year-old great-grandmother in this famil y demonstrated diffuse involvement of sensory and motor nerves, with l oss of myelin in the posterior columns of the spinal cord and loss of anterior horn neurons but without other involvement of the central ner vous system. This family demonstrates the long-term phenotypic consequ ences on the peripheral nervous system of a specific point mutation in the P-0 myelin gene.