Clinical and pathological phenotype of the original family with Charcot‐Marie‐Tooth type 1B: A 20‐year study

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Abstract
Charcot‐Marie‐Tooth type 1B is an uncommon form of hereditary motor and sensory neuropathy caused by mutations in the Po myelin protein gene on chromosome 1. We report here a 20‐year observation of 13 members of the first family with Charcot‐Marie‐Tooth disease to demonstrate linkage to chromosome 1 and now known to have a C270A mutation in the Po gene altering the extracellular domain of the protein. Affected individuals generally show an early age at onset, often indicated by delayed 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 of 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 Po mutation play a role in the final phenotype. Nerve biopsy specimens demonstrate hypertrophy, onion bulb formation, loss of myelinated fibers, and occasional myelin thickening similar to that described in Po myelin knockout mice. Autopsy of the 92‐year‐old great‐grandmother in this family demonstrated diffuse involvement of sensory and motor nerves, with loss of myelin in the posterior columns of the spinal cord and loss of anterior horn neurons but without other involvement of the central nervous system. This family demonstrates the long‐term phenotypic consequences on the peripheral nervous system system of a specific point mutation in the Po myelin gene.