De novo mutation (Arg98-->Cys) of the myelin P0 gene and uncompaction of the major dense line of the myelin sheath in a severe variant of Charcot-Marie-Tooth disease type 1B.

A point mutation (Arg98-->Cys) of exon 3 coding for the extracellular domain of the myelin protein zero (P0) gene was found in a sporadic case of an eighteen year old Japanese man with a severe variant of Charcot-Marie-Tooth disease type 1B (CMT1B). A de novo mutation was established by parentage testing and analyses of the P0 gene in the family. This patient showed delayed motor development, nonprogressive limb weakness and kyphoscoliosis. In addition to the nerve biopsy findings typical of CMT1B, such as segmental demyelination, marked decrease in the density of myelinated fibers, and frequent onion-bulb formation, ultrastructural examination disclosed uncompaction of the major dense lines with slight widening of the intraperiod distance in the inner layers of the myelin sheath. Although mutations in the extracellular domain of P0 should affect homophilic adhesion between external surfaces of Schwann cell processes, resulting in the separation at the intraperiod lines, our study shows uncompacted major dense lines as a main myelin abnormality where the cytoplasmic domain of P0 resides.