Clinical Phenotypes of Different MPZ (P0) Mutations May Include Charcot–Marie–Tooth Type 1B, Dejerine–Sottas, and Congenital Hypomyelination

TLDR

Hereditary demyelinating peripheral neuropathies, including HNPP, CMT, DSS, and CH, form a heterogeneous group whose clinical and pathological overlap makes discrete classification challenging. The study hypothesizes that clinical severity differences in MPZ mutations are linked to mutation type and its effect on protein function (loss of function versus dominant negative). Five novel MPZ mutations were identified in patients with CMT1B, DSS, or CH, indicating these conditions represent a spectrum of related myelinopathies caused by a myelination defect.

Abstract

Hereditary demyelinating peripheral neuropathies consist of a heterogeneous group of genetic disorders that includes hereditary neuropathy with liability to pressure palsies (HNPP), Charcot–Marie–Tooth disease (CMT), Dejerine–Sottas syndrome (DSS), and congenital hypomyelination (CH). The clinical classification of these neuropathies into discrete categories can sometimes be difficult because there can be both clinical and pathologic variation and overlap between these disorders. We have identified five novel mutations in the myelin protein zero (MPZ) gene, encoding the major structural protein (P0) of peripheral nerve myelin, in patients with either CMT1B, DSS, or CH. This finding suggests that these disorders may not be distinct pathophysiologic entities, but rather represent a spectrum of related "myelinopathies" due to an underlying defect in myelination. Furthermore, we hypothesize the differences in clinical severity seen with mutations in MPZ are related to the type of mutation and its subsequent effect on protein function (i.e., loss of function versus dominant negative).