The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot–Marie–Tooth phenotype

TLDR

We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot–Marie–Tooth families and two isolated Belgian patients. Allele‑sharing analysis shows a shared ancestor for all carriers, and the Thr124Met mutation defines a distinct late‑onset CMT phenotype with marked sensory loss, occasional deafness and pupillary abnormalities, variable motor nerve conduction velocities, axonal regeneration on sural biopsy, and difficulty distinguishing CMT1 from CMT2, so patients with near‑normal conduction velocities and these clinical features should be screened for MPZ mutations.

Abstract

We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot–Marie–Tooth (CMT) families and in two isolated CMT patients of Belgian ancestry. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the Thr124Met mutation have one common ancestor. The mutation is associated with a clinically distinct phenotype characterized by late onset, marked sensory abnormalities and, in some families, deafness and pupillary abnormalities. Nerve conduction velocities of the motor median nerve vary from <38 m/s to normal values in these patients. Clusters of remyelinating axons in a sural nerve biopsy demonstrate an axonal involvement, with axonal regeneration. Phenotype–genotype correlations in 30 patients with the Thr124Met MPZ mutation indicate that, based on nerve conduction velocity criteria, these patients are difficult to classify as CMT1 or CMT2. We therefore conclude that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities or deafness are also present.