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

We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot-Marie-Tooth (CMT) families and in two iso lated CMT patients of Belgian ancestry. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the Thr124Met mutati on have one common ancestor. The mutation is associated with a clinically d istinct phenotype characterized by late onset, marked sensory abnormalities and, in some families, deafness and pupillary abnormalities. Nerve conduct ion 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-gen otype correlations in 30 patients with the Thr124Met MPZ mutation indicate that, based on nerve conduction velocity criteria, these patients are diffi cult to classify as CMT1 or CMT2, We therefore conclude that CMT patients w ith slightly reduced or nearly normal nerve conduction velocity should be s creened for MPZ mutations, particularly when additional clinical features s uch as marked sensory disturbances, pupillary abnormalities or deafness are also present.