Brain, Vol. 122, No. 2, 281-290,
February 1999
© 1999 Oxford University Press
The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot–Marie–Tooth phenotype
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1 Laboratory of Neurogenetics, Department of Biochemistry, Flanders Interuniversity Institute for Biotechnology (VIB), Born-Bunge Foundation (BBS), University of Antwerp (UIA), 2 Division of Neurology, University Hospital Antwerpen (UZA), 3 Laboratory of Neuropathology, Department of Medicine, Born-Bunge Foundation (BBS), University of Antwerp (UIA), Antwerp, 4 Division of Neurology, AZ Maria-Middelares, Sint-Niklaas, 5 Department of Medical Genetics, University of Louvain (UCL), Brussels and 6 Institute of Pathology and Genetics (IPG), Loverval, Belgium
Correspondence to:
Dr Peter De Jonghe, MD, Laboratory of Neurogenetics, University of Antwerp (UIA), Department of Biochemistry, Universiteitsplein 1, B-2610 Antwerpen, Belgium. E-mail: dejonghe{at}uia.ua.ac.be
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.
myelin protein zero; Charcot–Marie–Tooth disease; hereditary motor and sensory neuropathies
bp = base pairs; CMT = Charcot–Marie–Tooth disease; HMSN = hereditary motor and sensory neuropathies; MPZ = myelin protein zero; NCV = nerve conduction velocity; PCR = polymerase chain reaction; SSCP = single-strand conformation polymorphism; STR = short tandem repeat
* Both authors contributed equally to this manuscript
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