Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosoma

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J Peripher Nerv Syst. 2010 Dec;15(4):334-344

Phenotypical features of the p.R120W mutation in the GDAP1 gene causing

autosomal dominant Charcot-Marie-Tooth disease.

Sivera R, Espinós C, Vílchez JJ, Mas F, Martínez-Rubio D, Chumillas MJ,

Mayordomo F, Muelas N, Bataller L, Palau F, Sevilla T.

Department of Neurology, University Hospital Universitari La Fe, Valencia Centro

de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia

Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas

(CIBERNED), Valencia Department of Radiology, University Hospital Universitari

La Fe, Valencia Laboratory of Genetics and Molecular Medicine, Instituto de

Biomedicina de Valencia-CSIC, Valenciaa Clinical Neurophysiology, University

Hospital Universitari La Fe, Valencia, Spain.

Abstract

Mutations in the ganglioside-induced-differentiation-associated protein 1 gene

(GDAP1) can cause Charcot-Marie-Tooth (CMT) disease with demyelinating (CMT4A)

or axonal forms (CMT2K and ARCMT2K). Most of these mutations present a recessive

inheritance, but few autosomal dominant GDAP1 mutations have also been reported.

We performed a GDAP1 gene screening in a clinically well-characterized series of

81 index cases with axonal CMT neuropathy, identifying 17 patients belonging to

4 unrelated families in whom the heterozygous p.R120W was found to be the only

disease-causing mutation.

The main objective was to fully characterize the neuropathy caused by this

mutation.

The clinical picture included a mild-moderate phenotype with onset around

adolescence, but great variability. Consistently, ankle dorsiflexion and plantar

flexion were impaired to a similar degree.

Nerve conduction studies revealed an axonal neuropathy. Muscle magnetic

resonance imaging studies demonstrated selective involvement of intrinsic foot

muscles in all patients and a uniform pattern of fatty infiltration in the calf,

with distal and superficial posterior predominance.

Pathological abnormalities included depletion of myelinated fibers, regenerative

clusters and features of axonal degeneration with mitochondrial aggregates. Our

findings highlight the relevance of dominantly transmitted p.R120W GDAP1 gene

mutations which can cause an axonal CMT with a wide clinical profile.