Neurology 2002;59:1865-1872
© 2002 American Academy of Neurology
Mutations in GDAP1
Autosomal recessive CMT with demyelination and axonopathy
E. Nelis, PhD,
S. Erdem, MD,
P. Y.K. Van den Bergh, MD PhD,
M.-C. Belpaire–Dethiou, MD,
C. Ceuterick, PhD,
V. Van Gerwen,
A. Cuesta, PharmB MSc,
L. Pedrola, BSc,
F. Palau, MD PhD,
A. A.W.M. Gabreëls–Festen, MD PhD,
C. Verellen, MD PhD,
E. Tan, MD,
M. Demirci, MD,
C. Van Broeckhoven, PhD DSc,
P. De Jonghe, MD PhD,
H. Topaloglu, MD PhD and
V. Timmerman, PhD
From the Molecular Genetics Department (Drs. Nelis, Van Broeckhoven, De Jonghe, and Timmerman, V. Van Gerwen), Flanders Interuniversity Institute of Biotechnology, Born–Bunge Foundation, University of Antwerp, Laboratory of Neuropathology (Dr. Ceuterick), Born–Bunge Foundation, University of Antwerp, and Department of Neurology (Dr. De Jonghe), University Hospital Antwerp, Antwerpen, and Centre de Référence Neuromusculaire (Drs. Van den Bergh and Belpaire–Dethiou), Cliniques Universitaires St.-Luc, Université Catholique de Louvain, and Unité de Génétique Médicale (Dr. Verellen), Université Catholique de Louvain, Brussels, Belgium; Department of Neurology and Neuromuscular Diseases Research Laboratory (Drs. Erdem, Tan, and Demirci), Hacettepe University, and Department of Pediatric Neurology (Dr. Topaloglu), Hacettepe Children’s Hospital, Ankara, Turkey; Laboratory of Genetics and Molecular Medicine (Dr. Palau, A. Cuesta and L. Pedrola), Instituto de Biomedicina, CSIC, Valencia, and Department of Genetics (Dr. Palau), Universitat de Valencia, Burjassot, Spain; and Institute of Neurology (Dr. Gabreëls–Festen), University Hospital Nijmegen, the Netherlands.
Address correspondence and reprint requests to Prof. Dr. Vincent Timmerman, Molecular Genetics Laboratory (VIB8), Peripheral Neuropathy Group, University of Antwerpen, Universiteitsplein 1, B-2610 Antwerpen, Belgium; e-mail: vincent.timmerman{at}ua.ac.be
Background: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot–Marie–Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis.
Methods: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1.
Results: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C).
Conclusions: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.
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