Brain Advance Access originally published online on March 8, 2007
Brain 2007 130(4):1062-1075; doi:10.1093/brain/awm014
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Autosomal recessive axonal Charcot–Marie–Tooth disease (ARCMT2): phenotype–genotype correlations in 13 Moroccan families
1Laboratoire de Neurogénétique, Service de Neurologie B, Hôpital des Spécialités, 2Service de Neurophysiologie clinique, Hôpital des Spécialités, Rabat, 3Service de Neurologie, Hôpital Ibn Rochd, Casablanca, Morocco, 4UMR679 INSERM - Université Paris VI (Pierre et Marie Curie), Hôpital de la Pitié-Salpêtrière, 5Laboratoire de Neuropathologie Raymond Escourolle, Hôpital de la Pitié-Salpêtrière, AP-HP and 6Laboratoire de neurogénétique moléculaire et cellulaire, Département de génétique, cytogénétique et embryologie, Hôpital de la Pitié-Salpêtrière, Paris, France
Correspondence to: Ahmed Bouhouche, Laboratoire de Neurogénétique, Service de Neurologie B, Hôpital des Spécialités, BP 6402, Rabat Morocco and Hamid Azzedine, INSERM U679 Bât. Pharmacie, Hôpital de la Salpêtrière, 47 Bd de l’Hôpital 75651, Paris, France E-mail: azzedine.hamid{at}yahoo.fr
Charcot–Marie–Tooth disease is a genetically heterogeneous group of hereditary motor and sensory neuropathies. Three loci for the axonal autosomal recessive subgroup (ARCMT2) have been reported in 1q21 (CMT2B1, LMNA), 8q21 (CMT4A and CMT2K, GDAP1) and 19q13 (CMT2B2). We report here a clinical, electrophysiological, pathological and genetic study in 13 Moroccan families with ARCMT2 phenotypes. Clinical and electrophysiological examinations were performed in all index cases and 64 ‘at-risk’ relatives. Thirty-one patients were clinically affected. A peroneal nerve biopsy was obtained from three patients. Four families were linked to the 1q21 locus, all had the LMNA R298C mutation. Six families were linked to the 8q21 locus, all had the GDAP1 S194X mutation. Founder effects for both mutations were suggested by the analysis of microsatellite markers close to the genes. The three remaining families were excluded from the three known loci. The electrophysiological findings were consistent with an axonal neuropathy. The clinical data show that in CMT2B1 the disease began most often in the second decade and progressed gradually from distal to proximal muscles. Three of our patients with the longest disease durations (>24 years) had also severe impairment in the scapular muscles. Reported here for the first time, this might be a hallmark of CMT2B1. Patients with CMT4A/2K had onset most often before the age of 2 years. Most had severe clubfoot from the beginning, one of the hallmarks of CMT4A/2K. None of our patients with CMT4A/2K had vocal cord paralysis. The clinical phenotype of the three families that are not linked to the three known loci presented some particularities that were not seen in those with known genetic defects. One family was characterized by late onset of the disease (>20 years) or a mild neuropathy that was diagnosed only when the family was examined. In a second family, dorsal scoliosis was the most prominent symptom. In the third family, symptoms began in the second decade with a moderate neuropathy associated with a pronounced scoliosis. These families illustrate the extent of clinical and genetic heterogeneity in ARCMT2.
Key Words: Charcot–Marie–Tooth disease; LMNA gene; GDAP1 gene; peripheral neuropathy; founder effect
Abbreviations: ARCMT2, autosomal recessive axonal Charcot–Marie–Tooth disease; CMAP, compound muscle action potential; DML, distal motor latency; MNCV, motor nerve conduction velocity; SNAP, sensory nerve action potential
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Received November 28, 2006. Revised December 24, 2006. Accepted January 15, 2007.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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