Brain Advance Access originally published online on November 7, 2003
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Brain, Vol. 127, No. 1, 154-163, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh021
Phenotypic variability in autosomal recessive axonal Charcot–Marie–Tooth disease due to the R298C mutation in lamin A/C
1 Service de Neurologie, Centre Hospitalier Universitaire Mustapha, 2 Laboratoire de Biologie Moleculaire, Institut Pasteur, 3 Service de Neurologie, Centre Hospitalier Universitaire de Ben-Aknoun, Alger, Algeria, 4 U 289 INSERM, 5 Département de Génétique, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Paris, 6 Centre Hospitalier Universitaire Dupuytren, Service de Neurologie, Limoges and 7 Généthon, Evry, France
Correspondence to: Pr M. Tazir, Service de Neurologie, CHU Mustapha 16.000 Algiers, Algeria E-mail: meriemtazir{at}hotmail.com
Autosomal recessive forms of axonal Charcot–Marie–Tooth (ARCMT2) disease are frequent in some areas, such as North Africa and the Middle East, since consanguineous marriages are still common there. Recently, a unique homozygous mutation in LMNA, which encodes lamin A/C, a component of the nuclear envelope, was identified in members of three Algerian families with ARCMT2 linked to chromosome 1q21.2-q21.3. In the present study we describe a group of 21 ARCMT2 patients from seven unrelated Algerian families with the same R298C mutation in the lamin A/C gene and marked variability of the clinical phenotype. There is a wide range of age of onset, from 6 to 27 years, with a mean of 14.4 ± 4.6 years. The course of the disease varies considerably from one patient to another. Twelve patients with a disease duration of 10–15 years had a severe CMT phenotype with distal wasting and weakness of all four limbs and areflexia associated with involvement of the proximal lower limb muscles. In contrast, nine patients had the classical CMT phenotype with mild functional disability without proximal lower limb involvement after a disease duration of 5–18 years. Electrophysiological studies showed a median motor nerve conduction velocity (MNCV) in the normal range in almost all the patients. MNCV and compound muscle action potential (CMAP) values were inversely correlated with the disease duration and the MNCV was strictly related to the CMAP, strongly supporting a pure axonal process without a demyelinating component. Six patients had a nerve biopsy, which revealed severe rarefaction of myelinated fibres in all cases and an increased density of unmyelinated fibres in the majority of cases. In conclusion, the ARCMT2 associated with the R298C mutation differs from other types of ARCMT2. The variability among patients in the age of onset and the course of the disease strongly suggests the action of modifying genes, which remain to be identified.
Key Words: autosomal recessive CMT; lamin A/C gene mutation; phenotypic variability; modifying genes
Abbreviations: ARCMT = autosomal recessive Charcot–Marie–Tooth; CMAP = compound muscle action potential; GDAP = ganglioside-induced differentiation-associated protein; MNCV = motor nerve conduction velocity
Received April 24, 2003. Revised July 11, 2003. Accepted July 30, 2003.
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