Neurology
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Published online before print May 25, 2006, doi:10.1212/01.wnl.0000223834.55225.2d)
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Received January 17, 2006
Accepted March 17, 2006

A gene for an autosomal recessive lower motor neuron disease with childhood onset maps to 1p36

I. Maystadt MD, M. Zarhrate , D. Leclair-Richard MD, B. Estournet MD, A. Barois MD, F. Renault MD, M.-C. Routon MD, M.-C. Durand MD, S. Lefebvre PhD, A. Munnich MD, PhD, C. Verellen-Dumoulin MD, PhD, and L. Viollet MD, PhD

From Unité de Recherches sur les Handicaps Génétiques de l’Enfant (I.M., M.Z., A.M., L.V.), INSERM U393, Hôpital Necker Enfants Malades, Unité de Neurophysiologie (F.R.), Hôpital Armand-Trousseau, Unité de Neuro-Anatomo-Pathologie (M.-C.R.), Hôpital Armand-Trousseau, and Institut Jacques-Monod (S.L.), UMR CNRS 7592 Université Paris 6-7, Paris, and Fédération de Médecine de l’Enfant (D.L.-R.) and Service d’Exploration Fonctionnelle (M.-C.D.), Hopital Raymond Poincaré, Garches, France; and Centre de Génétique Humaine (I.M., C.V.-D.), Université Catholique de Louvain, Bruxelles, Belgique.


Abstract-- Objective: To describe the clinical features of a novel variant of autosomal recessive lower motor neuron disease (LMND) with childhood onset and to map the disease-causing gene.

Methods: The authors performed a clinical study in a large consanguineous African family. After linkage exclusion to SMN1 and SOD1 loci, they performed a genome-wide linkage analysis to map the underlying genetic defect.

Results: This novel variant of LMND with childhood onset and autosomal recessive mode of inheritance is characterized by a progressive symmetric and generalized involvement of the musculature. Four of the five affected patients had muscle weakness since age 3, strongly worsening during childhood and leading to generalized tetraplegia in adulthood. Genetic analyses using homozygosity mapping strategy assigned this progressive generalized LMND locus to an interval of 3.9 cM (or 1.5 megabases) on chromosome 1p36, between loci D1S508 and D1S2633 (Zmax = 3.79 at {theta} = 0.00 at locus D1S253). This region encloses 27 candidate genes.

Conclusion: Genetic mapping of a novel rare phenotype of lower motor neuron disease opens the way toward the identification of a new gene involved in motor neuron degeneration, located in the 1p36 chromosomal region.






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