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

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.

Address correspondence and reprint requests to Dr. L. Viollet, Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U393, Hôpital Necker Enfants Malades, 149 rue de Sèvres, F-75743 Paris Cedex 15, France; e-mail: viollet{at}necker.fr

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 (Z_max = 3.79 at = 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.

Additional material related to this article can be found on the Neurology Web site. Go to www.neurology.org and scroll down the Table of Contents for the July 11 issue to find the title link for this article.

This article was previously published in electronic format as an Expedited E-Pub on May 25, 2006, at www.neurology.org.

Supported by the Association Française contre les Myopathies (A.F.M.), the Fond National Belge de la Recherche Scientifique (F.N.R.S.), and the Association Belge contre les Maladies Neuro-Musculaires (A.B.M.M.).

Disclosure: The authors report no conflicts of interest.

Received January 17, 2006. Accepted in final form March 17, 2006.