Résumé :
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Spinal muscular atrophy (SMA) is a clinically and genetically heterogeneous disease characterized by degeneration of lower motor neurons leading to progressive muscle paralysis. The most frequent form is linked to mutations of the SMN1 gene on Chr. 5q13. Genetically separate entities with additional features such as central nervous involvement have been described. A rare variant has been reported by several authors associating lower motor neuron disease and progressive myoclonic epilepsia in childhood. This condition has been reported as an autosomal recessive trait. Our goal is to identify the gene responsible for this defined clinical entity. We collected three families with such phenotype. Extensive metabolic investigation was normal and SMN1 gene was excluded. These data indicate that SMA-PME represents a clinically and genetically separate entity.Whole genome scanning was performed by using Affymetrix 250K SNP microarrays in the two multiplex families, one of them being consanguineous. By using Merlin software, linkage analysis and homozygosity mapping allowed identifying two highly candidate loci on chromosome 8p21 and 13q12 (Zmax= 2.65, _=0). Candidate genes have been selected based on their localization in the candidate regions and their function. Sanger sequencing of 10 genes highly candidate by their function and position are in progress.The identification of such gene should contribute to elucidate the molecular pathway linking myoclonic epilepsia with a motor neuron disease. In addition, we will study the putative link of the pathogenic pathway found in SMA-PME with those already established in several motor neuron diseases which include alterations in DNA/RNA metabolism, axonal transport, intracellular trafficking or mitochondrial functions. Acknowledgement: The authors would like to thank AFM for support.
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