Résumé :
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ALS is the most common adult-onset motor neuron disease. Described in 1869, by the French Neurobiologist J. M. Charcot, the primary disease hallmark is the selective and progressive degeneration of the neurons in the corticospinal tracts. ALS presents a wide range of heritability from sporadic patients (90%), who lack a family history (SALS), to families with a fully penetrant ALS phenotype (FALS), that is mostly consistent with an autosomal dominant Mendelian inheritance pattern (10%). Sporadic and familial ALS produce similar clinical and pathological features, affecting the same neurons, and cannot be distinguished from each other on clinical grounds. Five well-defined Mendelian gene defects have been reported to give rise to FALS; these genes are SOD1, alsin, senataxin, VAPB and dynactin. Many other distinct loci have been identified on several other chromosomes in recent years. The discovery of SOD1 mutations to give rise to ALS was a major breakthrough in ALS research. SOD1 mutations give rise to the most common form of inherited ALS, accounting for around 20% of FALS patients. To date, more than 130 SOD1 gene mutations have been reported, that are scattered throughout all five exons, and lead to specific degeneration of motor neurons, mostly with a gain-of-function type of mechanism. Analyses of these gene defects in animal and cell culture models, have generated new insights into the diverse molecular pathways involved in ALS pathogenesis. Insights from studies of ALS-causing gene mutations are predicted to apply also to sporadic ALS, which is thought to be multifactorial, both environmental and genetic components contributing to its pathogenesis. It is suspected, that the sporadic forms of ALS (and also other neurodegenerative disorders) are caused by multiple genetic variants, that individually make relatively low contributions to risk. Genome-wide association studies are the most efficient way to discover genetic factors with weak contributions to risk for any disease. Today, this technology is efficiently being applied to ALS.
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