[Genetics of amyotrophic lateral sclerosis]

Although the pathophysiology of amyotrophic lateral sclerosis remains currently unknown, involvement of genetic factors is worldwide accepted as a key clue in the motor neuron death. Since 1993 and the discovery of mutation in the SOD1 gene, number of genes linked to or promoting ALS had always growing. Among them, only four (SOD1, TARDBP, FUS and C9ORF72 genes) are unanimously recognized as convincing causative genetic factors for more than 60% of familial and probably 10% of sporadic ALS cases. Geographic origin of the studied populations tends to become one of the major items in the gene-ALS relationship: this was extremely stressed for C9ORF72. Concerning susceptibility genes factors, an increase of the risk of ALS is clearly shown for SMN1 and ATXN2 genes and accepted for some VEGF haplotypes. Finally, some modulating effects might also exist as underline for the relationships between ApoE and ALS that differ between European and North American studies. In inherited ALS, The European Federation of Neurological Societies (EFNS) edited rules that gave a legal frame to situations for which research of mutations were justified. Progress in the field of genetic raises major questions concerning the relevance of genetic studies from asymptomatic relatives. This first implies that the mutation identified in the proband case is perfectly characterized as a pathogenic mutation.