Clinical and molecular advances in autosomal dominant cerebellar ataxias: from genotype to phenotype and physiopathology

Major advances have been made in the understanding of autosomal dominant ce rebellar ataxias since genetic markers came into use in the 1980s. The subs equent mapping of nine genes, six of which have been identified, involved i n this clinically diverse group of disorders highlighted their great geneti c heterogeneity. Evidence is now accumulating that, except for SCA8, the sa me molecular and physiopathological processes, underlie these diseases and other neurodegenerative disorders sharing the same mutational basis, the ex pansion of a (CAG)n-polyglutamine coding sequence. The clinical overlap amo ng the different genetic entities makes prediction of the molecular origin impossible in a single patient so that molecular characterisation is necess ary. However, extended clinical and neuropathological comparisons have show n that each genetic entity has a characteristic constellation of signs and symptoms that are related to CAG repeat size and disease duration. The comb ined genetic and clinical information form the basis of a new classificatio n that will aid better understanding of disease evolution; assure follow up and permit genetic counselling by the clinician.