Dominantly inherited ataxias

Molecular genetic studies in the past decade have demonstrated the enormous genetic heterogeneity among the dominantly inherited ataxias. Mutations at several distinct loci give rise to the progressive dominant ataxias and at least 2 different mutations cause episodic ataxias with dominant inheritan ce. The well-established genotypes for progressive dominant ataxias have al l involved expansions of repeated CAG sequences. Clinically these patients present with progressive cerebellar deficits as well as signs relating to p athology in other neural systems in a variable fashion. Some of these other signs serve as diagnostic clues to the underlying genotype, but the identi fication of the genotype from the clinical phenotype alone is usually diffi cult. The CAG expansions involved usually are unstable with intergeneration al expansions as well as contractions of the repeat size. Phenotypic featur es such as age of onset and to a lesser extent disease progression rate and the presence of specific clinical signs depend on the CAG repeat size. Ide ntification of the mutations has allowed precise genotypic diagnosis in sev eral families allowing more accurate genetic counseling, including predicti ve testing of at risk individuals when sought. Also, increasing information about the gene products and their abnormal distributions in disease brain is rapidly giving rise to rational ideas about the pathogenesis of neuronal degeneration in these diseases and raising hope for meaningful treatment s trategies.