A De Novo ADCY5 Mutation Causes Early-Onset Autosomal Dominant Chorea and Dystonia

ImportanceApart from Huntington's disease, little is known of the genetics of autosomal dominant chorea associated with dystonia. Here we identify adenylate cyclase 5 (ADCY5) as a likely new causal gene for early-onset chorea and dystonia. ObservationsWhole exome sequencing in a three-generation family affected with autosomal dominant chorea associated with dystonia identified a single de novo mutationc.2088+1G>A in a 5' donor splice-site of ADCY5segregating with the disease. This mutation seeming leads to RNA instability and therefore ADCY5 haploinsufficiency. Conclusions and RelevanceOur finding confirms the genetic/clinical heterogeneity of the disorder; corroborated by previous identification of ADCY5 mutations in one family with dyskinesia-facial myokymia and in two unrelated sporadic cases of paxoysmal choreic/dystonia-facial myokymia; ADCY5's high expression in the striatum and movement disorders in ADCY5-deficient mice. Hence ADCY5 genetic analyses may be relevant in the diagnostic workup of unexplained early-onset hyperkinetic movement disorders. (c) 2014 International Parkinson and Movement Disorder Society