A de novoADCY5 mutation causes early‐onset autosomal dominant chorea and dystonia

• DOI: 10.1002/mds.26115
• Publication Date: 2014-12-27T16:41:33Z
• Authors: Raphael Carapito; Nicodème Paul; Meiggie Untrau; Marion Le Gentil; Louise Ott; Ghada Alsaleh; Pierre Jochem; Mirjana Radosavlj...; Cédric Le Caignec; Albert David; Philippe Damier; Bertrand Isidor; Seiamak Bahram
• Keywords: Adult; Family Health; Male; 0301 basic medicine; Adolescent; DNA Mutational Analysis; 03 medical and health sciences; Chorea; Dystonic Disorders; Mutation; Humans; Female; Adenylyl Cyclases

ABSTRACTImportanceApart 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 mutation—c.2088+1G>A in a 5' donor splice‐site of ADCY5—segregating 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. © 2014 International Parkinson and Movement Disorder Society