A de novo ADCY5 mutation causes early-onset autosomal dominant chorea and dystonia
Funding agencies: This study was supported by funds from the Strasbourg High Throughput Next Generation Sequencing facility (GENOMAX) and INSERM UMR_S 1109.
Relevant conflicts of interest/financial disclosures: Nothing to report.
Author roles may be found in the online version of this article.
ABSTRACT
Importance
Apart 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.
Observations
Whole 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 Relevance
Our 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
