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A de novo ADCY5 mutation causes early‐onset autosomal dominant chorea and dystonia
Author(s) -
Carapito Raphael,
Paul Nicodème,
Untrau Meiggie,
Le Gentil Marion,
Ott Louise,
Alsaleh Ghada,
Jochem Pierre,
Radosavljevic Mirjana,
Le Caignec Cédric,
David Albert,
Damier Philippe,
Isidor Bertrand,
Bahram Seiamak
Publication year - 2015
Publication title -
movement disorders
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.352
H-Index - 198
eISSN - 1531-8257
pISSN - 0885-3185
DOI - 10.1002/mds.26115
Subject(s) - chorea , dystonia , athetosis , movement disorders , dyskinesia , paroxysmal dyskinesia , haploinsufficiency , frameshift mutation , genetics , neuroscience , medicine , mutation , psychology , parkinson's disease , disease , biology , pathology , gene , phenotype
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