ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations

Dong Hui Chen, Aurélie Méneret, Jennifer R. Friedman, Olena Korvatska, Alona Gad, Emily S. Bonkowski, Holly A. Stessman, Diane Doummar, Cyril Mignot, Mathieu Anheim, Saunder Bernes, Marie Y. Davis, Nathalie Damon-Perrière, Bertrand Degos, David Grabli, Domitille Gras, Fuki M. Hisama, Katherine M. MacKenzie, Phillip D. Swanson, Christine TranchantMarie Vidailhet, Steven Winesett, Oriane Trouillard, Laura M. Amendola, Michael O. Dorschner, Michael Weiss, Evan E. Eichler, Ali Torkamani, Emmanuel Roze, Thomas D. Bird, Wendy H. Raskind

Research output: Contribution to journalArticlepeer-review

86 Scopus citations


To investigate the clinical spectrum and distinguishing features of adenylate cyclase 5 (ADCY5)-related dyskinesia and genotype-phenotype relationship. Methods: We analyzed ADCY5 in patients with choreiform or dystonic movements by exome or targeted sequencing. Suspected mosaicism was confirmed by allele-specific amplification. We evaluated clinical features in our 50 new and previously reported cases. Results: We identified 3 new families and 12 new sporadic cases with ADCY5 mutations. These mutations cause a mixed hyperkinetic disorder that includes dystonia, chorea, and myoclonus, often with facial involvement. The movements are sometimes painful and show episodic worsening on a fluctuating background. Many patients have axial hypotonia. In 2 unrelated families, a p.A726T mutation in the first cytoplasmic domain (C1) causes a relatively mild disorder of prominent facial and hand dystonia and chorea. Mutations p.R418W or p.R418Q in C1, de novo in 13 individuals and inherited in 1, produce a moderate to severe disorder with axial hypotonia, limb hypertonia, paroxysmal nocturnal or diurnal dyskinesia, chorea, myoclonus, and intermittent facial dyskinesia. Somatic mosaicism is usually associated with a less severe phenotype. In one family, a p.M1029K mutation in the C2 domain causes severe dystonia, hypotonia, and chorea. The progenitor, whose childhood-onset episodic movement disorder almost disappeared in adulthood, was mosaic for the mutation. Conclusions: ADCY5-related dyskinesia is a childhood-onset disorder with a wide range of hyperkinetic abnormal movements. Genotype-specific correlations and mosaicism play important roles in the phenotypic variability. Recurrent mutations suggest particular functional importance of residues 418 and 726 in disease pathogenesis.

Original languageEnglish (US)
Pages (from-to)2026-2035
Number of pages10
Issue number23
StatePublished - Dec 8 2015
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Clinical Neurology


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