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 Tranchant, Marie 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, 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 Tranchant, Marie 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
Abstract
Objective: 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.
© 2015 American Academy of Neurology.
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Source: PubMed