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 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 & 11 others 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

Research output: Contribution to journalArticle

51 Citations (Scopus)

Abstract

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
JournalNeurology
Volume85
Issue number23
DOIs
StatePublished - Dec 8 2015
Externally publishedYes

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Dyskinesias
Genetic Association Studies
Adenylyl Cyclases
Chorea
Mutation
Muscle Hypotonia
Mosaicism
Dystonia
Genotype
Hyperkinesis
Exome
Dystonic Disorders
Phenotype
Myoclonus
Movement Disorders
Extremities
Hand
Alleles

All Science Journal Classification (ASJC) codes

  • Clinical Neurology

Cite this

Chen, D. H., Méneret, A., Friedman, J. R., Korvatska, O., Gad, A., Bonkowski, E. S., ... Raskind, W. H. (2015). ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations. Neurology, 85(23), 2026-2035. https://doi.org/10.1212/WNL.0000000000002058

ADCY5-related dyskinesia : Broader spectrum and genotype-phenotype correlations. / Chen, Dong Hui; Méneret, Aurélie; Friedman, Jennifer R.; Korvatska, Olena; Gad, Alona; Bonkowski, Emily S.; Stessman, Holly; Doummar, Diane; Mignot, Cyril; Anheim, Mathieu; Bernes, Saunder; Davis, Marie Y.; Damon-Perrière, Nathalie; Degos, Bertrand; Grabli, David; Gras, Domitille; Hisama, Fuki M.; MacKenzie, Katherine M.; Swanson, Phillip D.; Tranchant, Christine; Vidailhet, Marie; Winesett, Steven; Trouillard, Oriane; Amendola, Laura M.; Dorschner, Michael O.; Weiss, Michael; Eichler, Evan E.; Torkamani, Ali; Roze, Emmanuel; Bird, Thomas D.; Raskind, Wendy H.

In: Neurology, Vol. 85, No. 23, 08.12.2015, p. 2026-2035.

Research output: Contribution to journalArticle

Chen, DH, Méneret, A, Friedman, JR, Korvatska, O, Gad, A, Bonkowski, ES, Stessman, H, Doummar, D, Mignot, C, Anheim, M, Bernes, S, Davis, MY, Damon-Perrière, N, Degos, B, Grabli, D, Gras, D, Hisama, FM, MacKenzie, KM, Swanson, PD, Tranchant, C, Vidailhet, M, Winesett, S, Trouillard, O, Amendola, LM, Dorschner, MO, Weiss, M, Eichler, EE, Torkamani, A, Roze, E, Bird, TD & Raskind, WH 2015, 'ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations', Neurology, vol. 85, no. 23, pp. 2026-2035. https://doi.org/10.1212/WNL.0000000000002058
Chen DH, Méneret A, Friedman JR, Korvatska O, Gad A, Bonkowski ES et al. ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations. Neurology. 2015 Dec 8;85(23):2026-2035. https://doi.org/10.1212/WNL.0000000000002058
Chen, Dong Hui ; Méneret, Aurélie ; Friedman, Jennifer R. ; Korvatska, Olena ; Gad, Alona ; Bonkowski, Emily S. ; Stessman, Holly ; Doummar, Diane ; Mignot, Cyril ; Anheim, Mathieu ; Bernes, Saunder ; Davis, Marie Y. ; Damon-Perrière, Nathalie ; Degos, Bertrand ; Grabli, David ; Gras, Domitille ; Hisama, Fuki M. ; MacKenzie, Katherine M. ; Swanson, Phillip D. ; Tranchant, Christine ; Vidailhet, Marie ; Winesett, Steven ; Trouillard, Oriane ; Amendola, Laura M. ; Dorschner, Michael O. ; Weiss, Michael ; Eichler, Evan E. ; Torkamani, Ali ; Roze, Emmanuel ; Bird, Thomas D. ; Raskind, Wendy H. / ADCY5-related dyskinesia : Broader spectrum and genotype-phenotype correlations. In: Neurology. 2015 ; Vol. 85, No. 23. pp. 2026-2035.
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abstract = "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.",
author = "Chen, {Dong Hui} and Aur{\'e}lie M{\'e}neret and Friedman, {Jennifer R.} and Olena Korvatska and Alona Gad and Bonkowski, {Emily S.} and Holly Stessman and Diane Doummar and Cyril Mignot and Mathieu Anheim and Saunder Bernes and Davis, {Marie Y.} and Nathalie Damon-Perri{\`e}re and Bertrand Degos and David Grabli and Domitille Gras and Hisama, {Fuki M.} and MacKenzie, {Katherine M.} and Swanson, {Phillip D.} and Christine Tranchant and Marie Vidailhet and Steven Winesett and Oriane Trouillard and Amendola, {Laura M.} and Dorschner, {Michael O.} and Michael Weiss and Eichler, {Evan E.} and Ali Torkamani and Emmanuel Roze and Bird, {Thomas D.} and Raskind, {Wendy H.}",
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T2 - Broader spectrum and genotype-phenotype correlations

AU - Chen, Dong Hui

AU - Méneret, Aurélie

AU - Friedman, Jennifer R.

AU - Korvatska, Olena

AU - Gad, Alona

AU - Bonkowski, Emily S.

AU - Stessman, Holly

AU - Doummar, Diane

AU - Mignot, Cyril

AU - Anheim, Mathieu

AU - Bernes, Saunder

AU - Davis, Marie Y.

AU - Damon-Perrière, Nathalie

AU - Degos, Bertrand

AU - Grabli, David

AU - Gras, Domitille

AU - Hisama, Fuki M.

AU - MacKenzie, Katherine M.

AU - Swanson, Phillip D.

AU - Tranchant, Christine

AU - Vidailhet, Marie

AU - Winesett, Steven

AU - Trouillard, Oriane

AU - Amendola, Laura M.

AU - Dorschner, Michael O.

AU - Weiss, Michael

AU - Eichler, Evan E.

AU - Torkamani, Ali

AU - Roze, Emmanuel

AU - Bird, Thomas D.

AU - Raskind, Wendy H.

PY - 2015/12/8

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N2 - 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.

AB - 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.

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