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 language | English (US) |
|---|---|
| Pages (from-to) | 2026-2035 |
| Number of pages | 10 |
| Journal | Neurology |
| Volume | 85 |
| Issue number | 23 |
| DOIs | |
| State | Published - Dec 8 2015 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Clinical Neurology
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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 journal › Article
}
TY - JOUR
T1 - ADCY5-related dyskinesia
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
Y1 - 2015/12/8
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.
UR - http://www.scopus.com/inward/record.url?scp=84949488896&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84949488896&partnerID=8YFLogxK
U2 - 10.1212/WNL.0000000000002058
DO - 10.1212/WNL.0000000000002058
M3 - Article
C2 - 26537056
AN - SCOPUS:84949488896
VL - 85
SP - 2026
EP - 2035
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 23
ER -