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ADCY5 mutations are another cause of benign hereditary chorea

Mencacci, NE; Erro, R; Wiethoff, S; Hersheson, J; Ryten, M; Balint, B; Ganos, C; ... Bhatia, KP; + view all (2015) ADCY5 mutations are another cause of benign hereditary chorea. Neurology , 85 (1) pp. 80-88. 10.1212/WNL.0000000000001720. Green open access

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Abstract

OBJECTIVE: To determine the contribution of ADCY5 mutations in cases with genetically undefined benign hereditary chorea (BHC). METHODS: We studied 18 unrelated cases with BHC (7 familial, 11 sporadic) who were negative for NKX2-1 mutations. The diagnosis of BHC was based on the presence of a childhood-onset movement disorder, predominantly characterized by chorea and no other major neurologic features. ADCY5 analysis was performed by whole-exome sequencing or Sanger sequencing. ADCY5 and NKX2-1 expression during brain development and in the adult human brain was assessed using microarray analysis of postmortem brain tissue. RESULTS: The c.1252C>T; p.R418W mutation was identified in 2 cases (1 familial, 1 sporadic). The familial case inherited the mutation from the affected father, who had a much milder presentation, likely due to low-grade somatic mosaicism. The mutation was de novo in the sporadic case. The clinical presentation of these cases featured nonparoxysmal generalized chorea, as well as dystonia in the most severely affected, but no facial myokymia. We observed significant progression of symptoms in ADCY5 mutation carriers, in contrast to BHC secondary to NKX2-1 mutations. The difference in the clinical course is mirrored by the brain expression data, showing increasing ADCY5 expression in the striatum during brain development, whereas NKX2-1 shows an opposite trend. CONCLUSIONS: Our study identifies mutations in ADCY5, the gene previously linked to familial dyskinesia with facial myokymia, as a cause of familial and sporadic BHC. ADCY5 genetic analysis should be performed in cases with a benign choreiform movement disorder even in the absence of facial myokymia.

Type: Article
Title: ADCY5 mutations are another cause of benign hereditary chorea
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1212/WNL.0000000000001720
Publisher version: http://dx.doi.org/10.1212/WNL.0000000000001720
Language: English
Additional information: Copyright © 2015 American Academy of Neurology. This article is available under Creative Commons Attribution Licence (CC BY)
Keywords: Adenylyl Cyclases, Adult, Chorea, Humans, Male, Middle Aged, Mutation, Pedigree, Young Adult
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Clinical and Movement Neurosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Genetics and Genomic Medicine Dept
URI: https://discovery.ucl.ac.uk/id/eprint/1480405
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