title: Phenotypic insights into ADCY5-associated disease.
abstract: Adenylyl cyclase 5 (ADCY5) mutations is associated with heterogenous syndromes: familial dyskinesia and facial myokymia; paroxysmal chorea and dystonia; autosomal-dominant chorea and dystonia; and benign hereditary chorea. We provide detailed clinical data on 7 patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations.
  
  
  
  In 5 of the 7 patients, followed over a period of 9 to 32 years, ADCY5 was sequenced by Sanger sequencing. The other 2 unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders and underwent whole-exome sequencing.
  
  
  
  Five patients had the previously reported p.R418W ADCY5 mutation; we also identified two novel mutations at p.R418G and p.R418Q. All patients presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis, dystonia, or myoclonus, with episodic exacerbations during drowsiness being a characteristic feature. Axial hypotonia, impaired upward saccades, and intellectual disability were variable features. The p.R418G and p.R418Q mutation patients had a milder phenotype. Six of seven patients had mild functional gain with clonazepam or clobazam. One patient had bilateral globus pallidal DBS at the age of 33 with marked reduction in dyskinesia, which resulted in mild functional improvement.
  
  
  
  We further delineate the clinical features of ADCY5 gene mutations and illustrate its wide phenotypic expression. We describe mild improvement after treatment with clonazepam, clobazam, and bilateral pallidal DBS. ADCY5-associated dyskinesia may be under-recognized, and its diagnosis has important prognostic, genetic, and therapeutic implications. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.
authors.affiliation: Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney, Australia.
authors.forename: Florence C F
authors.initials: FC
authors.lastname: Chang
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Ana
authors.initials: A
authors.lastname: Westenberger
authors.affiliation: TY Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Westmead, Australia.|University of Sydney, Sydney, Australia.
authors.forename: Russell C
authors.initials: RC
authors.lastname: Dale
authors.affiliation: Department of Neurology, Birmingham Children's Hospital, Birmingham, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Smith
authors.affiliation: College of Medical and Dental Studies, University of Birmingham, Birmingham, United Kingdom.
authors.forename: Hardev S
authors.initials: HS
authors.lastname: Pall
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences Program, Institute of Child Health, University College London, London, United Kingdom.|Department of Child Neurology, Sant Joan de Déu Hospital, University of Barcelona, Spain.
authors.forename: Belen
authors.initials: B
authors.lastname: Perez-Dueñas
authors.affiliation: TY Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Padraic
authors.initials: P
authors.lastname: Grattan-Smith
authors.affiliation: TY Nelson Department of Neurology and Neurosurgery, Children's Hospital at Westmead, Westmead, Australia.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ouvrier
authors.affiliation: Sydney Medical School, University of Sydney, Australia.
authors.forename: Neil
authors.initials: N
authors.lastname: Mahant
authors.affiliation: Hunter Genetics, John Hunter Hospital, Newcastle, Australia.
authors.forename: Bernadette C
authors.initials: BC
authors.lastname: Hanna
authors.affiliation: Hunter Genetics, John Hunter Hospital, Newcastle, Australia.|Genetics of Learning Disability Service, Newcastle, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Hunter
authors.affiliation: Sydney Children's Hospitals Network, Randwick, Australia.
authors.forename: John A
authors.initials: JA
authors.lastname: Lawson
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Max
authors.affiliation: Department of Medical Genetics, Sydney Children's Hospital, Randwick, Australia.
authors.forename: Rani
authors.initials: R
authors.lastname: Sachdev
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences Program, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Esther
authors.initials: E
authors.lastname: Meyer
authors.affiliation: Neurology Department, Gosford Hospital, Gosford, Australia.
authors.forename: Dennis
authors.initials: D
authors.lastname: Crimmins
authors.affiliation: Neurology Department, St George Hospital, Kogarah, Australia.
authors.forename: Donald
authors.initials: D
authors.lastname: Pryor
authors.affiliation: Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney, Australia.
authors.forename: John G L
authors.initials: JG
authors.lastname: Morris
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Alex
authors.initials: A
authors.lastname: Münchau
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Detelina
authors.initials: D
authors.lastname: Grozeva
authors.affiliation: Department of Haematology, University of Cambridge, NHS Blood and Transplant Center, Cambridge, United Kingdom.|Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom.
authors.forename: Keren J
authors.initials: KJ
authors.lastname: Carss
authors.affiliation: Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Lucy
authors.initials: L
authors.lastname: Raymond
authors.affiliation: Molecular Neurosciences, Developmental Neurosciences Program, Institute of Child Health, University College London, London, United Kingdom.
authors.forename: Manju A
authors.initials: MA
authors.lastname: Kurian
authors.affiliation: Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Klein
authors.affiliation: Movement Disorders Unit, Department of Neurology, Westmead Hospital, Sydney, Australia.|Sydney Medical School, University of Sydney, Australia.
authors.forename: Victor S C
authors.initials: VS
authors.lastname: Fung
mesh_terms: D000262:Adenylyl Cyclases / Q000235:genetics*; D000359:Aftercare; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009069:Movement Disorders / Q000235:genetics* / Q000503:physiopathology*; D010375:Pedigree
chemical_list: D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
keywords: adenylyl cyclase; cerebral palsy; chorea; dyskinesia; dystonia