Phenotypic insights into ADCY5-associated disease

Florence Chang, Hardev Pall

Research output: Contribution to journalArticlepeer-review

70 Citations (Scopus)


Background: Adenylyl cyclase 5 (ADCY5) mutations have recently been reported to as the cause ofcausis associated with a number of different heterogenous syndromes:e familial dyskinesia and facial myokymia, paroxysmal chorea and dystonia, autosomal-dominant chorea and dystonia, and benign hereditary chorea.

Objective: We provide detailed clinical data on seven patients from six new kindreds with mutations in the ADCY5 gene, in order to expand and define the phenotypic spectrum of ADCY5 mutations.

Method: In five of the seven patients, followed over a period of 9 to -32 years, ADCY5 was sequenced by Sanger sequencing. The other two unrelated patients participated in studies for undiagnosed pediatric hyperkinetic movement disorders, and underwent whole exome sequencing.

Results: Five Three patients (three from two kindreds and two sporadic) patients, all with the p.R418W ADCY5 mutation, had been diagnosed with dyskinetic cerebral palsy (CP) and presented with motor milestone delay, infantile-onset action-induced generalized choreoathetosis with episodic exacerbations during drowsiness, (CWEDD) and axial hypotonia leading to a previous diagnosis of cerebral palsy. A fifth probandsixth patient with had autosomal-dominant myoclonus-dystonia (MD) caused by a novel p.R418G ADCY5 changemutation presented with a milder phenotype of had autosomal-dominant myoclonus-dystonia (MD) caused by. The sixth subjectseventh patient, carrier of a novel p.R418Q mutation, was affected by sporadic infantile-onset isolated chorea (IOIC). Six out of seven patients had reduction of the episodic movement disorder with clonazepam or clobazam. Most patients had reduction of the episodic movement disorder with clonazepam or clobazam.

Conclusion: We further delineate the clinical features of ADCY5 gene mutations and illustrates its wide phenotypic presentation. We describe mild improvement following treatment with clonazepam, clobazem and bilateral pallidal deep brain stimulation. ADCY5 associated dyskinesia may be under-recognized and its diagnosis has important prognostic, genetic and therapeutic implications. We observed three distinct clinical syndromes each caused by a different mutation affecting the same amino acid, and thus, showing a strong genotype-phenotype correlation. In addition, we expand the phenotypic spectrum of ADCY5 mutations to include: 1) infantile-onset CWEDD, 2) MD, and 3) IOIC. A progressive movement disorder masquerading as dyskinetic CP may be the most common phenotype of ADCY5 mutations.
Original languageEnglish
Pages (from-to)1033-1040
JournalMovement Disorders
Issue number7
Early online date8 Apr 2016
Publication statusPublished - 4 Jul 2016

Bibliographical note

Authors: Florence CF Chang, FRACP1, Ana Westenberger, Phd2, Russell C Dale, Phd3,4, Martin Smith, Phd FRCPCH5, Hardev S Pall, FRCP18, Belen Perez-Dueñas, MD Phd6,7, Padraic Grattan-Smith, MD3, Robert A Ouvrier, MD FRACP3, Neil Mahant, FRACP Phd8, Bernedette C Hanna, MBBS9 , Matthew Hunter, FRACP9,10, John A Lawson, FRACP PhD11, Christoph Max, MD2, Rani Sachdev, MD12, Esther Meyer, Phd6, Dennis Crimmins, FRACP13, Donald Pryor, FRACP14, John GL Morris, MD1, Alex Münchau, MD2, Detelina Grozeva, Phd15, Keren J Carss, Phd15-17, Lucy Raymond, Phd FRCP15, Manju A Kurian, Phd MRCPCH6, Christine Klein, MD2, Victor SC Fung, FRACP Phd1,8.


  • Adenylyl cyclase
  • dyskinesia
  • chorea
  • dystonia
  • cerebral palsy


Dive into the research topics of 'Phenotypic insights into ADCY5-associated disease'. Together they form a unique fingerprint.

Cite this