Phenotypic insights into ADCY5-associated disease.

Neil Mahant,Martin A. Smith ,John A. Lawson,Lucy Raymond,Florence Chang ,Ana Westenberger,Manju A. Kurian,Padraic J. Grattan-Smith ,Christine Klein,Christoph Max,Alex Münchau,Donald Pryor,Dennis Crimmins,Detelina Grozeva,Hardev Pall ,Esther Meyer,Rani Sachdev,Robert Ouvrier ,Matthew Hunter,Victor S.C. Fung,Keren Carss ,Bernadette Hanna ,Belén Pérez‐Dueñas ,Russell C. Dale,John G. Morris

doi:10.1002/mds.26598

Abstract

ABSTRACTBackgroundAdenylyl 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.MethodsIn 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.ResultsFive 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.ConclusionWe 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

Highlights

MethodsFour patients from 3 kindreds (K1, K2, and K5) and 1 sporadic patient (K3-1) followed in one institution over a period of 9 to 32 years were suspected of harboring adenylyl cyclase 5 (ADCY5) mutations based on their clinical features
In 2011, at the 5th International Dystonia Symposium in Barcelona, we reported on 4 patients with a syndrome we described as “familial choreoathetosis with exacerbations during drowsiness”[6] (Supporting Fig. 1)
We describe novel clinical features associated with adenylyl cyclase 5 (ADCY5)-related dyskinesia that distinguish this disorder from other hyperkinetic movement disorders

Summary

Methods

Four patients from 3 kindreds (K1, K2, and K5) and 1 sporadic patient (K3-1) followed in one institution over a period of 9 to 32 years were suspected of harboring ADCY5 mutations based on their clinical features. For subjects K1-1, K2-1, K3-1, and K5-1 (Fig. 1), as well as the clinically unaffected parents of K3-1, Sanger sequencing of exons 2, 8, and 10 (harboring mutations reported in the literature) and corresponding exon-intron junctions (a minimum of 50 base pairs of intronic DNA flanking each of the three analyzed exons) of the ADCY5 gene was carried out using an ABI 3500XL automated sequencer (Applied Biosystems, Foster City, CA). A further 2 unrelated patients (K4-1 and K6-1 and their clinically unaffected parents) who participated in a whole-exome sequencing study of undiagnosed pediatric movement disorder cases were identified as having ADCY5 mutations and included in the clinical analysis (Supporting Methods)

Results

Discussion

Conclusion