Phenotypic insights into ADCY5 ‐associated disease

Abstract

BackgroundAdenylyl 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

Facial twitches in ADCY5 -associated disease - Myokymia or myoclonus? An electromyography study

“…In line with the descriptions of Chang et al [1] and Mencacci et al [6], who did not find myokymia during EMG recordings, we also could not demonstrate discharge patterns typical for myokymia.…”

“…However, a subsequent EMG study in the same individuals did not show fibrillations, fasciculations, myokymia, or myotonia in different muscles [3]. These findings were supported by other studies where EMG in ADCY5 mutation carriers failed to show myokymia [1,4,6]. Myokymia typically but not exclusively occurs in peripheral nerve damage and is defined as an EMG pattern with repetitive discharges of doublets, triplets and groups of monomorphic motor unit potential discharges [7].…”

International Union of Basic and Clinical Pharmacology. CI. Structures and Small Molecule Modulators of Mammalian Adenylyl Cyclases

“…Expression of the two AC5 mutants in intact HEK293 cells massively increased cAMP accumulation compared with wild-type AC5 upon stimulation with the bAR agonist isoproterenol (Chen et al, 2014b). These data indicate a gain-offunction in the nonconservative R418W and A726T mutants at the molecular level and are consistent with a gain-of-function on the extrapyramidal movement level (Chen et al, 2012c(Chen et al, , 2014bChang et al, 2016). The AC regions in which the mutations are localized have not yet been resolved crystallographically.…”

“…The AC regions in which the mutations are localized have not yet been resolved crystallographically. Other nonconservative mutations in the ADCY5 gene (R418G and R418Q) are associated with dystonia, myoclonus, and choreoathetosis, too (Chen et al, 2015b;Chang et al, 2016). In line with these data, the R418W mutation may cause benign hereditary chorea (Mencacci et al, 2015).…”

ADCY5-related dyskinesia: Comments on characteristic manifestations and variant-associated severity

“…We have been gratified by the spate of publications on ADCY5-related dyskinesia, including that of Chang and colleagues, 1 since we first identified the causative gene. 2 This heightened awareness will enable expansion of the spectrum of mutations and definition of the range of manifestations.…”