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Review
. 2019 Aug 19;6(7):512-520.
doi: 10.1002/mdc3.12816. eCollection 2019 Sep.

ADCY5-Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder

Nirosen Vijiaratnam  1 , Kailash P Bhatia  2 , Anthony E Lang  3 , Wendy H Raskind  4 , Alberto J Espay  5
Affiliations
Review

ADCY5-Related Dyskinesia: Improving Clinical Detection of an Evolving Disorder

Nirosen Vijiaratnam et al. Mov Disord Clin Pract. .

Abstract

Background: The phenotypic spectrum of adenylyl cyclase 5 (ADCY5)-related disease has expanded considerably since the first description of the disorder in 1978 as familial essential chorea in a multiplex family.

Objective: To examine recent advances in the understanding of ADCY5-related dyskinesia and outline a diagnostic approach to enhance clinical detection.

Methods: A pragmatic review of the ADCY5 literature was undertaken to examine unique genetic and pathophysiological features as well as distinguishing clinical features.

Results: With over 70 cases reported to date, the phenotype is recognized to be broad, although distinctive features include prominent facial dyskinesia, motor exacerbations during drowsiness or sleep arousal, episodic painful dystonic posturing increased with stress or illness, and axial hypotonia with delayed developmental milestones. Uncommon phenotypes include childhood-onset chorea, myoclonus-dystonia, isolated nongeneralized dystonia, and alternating hemiplegia.

Conclusion: The ongoing expansion in clinical features suggests that ADCY5 remains underdiagnosed and may account for a proportion of "idiopathic" hyperkinetic movement disorders. Enhanced understanding of its clinical features may help clinicians improve the detection of complex or uncommon cases.

Keywords: ADCY5 mutation; episodic movement disorders; phenotypic spectrum.

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Figures

Figure 1
Figure 1
Proposed disease mechanism. Stress increases striatal dopamine synthesis and release, heightening receptor sensitivity while activating ADCY5 through GαOLF. ADCY5 mutations result in a gain‐of‐function response to this stimulus with increased binding of ATP by the catalytic pocket (C1a and C2a) as well as downstream decreased PDE10A expression. Both of these increase levels of cAMP and subsequent downstream cellular activity. Abbreviations: D, dopamine; D1R, dopamine receptor 1; GαOLF, stimulatory G protein; ATP, adenosine triphosphate; PKA, protein kinase A; Epac, exchange proteins activated by cAMP; CaC, calcium channels; PDE10A, phosphodiesterase 10A.
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