Functional characterization of AC5 gain-of-function variants: Impact on the molecular basis of ADCY5-related dyskinesia

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.

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Vijiaratnam

Bhatia

Lang

et al. 2019

“…We have previously shown that this missense variant confers gain of function in vitro with respect to generation of cAMP upon stimulation. 8 The relationship of increased function to increased ADCY5 immunoreactivity is unknown. Perhaps the mutation affects ADCY5 degradation, allowing it to accumulate.…”

Section: Discussionmentioning

confidence: 99%

“…Although of unclear biological significance, we were struck by the widespread increased ADCY5 immunoreactivity in a granular pattern in neurons throughout the brain. We have previously shown that this missense variant confers gain of function in vitro with respect to generation of cAMP upon stimulation . The relationship of increased function to increased ADCY5 immunoreactivity is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…All five missense and in-frame deletion variants that we studied in vitro confer increased ability to generate cAMP in response to beta-adrenergic or G αs -mediated stimulation and significantly reduce inhibition following D2 dopamine receptor activation. 7,8 The homozygous missense variants reported in two families 4,5 and a splice site variant in another 9 are thought to act through loss of function.…”

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confidence: 99%

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Hyperphosphorylated Tau, Increased Adenylate Cyclase 5 (ADCY5) Immunoreactivity, but No Neuronal Loss in ADCY5‐Dyskinesia

Chen

Latimer

Spencer

et al. 2019

Background Background: Adenylate cyclase 5 (ADCY5)-related dyskinesia is a childhood-onset movement disorder. Manifestations vary in frequency and severity and may include chorea, tremor, dystonia, facial twitches, myoclonus, axial hypotonia, and limb hypertonia. Psychosis is likely part of the broader spectrum. ADCY5 is widely expressed in the brain, especially in the striatum. Previous reports of brain autopsies of 2 subjects with likely ADCY5-dyskinesia were limited by the absence of a molecular diagnosis. In 1 case, normal gross pathology was reported. In the other case, ADCY5 expression was not examined and neuropathological findings were confounded by age and comorbidities. Objectives Objectives: To examine ADCY5 expression and neuropathological changes in ADCY5-dyskinesia. Methods Methods: An extensive brain autopsy, including immunohistochemical analyses with antibodies to paired helical filament tau, α-synuclein, amyloid-β, microtubule-associated protein 2, and ADCY5, was performed. ResultsResults: The patient, with a p.M1029K ADCY5 variant, had severe dyskinesias from early childhood, later recurrent episodes of psychosis, and died at age 46. Gross pathology was unremarkable, but we detected increased immunoreactivity for ADCY5 in neurons in multiple brain regions. Despite no history of brain trauma to suggest chronic traumatic encephalopathy, we found tau deposits in the deep cortical sulci, midbrain, and hippocampus with minimal amyloid pathology and no Lewy bodies. Conclusions Conclusions: We present the first brain autopsy findings in a molecularly proven case of ADCY5-dyskinesia, showing increased ADCY5 immunoreactivity in neurons and evidence of tau deposition. Additional patients will need to be studied to determine whether increased immunoreactivity for ADCY5 is a signature for ADCY5-dyskinesia and whether this disease has a tauopathy component.

Scoping Review onADCY5‐Related Movement Disorders

Menon,

Nilles,

Silveira‐Moriyama

et al. 2023

Background Adenylyl cyclase 5 (ADCY5)‐related movement disorder (ADCY5‐RMD) is a rare, childhood‐onset disease resulting from pathogenic variants in the ADCY5 gene. The clinical features, diagnostic options, natural history, and treatments for this disease are poorly characterized and have never been established through a structured approach. Objective This scoping review attempts to summarize all available clinical literature on ADCY5‐RMD. Methods Eighty‐seven articles were selected for inclusion in this scoping review. The majority of articles identified were case reports or case series. Results These articles demonstrate that patients with ADCY5‐RMD suffer from permanent and/ or paroxysmal hyperkinetic movements. The paroxysmal episodes can be worsened by environmental triggers, in particular the sleep–wake transition phase in the early morning. Occurrence of nocturnal paroxysmal dyskinesias and perioral twitches are highly suggestive of the diagnosis when present. In the majority of patients intellectual capacity is preserved. ADCY5‐RMD is considered a non‐progressive disorder, with inter‐individual variations in evolution with aging. Somatic mosaicism, mode of inheritance and the location of the mutation within the protein can influence phenotype. Conclusions The current evidence for therapeutic options for ADCY5‐RMD is limited: caffeine, benzodiazepines and deep brain stimulation have been consistently reported to be useful in case reports and case series.