Recurrent ADCY5 Mutation in Mosaic Form with Nocturnal Paroxysmal Dyskinesias and Video Electroencephalography Documentation of Dramatic Response to Caffeine Treatment

Shetty, Kuldeep; Sarma, Asodu Sandeep; Devan, Meera; Dalal, Ashwin; Dash, Gopal Krishna; Jannabhatla, Apuroopa; Patil, Siddaramappa Jagadish

doi:10.14802/jmd.20014

Cited by 14 publications

(18 citation statements)

References 7 publications

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“…Caffeine is a psychotropic agent acting as an antagonist of adenosine GPCRs in mammals ( 39 ). Recent observations suggest that this drug may improve motor symptoms in subjects with dominant mutations in the ADCY5 gene ( 40 , 41 ), coding for the cAMP-generating enzyme adenylyl cyclase 5 (AC5), the predominant AC isoform in the striatum ( 42 ). GOF variants in this gene underlie familial dyskinesia with facial myokymia (MIM # 606 703), an autosomal dominant childhood-onset disease characterized by hyperkinetic MD resembling that observed in NEDIM ( 12 ).…”

Section: Resultsmentioning

confidence: 99%

“…Caffeine-induced improvement of cognitive performance in PD patients ( 65 ) further supports the view that this drug acts as a neuroprotective agent, with great benefits in terms of motor control ( 66 ). Finally, caffeine may improve motor symptoms in subjects with dominant ADCY5 mutations ( 40 , 41 ), which cause a childhood-onset hyperkinetic MD reminiscent of NEDIM ( 12 ). A related clinical trial is currently in progress ( ClinicalTrials.gov Identifier: NCT04469283).…”

Section: Discussionmentioning

confidence: 99%

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Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia

Rocco

Galosi

Lanza

et al. 2021

Human Molecular Genetics

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Dominant GNAO1 mutations cause an emerging group of childhood-onset neurological disorders characterized by developmental delay, intellectual disability, movement disorders, drug-resistant seizures, and neurological deterioration. GNAO1 encodes the α-subunit of an inhibitory GTP/GDP-binding protein regulating ion channel activity and neurotransmitter release. The pathogenic mechanisms underlying GNAO1-related disorders remain largely elusive and there are no effective therapies. Here, we assessed the functional impact of two disease-causing variants associated with distinct clinical features, c.139A > G (p.S47G) and c.662C > A (p.A221D), using Caenorhabditis elegans as a model organism. The c.139A > G change was introduced into the orthologous position of the C. elegans gene via CRISPR/Cas9, whereas a knock-in strain carrying the p.A221D variant was already available. Like null mutants, homozygous knock-in animals showed increased egg laying and were hypersensitive to aldicarb, an inhibitor of acetylcholinesterase, suggesting excessive neurotransmitter release by different classes of motor neurons. Automated analysis of C. elegans locomotion indicated that goa-1 mutants move faster than control animals, with more frequent body bends and a higher reversal rate, and display uncoordinated locomotion. Phenotypic profiling of heterozygous animals revealed a strong hypomorphic effect of both variants, with a partial dominant-negative activity for the p.A221D allele. Finally, caffeine was shown to rescue aberrant motor function in C. elegans harboring the goa-1 variants; this effect is mainly exerted through adenosine receptor antagonism. Overall, our findings establish a suitable platform for drug discovery, which may assist in accelerating the development of new therapies for this devastating condition, and highlight the potential role of caffeine in controlling GNAO1-related dyskinesia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia

Rocco

Galosi

Lanza

et al. 2021

Human Molecular Genetics

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“…In addition, caffeine was shown to improve hyperactivity and locomotion in Caenorhabditis elegans mutants harboring mutations causing the closely related disorder of GNAO1 ‐related dyskinesia, which likely result in AC5 activation 10 . Caffeine was therefore tried in other patients, with remarkable efficacy 11,12 . Due to the rarity of ADCY5 ‐related dyskinesia and the fact that caffeine is an everyday consumer product, the conduct of a regular randomized study is extremely challenging: first, for most patients, stopping caffeine and possibly receiving a placebo for weeks was unconceivable; second, there was a risk of not achieving significance due to the high variability in doses and intervals, irrespective of weight, between patients.…”

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confidence: 99%

Efficacy of Caffeine in ADCY5‐Related Dyskinesia: A Retrospective Study

et al. 2022

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Background ADCY5‐related dyskinesia is characterized by early‐onset movement disorders. There is currently no validated treatment, but anecdotal clinical reports and biological hypotheses suggest efficacy of caffeine. Objective The aim is to obtain further insight into the efficacy and safety of caffeine in patients with ADCY5‐related dyskinesia. Methods A retrospective study was conducted worldwide in 30 patients with a proven ADCY5 mutation who had tried or were taking caffeine for dyskinesia. Disease characteristics and treatment responses were assessed through a questionnaire. Results Caffeine was overall well tolerated, even in children, and 87% of patients reported a clear improvement. Caffeine reduced the frequency and duration of paroxysmal movement disorders but also improved baseline movement disorders and some other motor and nonmotor features, with consistent quality‐of‐life improvement. Three patients reported worsening. Conclusion Our findings suggest that caffeine should be considered as a first‐line therapeutic option in ADCY5‐related dyskinesia. © 2022 International Parkinson and Movement Disorder Society

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“…The presence of axial hypotonia, orofacial myoclonus, and various types of paroxysmal movement disorders (in particular nocturnal episodes) as well as marked fluctuations of the motor state are strong clues to the diagnosis ( 176 ). Treatment with caffeine can induce dramatic improvement of paroxysmal episodes, and should therefore be tried in all patients ( 177 , 178 ).…”

Section: Genetic Diseasesmentioning

confidence: 99%

Treatable Hyperkinetic Movement Disorders Not to Be Missed

et al. 2021

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Hyperkinetic movement disorders are characterized by the presence of abnormal involuntary movements, comprising most notably dystonia, chorea, myoclonus, and tremor. Possible causes are numerous, including autoimmune disorders, infections of the central nervous system, metabolic disturbances, genetic diseases, drug-related causes and functional disorders, making the diagnostic process difficult for clinicians. Some diagnoses may be delayed without serious consequences, but diagnosis delays may prove detrimental in treatable disorders, ranging from functional disabilities, as in dopa-responsive dystonia, to death, as in Whipple's disease. In this review, we focus on treatable disorders that may present with prominent hyperkinetic movement disorders.

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Recurrent ADCY5 Mutation in Mosaic Form with Nocturnal Paroxysmal Dyskinesias and Video Electroencephalography Documentation of Dramatic Response to Caffeine Treatment

Cited by 14 publications

References 7 publications

Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia

Caenorhabditis elegans provides an efficient drug screening platform for GNAO1-related disorders and highlights the potential role of caffeine in controlling dyskinesia

Efficacy of Caffeine in ADCY5‐Related Dyskinesia: A Retrospective Study

Treatable Hyperkinetic Movement Disorders Not to Be Missed

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