Caffeine Efficacy in ADCY5-related Dyskinesia

Study Overview
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Brief Summary
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Heterozygous mutations in ADCY5 induce hyperactivity of striatal adenylate cyclase type 5 (AC5), manifesting as early-onset hyperkinetic movement disorders. Numerous treatments have been tried without much efficacy thus far. Two patients from the same family reported efficacy of caffeine on paroxysmal episodes, both to prevent episodes and to reduce their duration (efficacy estimated to be around 80%), which was specific to caffeine as it was reproduced with caffeine citrate capsules. Interestingly, there is a rationale underlying this observation. Indeed, caffeine is an antagonist of adenosine A2A receptors (A2AR), which activate AC5 and are localized preferentially in striatal neurons that express dopamine receptors D2 .Caffeine therefore likely induces AC5 inhibition, and thus clinical improvement in patients with hyperactivity of this protein. This observation has been recently published in2019. The investigators will collect preliminary data by interviewing our neurologist and neuropediatric colleagues, in France and abroad since it is a rare disease, on the effect of caffeine on motor symptoms and global clinical status in their ADCY5 patients.

Detailed Description
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Heterozygous mutations in ADCY5 induce hyperactivity of striatal adenylate cyclase type 5 (AC5) manifesting as early-onset hyperkinetic movement disorders. The phenotype combines chorea, dystonia and/or myoclonus with frequent facial involvement, axial hypotonia, fluctuations and/or episodes of paroxysmal dyskinesia which can be nocturnal and/or painful, generally without intellectual deficiency, epilepsy or cerebellar syndrome . It is a very rare disease, affecting around twenty patients in France. Scientific context of the research: Numerous treatments have been tried without much efficacy thus far. Scientific justification for the study: Two patients from the same family reported efficacy of caffeine on paroxysmal episodes, both to prevent episodes and to reduce their duration (efficacy estimated to be around 80%), which was specific to caffeine as it was reproduced with caffeine citrate capsules. Interestingly there is a rationale underlying this situation. Indeed, caffeine is an antagonist of adenosine A2A receptors (A2AR), which activate AC5 and are localized preferentially in striatal neurons that express dopamine receptors D2. Caffeine therefore likely induces inhibition of AC5, and thus clinical improvement in patients with hyperactivity of this protein. This observation has been recently published in 2019 HYPOTHESIS Our hypothesis is that most patients with ADCY5-related dyskinesia respond well to caffeine. This study is a multicentric retrospective study, which will be conducted in neurology and neuropediatric departments across the world. Participants will be recruited by their own physician. This research will take place over 18 months in total: 12 month to collect all patients' data and 6 months to analyse data. The number of participants will be between 5 and 20, depending on colleagues replies. This research will take place over 18 months in total: 12 month to collect all patients' data and 6 months to analyse data.

Official Title
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Study of Caffeine Efficacy in ADCY5-related Dyskinesia - a Retrospective Study

Conditions
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ADCY5-related Dyskinesia

Intervention / Treatment
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* Other: caffeine and movement disorders


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Proven genetic diagnosis of ADCY5-related dyskinesia Adults or children without age limits Past or present caffeine intake Non-opposition by the patient (adults) or the legal representatives (minors) in France, and patient information according to each country's legislation in other countries. 4.2. Exclusion criteria None.
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| caffeine efficacy<br>Collection of preliminary data on caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia. | Other: caffeine and movement disorders<br>* Caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of responders to caffeine | the response being defined as an improvement of overall involuntary movements of 40% or more. | 12 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Global improvement of involuntary movements, | Global change of involuntary movements ranging from 0 (no change) to 10 (disappearance of involuntary movements) | 12 MONTHS | 
| Global clinical change | Global clinical change ranging from 0 (no change) to 10 (normalization of the global clinical state) | 12 months | 
| Duration of paroxysmal episodes of movement disorders | Change of the duration of paroxysmal episodes of movement disorders with caffeine | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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dyskinesia, ADCY5, caffeine