Caffeine Efficacy in ADCY5-related Dyskinesia

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.

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.

Eligibility Criteria:
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.