Clinical trial NCT04469283: Caffeine Efficacy in ADCY5-related Dyskinesia
Official title: Study of Caffeine Efficacy in ADCY5-related Dyskinesia - a Retrospective Study
Study type: OBSERVATIONAL
Overall status: UNKNOWN
Conditions: ADCY5-related Dyskinesia
Keywords: ADCY5
dyskinesia
caffeine
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
First posted: 2020-07-14
Enrollment: 20
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: patients with genetically proven ADCY5-related dyskinesia

Brief summary: 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: 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.

Primary outcomes:
measure: Percentage of responders to caffeine
timeFrame: 12 months
Secondary outcomes:
measure: Global improvement of involuntary movements,
timeFrame: 12 MONTHS
measure: Global clinical change
timeFrame: 12 months
measure: Duration of paroxysmal episodes of movement disorders
timeFrame: 12 months
Other outcomes:
Locations:
Study officials:
References:
citation: Meneret A, Gras D, McGovern E, Roze E. Caffeine and the Dyskinesia Related to Mutations in the ADCY5 Gene. Ann Intern Med. 2019 Sep 17;171(6):439. doi: 10.7326/L19-0038. Epub 2019 Jun 11. No abstract available.