Caffeine Efficacy in ADCY5-related Dyskinesia (ADCY5-CAF)

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

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.

Study Overview

• Status: Unknown
• Conditions: ADCY5-related Dyskinesia
• Intervention / Treatment: Other: caffeine and movement disorders

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.

• Study Type: Observational
• Enrollment (Anticipated): 20

Contacts and Locations

• Study Contact: Name: Aurélie MENERET, MD; Phone Number: +33 1 42 16 24 61; Email: aurelie.meneret@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

patients with genetically proven ADCY5-related dyskinesia

Description

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.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Retrospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
caffeine efficacy; Collection of preliminary data on caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia.	Other: caffeine and movement disorders; Caffeine efficacy on movement disorders in patients with ADCY5-related dyskinesia.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Anticipated): July 15, 2020
• Primary Completion (Anticipated): July 15, 2021
• Study Completion (Anticipated): July 15, 2021

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: July 8, 2020
• First Posted (Actual): July 14, 2020

Study Record Updates

• Last Update Posted (Actual): July 14, 2020
• Last Update Submitted That Met QC Criteria: July 8, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: caffeine; dyskinesia; ADCY5
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesias; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Central Nervous System Stimulants; Caffeine
• Other Study ID Numbers: APHP200193

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No