Pilot Study on Caffeine Efficiency in ADCY5-related Dyskinesia (CAF-ADCY5)

Pilot Study on Subjective Efficiency of Caffeine in ADCY5-related Dyskinesia

Heterozygous mutations in the ADCY5 gene cause involuntary early-onset hyperkinetic movements. In addition, patients may have associated psychiatric disorders.There is currently no treatment. As the pathophysiology is linked to ADCY5 hyperactivity, the investigative team has treated patients with caffeine, an antagonist. The investigator wishes to interview patients on the effect of caffeine on their motor symptoms and their overall clinical condition, and on the possible existence of psychiatric comorbidities using phone questionnaires.

Study Overview

• Status: Unknown
• Conditions: Dyskinesias

Detailed Description

Heterozygous mutations in the ADCY5 gene cause involuntary early-onset hyperkinetic movements. 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.

Many treatments have been tried, with no obvious efficacy. Two patients from the same family (a father and daughter) told investigators that caffeine had a dramatic effect on their paroxysmal episodes. They said that taking coffee would prevent episodes and reduce their duration (efficacy estimated at 80%), an effect specific to caffeine since it was reproduced by the ingestion of caffeine citrate capsules. Very interestingly, there is a rationale underlying this phenomenon. Indeed, caffeine is an antagonist of the adenosine A2A receptors (A2AR), receptors which activate ADCY5 and which are localized preferentially in striatal neurons expressing dopamine D2 receptors. As caffeine is an A2AR antagonist, it likely inhibits ADCY5, and therefore induces clinical improvement in patients with hyperactivity of this protein.

In addition, the investigative team noted anxiety in some of its patients, and the question of the presence of psychiatric disorders in ADCY5 patients was recently raised in the literature.

The investigative team wishes to collect standardized preliminary data by questioning patients on the effect of caffeine on their motor symptoms and their overall clinical state, and on the possible existence of psychiatric comorbidities using structured questionnaires which will be carried out by phone.

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

Contacts and Locations

• Study Contact: Name: Aurélie Méneret, MD, PhD; Phone Number: 0142161752 +33 1 42 16 24 61; Email: aurelie.meneret@aphp.fr
• Study Contact Backup: Name: Aurélie Meneret; Phone Number: 0142161752 0142161752; Email: aurelie.meneret@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years and older (ADULT, OLDER_ADULT, CHILD)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with ADCY5-related dyskinesia being actively treated, or who have been previously treated, with caffeine.

Description

Inclusion Criteria:

• Proven genetic diagnosis of ADCY5-related dyskinesia
• Caffeine intake
• Non opposition by the patient or the legal representatives if the patient is a minor.

No Exclusion Criteria.

Study Plan

How is the study designed?

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.	one hour

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Global change of involuntary movements ranging from 0 (no change) to 10 (disappearance of involuntary movements)	evaluated by patients	one hour
Global clinical change ranging from 0 (no change) to 10 (normalization of the global clinical state)	evaluated by patients	one hour
Change of the duration of paroxysmal episodes of movement disorders with caffeine	evaluated by patients	one hour
Frequency change of paroxysmal episodes of movement disorders with caffeine	evaluated by patients	one hour
Presence or absence of psychiatric symptoms	according to the MINI (Mini International Neuropsychiatric Interview)	one hour

Collaborators and Investigators

• Sponsor: Institut National de la Santé Et de la Recherche Médicale, France
• Investigators: Principal Investigator: Aurélie Meneret, APHP

Publications and helpful links

General Publications

• Chen DH, Meneret A, Friedman JR, Korvatska O, Gad A, Bonkowski ES, Stessman HA, Doummar D, Mignot C, Anheim M, Bernes S, Davis MY, Damon-Perriere N, Degos B, Grabli D, Gras D, Hisama FM, Mackenzie KM, Swanson PD, Tranchant C, Vidailhet M, Winesett S, Trouillard O, Amendola LM, Dorschner MO, Weiss M, Eichler EE, Torkamani A, Roze E, Bird TD, Raskind WH. ADCY5-related dyskinesia: Broader spectrum and genotype-phenotype correlations. Neurology. 2015 Dec 8;85(23):2026-35. doi: 10.1212/WNL.0000000000002058. Epub 2015 Nov 4.
• Friedman JR, Meneret A, Chen DH, Trouillard O, Vidailhet M, Raskind WH, Roze E. ADCY5 mutation carriers display pleiotropic paroxysmal day and nighttime dyskinesias. Mov Disord. 2016 Jan;31(1):147-8. doi: 10.1002/mds.26494. Epub 2015 Dec 21. No abstract available.
• Lee KW, Hong JH, Choi IY, Che Y, Lee JK, Yang SD, Song CW, Kang HS, Lee JH, Noh JS, Shin HS, Han PL. Impaired D2 dopamine receptor function in mice lacking type 5 adenylyl cyclase. J Neurosci. 2002 Sep 15;22(18):7931-40. doi: 10.1523/JNEUROSCI.22-18-07931.2002.
• 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.
• Vijiaratnam N, Newby R, Kempster PA. Depression and psychosis in ADCY5-related dyskinesia-part of the phenotypic spectrum? J Clin Neurosci. 2018 Nov;57:167-168. doi: 10.1016/j.jocn.2018.08.049. Epub 2018 Aug 30.
• Yamada K, Kobayashi M, Kanda T. Involvement of adenosine A2A receptors in depression and anxiety. Int Rev Neurobiol. 2014;119:373-93. doi: 10.1016/B978-0-12-801022-8.00015-5.

Study record dates

Study Major Dates

• Study Start (ANTICIPATED): April 10, 2020
• Primary Completion (ANTICIPATED): April 10, 2021
• Study Completion (ANTICIPATED): April 10, 2021

Study Registration Dates

• First Submitted: April 13, 2020
• First Submitted That Met QC Criteria: April 15, 2020
• First Posted (ACTUAL): April 17, 2020

Study Record Updates

• Last Update Posted (ACTUAL): April 17, 2020
• Last Update Submitted That Met QC Criteria: April 15, 2020
• Last Verified: February 1, 2020

More Information

Terms related to this study

• Keywords: ADCY5 mutation
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Movement Disorders; Dyskinesias
• Other Study ID Numbers: C19-26; 2020-A00166-33 (REGISTRY: 2020-A00166-33)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

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