Pilot Study on Caffeine Efficiency in ADCY5-related Dyskinesia

Dyskinesias Clinical Trial

— CAF-ADCY5  

Official title:

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

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT04351360
• Other study ID #: C19-26
• Secondary ID: 2020-A00166-33
• Status: Not yet recruiting
• Start date: April 10, 2020
• Est. completion date: April 10, 2021

Study information

• Verified date: February 2020
• Source: Institut National de la Santé Et de la Recherche Médicale, France
• Contact: Aurélie Méneret, MD, PhD
• Phone: +33 1 42 16 24 61
• Email: aurelie.meneret[@]aphp.fr
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 20
• Est. completion date: April 10, 2021
• Est. primary completion date: April 10, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 8 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Dyskinesias

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
Institut National de la Santé Et de la Recherche Médicale, France

References & Publications (6)

Chen DH, Méneret A, Friedman JR, Korvatska O, Gad A, Bonkowski ES, Stessman HA, Doummar D, Mignot C, Anheim M, Bernes S, Davis MY, Damon-Perrière 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. — View Citation

Friedman JR, Méneret 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. — View Citation

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. — View Citation

Méneret A, Gras D, McGovern E, Roze E. Caffeine and the Dyskinesia Related to Mutations in the ADCY5 Gene. Ann Intern Med. 2019 Jun 11. doi: 10.7326/L19-0038. [Epub ahead of print] — View Citation

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. — View Citation

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. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of responders to caffeine	the response being defined as an improvement of overall involuntary movements of 40% or more.	one hour
Secondary	Global change of involuntary movements ranging from 0 (no change) to 10 (disappearance of involuntary movements)	evaluated by patients	one hour
Secondary	Global clinical change ranging from 0 (no change) to 10 (normalization of the global clinical state)	evaluated by patients	one hour
Secondary	Change of the duration of paroxysmal episodes of movement disorders with caffeine	evaluated by patients	one hour
Secondary	Frequency change of paroxysmal episodes of movement disorders with caffeine	evaluated by patients	one hour
Secondary	Presence or absence of psychiatric symptoms	according to the MINI (Mini International Neuropsychiatric Interview)	one hour