Improvement of ADCY5 ‐related dyskinesias with coffee

A 4-year-old girl with de novo heterozygous pathogenic R418Q (c.1253G>A; NM_183357.3) mutation in the ADCY5 gene (found with whole-exome sequencing and Sanger confirmed) presented with infantile-onset generalized chorea, axial hypotonia, and hypersalivation (at 6 months). At age 2, she developed mild clumsiness, periodic foot dystonia, and episodes of dysphoria, and at age 4, mild dysarthria and pain in the dorsal aspect of either foot while resting and before falling asleep. Dyskinesias progressed from age 5 months to 2 years and then became relatively stable. No typical night bouts were observed, although episodic worsening of dyskinesias on awakening, excitement, fatigue, during the night, or while having respiratory infections was present. Because of muscle hypotonia, the patient experienced difficulties sitting until 1 year and showed delayed independent walking. At the age of 1 year, brain magnetic resonance imaging was unremarkable. At 1.5 years, acetazolamide (up to 125 mg/day within 1 month) did not improve dyskinesias. Mutations in the ADCY5 gene are characterized by a broad spectrum of phenotypes.1 The R418Q mutation is associated with a gain of function of adenylate cyclase type 5, which results in hyperkinetic disorders because of elevated intracellular cAMP (cyclic adenosine-3′,5′-monophosphate) in the striatal medium spiny neurons. ADCY5-related dyskinesias can present either with continuous chorea throughout the day from the beginning of the disease (as in our patient) or with paroxysmal hyperkinesis at the disease onset.2 Acetazolamide and a variety of antiepileptic drugs were suggested to control chorea with various treatment responses.1 Recently, Méneret et al3 reported the use of caffeine as a way to improve diurnal and nocturnal paroxysmal episodes of hyperkinetic involuntary movements of the face and upper limbs in a patient with ADCY5-related. Parents refused to try other medicinal products and preferred caffeine as a more “natural” treatment. Taking that into account, we decided to try coffee as a therapeutic option for our patient with permanent dyskinesias. Whole bean medium roast coffee was prescribed. The patient started consuming a moderately strong cappuccino three times a day (with the third dose given no later than 6 pm) with a total daily caffeine dose of 60 mg, which was sufficient to significantly alleviate chorea throughout the whole day. The response was observed ~20 to 30 min following the cup of coffee. The patient's mother reported more than 50% improvement in the severity of dyskinesias (Video 1) and mood. Adverse reactions included hyperactivity and episodes of loss of energy. Pain episodes did not respond to coffee. Our clinical observation is in agreement with the results of the recently published pilot study of patients with ADCY5 pathogenic variants where caffeine was overall well-tolerated, and 87% of individuals reported improvement in dyskinesias of 40% or more.4 Interestingly, sustained improvement of ADCY5-related choreo-dystonic movements was reported with a selective adenosine A2AR antagonist—istradefylline—marketed in the United States as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease experiencing “off” episodes.5 We report a patient with a de novo ADCY5 mutation with a clinical phenotype of continuous generalized chorea and a significant improvement of dyskinesias with coffee supplementation. More controlled studies are needed to investigate the effect of caffeine and other potential A2AR antagonists in various ADCY5-related phenotypes, including motor and non-motor symptoms. We thank the patient and her family for permission to publish the video. Open Access funding enabled and organized by Projekt DEAL. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. Y.S.: 1A, 1B, 1C, 2A, 2B. N.K.: 1A, 2B. Ethical compliance statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The work was approved by the Institutional Review Board of the Kazaryan Clinic of Epileptology and Neurology. The authors confirm that the patient provided verbal and written consent for this work. Funding Sources and Conflicts of Interest: Open Access funding enabled and organized by Projekt DEAL. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: Y.S. received speaker honoraria from Roche and Johnson and Johnson. N.K. declares that there are no additional disclosures to report.