Efficacy of Istradefylline for the Treatment of ADCY5-Related Disease Ryosuke Miyamoto, MD,1,* Ryuji Kaji, MD1,4

Toshitaka Kawarai, MD,1

Toshiaki Takeuchi, MD,1,2 Yuishin Izumi, MD,1 Satoshi Goto, MD,3 and

ADCY5-related disease is an emerging entity in early-onset hyperkinetic movement disorders. Accumulating reports have shown phenomenological diversity, ranging from facial dyskinesia to alternating hemiplegia.1 Treatment is highly challenging; however, clonazepam, clobazam, and bilateral pallidal deep brain stimulation may result in mild functional improvement,2 and a recent report suggested that methylphenidate might be helpful.3 Here, we report a patient with ADCY5-related disease who responded to an adenosine A2A receptor (A2AR) antagonist.

Case Report The patient was born to healthy, nonconsanguineous parents. He has 2 siblings who do not present neurological or psychiatric symptoms. He began presenting generalized stiffness triggered by fever, fatigue, surprise, or crying at age 1 year. Each episode started suddenly and made him crouch down for 1 to 2 minutes until the symptom disappeared. He never experienced a decline in consciousness, and video–electroencephalogram monitoring did not detect epileptic discharges during attacks. He walked on tiptoe at age 16 months. Dysarthria was noticed since he spoke his first words at age 2 years. At age 3 years, he showed mild mental retardation and significant restlessness, and later he was diagnosed with attention deficit hyperactivity disorder. At age 6 years, he began presenting paroxysmal brief myoclonic jerks in his limbs, which caused frequent falls (when most frequent 10 times a day). Clonazepam and methylphenidate showed no effect. At age 8 years, he developed generalized choreic movements that were most prominent during attempted action. Brain magnetic resonance imaging showed no abnormalities. At age 16 years, he began presenting episodic myoclonic–dystonic

spasms that usually occurred when he woke up in the morning. The spasms were painful, lasted for 10 seconds to 10 minutes, and occurred in clusters. He presented to us at age 16 years. On examination, he exhibited inattention, impulsiveness, and mixed movement abnormalities, including generalized choreic movements, facial dyskinesia, spasmodic dysphonia, dystonic gait, axial hypotonia, and action-induced choreo-dystonic movements (Video S1). The hyperkinetic movements almost resolved while lying in bed. He presented increased deep tendon reflexes in the lower limbs, but otherwise he was neurologically intact. The Wechsler Adult Intelligence Scale–3rd edition score indicated mild intellectual disability (Full scale intelligence quotient = 65). The dopamine-transporter single-photon emission computerized tomography demonstrated normal uptake. Haloperidol, zolpidem, levetiracetam, and primidone were ineffective. Inattention and impulsiveness spontaneously subsided with age, and the severity of generalized choreic movements and the frequency of falls also gradually decreased. However, this improvement stopped by age 21 years, and the severity of choreo-dystonic movements during attempted action did not substantially change. At 24 years of age, genetic testing of the ADCY5 gene revealed a heterozygous p.Arg418Trp (R418W) mutation. His father and siblings did not harbor the mutation (Fig. S1). At age 24 years, istradefylline, an adenosine A2AR antagonist, was introduced. His symptoms remained unchanged for 1 week with 20 mg, and the dose was increased to 40 mg. Three weeks later, his back became straightened, and 6 weeks later, he demonstrated better dexterity of the upper limbs, mildly reduced choreo-dystonic movements during attempted action, and some improvement in gait. Four months later, his preadministration Unified Huntington’s Disease Rating Scale score of 46 was decreased to 35 (Video S2). Sustained improvement was achieved for 21 months without adverse events.


Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan; 2Department of Rehabilitation, National Hospital Organization Utano Hospital, Kyoto, Japan; 3Department of Neurodegenerative Disorders Research, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan; 4Department of Neurology, National Hospital Organization Utano Hospital, Kyoto, Japan *Correspondence to: Dr. Ryosuke Miyamoto, Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, 3-18-15 Kuramoto-cho, Tokushima, Japan; E-mail: [email protected] Keywords: ADCY5, dyskinesia, istradefylline, adenosine A2A receptor antagonist, hyperkinetic movement disorder. Relevant disclosures and conflicts of interest are listed at the end of this article. Received 18 May 2020; revised 29 July 2020; accepted 3 August 2020. Published online 00 Month 2020 in Wiley Online Library ( DOI: 10.1002/mdc3.13067

MOVEMENT DISORDERS CLINICAL PRACTICE 2020. doi: 10.1002/mdc3.13067 © 2020 International Parkinson and Movement Disorder Society






The patient displayed infantile-onset episodic stiffness, childhood-onset paroxysmal myoclonic jerks, and adolescent-onset painful myoclonic-dystonic spasms upon waking in addition to choreic movements, dystonia, and facial dyskinesia. These movement abnormalities that occurred in different contexts of time and situations illustrated his disease and caused significant impairment in daily life activities. Peroral bolus administration of istradefylline, a selective adenosine A2AR antagonist, is used to treat off-period symptoms in Parkinson’s disease in Japan and has recently been approved in the United States. Istradefylline is thought to exert antiparkinsonian effects by attenuating the increased excitation of the striatopallidal indirect pathway elicited by dopamine depletion.4 Recent reports have also suggested potential therapeutic effects of adenosine A2AR antagonism on hyperkinetic movement disorders in animal models of DYT1 and DYT11.5,6 In our case, with an ADCY5 “gain-of-function” mutation, which leads to an increased level of cyclic adenosine monophosphate (cAMP) in striatal cells, chronic administration of istradefylline progressively attenuated hyperkinetic symptoms. The cAMP signal activities in the striatum are regulated by the olfactory type G-protein α subunit (Gαolf ), which positively couples with the D1-type dopamine receptor and adenosine A2AR to increase cAMP production in medium spiny neurons.7 It is also known that the agonist-induced activation of D1-type dopamine receptors or A2ARs causes the degradation of Gαolf proteins in striatal medium spiny neurons through a posttranslational usage-dependent mechanism.7 Accordingly, we suggest that the chronic administration of istradefylline might cause increased homeostatic levels of Gαolf and cAMP and thereby exert an antagonistic action on the D2-type dopamine receptor-mediated signals in the striatopallidal cells, resulting in the attenuation of hyperkinetic symptoms in this patient with the ADCY5 mutation. This assumption may corroborate our previous evidence suggesting that A2AR antagonism might exert a therapeutic effect on not only off-period motor deficits but also levodopa-induced dyskinesia in a parkinsonian mouse model.7

Ethical Compliance Statement: The study was conducted in accordance with the Declaration of Helsinki. The patient gave written informed consent regarding being videotaped for online publication. The genetic study was performed under the approval of an institutional review board of Tokushima University, and written informed consent was obtained from the patient. 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. Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest. Financial Disclosures for Previous 12 Months: The authors declare that there are no disclosures to report. ■

Author Roles (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. R.M.: 1C, 2A T.K.: 1C T.T.: 1C Y.I.: 1C S.G.: 2A R.K.: 1A, 1B, 1C, 2A, 2B 2

References 1. Vijiaratnam N, Bhatia KP, Lang AE, Raskind WH, Espay AJ. ADCY5-related dyskinesia: Improving clinical detection of an evolving disorder. Mov Disord Clin Pract 2019;6(7):512–520. 2. Chang FC, Westenberger A, Dale RC, et al. Phenotypic insights into ADCY5-associated disease. Mov Disord 2016;31(7):1033–1040. 3. Tubing J, Bohnenpoll J, Spiegler J, et al. Methylphenidate can improve chorea in NKX2.1 and ADCY5 mutation-positive patients-a report of two children. Mov Disord Clin Pract 2018;5(3):343–345. 4. Mori A. Mode of action of adenosine A2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol 2014;119:87–116. 5. Napolitano F, Pasqualetti M, Usiello A, et al. Dopamine D2 receptor dysfunction is rescued by adenosine A2A receptor antagonism in a model of DYT1 dystonia. Neurobiol Dis 2010;38(3):434–445. 6. Maltese M, Martella G, Imbriani P, et al. Abnormal striatal plasticity in a DYT11/SGCE myoclonus dystonia mouse model is reversed by adenosine A2A receptor inhibition. Neurobiol Dis 2017;108:128–139. 7. Goto S. Striatal Galphaolf/cAMP signal-dependent mechanism to generate levodopa-induced dyskinesia in Parkinson’s disease. Front Cell Neurosci 2017;11:364.

Supporting Information Supporting information may be found in the online version of this article. Figure S1 (A) Pedigree chart. Black arrow indicates the patient. Note that his mother has been dead and was not available for genetic testing. (B) Sanger sequencing results of identified mutation. The affected residue is indicated with red arrow. The patient’s father and brothers did not harbor the mutation. Video S1 Age 16 years. The patient demonstrated mixed movement abnormalities, including generalized choreic movements, facial dyskinesia, spasmodic dysphonia, dystonic gait, axial hypotonia, and action-induced choreo-dystonic movements. Note that he also exhibited inattention and impulsiveness. Video S2 Segment 1: age 24 years (before starting istradefylline). Note that generalized choreic movements and impulsive movement have become less prominent than at age 16 years. Segment 2: age 25 years (4 months after starting istradefylline). The patient demonstrated better dexterity of the upper limbs and mildly reduced facial dyskinesia, truncal flexion, dystonic gait, and choreo-dystonic movements during attempted action.

MOVEMENT DISORDERS CLINICAL PRACTICE 2020. doi: 10.1002/mdc3.13067

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CASE REPORT CLINICAL PRACTICE Efficacy of Istradefylline for the Treatment of ADCY5-Related Disease Ryosuke Miyamoto, MD,1,* Ryuji Kaji, MD1,4 Toshi...
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