Reduced Dopamine Transporter Uptake in Dentatorubral‐Pallidoluysian Atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder that primarily affects the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus, while dopaminergic system involvement is considered uncommon.1 Here, we report a patient with genetically confirmed DRPLA showing a mismatch between dopamine transporter single-photon emission computed tomography (DAT SPECT) findings and the degree of striatal atrophy observed on magnetic resonance imaging (MRI), with markedly reduced striatal uptake that was disproportionate to the degree of atrophy. A 31-year-old Japanese man with childhood-onset epilepsy and progressive choreoathetosis was admitted to our hospital. His perinatal course was unremarkable, with learning difficulties emerging during junior high school, followed by generalized tonic seizures at age 15 and the gradual onset of choreoathetosis. At admission, he was receiving zonisamide 400 mg/day, levetiracetam 2000 mg/day, and clonazepam 1.5 mg/day. His mother had a history of seizures and progressive gait disturbance, and a maternal uncle developed chorea and tested negative for Huntington's disease. On examination, the patient was awake. Choreoathetosis predominantly affecting the right upper limb was observed (Video 1), without parkinsonian features such as rigidity, bradykinesia, or resting tremor. Cerebellar ataxia was present in all limbs. Laboratory tests were unremarkable, and interictal electroencephalography was normal. Brain MRI revealed cerebellar and brainstem atrophy, with relatively preserved basal ganglia (Fig. 1A–D). In contrast, DAT SPECT revealed bilateral reduction in striatal dopamine transporter uptake, with left-predominant involvement (Fig. 1E). Cardiac I-metaiodobenzylguanidine (123I-MIBG) scintigraphy revealed preserved myocardial uptake (H/M ratio: early, 2.22; delay, 2.39). In the absence of Parkinsonism, levodopa therapy was not initiated. Increasing levetiracetam to 2500 mg/day reduced seizure frequency. Genetic testing identified an expanded CAG repeat of 67 in the ATN1 gene, confirming the diagnosis of DRPLA. This case highlights a mismatch between functional dopaminergic impairment on DAT SPECT and relatively preserved striatal volume on MRI in DRPLA. One possible explanation for the reduced DAT uptake is secondary downregulation of dopamine transporter expression in response to postsynaptic degeneration in the striatum and globus pallidus. Reduced DAT uptake does not necessarily indicate irreversible nigrostriatal neuron loss, as compensatory downregulation has been reported in Parkinson's disease.2 Additionally, in Huntington's disease, DAT SPECT studies have shown that striatal DAT binding can be reduced,3 suggesting that postsynaptic degeneration may influence DAT uptake. Another explanation is pathological involvement of the substantia nigra.4 However, the substantia nigra is generally reported to be relatively preserved in DRPLA,1 and the absence of Parkinsonism in this case suggests that nigral pathology was unlikely to be the primary cause. Similarly, although coincidental coexistence of Parkinson's disease has been reported in an autopsy-confirmed case,5 this is unlikely in the present case, given the absence of Parkinsonism and preserved cardiac 123I-MIBG uptake. In conclusion, this is the first case suggesting that striatal DAT uptake on DAT SPECT may be reduced in DRPLA relative to the degree of striatal atrophy observed on MRI. (1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. C. Final Approval. K.O.: 3A, 3C S.F.: 1A, 1C, 3A, 3C H.K.: 3B, 3C G.O.: 1A, 1B, 3B, 3C We would like to thank Editage (www.editage.com) for the English language editing. Ethics Approval Statement: This study was conducted in accordance with the ethical standards of the 1964 Declaration of Helsinki and its amendments. Written informed consent for publication of clinical data, including video recordings, was obtained from the patient. The authors confirm that this work complies with the Journal's Ethical Publication Guidelines. Financial Disclosures and Conflicts of Interest: KO declares no conflict of interest SF receives speaker honoraria from Eisai Co., Ltd., AbbVie GK, Ono Pharmaceutical Co., Ltd., Kowa Co., Ltd., Novartis Pharma KK, and Chugai Pharmaceutical Co., Ltd. HK receives speaker honoraria from Daiichi Sankyo Co., Ltd., Argenx Japan Co., Ltd., Chugai Pharmaceutical Co., Ltd., and AbbVie GK. GO receives speaker honoraria from Medtronic Japan Co., Ltd., Boston Scientific Japan KK, Abbott Japan Co., Ltd., Sumitomo Pharma Co., Ltd., Kyowa Kirin Co., Ltd., FP Pharmaceutical Corporation, Takeda Pharmaceutical Company Limited, Eisai Co., Ltd., EA Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd., Biogen Japan Ltd., Nihon Mediphysics Co., Ltd., Benesse Style Care Co., Ltd., Viatris Inc., Eli Lilly Japan KK, and AbbVie GK. GO also receives consultation fees from Teijin Pharma Ltd., NysnoBio, and Lundbeck Japan KK. All authors have completed and submitted the ICMJE Conflict of Interest Disclosure Form, and the disclosed relationships are consistent with the statements above. Author disclosures are available in the Supporting Information. Funding agency: GO received research support from JSPS KAKENHI Grant-in-Aid for Scientific Research C (24K10667), JSPS KAKENHI Grant-in-Aid for Challenging Research (Pioneering) (25 K21808), and Medi-physics. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Data S1. COI_disclosure. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.