Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients

Ru-Ying Yuan^#¹, Ya-Fang Chen^#^{1

2}, Wei Lin^#¹, Meng-Cheng Li³, Yi-Heng Zeng¹, Bi Cheng¹, Xin-Tong Yu¹, Dan-Dan Zuo¹, Hua-Mei Sun¹, Bei-Ning Ye¹, Ying-Xin Ye¹, Mao-Lin Cui¹, Nai-Qing Cai^{1

4}, Yu Lin^{1

4}, Qi-Jie Zhang^{1

4}, Yu-Sen Qiu⁵, Lin-Wei Zhang⁶, Xing-Wang Song^{7

8}, Jia-Na Wei^{7

8}, Li-Ying Pan⁹, Ya-Yun Yan¹⁰, Yi-Min Sun¹¹, Jin-Tai Yu¹², Zhi-Ying Wu¹³, Yi Dong¹³, Chun-Yan Cao¹⁴, Chao Wu¹⁵, Jie Zu¹⁶, Yuan-Yuan Dai¹⁷, Xian-Jin Shang¹⁸, Hai-Tao Zhou¹⁹, Min-Jin Wang²⁰, Qing Ke²¹, En-Lin Dong²², Yi-Feng Xiao²³, Zi-Yue Ouyang²⁴, Xin-Yuan Chen²⁵, Jian-Ping Hu³, Min-Ting Lin^{1

4}, Ying Fu^{1

4}, Wan-Jin Chen^{1

4}, Ning Wang^{1

4}, Shi-Rui Gan^{1

4}; OSCCAR Investigators

Affiliations

¹ Department of Neurology, the First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
² Department of Neurology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
³ Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
⁴ Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁵ Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Rare Disease Center, The First Affiliated Hospital of Nanchang University, Nanchang, China.
⁶ Department of Neurology, China Japan Friendship Hospital, Beijing, China.
⁷ Department of Neurology, Institute of Neuroscience, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁸ Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
⁹ Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
¹⁰ Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.
¹¹ Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China.
¹² Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
¹³ Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹⁴ Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.
¹⁵ Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
¹⁶ Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
¹⁷ Department of Paediatrics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
¹⁸ The first affiliated hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China.
¹⁹ Central Laboratory, Luoyang Central Hospital Affiliated to Zhengzhou University; Neurology Department, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China.
²⁰ Department of Neurology, West China Hospital of Sichuan University, China; Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
²¹ Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
²² Department of Neurology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China.
²³ Department of Neurology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China.
²⁴ China Spinocerebellar Ataxia Association, Beijing, China.
²⁵ Department of Rehabilitation Medicine of First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

^# Contributed equally.

PMID: 40552560
DOI: 10.1002/ana.27293

Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients

Ru-Ying Yuan et al. Ann Neurol. 2025.

. 2025 Jun 24.

doi: 10.1002/ana.27293. Online ahead of print.

Authors

Affiliations

¹ Department of Neurology, the First Affiliated Hospital, Institute of Neuroscience, Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, China.
² Department of Neurology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
³ Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.
⁴ Department of Neurology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, China.
⁵ Department of Neurology, The First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China; Rare Disease Center, The First Affiliated Hospital of Nanchang University, Nanchang, China.
⁶ Department of Neurology, China Japan Friendship Hospital, Beijing, China.
⁷ Department of Neurology, Institute of Neuroscience, Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
⁸ Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
⁹ Longyan First Affiliated Hospital of Fujian Medical University, Longyan, China.
¹⁰ Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, China.
¹¹ Department of Neurology and National Research Center for Aging and Medicine & National Center for Neurological Disorders, State Key Laboratory of Medical Neurobiology, Huashan Hospital, Fudan University, Shanghai, China.
¹² Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Shanghai Medical College, Fudan University, Shanghai, China.
¹³ Department of Medical Genetics and Center for Rare Diseases, Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
¹⁴ Department of Neurology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, China.
¹⁵ Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University; Guangdong Provincial Key Laboratory of Diagnosis and Treatment of Major Neurological Diseases, National Key Clinical Department and Key Discipline of Neurology, Guangzhou, China.
¹⁶ Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
¹⁷ Department of Paediatrics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
¹⁸ The first affiliated hospital of Wannan Medical College (Yijishan Hospital), Wuhu, China.
¹⁹ Central Laboratory, Luoyang Central Hospital Affiliated to Zhengzhou University; Neurology Department, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, China.
²⁰ Department of Neurology, West China Hospital of Sichuan University, China; Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
²¹ Department of Neurology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
²² Department of Neurology, Huangshi Central Hospital, Affiliated Hospital of Hubei Polytechnic University, Huangshi, China.
²³ Department of Neurology, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, China.
²⁴ China Spinocerebellar Ataxia Association, Beijing, China.
²⁵ Department of Rehabilitation Medicine of First Affiliated Hospital, Fujian Medical University, Fuzhou, China.

^# Contributed equally.

PMID: 40552560
DOI: 10.1002/ana.27293

Abstract

Objective: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, inherited neurodegenerative disorder caused by the expansion of cytosine-adenine-guanine repeats in ATN1. Most studies on DRPLA to date are limited to case reports. We aimed to provide a comprehensive summary of the clinical, genetic, biological, and magnetic resonance imaging characteristics of DRPLA using cross-sectional baseline data.

Methods: This is a cross-sectional observational cohort study. We used an extensive battery of assessments, included clinical phenotypes, genotypes, cognitive performance, biological markers, and magnetic resonance imaging characteristics.

Results: We enrolled 116 DRPLA patients, including 96 manifest patients and 20 prodromal patients. We identified a previously unreported ATN1 haplotype consisting of 8 single-nucleotide polymorphisms. Cognitive assessments revealed that 51 manifest patients (96%) and 4 prodromal patients (29%) scored <26 on the Montreal Cognitive Assessment. Manifest patients showed impairments across all cognitive domains, whereas prodromal patients showed deficits only in phonemic fluency. Biological analyses showed significantly elevated plasma neurofilament light levels in manifest patients compared with prodromal patients (P < 0.001) and healthy controls (P < 0.001). Magnetic resonance imaging findings revealed widespread gray matter loss across the whole brain in manifest patients, whereas prodromal patients showed gray matter loss localized to the bilateral cerebellar hemispheres.

Interpretation: This is the first DRPLA cohort study to comprehensively report clinical, genetic, cognitive, imaging, and plasma neurofilament light data. This study provides robust data to enhance our understanding of the overall features of DRPLA. We also propose clear definitions for the preclinical stage of DRPLA, and demonstrate the high diagnostic utility of plasma neurofilament light as a biomarker. ANN NEUROL 2025.

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References

1. Chaudhry A, Anthanasiou‐Fragkouli A, Houlden H. DRPLA: understanding the natural history and developing biomarkers to accelerate therapeutic trials in a globally rare repeat expansion disorder. J Neurol 2021;268:3031–3041.
1. Koide R, Ikeuchi T, Onodera O, et al. Unstable expansion of CAG repeat in hereditary dentatorubral‐pallidoluysian atrophy (DRPLA). Nat Genet 1994;6:9–13.
1. Nagafuchi S, Yanagisawa H, Sato K, et al. Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p. Nat Genet 1994;6:14–18.
1. Spinocerebellar ataxia. Nat Rev Dis Primers 2019;5:25.
1. Jellinger KA. Pallidal degenerations and related disorders: an update. J Neural Transm (Vienna) 2022;129:521–543.

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Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients

Affiliations

Clinical and Genetic Findings in a Chinese Cohort of Dentatorubral-Pallidoluysian Atrophy Patients

Authors

Affiliations

Abstract

References

Grants and funding

LinkOut - more resources

Full Text Sources