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Mitochondrial Dysfunction due to Novel COQ8A Variation with Poor Response to CoQ10 Treatment: A Comprehensive Study and Review of Literatures

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Abstract

COQ8A plays an important role in the biosynthesis of coenzyme Q10 (CoQ10), and variations in COQ8A gene are associated with primary CoQ10 deficiency-4 (COQ10D4), also known as COQ8A-ataxia. The current understanding of the association between the specific variant type, the severity of CoQ10 deficiency, and the degree of oxidative stress in individuals with primary CoQ10 deficiencies remains uncertain. Here we provide a comprehensive analysis of the clinical and genetic characteristics of an 18-year-old patient with COQ8A-ataxia, who exhibited novel compound heterozygous variants (c.1904_1906del and c.637C > T) in the COQ8A gene. These variants reduced the expression levels of COQ8A and mitochondrial proteins in the patient’s muscle and skin fibroblast samples, contributed to mitochondrial respiration deficiency, increased ROS production and altered mitochondrial membrane potential. It is worth noting that the optimal treatment for COQ8A-ataxia remains uncertain. Presently, therapy consists of CoQ10 supplementation, however, it did not yield significant improvement in our patient's symptoms. Additionally, we reviewed the response of CoQ10 supplementation and evolution of patients in previous literatures in detail. We found that only half of patients could got notable improvement in ataxia. This research aims to expand the genotype–phenotype spectrum of COQ10D4, address discrepancies in previous reviews regarding the effectiveness of CoQ10 in these disorders, and help to establish a standardized treatment protocol for COQ8A-ataxia.

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Acknowledgements

We appreciate the patient and his families for contributing samples and providing invaluable clinical information for this study.

Funding

This study was supported by the National Natural Science Foundation of China (No. 82301590, 82071412 and 82171394), China Postdoctoral Science Foundation (2023M742116), Natural Science Foundation of Shandong Province (No. ZR2023QH106), Shandong Provincial Postdoctoral Innovation Talent Support Program (SDBX2022061), Grants from the National Key R&D Program of China (No.2021YFC2700904), People's Benefit Project of Science and Technology in Qingdao (20–3-4–42-nsh, 22–8-7-smjk-1-nsh), and the Taishan Scholars Program of Shandong Province.

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Authors and Affiliations

  1. Research Institute of Neuromuscular and Neurodegenerative Diseases and Department of Neurology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China

    Jiayin Wang, Yan Lin, Zhihong Xu, Chuanzhu Yan, Yuying Zhao & Kunqian Ji

  2. Mitochondrial Medicine Laboratory, Qilu Hospital (Qingdao), Shandong University, Qingdao, 266035, Shandong, China

    Chuanzhu Yan

  3. Brain Science Research Institute, Shandong University, Jinan, 250012, Shandong, China

    Chuanzhu Yan

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  1. Jiayin Wang
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  2. Yan Lin
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  3. Zhihong Xu
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Contributions

JYW performed the experiments and drafted the manuscript; YL help to designed the study and provide technical assistant; ZHX help some of the experiments; CZY supervised the study; YYZ provide the clinic case; KQJ involved in the critical revision of the manuscript. The authors read and approved the final manuscript.

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Correspondence to Yuying Zhao or Kunqian Ji.

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Wang, J., Lin, Y., Xu, Z. et al. Mitochondrial Dysfunction due to Novel COQ8A Variation with Poor Response to CoQ10 Treatment: A Comprehensive Study and Review of Literatures. Cerebellum (2024). https://doi.org/10.1007/s12311-024-01671-4

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