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Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia

Journal of Human Genetics (2024)Cite this article

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Abstract

Background

Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement.

Methods

GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement.

Results

Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage.

Conclusions

GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We sincerely wish to thank all patients and their relatives for participating in this study. This work was sponsored by the grants 2021ZQNZD003 (W.-J.C.) from Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province, 2022YFC2703900 and 2022YFC2703904 (W.-J.C.) from the National Key Research and Development Program of China, 2022ZD01002 (W.-J.C.) from the Fujian provincial health technology project, LHGJ20230447 (C.-Y.C.) from Henan provincial Medical Science and Technology Research Project, and 232103810051(C-Y.C.) from Henan provincial Science and Technology Research Development Program Joint Funds (Application research category) Project.

Funding

This work was sponsored by the grants 2021ZQNZD003 (W.-J.C.) from Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province, 2022YFC2703900 and 2022YFC2703904 (W.-J.C.) from the National Key Research and Development Program of China, 2022ZD01002 (W.-J.C.) from the Fujian provincial health technology project, LHGJ20230447 (C.-Y.C.) from Henan provincial Medical Science and Technology Research Project, and 232103810051(C-Y.C.) from Henan provincial Science and Technology Research Development Program Joint Funds (Application research category) Project.

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  1. These authors contributed equally: Ze-Hong Zheng, Chun-Yan Cao, Bi Cheng, Ru-Ying Yuan.

Authors and Affiliations

  1. Department of Neurology and Institute of Neurology of First Affiliated Hospital, Institute of Neuroscience, and Fujian Key Laboratory of Molecular Neurology, Fujian Medical University, Fuzhou, 350005, China

    Ze-Hong Zheng, Bi Cheng, Ru-Ying Yuan, Yi-Heng Zeng, Zhang-Bao Guo, Yu-Sen Qiu, Wen-Qi Lv, Hui Liang, Jin-Lan Li, Min-Kun Fang, Yu-Hao Sun, Wei Lin, Jing-Mei Hong, Shi-Rui Gan, Ning Wang, Wan-Jin Chen & Ling Fang

  2. The First Affiliated Hospital, College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China

    Chun-Yan Cao, Wei-Xiong Zhang & Gan-Qin Du

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Contributions

All authors contributed to the study conception and design. Ze-Hong Zheng, Chun-Yan Cao, Bi Cheng, Gan-Qin Du, Wan-Jin Chen and Ling Fang contributed to the conception and design of the study; Ze-Hong Zheng, Chun-Yan Cao, Ru-Ying Yuan, Bi Cheng, Wei-Xiong Zhang, Ning Wang, Yi-Heng Zeng and Gan-Qin Du contributed to follow-up of patients; Ze-Hong Zheng, Bi Cheng, Shi-Rui Gan, Zhang-Bao Guo, Yu-Sen Qiu, Hui Liang, Jin-Lan Li, Min-Kun Fang, Wei Lin, and Yu-Hao Sun contributed to collection of samples and screening for GAA-FGF14 repeat expansion. Chun-Yan Cao and Jing-Mei Hong contributed to the acquisition and analysis of sympathetic skin response. Ze-Hong Zheng, Yi-Heng Zeng, Wen-Qi Lv, Wan-Jin Chen and Ling Fang contributed to drafting the text and preparing the figures. all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Gan-Qin Du or Ling Fang.

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This study was performed in line with the principles of the Declaration of Helsinki. All participant were recruited at The First Affiliated Hospital of Fujian Medical University via the cohort study registered at ClinicalTrials.gov (NCTO4010214).

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Zheng, ZH., Cao, CY., Cheng, B. et al. Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01262-5

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