Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Journal of Human Genetics volume 69, pages 433–440 (2024)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

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

References

  1. Pellerin D, Danzi MC, Wilke C, Renaud M, Fazal S, Dicaire MJ, et al. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388:128–41. https://doi.org/10.1056/NEJMoa2207406

    Article  CAS  PubMed  Google Scholar 

  2. Wilke C, Pellerin D, Mengel D, Traschutz A, Danzi MC, Dicaire MJ, et al. GAA-FGF14 ataxia (SCA27B): phenotypic profile, natural history progression and 4-aminopyridine treatment response. Brain. 2023. https://doi.org/10.1093/brain/awad157

  3. Rafehi H, Read J, Szmulewicz DJ, Davies KC, Snell P, Fearnley LG, et al. An intronic GAA repeat expansion in FGF14 causes the autosomal-dominant adult-onset ataxia SCA50/ATX-FGF14. Am J Hum Genet. 2023;110:105–19. https://doi.org/10.1016/j.ajhg.2022.11.015

    Article  CAS  PubMed  Google Scholar 

  4. Hengel H, Pellerin D, Wilke C, Fleszar Z, Brais B, Haack T, et al. As Frequent as Polyglutamine Spinocerebellar Ataxias: SCA27B in a Large German Autosomal Dominant Ataxia Cohort. Mov Disord. 2023;38:1557–8. https://doi.org/10.1002/mds.29559

    Article  CAS  PubMed  Google Scholar 

  5. Milovanovic A, Dragasevic-Miskovic N, Thomsen M, Borsche M, Hinrichs F, Westenberger A, et al. RFC1 and FGF14 Repeat Expansions in Serbian Patients with Cerebellar Ataxia. Mov Disord Clin Pract. 2024. https://doi.org/10.1002/mdc3.14020

  6. Mereaux JL, Davoine CS, Pellerin D, Coarelli G, Coutelier M, Ewenczyk C, et al. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions. EBioMedicine. 2024;99:104931 https://doi.org/10.1016/j.ebiom.2023.104931

    Article  CAS  PubMed  Google Scholar 

  7. Kartanou C, Mitrousias A, Pellerin D, Kontogeorgiou Z, Iruzubieta P, Dicaire MJ, et al. The FGF14 GAA repeat expansion in Greek patients with late-onset cerebellar ataxia and an overview of the SCA27B phenotype across populations. Clin Genet. 2024;105:446–52. https://doi.org/10.1111/cge.14482

    Article  CAS  PubMed  Google Scholar 

  8. Zeng YH, Gan SR, Chen WJ. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023;388, https://doi.org/10.1056/NEJMc2301605

  9. Ouyang R, Wan L, Pellerin D, Long Z, Hu J, Jiang Q, et al. The genetic landscape and phenotypic spectrum of GAA-FGF14 ataxia in China: a large cohort study. EBioMedicine. 2024;102:105077 https://doi.org/10.1016/j.ebiom.2024.105077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Ando M, Higuchi Y, Yuan J, Yoshimura A, Kojima F, Yamanishi Y, et al. Clinical variability associated with intronic FGF14 GAA repeat expansion in Japan. Ann Clin Transl Neurol. 2024;11:96–104. https://doi.org/10.1002/acn3.51936

    Article  CAS  PubMed  Google Scholar 

  11. Harding AE. “Idiopathic” late onset cerebellar ataxia. A clinical and genetic study of 36 cases. J Neurol Sci. 1981;51:259–71. https://doi.org/10.1016/0022-510x(81)90104-0

    Article  CAS  PubMed  Google Scholar 

  12. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology. 2008;71:670–6. https://doi.org/10.1212/01.wnl.0000324625.00404.15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Schmitz-Hübsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66:1717–20. https://doi.org/10.1212/01.wnl.0000219042.60538.92

    Article  PubMed  Google Scholar 

  14. Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The Ataxia Neuropharmacology Committee of the World Federation of Neurology. J Neurol Sci. 1997;145:205–11. https://doi.org/10.1016/s0022-510x(96)00231-6

    Article  CAS  PubMed  Google Scholar 

  15. Maas RP, van Gaalen J, Klockgether T, van de Warrenburg BP. The preclinical stage of spinocerebellar ataxias. Neurology. 2015;85:96–103. https://doi.org/10.1212/wnl.0000000000001711

    Article  PubMed  Google Scholar 

  16. Qiu H, Wu C, Liang J, Hu M, Chen Y, Huang Z, et al. Structural alterations of spinocerebellar ataxias type 3: from pre-symptomatic to symptomatic stage. Eur Radiol. 2023;33:2881–94. https://doi.org/10.1007/s00330-022-09214-3

    Article  CAS  PubMed  Google Scholar 

  17. Nolano M, Provitera V, Manganelli F, Iodice R, Stancanelli A, Caporaso G, et al. Loss of cutaneous large and small fibers in naive and l-dopa-treated PD patients. Neurology. 2017;89:776–84. https://doi.org/10.1212/wnl.0000000000004274

    Article  CAS  PubMed  Google Scholar 

  18. Andrich J, Schmitz T, Saft C, Postert T, Kraus P, Epplen JT, et al. Autonomic nervous system function in Huntington’s disease. J Neurol Neurosurg Psychiatry. 2002;72:726–31. https://doi.org/10.1136/jnnp.72.6.726

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Bonnet C, Pellerin D, Roth V, Clement G, Wandzel M, Lambert L, et al. Optimized testing strategy for the diagnosis of GAA-FGF14 ataxia/spinocerebellar ataxia 27B. Sci Rep. 2023;13:9737 https://doi.org/10.1038/s41598-023-36654-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Li H. Minimap2: pairwise alignment for nucleotide sequences. Bioinformatics. 2018;34:3094–100. https://doi.org/10.1093/bioinformatics/bty191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6. https://doi.org/10.1038/nbt.1754

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Chiu R, Rajan-Babu IS, Friedman JM, Birol I. Straglr: discovering and genotyping tandem repeat expansions using whole genome long-read sequences. Genome Biol. 2021;22:224 https://doi.org/10.1186/s13059-021-02447-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Yau WY, Sullivan R, Chen Z, Lynch DS, Vandrovcova J, Wood NW, et al. GGC Repeat Expansion in NOTCH2NLC Is Rare in European Leukoencephalopathy. Ann Neurol. 2020;88:641–2. https://doi.org/10.1002/ana.25818

    Article  CAS  PubMed  Google Scholar 

  24. Chen Z, Yan Yau W, Jaunmuktane Z, Tucci A, Sivakumar P, Gagliano Taliun SA, et al. Neuronal intranuclear inclusion disease is genetically heterogeneous. Ann Clin Transl Neurol. 2020;7:1716–25. https://doi.org/10.1002/acn3.51151

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Labuda M, Labuda D, Miranda C, Poirier J, Soong BW, Barucha NE, et al. Unique origin and specific ethnic distribution of the Friedreich ataxia GAA expansion. Neurology. 2000;54:2322–4. https://doi.org/10.1212/wnl.54.12.2322

    Article  CAS  PubMed  Google Scholar 

  26. Depienne C, Mandel JL. 30 years of repeat expansion disorders: What have we learned and what are the remaining challenges? Am J Hum Genet. 2021;108:764–85. https://doi.org/10.1016/j.ajhg.2021.03.011

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pianese L, Cavalcanti F, De Michele G, Filla A, Campanella G, Calabrese O, et al. The effect of parental gender on the GAA dynamic mutation in the FRDA gene. Am J Hum Genet. 1997;60:460–3.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Vetrugno R, Liguori R, Cortelli P, Montagna P. Sympathetic skin response: basic mechanisms and clinical applications. Clin Auton Res. 2003;13:256–70. https://doi.org/10.1007/s10286-003-0107-5

    Article  PubMed  Google Scholar 

  29. Corral-Juan M, Casquero P, Giraldo-Restrepo N, Laurie S, Martinez-Pineiro A, Mateo-Montero RC, et al. New spinocerebellar ataxia subtype caused by SAMD9L mutation triggering mitochondrial dysregulation (SCA49). Brain Commun. 2022;4:fcac030. https://doi.org/10.1093/braincomms/fcac030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Indelicato E, Fanciulli A, Ndayisaba JP, Nachbauer W, Granata R, Wanschitz J, et al. Autonomic function testing in spinocerebellar ataxia type 2. Clin Auton Res. 2018;28:341–6. https://doi.org/10.1007/s10286-018-0504-4

    Article  PubMed  PubMed Central  Google Scholar 

  31. Jin Y, Chen Y, Li D, Qiu M, Zhou M, Hu Z, et al. Autonomic dysfunction as the initial presentation in spinocerebellar ataxia type 3: A case report and review of the literature. Front Neurol. 2022;13:967293 https://doi.org/10.3389/fneur.2022.967293

    Article  PubMed  PubMed Central  Google Scholar 

  32. Franca MC Jr., D’Abreu A, Nucci A, Lopes-Cendes I. Clinical correlates of autonomic dysfunction in patients with Machado-Joseph disease. Acta Neurol Scand. 2010;121:422–5. https://doi.org/10.1111/j.1600-0404.2009.01249.x

    Article  PubMed  Google Scholar 

  33. Schmitt GDS, Lima FD, Matos P, Martinez ARM, Gonzalez-Salazar C, Nucci A, et al. Dysautonomia in RFC1-related disorder: Clinical and neurophysiological evaluation. Clin Neurophysiol. 2022;142:68–74. https://doi.org/10.1016/j.clinph.2022.07.501

    Article  PubMed  Google Scholar 

Download references

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.

Author information

Author notes

  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

Authors
  1. Ze-Hong Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chun-Yan Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Bi Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ru-Ying Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yi-Heng Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhang-Bao Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yu-Sen Qiu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wen-Qi Lv
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hui Liang
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Jin-Lan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Wei-Xiong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Min-Kun Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Yu-Hao Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Wei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Jing-Mei Hong
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Shi-Rui Gan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Ning Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Wan-Jin Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Gan-Qin Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Ling Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

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.

Corresponding authors

Correspondence to Gan-Qin Du or Ling Fang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval

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).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zheng, ZH., Cao, CY., Cheng, B. et al. Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia. J Hum Genet 69, 433–440 (2024). https://doi.org/10.1038/s10038-024-01262-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s10038-024-01262-5

Search

Advanced search

Quick links