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  • Review Article
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Progress and challenges in sporadic late-onset cerebellar ataxias

Nature Reviews Neurology volume 21, pages 687–705 (2025)Cite this article

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Abstract

Sporadic late-onset cerebellar ataxia (SLOCA) is a syndrome defined by subacute or chronic and progressive ataxia occurring after the age of 40 years in individuals without a family history of ataxia. The 2022 publication of revised consensus diagnostic criteria for multiple system atrophy and the emergence of promising biomarkers provides a thorough diagnostic framework that now enables the diagnosis of numerous acquired causes of SLOCA, including autoimmune disorders and neurodegenerative diseases. The ongoing development and increased availability of DNA sequencing technology have uncovered several molecular causes of SLOCA besides spastic paraplegia type 7 and very late-onset Friedreich ataxia. These additional causes include sporadic genetic disorders, such as spinocerebellar atrophy type 27B, caused by GAA expansion in the FGF14 gene, and cerebellar ataxia with neuropathy and vestibular areflexia syndrome (CANVAS), caused by biallelic expansions in the RFC1 gene. This Review presents an updated clinical approach to the diagnosis and management of SLOCA that focuses on the most important developments in this field. Future challenges are also discussed, including the identification of additional missing genetic causes of SLOCA, especially via the use of long-read genome sequencing, improvements in SLOCA prognostication and the implementation of clinical trials of neuroprotective interventions.

Key points

  • Sporadic late-onset cerebellar ataxia (SLOCA) is a syndrome defined by subacute or chronic, progressive ataxia occurring after the age of 40 years in individuals with no family history of ataxia.

  • The most frequent cause of SLOCA is multiple system atrophy, a rapidly progressive neurodegenerative condition that combines cerebellar ataxia, dysautonomia (typically genitourinary impairment or orthostatic hypotension) and parkinsonism.

  • Autoimmune cerebellar ataxias are rare causes of non-genetic, usually rapidly progressive SLOCA that are frequently responsive to immunosuppressive treatment, which can improve the disease course.

  • The ongoing development of DNA sequencing technologies has revealed that a substantial proportion of SLOCA can be explained by specific pathogenic genetic variants.

  • The most frequent genetic causes of SLOCA are heterozygous GAA expansions in FGF14 (spinocerebellar atrophy type 27B) and biallelic expansions in RFC1 (cerebellar ataxia with neuropathy and vestibular areflexia (CANVAS)).

  • Long-read genome sequencing could facilitate the discovery of additional SLOCA-causing gene variants, and validation of surrogate biomarkers would promote the identification of disease-modifying drugs.

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Fig. 1: Classification of cerebellar ataxia.
Fig. 2: Clinical features of sporadic late-onset cerebellar ataxia.
Fig. 3: Neuroimaging features of sporadic late-onset cerebellar ataxia.
Fig. 4: Diagnostic algorithm for the investigation of potential causes of SLOCA.

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Acknowledgements

The authors thank Thibault Willaume from the Radiology Department of Strasbourg University Hospital for providing the imaging scan shown in Fig. 3o. J.H. declares that he is supported by a public grant overseen by the Agence Nationale de la Recherche (French Research Agency) as part of the Investissements d’Avenir programme (ANR-18-RHUS-0012) and by the European Reference Network Rare Immunodeficiency, Autoinflammatory and Autoimmune diseases network (RITA).

Author information

Authors and Affiliations

  1. Department of Neurology, University Hospital of Strasbourg, Strasbourg, France

    Thomas Wirth, Christine Tranchant & Mathieu Anheim

  2. Strasbourg Neuroscience Institute, Strasbourg University, Strasbourg, France

    Thomas Wirth, Christine Tranchant & Mathieu Anheim

  3. Institute of Genetics and Cellular and Molecular Biology, INSERM-U964, CNRS-UMR7104, University of Strasbourg, Illkirch-Graffenstaden, France

    Thomas Wirth, Christine Tranchant & Mathieu Anheim

  4. Center of Neurology, University Hospital Bonn, Bonn, Germany

    Jennifer Faber & Thomas Klockgether

  5. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany

    Jennifer Faber & Thomas Klockgether

  6. Institute of Human Genetics, Essen University Hospital, University of Duisburg-Essen, Essen, Germany

    Christel Depienne

  7. Département de Neurologie, Hôpital de la Pitié Salpêtrière, Assistance Publique-Hôpitaux de Paris, Institut du Cerveau, Sorbonne Universités INSERM-U1127, CNRS-UMR7225, Paris, France

    Emmanuel Roze

  8. French Reference Center on Paraneoplastic Neurological Syndromes and Autoimmune Encephalitis, Hospices Civils de Lyon, Lyon, France

    Jérôme Honnorat

  9. MeLiS Institute, INSERM-U1314, CNRS-UMR5284, Université Claude Bernard Lyon 1, Lyon, France

    Jérôme Honnorat

  10. Centre Hospitalo-Universitaire de Bordeaux, Service de Neurologie — Maladies Neurodégénératives, Centre de Référence Maladies Rares Atrophie Multisystématisée, Bordeaux, France

    Wassilios G. Meissner

  11. Institut des Maladies Neurodégénératives Cliniques, Université de Bordeaux, CNRS-UMR5293, Bordeaux, France

    Wassilios G. Meissner

  12. Department of Medicine, University of Otago, Christchurch, New Zealand

    Wassilios G. Meissner

  13. New Zealand Brain Research Institute, Christchurch, New Zealand

    Wassilios G. Meissner

  14. Ataxia Centre, Department of Clinical and Movement Neurosciences, University College London (UCL) Queen Square Institute of Neurology, London, UK

    Paola Giunti

  15. National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK

    Paola Giunti

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  1. Thomas Wirth
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Contributions

The authors contributed to all aspects of the article. Specifically, T.W. and M.A. jointly conceptualized the manuscript, which was coordinated by M.A. T.W. wrote the Abstract, the Introduction, the sections ‘Molecular causes of SLOCA’ and ‘Hidden genetic causes of idiopathic SLOCA’ (with C.D. and P.G.) and the Conclusion. T.W. prepared Figs. 1–4, Table 1 (with C.T.), Table 3, and Supplementary Fig. 1 (with T.K.). J.F. wrote the section ‘Biomarkers of disease trajectory’. J.H. wrote the section ‘Autoimmune and inflammatory causes’ and prepared Table 2. W.G.M. wrote the section ‘Multiple system atrophy’. C.T. wrote the section ‘Acquired causes of SLOCA’. T.K. wote the section ‘Towards disease-modifying treatments’. M.A. and E.R. synthesized all co-author drafts into the final version of the manuscript.

Corresponding author

Correspondence to Mathieu Anheim.

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Competing interests

T.W. declares that he has received honoraria from Abbvie, Edimark and Ipsen; research grants from APTES, Fondation Planiol, the France Parkinson organizations and Revue Neurologique; prize money from the Société Française de Neurologie; and travel funding from Homeperf, Lübeck, LVL Medical and the Movement Disorder Society. C.T. declares that she has received honoraria from Abbvie, Biogen, Ipsen and Lynde. M.A. declares that he has received honoraria from Abbvie, Aguettant, Asdia Biogen, Ever Pharma, Ipsen, Merz, Orkyn, Reata Pharmaceuticals and Teva. The other authors declare no competing interests.

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Wirth, T., Faber, J., Depienne, C. et al. Progress and challenges in sporadic late-onset cerebellar ataxias. Nat Rev Neurol 21, 687–705 (2025). https://doi.org/10.1038/s41582-025-01136-0

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