Best Oculomotor Endpoints for Clinical Trials in Hereditary Ataxias: A Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital‑Motor Biomarkers

Elena Pretegiani¹, Pilar Garces², Chrystalina A Antoniades³, Anna Sobanska⁴, Norbert Kovacs⁵, Sarah H Ying⁶, Anoopum S Gupta⁷, Susan Perlman⁸, David J Szmulewicz^{9

10}, Chiara Pane¹¹, Andrea H Németh^{12

13}, Laura B Jardim^{14

15}, Giulia Coarelli¹⁶, Michaela Kuzmiak¹⁷, Andona Milovanovic¹⁸, Andreas Traschütz^{19

20}, Alexander A Tarnutzer^{21

22}

Affiliations

¹ Unit of Neurology, Centre Hospitalier Universitaire Vaudoise Lausanne, Lausanne, Switzerland.
² Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland.
³ NeuroMetrology Lab, Nuffield Department of Clinical Neurosciences, Clinical Neurology, Medical Sciences Division, University of Oxford, Oxford, OX3 9DU, UK.
⁴ Institute of Psychiatry and Neurology, Warsaw, Poland.
⁵ Department of Neurology, Medical School, University of Pécs, Pécs, Hungary.
⁶ Department of Otology and Laryngology and Department of Neurology, Harvard Medical School, Boston, MA, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ University of California Los Angeles, Los Angeles, CA, USA.
⁹ Balance Disorders and Ataxia Service, Royal Victoria Eye and Ear Hospital, East Melbourne, Melbourne, VIC, 3002, Australia.
¹⁰ The Bionics Institute, East Melbourne, Melbourne, VIC, 3002, Australia.
¹¹ Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples "Federico II", Naples, Italy.
¹² Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹³ Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
¹⁴ Departamento de Medicina Interna, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil.
¹⁵ Serviço de Genética Médica/Centro de Pesquisa Clínica E Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁶ APHPSorbonne Université, Paris Brain Institute, Inserm, CNRS, Pitié-Salpêtrière Hospital, DMU Biogem, APHP, 75013, Paris, France.
¹⁷ Department of Neurology, 2nd Faculty of Medicine, Centre of Hereditary Ataxias, Charles University and Motol University Hospital, Prague, Czech Republic.
¹⁸ Clinic for Neurology, University Clinical Center of Serbia, Belgrade, Serbia.
¹⁹ Hertie-Institute for Clinical Brain Research and Center of Neurology, Division Translational Genomics of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
²¹ Cantonal Hospital of Baden, Baden, Switzerland. alexander.tarnutzer@access.uzh.ch.
²² Faculty of Medicine, University of Zurich, Zurich, Switzerland. alexander.tarnutzer@access.uzh.ch.

PMID: 40801974
PMCID: PMC12350468
DOI: 10.1007/s12311-025-01894-z

Best Oculomotor Endpoints for Clinical Trials in Hereditary Ataxias: A Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital‑Motor Biomarkers

Elena Pretegiani et al. Cerebellum. 2025.

. 2025 Aug 13;24(5):141.

doi: 10.1007/s12311-025-01894-z.

Authors

Affiliations

¹ Unit of Neurology, Centre Hospitalier Universitaire Vaudoise Lausanne, Lausanne, Switzerland.
² Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, Basel, Switzerland.
³ NeuroMetrology Lab, Nuffield Department of Clinical Neurosciences, Clinical Neurology, Medical Sciences Division, University of Oxford, Oxford, OX3 9DU, UK.
⁴ Institute of Psychiatry and Neurology, Warsaw, Poland.
⁵ Department of Neurology, Medical School, University of Pécs, Pécs, Hungary.
⁶ Department of Otology and Laryngology and Department of Neurology, Harvard Medical School, Boston, MA, USA.
⁷ Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁸ University of California Los Angeles, Los Angeles, CA, USA.
⁹ Balance Disorders and Ataxia Service, Royal Victoria Eye and Ear Hospital, East Melbourne, Melbourne, VIC, 3002, Australia.
¹⁰ The Bionics Institute, East Melbourne, Melbourne, VIC, 3002, Australia.
¹¹ Department of Neurosciences and Reproductive and Odontostomatological Sciences, University of Naples "Federico II", Naples, Italy.
¹² Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
¹³ Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
¹⁴ Departamento de Medicina Interna, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil.
¹⁵ Serviço de Genética Médica/Centro de Pesquisa Clínica E Experimental, Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil.
¹⁶ APHPSorbonne Université, Paris Brain Institute, Inserm, CNRS, Pitié-Salpêtrière Hospital, DMU Biogem, APHP, 75013, Paris, France.
¹⁷ Department of Neurology, 2nd Faculty of Medicine, Centre of Hereditary Ataxias, Charles University and Motol University Hospital, Prague, Czech Republic.
¹⁸ Clinic for Neurology, University Clinical Center of Serbia, Belgrade, Serbia.
¹⁹ Hertie-Institute for Clinical Brain Research and Center of Neurology, Division Translational Genomics of Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany.
²⁰ German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany.
²¹ Cantonal Hospital of Baden, Baden, Switzerland. alexander.tarnutzer@access.uzh.ch.
²² Faculty of Medicine, University of Zurich, Zurich, Switzerland. alexander.tarnutzer@access.uzh.ch.

PMID: 40801974
PMCID: PMC12350468
DOI: 10.1007/s12311-025-01894-z

Abstract

Oculomotor deficits are common in hereditary cerebellar ataxias (HCAs) and their quantitative assessment offers a sensitive and reliable manner to capture disease-severity and progression. As a group of experts of the Ataxia Global Initiative to support trial readiness, we previously established harmonized methodology for quantitative oculomotor assessments in HCAs. Here, we aimed to identify to most promising oculomotor/vestibular outcomes as endpoints for future trials. Through a systematic MEDLINE search we identified 130 articles reporting oculomotor/vestibular recordings in patients with HCAs. A total of 2,018 subjects were included: 1,776 with genetically-confirmed and 242 with clinically-defined HCAs. Studied diseases included spinocerebellar ataxias (SCA) 1/2/3/6/7/27B, episodic ataxia type 2, Friedreich ataxia, RFC1-related ataxia, fragile X-associated tremor/ataxia syndrome, cerebrotendinous xanthomatosis, ataxia-telangiectasia, ataxia with oculomotor apraxia types 1&2, and Niemann-Pick disease type C. We identified up to four oculomotor/vestibular outcomes per diagnostic entity, based on their ability to robustly discriminate patients from controls, correlate with disease-severity, detect longitudinal change, and represent different disease stages. For each parameter we provide recommendations for recordings. While the implementation of quantitative assessments into clinical trials offers a unique opportunity to track dysfunction of oculomotor/vestibular networks and to assess the impact of interventions, in some HCAs, endpoint qualification of available outcomes requires further validation to characterize their reliability, sensitivity to change, and minimally important change to patients. For all HCAs for which quantitative data are scarce or lacking, there is an urgent need for prospective studies covering a broader range of oculomotor/vestibular domains as approaching new treatments require harmonized and reliable endpoints.

Keywords: Eye movement recordings; Hereditary ataxia; Oculomotor; Recommendations; Systematic review; Vestibular.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethical Approval: Not applicable. Competing Interests: PG is a full-time employee of F. Hoffmann–la Roche Ltd.

Figures

**Fig. 1**
* MEDLINE was accessed via PubMed. † Individual hand search of citation lists from selected studies and investigator files identified 17 additional manuscripts for review. ‡ Abstracts coded as “yes” or “maybe” by at least one reviewer were included in full-text review. § After full-text evaluation by two reviewers, any differences were resolved by discussion and – if needed—adjudication by a third, independent reviewer

See this image and copyright information in PMC

References

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Best Oculomotor Endpoints for Clinical Trials in Hereditary Ataxias: A Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital‑Motor Biomarkers

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Best Oculomotor Endpoints for Clinical Trials in Hereditary Ataxias: A Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital‑Motor Biomarkers

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