The genetic landscape of sporadic adult-onset degenerative ataxia: a multi-modal genetic study of 377 consecutive patients from the longitudinal multi-centre SPORTAX cohortResearch in context
Danique Beijer,
David Mengel,
Demet Önder,
Carlo Wilke,
Andreas Traschütz,
Jennifer Faber,
Dagmar Timmann,
Sylvia Boesch,
Stefan Vielhaber,
Thomas Klopstock,
Bart P. van de Warrenburg,
Gabriella Silvestri,
Christoph Kamm,
Iselin Marie Wedding,
Zofia Fleszar,
Florian Harmuth,
Claudia Dufke,
Bernard Brais,
Olaf Rieß,
Ludger Schöls,
Tobias Haack,
Stephan Züchner,
David Pellerin,
Thomas Klockgether,
Matthis Synofzik,
Friedrich Erdlenbruch,
Andreas Thieme,
Judith van Gaalen,
Christos Ganos,
Jun-Suk Kang,
Marcus Grobe-Einsler,
Ilaria Giordano
Affiliations
Danique Beijer
Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
David Mengel
Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
Demet Önder
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Center for Neurology, Department of Parkinson's Disease, Sleep and Movement Disorders, University Hospital Bonn, Bonn, Germany
Carlo Wilke
Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Germany
Andreas Traschütz
Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany
Jennifer Faber
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Center for Neurology, Department of Parkinson's Disease, Sleep and Movement Disorders, University Hospital Bonn, Bonn, Germany; Department of Neuroradiology, University Hospital Bonn, Bonn, Germany
Dagmar Timmann
Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen University Hospital, Duisburg-Essen, 45147, Essen, Germany
Sylvia Boesch
Center for Rare Movement Disorders Innsbruck, Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
Department of Neurology with Friedrich-Baur-Institute, LMU University Hospital of Ludwig-Maximilians-Universität München, 80336, Munich, Germany; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
Bart P. van de Warrenburg
Department of Neurology, Radboud University Medical Center, 6525, Nijmegen, the Netherlands
Gabriella Silvestri
Department of Neurosciences, Università Cattolica del Sacro Cuore, Rome, Italy; UOC Neurologia Dipartimento Neuroscienze, Fondazione Policlinico Universitario A Gemelli IRCCS, Organi Di Senso e Torace, Rome, Italy
Christoph Kamm
Department of Neurology, University of Rostock, Rostock, Germany
Iselin Marie Wedding
Department of Neurology, Oslo University Hospital, Oslo, Norway
Zofia Fleszar
Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Germany
Florian Harmuth
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
Claudia Dufke
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
Bernard Brais
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada
Olaf Rieß
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
Ludger Schöls
German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurodegenerative Diseases and Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Germany
Tobias Haack
Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
Stephan Züchner
Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, 33136, FL, USA
David Pellerin
Department of Neurology and Neurosurgery, Montreal Neurological Hospital and Institute, McGill University, Montreal, QC, Canada; Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, 33136, FL, USA
Thomas Klockgether
German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurology, University Hospital Bonn, Bonn, Germany
Matthis Synofzik
Division of Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), Tübingen, Germany; Corresponding author. Division Translational Genomics of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Hoppe-Seyler-Str. 3, 72076, Tübingen, Germany.
Summary: Background: While most sporadic adult-onset neurodegenerative diseases have only a minor monogenic component, given several recently identified late adult-onset ataxia genes, the genetic burden may be substantial in sporadic adult-onset ataxias. We report systematic mapping of the genetic landscape of sporadic adult-onset ataxia in a well-characterised, multi-centre cohort, combining several multi-modal genetic screening techniques, plus longitudinal natural history data. Methods: Systematic clinico-genetic analysis of a prospective longitudinal multi-centre cohort of 377 consecutive patients with sporadic adult-onset ataxia (SPORTAX cohort), including clinically defined sporadic adult-onset ataxia of unknown aetiology (SAOA) (n = 229) and ‘clinically probable multiple system atrophy of cerebellar type’ (MSA-Ccp) (n = 148). Combined GAA-FGF14 (SCA27B) and RFC1 repeat expansion screening with next-generation sequencing (NGS) was complemented by natural history and plasma neurofilament light chain analysis in key subgroups. Findings: 85 out of 377 (22.5%) patients with sporadic adult-onset ataxia carried a pathogenic or likely pathogenic variant, thereof 67/229 (29.3%) patients with SAOA and 18/148 (12.2%) patients meeting the MSA-Ccp criteria. This included: 45/377 (11.9%) patients with GAA-FGF14≥250 repeat expansions (nine with MSA-Ccp), 17/377 (4.5%) patients with RFC1 repeat expansions (three with MSA-Ccp), and 24/377 (6.4%) patients with single nucleotide variants (SNVs) identified by NGS (six with MSA-Ccp). Five patients (1.3%) were found to have two relevant genetic variants simultaneously (dual diagnosis). Interpretation: In this cohort of sporadic adult-onset ataxia, a cohort less likely to have a monogenic cause, a substantial burden of monogenic variants was identified, particularly GAA-FGF14 and RFC1 repeat expansions. This included a substantial share of patients meeting the MSA-Ccp criteria, suggesting a reduced specificity of this clinical diagnosis and potential co-occurrence of MSA-C plus a second, independent genetic condition. These findings have important implications for the genetic work-up and counselling of patients with sporadic ataxia, even when presenting with MSA-like features. With targeted treatments for genetic ataxias now on the horizon, these findings highlight their potential utility for these patients. Funding: This work was supported by the Clinician Scientist programme “PRECISE.net” funded by the Else Kröner-Fresenius-Stiftung (to DM, AT, CW, OR, and MS), by the Deutsche Forschungsgemeinschaft (as part of the PROSPAX project), and by the Canadian Institutes of Health Research and the Fondation Groupe Monaco. Support was also provided by Humboldt Research Fellowship for Postdocs and the Hertie-Network of Excellence in Clinical Neuroscience and a Fellowship award from the Canadian Institutes of Health Research.
