Autosomal Recessive Cerebellar Ataxias in Europe: Frequency, Onset, and Severity in 677 Patients

Abstract

Progress in next-generation sequencing has led to an explosion of novel genes and phenotypes of autosomal recessive cerebellar ataxias (ARCAs) in the last decade, with >170 recessive conditions manifesting with ataxia identified.1 With large-scale natural history and mechanistic treatment trials on the horizon for many ARCAs, up-to-date knowledge is required not only on relative frequencies but also on real-world age and disease severity distributions as key information for trial design planning and recruitment. In this multicenter study, we provide data on the relative frequency of ARCAs in Europe, delineate the spectrum of age at disease onset, and present real-world data on disease severity distributions of patients with ARCA that help to inform future trial planning. Prospective cross-sectional and longitudinal data from consecutive patients enrolled between 2013 and June 2022 from 23 European sites (Fig. 1A) were included, all collected through the international ARCA Registry.2 Patients had been eligible for inclusion into the ARCA Registry if they had (1) a genetically confirmed ARCA; and/or (2) onset before age 40 years without evidence of an autosomal dominant family history, repeat expansion in spinocerebellar ataxia genes, or acquired cause, thus representing a stratum of patients with ataxia known to be enriched for recessive ataxia disease.3, 4 Patients with Friedreich's ataxia (FA; n = 112) were not included because (1) FA is already covered in parallel by other European natural history registries (eg, EFACTS),5 which would lead to a distorted, nonrepresentative frequency estimate in the current study; (2) this study focused on the rare and less well-studied ARCAs; and (3) disease data as investigated in this study are thus already available elsewhere.5 A total of 677 patients were included in this study, rendering it the largest European ARCA frequency study to date. Fifty-nine percent had a genetic diagnosis (Fig. 1B), with autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS; 13%) and spastic paraplegia type 7 (SPG7; 10%) being the most frequent, followed by RFC1, ataxia with oculomotor apraxia type 2 (AOA2), ataxia telangiectasia (AT), and SYNE1 (all 7%), and then in decreasing frequency, COQ8A (5%), POLG (4%), ANO10 (3%), and AOA1 (3%), and a large number of 62 ultra-rare ARCAs (each ≤2%, often only n = 1–3 patients/ARCA) (Fig. 1C). Age of onset of ARSACS, AT, and COQ8A was typically in the first decade of life (Fig. 1D), whereas SPG7, POLG, and ANO10 started on average in the fourth decade. Patients with RFC1 mutations had a later onset, on average at age 53 (interquartile range: 49–61) years (Fig. 1D). Cross-sectional disease progression estimates (Scale for the Assessment and Rating of Ataxia score [SARA]/disease duration) suggest a relatively faster disease progression for AT (median: 1.4 SARA points/years), but a slower disease progression for ARSACS (0.6 SARA point/years), RFC1 (0.9 SARA point/years), and SPG7 (0.6 SARA point/years) (Fig. 1F,G). Most patients with ARCA currently attending ataxia clinics already have on average >10 years’ disease duration, with patients with ARSACS even being on average 26 years into their disease (Fig. 1E). Most SPG7, COQ8, and ANO10 patients currently attending ataxia clinics are still ambulatory, whereas >40% of patients with ARSACS, SYNE1, AOA2, or POLG cannot walk independently anymore (Fig. 1H). This large multicenter study provides a comprehensive overview on the frequency of non-FA ARCAs in Europe. It confirms the relatively high frequency of ARSACS, RFC1, and AT in ARCAs, as recently observed in a large South American ARCA cohort.3 The high frequency of SPG7 might have been missed in the South American ARCA cohort because SPG7 has for long not been sequenced as part of the ataxia genetic workup. The larger number and more comprehensive spread of rare ARCAs in this European cohort probably reflect broader availability of large-scale next-generation sequencing as a diagnostic tool in Europe. This study takes the next step toward trial readiness for ARCAs in Europe. The large number of ultra-rare ARCAs highlights the need for novel treatment programs focusing on nano-rare ARCAs, developing, eg, even mutation-specific treatments for these n-of-few ARCAs.6 Molecular treatment trials will need to consider that most ARCA patients available for recruitment in real-world settings will already be >10 years into their disease, with a substantial share of patients no longer walking independently (in particular from ARSACS, SYNE1, AOA2, or POLG). Also, some ARCAs show a fairly slow disease progression (ARSACS, RFC1, SPG7; for detailed analyses, see Traschütz et al7), indicating the need for either large sample sizes, longer trial duration, and/or more sensitive nonclinical outcome measures in upcoming trials. This study is limited by its incomplete coverage of all ataxia centers in Europe and its focus on non-FA ARCAs. However, it might provide a representative perspective on the real-world trial availability of these rare, so far grossly understudied ARCAs in Europe. This study was approved by the Ethics Committee of the Medical Faculty Tübingen (598/2011BO1). Andreas Traschütz, Jonathan Baets, Björn H. Falkenburger, Janina Gburek-Augustat, Sarah Doss, Christoph Kamm, Peter Klivenyi, Marcus Grobe-Einsler, Thomas Klopstock, Martina Minnerop, Alexander Münchau, Chiara Pane, Mathilde Renaud, Filippo M. Santorelli, Stefan Vielhaber, Tobias B. Haack, Bart P. van de Warrenburg, and Ginevra Zanni have nothing to disclose. Astrid D. Adarmes-Gomez has received honorarium for lecturing from AbbVie, Bial, Italfarmaco, Merz, UCB, and Zambon, all unrelated to the present manuscript. Mathieu Anheim received consultancy honoraria from Merz, Orkyn, AbbVie, Ipsen, Reata, and Ever Pharma, all unrelated to the present manuscript. Ludger Schöls received consultancy honoraria from Vico Therapeutics, unrelated to the present manuscript. Dagmar Timmann received funding from the DFG, EU, and Bernd Fink Foundation, unrelated to the present manuscript. Matthis Synofzik received consultancy honoraria from Janssen, Orphazyme, Servier, Reata, AviadoBio, GenOrph, and Ionis Pharmaceuticals, all unrelated to the present manuscript. This work was supported by the European Union's Horizon 2020 research and innovation program as part of the innovation project EVIDENCE-RND under the EJP RD COFUND-EJP (825575 to M.S.), as part of Solve-RD (779257 to J.B., M.S., and B.P.v.d.W.), by the DFG under the frame of EJP-RD network PROSPAX (441409627 to M.S. and B.P.v.d.W.), and by the Clinician Scientist program “PRECISE.net” funded by the Else Kröner-Fresenius-Stiftung (to A.T.). The study was further funded by the Federal Ministry of Education and Research, Germany, and through the TreatHSP network (01GM1905 to L.S.). B.P.v.d.W. receives additional research support from ZonMW, NWO, Hersenstichting, Brugling fonds, Gossweiler Foundation, and Radboud university medical center. L.S., T.K., G.Z., B.P.v.d.W., and M.S. are members of the European Reference Network for Rare Neurological Diseases—Project ID 739510. A.T. receives funding from the University of Tübingen, medical faculty, for the Clinician Scientist Program Grant 439-0-0. P.K. receives funding from University of Szeged (Hetényi Géza: 5S330 A202) and Ministry of Innovation and Technology of Hungary, National Research, Development and Innovation Fund (TKP2021-EGA). J.B. was supported by a Senior Clinical Researcher mandate of the Research Fund—Flanders (FWO) under grant agreement number 1805021N and is a member of the μNEURO Research Centre of Excellence of the University of Antwerp. F.M.S. was supported by the Italian Ministry of Health (the EJP-RD network PROSPAX; Ricerca Finalizzata RF-2016-02361610; RF-2019-12370417; Ricerca Corrente, RC 5x1000). Several authors of this publication are members of the European Reference Network for Rare Neuromuscular Diseases (ERN EURO-NMD) and of the European Reference Network for Rare Neurological Diseases (ERN-RND). Open Access funding enabled and organized by Projekt DEAL. A. Traschütz: 1A, 1B, 1C, 2A, 3A, 3B. A. D. Adarmes-Gomez: 2A, 3B. M. Anheim: 2A, 3B. J. Baets: 2A, 3B. B. H. Falkenburger: 2A, 3B. J. Gburek-Augustat: 2A, 3B. S. Doss: 2A, 3B. C. Kamm: 2A, 3B. P. Klivenyi: 2A, 3B. M. Grobe-Einsler: 2A, 3B. T. Klopstock: 2A, 3B. M. Minnerop: 2A, 3B. M. Münchau: 2A, 3B. C. Pane: 2A, 3B. M. Renaud: 2A, 3B. F. M. Santorelli: 2A, 3B. L. Schöls: 2A, 3B. D. Timmann: 2A, 3B. S. Vielhaber: 2A, 3B. T. B. Haack: 2A, 3B. B. P. van de Warrenburg: 2A, 3B. G. Zanni: 2A, 3B. M. Synofzik: 1A, 1B, 1C, 2A, 3A, 3B. Additional study group contributors of the ARCA Registry/PREPARE consortium: Roderick Maas, MD, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, Nijmegen, the Netherlands; Enrico Bertini, MD, Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy; Peter de Jonghe, MD, PhD, Translational Neurosciences, Faculty of Medicine and Health Sciences, UAntwerpen, Antwerp, Belgium; Laboratory of Neuromuscular Pathology, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium; and Neuromuscular Reference Centre, Department of Neurology, Antwerp University Hospital, Antwerp, Belgium; Ivana Ricca, MD, IRCCS Fondazione Stella Maris, Pisa, Italy; Andreas Thieme, MD, Department of Neurology and Center for Translational Neuro- and Behavioral Sciences, Essen University Hospital, University of Duisburg-Essen, Essen, Germany; Jennifer Faber, MD, Department of Neurology, University Hospital Bonn, and German Center for Neurodegenerative Diseases, Bonn, Germany. Data available on request from the authors.

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