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Research paper
Friedreich and dominant ataxias: quantitative differences in cerebellar dysfunction measurements
  1. Audrey Tanguy Melac1,
  2. Caterina Mariotti2,
  3. Antoine Filipovic Pierucci3,
  4. Paola Giunti4,
  5. Javier Arpa5,
  6. Sylvia Boesch6,
  7. Thomas Klopstock7,8,9,
  8. Jennifer Müller vom Hagen10,11,
  9. Thomas Klockgether12,13,
  10. Katrin Bürk14,15,
  11. Jörg B Schulz16,
  12. Kathrin Reetz16,
  13. Massimo Pandolfo17,
  14. Alexandra Durr18,
  15. Sophie Tezenas du Montcel1,19,20
  16. on behalf of the EFACTS group
    1. 1 Department of Biostatistics and Medical Informatics, AP-HP, Groupe Hospitalier Pitié-Salpêtrière Charles-Foix, Paris, France
    2. 2 Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milano, Italy
    3. 3 URCEco and Santé publique, Assistance Publique Hopitaux de Paris, Paris, France
    4. 4 Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
    5. 5 Department of Neurology, Instituto de Investigación Hospital Universitario La Paz, Madrid, Spain
    6. 6 Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
    7. 7 Department of Neurology, Friedrich-Baur-Institute, University of Munich, Munich, Germany
    8. 8 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany
    9. 9 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
    10. 10 Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tuebingen, Germany
    11. 11 German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany
    12. 12 Department of Neurology, University of Bonn, Bonn, Germany
    13. 13 German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany
    14. 14 Department of Neurology, Philipps Universität Marburg, Marburg, Germany
    15. 15 Paracelsus-Elena-Klinik, Kassel, Germany
    16. 16 Department of Neurology, Center for Rare Diseases, Clinical Trial Centre, JARA-BRAIN Institute Molecular Neuroscience and Neuroimaging, Forschungszentrum Jülich GmbH and RWTH Aachen University, Aachen, Germany
    17. 17 Department of Neurology, Hôpital Erasme, Bruxelles, Belgium
    18. 18 Department of Genetics, ICM Institut du Cerveau et de la Moelle and APHP, University Hospital Pitié-Salpêtrière, Paris, France
    19. 19 Sorbonne Universités, UPMC Univ Paris 06 UMR_S1136, Paris, France
    20. 20 INSERM UMR_S 1136, Institut Pierre Louis d’Epidémiologie et de Santé Publique, Paris, France
    1. Correspondence to Dr Sophie Tezenas du Montcel, Département de Santé Publique, Unité de Biostatistiques et Information Médicale, Groupe Hospitalier Pitié - Salpêtrière, Paris 75651, France; sophie.tezenas{at}aphp.fr

    Abstract

    Background Sensitive outcome measures for clinical trials on cerebellar ataxias are lacking. Most cerebellar ataxias progress very slowly and quantitative measurements are required to evaluate cerebellar dysfunction.

    Methods We evaluated two scales for rating cerebellar ataxias: the Composite Cerebellar Functional Severity (CCFS) Scale and Scale for the Assessment and Rating of Ataxia (SARA), in patients with spinocerebellar ataxia (SCA) and controls. We evaluated these scales for different diseases and investigated the factors governing the scores obtained. All patients were recruited prospectively.

    Results There were 383 patients with Friedreich’s ataxia (FRDA), 205 patients with SCA and 168 controls. In FRDA, 31% of the variance of cerebellar signs with the CCFS and 41% of that with SARA were explained by disease duration, age at onset and the shorter abnormal repeat in the FXN gene. Increases in CCFS and SARA scores per year were lower for FRDA than for SCA (CCFS index: 0.123±0.123 per year vs 0.163±0.179, P<0.001; SARA index: 1.5±1.2 vs 1.7±1.7, P<0.001), indicating slower cerebellar dysfunction indexes for FRDA than for SCA. Patients with SCA2 had higher CCFS scores than patients with SCA1 and SCA3, but similar SARA scores.

    Conclusions Cerebellar dysfunction, as measured with the CCFS and SARA scales, was more severe in FRDA than in patients with SCA, but with lower progression indexes, within the limits of these types of indexes. Ceiling effects may occur at late stages, for both scales. The CCFS scale is rater-independent and could be used in a multicentre context, as it is simple, rapid and fully automated.

    Trial registration number ClinicalTrials.gov: NCT02069509.

    • friedreich ataxia
    • CCFS
    • SARA
    • clinical score
    • SCA1,2,3,7

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    Footnotes

    • Contributors All authors give final approval of the version to be published and take responsibility for the conduct of the research. ATM: design, execution, review and critique of the statistical analysis, writing of the first draft, review and critique of the manuscript. CM, PG, JA, SB, TK, JMvH, TK, KB, JBS, KR, MP: conception, organisation and execution of the research project, review and critique of the manuscript. AFP: design of the statistical analysis, review and critique of the manuscript. AD: conception, organisation and execution of the research project, obtaining of the funding, review and critique of the statistical analysis, review and critique of the manuscript. STdM: conception of the research project, design, review and critique of the statistical analysis, review and critique of the manuscript.

    • Funding Projects EFACTS (UE FP7-HEALTH-2009/contract no. E10015DD) and Programme Hospitalier de Recherche Clinique AOM03059 (contract no. R05129DD) to CM, PG, SB, JBS, KR, MP and AD.

    • Competing interests CM, PG, JA, TK, JMvH, TK, KR have nothing to disclose. AFP has worked for the Health Economics and Health Policy Research Unit of Greater Paris University Hospitals. SB reports personal fees from Gruenenthal, AbbVie, Ipsen and Allergan, outside the submitted work. KB reports grants from University of Aachen/EU, during the conduct of the study; grants from Actelion, Pfizer and CHDI; personal fees from Desitin, Medtronic, outside the submitted work. JBS reports grants from 7th Framework of the EU; Funding of the "European Friedreich Ataxia Consortium for Translational Studies (EFACTS), during the conduct of the study; he serves on scientific advisory boards for Lundbeck, TEVA, Novartis and Lilly and have received funding for travel and speaker honoraria from GlaxoSmithKline, Merz Pharmaceuticals, Medical Tribune, Lundbeck, Pfizer, Boehringer and Bayer and has received research support from the BMBF, DFG and the EU. MP reports grants and personal fees from Voyager Therapeutics, personal fees from Apopharma, grants and personal fees from Biomarin, outside the submitted work. AD partly has nothing to disclose. STdM reports personal fees from Boston Scientific, grants from Agence Nationale de la Recherche, outside the submitted work.

    • Ethics approval Local ethic committees of each participating centre.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Collaborators Affiliation of the EFACTS Coinvestigators: M Panzeri, MD (Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione Istituto di Ricovero eCura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy, Site Investigator); M H Parkinson MBBS (Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK, Site Investigator); I Sanz-Gallego, MD (Reference Unit of Hereditary Ataxias and Paraplegias, Department of Neurology, Instituto de Investigación Sanitaria, Hospital Universitario La Paz, Madrid, Spain, Site Investigator); W Nachbauer, MD (Department of Neurology, Medical University Innsbruck, Austria, Site Investigator); I Karin, MD (Friedrich-Baur-Institute, Department of Neurology, University of Munich, Germany, Site Investigator); C Depondt, MD (Laboratory of Experimental Neurology, Université Libre de Bruxelles, Brussels, Belgium, Site Investigator); L Schoels, MD PhD (Centre for Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany, Site Investigator); I Giordano, MD (Department of Neurology, University Hospital of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany, Site Investigator); L Nanetti, MD (Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione Istituto di Ricovero eCura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy, Site Investigator); A Castaldo, MS (Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Neurologico Carlo Besta, Milan, Italy, Site Investigator), A Eigentler, MD, PhD (Medical University Innsbruck, Department of Neurology, Innsbruck, Austria, Site Investigator).

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