title: Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study.
abstract: BACKGROUND
  Spinocerebellar ataxias are dominantly inherited neurodegenerative diseases. As potential treatments for these diseases are being developed, precise knowledge of their natural history is needed. We aimed to study the long-term disease progression of the most common spinocerebellar ataxias: SCA1, SCA2, SCA3, and SCA6. Furthermore, we aimed to establish the order and occurrence of non-ataxia symptoms, and identify predictors of disease progression.
  
  
  METHODS
  In this longitudinal cohort study (EUROSCA), we enrolled men and women with positive genetic testing for SCA1, SCA2, SCA3, or SCA6 and with progressive, otherwise unexplained ataxia who were aged 18 years or older from 17 ataxia referral centres in ten European countries. Patients were seen every year for 3 years, and at irregular intervals thereafter. The primary outcome was the scale for the assessment and rating of ataxia (SARA), and the inventory of non-ataxia signs (INAS). We used linear mixed models to analyse progression. To account for dropouts, we applied a pattern-mixture model. This study is registered with ClinicalTrials.gov, number NCT02440763.
  
  
  RESULTS
  Between July 1, 2005, and Aug 31, 2006, 526 patients with SCA1, SCA2, SCA3, or SCA6 were enrolled. We analysed data for 462 patients with at least one follow-up visit. Median observation time was 49 months (IQR 35-72). SARA progression data were best fitted with a linear model in all genotypes. Annual SARA score increase was 2.11 (SE 0.12) in patients with SCA1, 1.49 (0.07) in patients with SCA2, 1.56 (0.08) in patients with SCA3, and 0.80 (0.09) in patients with SCA6. The increase of the number of non-ataxia signs reached a plateau in SCA1, SCA2, and SCA3. In patients with SCA6, the number of non-ataxia symptoms increased linearly, but more slowly than in patients with SCA1, SCA2, and SCA3 (p<0.0001). Factors that were associated with faster progression of the SARA score were short duration of follow-up (p=0.0179), older age at inclusion (0.04 [SE 0.02] per additional year; p=0.0476), and longer repeat expansions (0.06 [SE 0.02] per additional repeat unit; p=0.0128) in SCA1, short duration of follow-up (p<0.0001), lower age at onset (-0.02 [SE 0.01] per additional year; p=0.0014), and lower baseline SARA score (-0.02 [SE 0.01] per additional SARA point; p=0.0083) in SCA2, and lower baseline SARA score (-0.03 [SE 0.01] per additional SARA point; p=0·0195) in SCA6. In SCA3, we did not identify factors that affected progression of the SARA score.
  
  
  CONCLUSIONS
  Our study provides quantitative data on the progression of the most common spinocerebellar ataxias based on a follow-up period that exceeds those of previous studies. Our data could prove useful for sample size calculation and patient stratification in interventional trials.
  
  
  BACKGROUND
  EU FP6 (EUROSCA), German Ministry of Education and Research (BMBF; GeneMove), Polish Ministry of Science, EU FP7 (NEUROMICS).
authors.affiliation: Department of Neurology, University Hospital of Bonn, Bonn, Germany.
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authors.lastname: Jacobi
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, UMR S 1136, INSERM U 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France; AP-HP, Biostatistics Unit, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Sophie Tezenas
authors.initials: ST
authors.lastname: du Montcel
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Peter
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authors.lastname: Bauer
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK.
authors.forename: Paola
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authors.lastname: Giunti
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK.
authors.forename: Arron
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authors.affiliation: Neurogenetic Laboratory, National Hospital of Neurology and Neurosurgery, UCLH, London, UK.
authors.forename: Robyn
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authors.lastname: Labrum
authors.affiliation: Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Parkinson
authors.affiliation: INSERM, U 1127, F-75013, Paris, France, CNRS, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, Paris, France; Institut du Cerveau et de la Moelle Epinière, ICM, Paris, France; AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Durr
authors.affiliation: INSERM, U 1127, F-75013, Paris, France, CNRS, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, Paris, France; Institut du Cerveau et de la Moelle Epinière, ICM, Paris, France; AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France.
authors.forename: Alexis
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authors.lastname: Brice
authors.affiliation: AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France.
authors.forename: Perrine
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authors.affiliation: Service de Neurologie, CMRR, CHRU Gui de Chauliac, Montpellier, France.
authors.forename: Cecilia
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authors.lastname: Marelli
authors.affiliation: SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Caterina
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authors.lastname: Mariotti
authors.affiliation: SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Lorenzo
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authors.lastname: Nanetti
authors.affiliation: SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
authors.forename: Marta
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authors.lastname: Panzeri
authors.affiliation: Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Maria
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authors.lastname: Rakowicz
authors.affiliation: Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Anna
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authors.affiliation: Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland.
authors.forename: Anna
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authors.affiliation: Charité Universitätsmedizin Berlin, Klinik für Neurologie, Berlin, Germany; NeuroCure Clinical Research Center, Charité- Universitätsmedizin Berlin, Germany.
authors.forename: Tanja
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authors.lastname: Schmitz-Hübsch
authors.affiliation: German Center for Neurodegenerative Diseases, Germany; Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Ludger
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authors.affiliation: German Center for Neurodegenerative Diseases, Germany; Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Holger
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authors.lastname: Hengel
authors.affiliation: Department of Neurology, Zala County Hospital, Zalaegerszeg, Hungary.
authors.forename: Laszlo
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authors.lastname: Baliko
authors.affiliation: Department of Medical Genetics, and Szentagothai Research Center, University of Pécs, Pécs, Hungary.
authors.forename: Bela
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authors.lastname: Melegh
authors.affiliation: Department of Neuroscience, and Reproductive and Odontostomatological Sciences, Federico II University Naples, Italy.
authors.forename: Alessandro
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authors.affiliation: Department of Neuroscience, and Reproductive and Odontostomatological Sciences, Federico II University Naples, Italy.
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authors.affiliation: Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
authors.forename: Jon
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authors.affiliation: Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
authors.forename: José
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authors.lastname: Berciano
authors.affiliation: Radboud University Medical Center, Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, Netherlands.
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authors.initials: BP
authors.lastname: van de Warrenburg
authors.affiliation: Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Timmann
authors.affiliation: Department of Neurology, St Josef Hospital, University Hospital of Bochum, Bochum, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Szymanski
authors.affiliation: Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Sylvia
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authors.lastname: Boesch
authors.affiliation: Department of Neurology, University of Frankfurt, Frankfurt am Main, Germany.
authors.forename: Jun-Suk
authors.initials: JS
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authors.forename: Massimo
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authors.lastname: Pandolfo
authors.affiliation: Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-Translational Brain Medicine, Aachen-Jülich, Germany.
authors.forename: Jörg B
authors.initials: JB
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authors.affiliation: AP-HP, Biostatistics Unit, Groupe Hospitalier Pitié-Salpêtrière, Paris, France.
authors.forename: Sonia
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authors.lastname: Molho
authors.affiliation: Sorbonne Universités, Université Pierre et Marie Curie (UPMC) Univ Paris 06, UMR S 1136, INSERM U 1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.
authors.forename: Alhassane
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authors.lastname: Diallo
authors.affiliation: Department of Neurology, University Hospital of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases, Germany. Electronic address: klockgether@uni-bonn.de.
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authors.lastname: Klockgether
mesh_terms: D000328:Adult; D000067696:Ataxin-1 / Q000235:genetics; D000067698:Ataxin-2 / Q000235:genetics; D000067699:Ataxin-3 / Q000235:genetics; D015220:Calcium Channels / Q000235:genetics; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D039781:PubMed / Q000706:statistics & numerical data; D012097:Repressor Proteins / Q000235:genetics; D020754:Spinocerebellar Ataxias / Q000145:classification* / Q000235:genetics / Q000503:physiopathology*; D055815:Young Adult; D020864:Calcium Channels, N-Type
chemical_list: D000067696:Ataxin-1; D000067698:Ataxin-2; D000067699:Ataxin-3; D015220:Calcium Channels; D012097:Repressor Proteins; C000593749:ATXN1 protein, human; C000593752:ATXN2 protein, human; C105656:CACNA1A protein, human; D020864:Calcium Channels, N-Type; C092341:ATXN3 protein, human