Alhassane Diallo1, Heike Jacobi2, Arron Cook3, Robyn Labrum4, Alexandra Durr5, Alexis Brice5, Perrine Charles6, Cecilia Marelli7, Caterina Mariotti8, Lorenzo Nanetti8, Marta Panzeri8, Maria Rakowicz9, Anna Sobanska9, Anna Sulek10, Tanja Schmitz-Hübsch11, Ludger Schöls12, Holger Hengel12, Bela Melegh13, Alessandro Filla14, Antonella Antenora14, Jon Infante15, José Berciano15, Bart P van de Warrenburg16, Dagmar Timmann17, Sylvia Boesch18, Massimo Pandolfo19, Jörg B Schulz20, Peter Bauer21, Paola Giunti3, Jun-Suk Kang22, Thomas Klockgether23, Sophie Tezenas du Montcel24. 1. Institut Pierre Louis d'Epidémiologie et de Santé Publique IPLESP, Sorbonne Université, INSERM, Paris, France. 2. Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. 3. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK. 4. Neurogenetics Laboratory, National Hospital of Neurology and Neurosurgery, University College London, London, UK. 5. Institut du cerveau et la moelle épinière (ICM), Sorbonne Université, INSERM, Paris, France; Assistance Publique-Hôpitaux de Paris AP-HP, Pitié-Salpêtrière University Hospital Paris, Paris, France. 6. Genetics Department, Pitié-Salpêtrière University Hospital Paris, Paris, France. 7. Service de Neurologie-CMRR, CHRU Gui de Chauliac, Montpellier, France. 8. SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 9. Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland. 10. Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland. 11. Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Charité-Universitätsmedizin Berlin, NeuroCure Clinical Research Center, Clinical Neuroimmunology Group, Berlin, Germany. 12. German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany; German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany; Department of Neurology, University Hospital of Bonn, Bonn, Germany. 13. Department of Medical Genetics, and Szentagothai Research Center, University of Pécs, Pécs, Hungary; Department of Neurology, Zala County Hospital, Zalaegerszeg, Hungary. 14. Department of Neuroscience, and Reproductive and Odontostomatological Sciences, Federico II University Naples, Italy. 15. Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria (UC), Santander, Spain; Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain. 16. Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, Netherlands. 17. Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany. 18. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. 19. Université Libre de Bruxelles (ULB), Neurology Service, ULB Hôpital Erasme, ULB Laboratory of Experimental Neurology, Brussels, Belgium. 20. Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-Translational Brain Medicine, Aachen-Jülich, Aachen, Germany. 21. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 22. Department of Neurology, University of Frankfurt, Frankfurt, Germany. 23. Department of Neurology, University Hospital of Heidelberg, Heidelberg, Germany; German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany; Department of Neurology, University Hospital of Bonn, Bonn, Germany. 24. Institut Pierre Louis d'Epidémiologie et de Santé Publique IPLESP, Sorbonne Université, INSERM, Paris, France; Assistance Publique-Hôpitaux de Paris AP-HP, Pitié-Salpêtrière University Hospital Paris, Paris, France. Electronic address: sophie.tezenas@aphp.fr.
Abstract
BACKGROUND: Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival. METHODS: In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias. Survival was defined as the time from enrolment to death for any reason. We used the Cox regression model adjusted for age at baseline to analyse survival. We used prognostic factors with a p value less than 0·05 from a multivariate model to build nomograms and assessed their performance based on discrimination and calibration. The EUROSCA study is registered with ClinicalTrials.gov, number NCT02440763. FINDINGS: Between July 1, 2005, and Aug 31, 2006, 525 patients with SCA1 (n=117), SCA2 (n=162), SCA3 (n=139), or SCA6 (n=107) were enrolled and followed up. The 10-year survival rate was 57% (95% CI 47-69) for SCA1, 74% (67-81) for SCA2, 73% (65-82) for SCA3, and 87% (80-94) for SCA6. Factors associated with shorter survival were: dysphagia (hazard ratio 4·52, 95% CI 1·83-11·15) and a higher value for the Scale for the Assessment and Rating of Ataxia (SARA) score (1·26, 1·19-1·33) for patients with SCA1; older age at inclusion (1·04, 1·01-1·08), longer CAG repeat length (1·16, 1·03-1·31), and higher SARA score (1·15, 1·10-1·20) for patients with SCA2; older age at inclusion (1·44, 1·20-1·74), dystonia (2·65, 1·21-5·53), higher SARA score (1·26, 1·17-1·35), and negative interaction between CAG and age at inclusion (0·994, 0·991-0·997) for patients with SCA3; and higher SARA score (1·17, 1·08-1·27) for patients with SCA6. The nomogram-predicted probability of 10-year survival showed good discrimination (c index 0·905 [SD 0·027] for SCA1, 0·822 [0·032] for SCA2, 0·891 [0·021] for SCA3, and 0·825 [0·054] for SCA6). INTERPRETATION: Our study provides quantitative data on the survival of patients with the most common spinocerebellar ataxias, based on a long follow-up period. These results have implications for the design of future interventional studies of spinocerebellar ataxias; for example, the prognostic survival nomogram could be useful for selection and stratification of patients. Our findings need validation in an external population before they can be used to counsel patients and their families. FUNDING: European Union 6th Framework programme, German Ministry of Education and Research, Polish Ministry of Scientific Research and Information Technology, European Union 7th Framework programme, and Fondation pour la Recherche Médicale.
BACKGROUND:Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival. METHODS: In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias. Survival was defined as the time from enrolment to death for any reason. We used the Cox regression model adjusted for age at baseline to analyse survival. We used prognostic factors with a p value less than 0·05 from a multivariate model to build nomograms and assessed their performance based on discrimination and calibration. The EUROSCA study is registered with ClinicalTrials.gov, number NCT02440763. FINDINGS: Between July 1, 2005, and Aug 31, 2006, 525 patients with SCA1 (n=117), SCA2 (n=162), SCA3 (n=139), or SCA6 (n=107) were enrolled and followed up. The 10-year survival rate was 57% (95% CI 47-69) for SCA1, 74% (67-81) for SCA2, 73% (65-82) for SCA3, and 87% (80-94) for SCA6. Factors associated with shorter survival were: dysphagia (hazard ratio 4·52, 95% CI 1·83-11·15) and a higher value for the Scale for the Assessment and Rating of Ataxia (SARA) score (1·26, 1·19-1·33) for patients with SCA1; older age at inclusion (1·04, 1·01-1·08), longer CAG repeat length (1·16, 1·03-1·31), and higher SARA score (1·15, 1·10-1·20) for patients with SCA2; older age at inclusion (1·44, 1·20-1·74), dystonia (2·65, 1·21-5·53), higher SARA score (1·26, 1·17-1·35), and negative interaction between CAG and age at inclusion (0·994, 0·991-0·997) for patients with SCA3; and higher SARA score (1·17, 1·08-1·27) for patients with SCA6. The nomogram-predicted probability of 10-year survival showed good discrimination (c index 0·905 [SD 0·027] for SCA1, 0·822 [0·032] for SCA2, 0·891 [0·021] for SCA3, and 0·825 [0·054] for SCA6). INTERPRETATION: Our study provides quantitative data on the survival of patients with the most common spinocerebellar ataxias, based on a long follow-up period. These results have implications for the design of future interventional studies of spinocerebellar ataxias; for example, the prognostic survival nomogram could be useful for selection and stratification of patients. Our findings need validation in an external population before they can be used to counsel patients and their families. FUNDING: European Union 6th Framework programme, German Ministry of Education and Research, Polish Ministry of Scientific Research and Information Technology, European Union 7th Framework programme, and Fondation pour la Recherche Médicale.
Authors: Jan Cendelin; Marija Cvetanovic; Mandi Gandelman; Hirokazu Hirai; Harry T Orr; Stefan M Pulst; Michael Strupp; Filip Tichanek; Jan Tuma; Mario Manto Journal: Cerebellum Date: 2021-08-10 Impact factor: 3.648
Authors: Sarah M Brooker; Chandrakanth Reddy Edamakanti; Sara M Akasha; Sheng-Han Kuo; Puneet Opal Journal: Ann Clin Transl Neurol Date: 2021-05-21 Impact factor: 4.511
Authors: Rui Jorge Nobre; Diana D Lobo; Carina Henriques; Sonia P Duarte; Sara M Lopes; Ana C Silva; Miguel M Lopes; Fanny Mariet; Lukas K Schwarz; M S Baatje; Valerie Ferreira; Astrid Vallès; Luis Pereira de Almeida; Melvin M Evers; Lodewijk J A Toonen Journal: Nucleic Acid Ther Date: 2021-12-07 Impact factor: 4.244