Alhassane Diallo1, Heike Jacobi2, Arron Cook3, Paola Giunti3, Michael H Parkinson3, Robyn Labrum4, Alexandra Durr5, Alexis Brice5, Perrine Charles6, Cecilia Marelli7, Caterina Mariotti8, Lorenzo Nanetti8, Marta Panzeri8, Anna Castaldo8, Maria Rakowicz9, Rafal Rola10, Anna Sulek11, Tanja Schmitz-Hübsch2,12, Ludger Schöls13,14, Holger Hengel13,14, Laszlo Baliko15, Bela Melegh15,16, Alessandro Filla17, Antonella Antenora17, Jon Infante18, José Berciano18, Bart P van de Warrenburg19, Dagmar Timmann20, Sylvia Boesch21, Wolfgang Nachbauer21, Massimo Pandolfo22, Jörg B Schulz23, Peter Bauer24, Kang Jun-Suk14, Thomas Klockgether2,25, Sophie Tezenas du Montcel1,26. 1. INSERM U 1136, Sorbonne Universités, Institut Pierre Louis d'Epidémiologie et de Santé Publique, IPLESP, Paris, France. 2. Department of Neurology, University Hospital of Heidelberg, Heidelberg, and German Center for Neurodegenerative Diseases (DZNE), Bonn, Germany. 3. Department of Molecular Neuroscience, UCL, Institute of Neurology, London, United Kingdom. 4. Neurogenetics Laboratory, National Hospital of Neurology and Neurosurgery, UCLH, London, United Kingdom. 5. Sorbonne Université, Institut du Cerveau et de la Moelle épinière (ICM), AP-HP, Inserm, CNRS, University Hospital Pitié-Salpêtrière, Paris, France. 6. Service de Neurologie-CMRR, CHRU Gui de Chauliac, Montpellier, France. 7. APHP, Genetics Department, Pitié-Salpêtrière University Hospital Paris, Paris, France. 8. Unit of Medical Genetics and Neurogenetics (department), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 9. First Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland. 10. Department of Neurology, Military Institute of Aviation Medicine, Warsaw, Poland. 11. Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland. 12. Charité-Universitätsmedizin Berlin, NeuroCure Clinical Research Center, Clinical Neuroimmunology Group, Berlin, Germany. 13. Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen and Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Tübingen, Germany. 14. Department of Neurology, University of Frankfurt, Frankfurt, Germany. 15. Department of Medical Genetics, and Szentagothai Research Center, University of Pécs, Pécs, Hungary. 16. Department of Neurology, Zala County Hospital, Zalaegerszeg, Hungary. 17. Department of Neuroscience, and Reproductive and Odontostomatological Sciences, Federico II University Naples, Naples, Italy. 18. Service of Neurology, University Hospital Marqués de Valdecilla (IDIVAL), University of Cantabria (UC) and Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain. 19. Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. 20. Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany. 21. Department of Neurology, Medical University, Innsbruck, Innsbruck, Austria. 22. Université Libre de Bruxelles (ULB), Neurology Service-ULB Hôpital Erasme, ULB Laboratory of Experimental Neurology, Brussels, Belgium. 23. Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-Translational Brain Medicine, Aachen-Jülich, Germany. 24. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 25. Department of Neurology, University Hospital of Bonn, Bonn, Germany. 26. Assistance Publique-Hôpitaux de Paris AP-HP, Hôpitaux Universitaires Pitié-Salpêtrière-Charles Foix, Paris, France.
Abstract
BACKGROUND: Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. OBJECTIVE: To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. METHODS: Four hundred sixty-two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. RESULTS: Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18-1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12-1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19-1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11-1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: "severe" (n = 13; 12%), "intermediate" (n = 31; 29%), and "moderate" (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. CONCLUSION: Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia.
BACKGROUND:Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. OBJECTIVE: To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. METHODS: Four hundred sixty-two spinocerebellar ataxiapatients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. RESULTS: Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18-1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12-1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19-1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11-1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: "severe" (n = 13; 12%), "intermediate" (n = 31; 29%), and "moderate" (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. CONCLUSION: Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia.
Authors: Heike Jacobi; Tamara Schaprian; Jan Beyersmann; Sophie Tezenas du Montcel; Matthias Schmid; Thomas Klockgether Journal: Ann Clin Transl Neurol Date: 2022-02-21 Impact factor: 4.511