Heike Jacobi1, Sophie Tezenas du Montcel2, Peter Bauer3, Paola Giunti4, Arron Cook4, Robyn Labrum5, Michael H Parkinson4, Alexandra Durr6, Alexis Brice6, Perrine Charles7, Cecilia Marelli8, Caterina Mariotti9, Lorenzo Nanetti9, Marta Panzeri9, Maria Rakowicz10, Anna Sulek11, Anna Sobanska10, Tanja Schmitz-Hübsch12, Ludger Schöls13, Holger Hengel13, Laszlo Baliko14, Bela Melegh15, Alessandro Filla16, Antonella Antenora16, Jon Infante17, José Berciano17, Bart P van de Warrenburg18, Dagmar Timmann19, Sandra Szymanski20, Sylvia Boesch21, Jun-Suk Kang22, Massimo Pandolfo23, Jörg B Schulz24, Sonia Molho25, Alhassane Diallo26, Thomas Klockgether27. 1. Department of Neurology, University Hospital of Bonn, Bonn, Germany. 2. 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. 3. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 4. Department of Molecular Neuroscience, UCL, Institute of Neurology, London, UK. 5. Neurogenetic Laboratory, National Hospital of Neurology and Neurosurgery, UCLH, London, UK. 6. 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. 7. AP-HP, Hôpital de la Pitié-Salpêtrière, Département de Génétique, Paris, France. 8. Service de Neurologie, CMRR, CHRU Gui de Chauliac, Montpellier, France. 9. SOSD Genetics of Neurodegenerative and Metabolic Diseases, Fondazione-IRCCS Istituto Neurologico Carlo Besta, Milan, Italy. 10. Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland. 11. Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland. 12. Charité Universitätsmedizin Berlin, Klinik für Neurologie, Berlin, Germany; NeuroCure Clinical Research Center, Charité- Universitätsmedizin Berlin, Germany. 13. German Center for Neurodegenerative Diseases, Germany; Department of Neurodegeneration and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany. 14. Department of Neurology, Zala County Hospital, Zalaegerszeg, Hungary. 15. Department of Medical Genetics, and Szentagothai Research Center, University of Pécs, Pécs, Hungary. 16. Department of Neuroscience, and Reproductive and Odontostomatological Sciences, Federico II University Naples, Italy. 17. 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. 18. Radboud University Medical Center, Department of Neurology, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, Netherlands. 19. Department of Neurology, Essen University Hospital, University of Duisburg-Essen, Essen, Germany. 20. Department of Neurology, St Josef Hospital, University Hospital of Bochum, Bochum, Germany. 21. Department of Neurology, Medical University Innsbruck, Innsbruck, Austria. 22. Department of Neurology, University of Frankfurt, Frankfurt am Main, Germany. 23. Neurology Service, Hôpital Erasme-Université Libre de Bruxelles (ULB), Brussels, Belgium. 24. Department of Neurology, RWTH Aachen University, Aachen, Germany; JARA-Translational Brain Medicine, Aachen-Jülich, Germany. 25. AP-HP, Biostatistics Unit, Groupe Hospitalier Pitié-Salpêtrière, Paris, France. 26. 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. 27. Department of Neurology, University Hospital of Bonn, Bonn, Germany; German Center for Neurodegenerative Diseases, Germany. Electronic address: klockgether@uni-bonn.de.
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: EU FP6 (EUROSCA), German Ministry of Education and Research (BMBF; GeneMove), Polish Ministry of Science, EU FP7 (NEUROMICS).
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. FINDINGS: 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. INTERPRETATION: 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. FUNDING: EU FP6 (EUROSCA), German Ministry of Education and Research (BMBF; GeneMove), Polish Ministry of Science, EU FP7 (NEUROMICS).
Authors: Pei-Hsin Kuo; Shi-Rui Gan; Jie Wang; Raymond Y Lo; Karla P Figueroa; Darya Tomishon; Stefan M Pulst; Susan Perlman; George Wilmot; Christopher M Gomez; Jeremy D Schmahmann; Henry Paulson; Vikram G Shakkottai; Sarah H Ying; Theresa Zesiewicz; Khalaf Bushara; Michael D Geschwind; Guangbin Xia; S H Subramony; Tetsuo Ashizawa; Sheng-Han Kuo Journal: Parkinsonism Relat Disord Date: 2017-10-23 Impact factor: 4.891
Authors: Heike Jacobi; Sophie Tezenas du Montcel; Peter Bauer; Paola Giunti; Arron Cook; Robyn Labrum; Michael H Parkinson; Alexandra Durr; Alexis Brice; Perrine Charles; Cecilia Marelli; Caterina Mariotti; Lorenzo Nanetti; Lidia Sarro; Maria Rakowicz; Anna Sulek; Anna Sobanska; Tanja Schmitz-Hübsch; Ludger Schöls; Holger Hengel; Laszlo Baliko; Bela Melegh; Alessandro Filla; Antonella Antenora; Jon Infante; José Berciano; Bart P van de Warrenburg; Dagmar Timmann; Sandra Szymanski; Sylvia Boesch; Wolfgang Nachbauer; Jun-Suk Kang; Massimo Pandolfo; Jörg B Schulz; Audrey Tanguy Melac; Alhassane Diallo; Thomas Klockgether Journal: J Neurol Date: 2018-06-29 Impact factor: 4.849
Authors: A Ranavolo; M Serrao; T Varrecchia; C Casali; A Filla; A Roca; A Silvetti; C Marcotulli; B M Rondinone; S Iavicoli; F Draicchio Journal: Cerebellum Date: 2019-10 Impact factor: 3.847