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Original article
Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6
  1. Sophie Tezenas du Montcel1,2,
  2. Alexandra Durr3,4,5,6,
  3. Maria Rakowicz7,
  4. Lorenzo Nanetti8,
  5. Perrine Charles3,4,5,6,
  6. Anna Sulek9,
  7. Caterina Mariotti8,
  8. Rafal Rola10,
  9. Ludger Schols11,12,
  10. Peter Bauer13,
  11. Isabelle Dufaure-Garé1,
  12. Heike Jacobi14,
  13. Sylvie Forlani3,4,5,
  14. Tanja Schmitz-Hübsch15,
  15. Alessandro Filla16,
  16. Dagmar Timmann17,
  17. Bart P van de Warrenburg18,
  18. Cecila Marelli3,4,5,6,19,
  19. Jun-Suk Kang20,
  20. Paola Giunti21,
  21. Arron Cook21,
  22. Laszlo Baliko22,
  23. Melegh Bela22,
  24. Sylvia Boesch23,
  25. Sandra Szymanski24,
  26. José Berciano25,26,
  27. Jon Infante25,26,
  28. Katrin Buerk27,
  29. Marcella Masciullo28,
  30. Roberto Di Fabio29,
  31. Chantal Depondt30,
  32. Susanne Ratka31,
  33. Giovanni Stevanin3,4,5,6,32,
  34. Thomas Klockgether33,34,
  35. Alexis Brice3,4,5,6,35,
  36. Jean-Louis Golmard1,2
  1. 1UPMC Univ Paris 06, ER4, Modelling in Clinical Research, Paris, France
  2. 2Department of Biostatistics and Medical Informatics, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France
  3. 3UPMC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France
  4. 4Inserm, U975, Paris, France
  5. 5Cnrs, UMR 7225, Paris, France
  6. 6Département de Génétique et Cytogénétique, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France
  7. 7Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland
  8. 8Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico “Carlo Besta”, Milan, Italy
  9. 9Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland
  10. 10First Department of Neurology Institute of Psychiatry and Neurology, Warsaw, Poland
  11. 11Department of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany
  12. 12German Center for Neurodgenerative Diseases (DZNE), Tübingen, Germany
  13. 13Institute of Medical Genetics and Applied Genomics, University Tübingen, Tübingen, Germany
  14. 14Department of Neurology, University Hospital of Bonn, Bonn, Germany
  15. 15Department of Neurology, Charité University Medicine, Berlin, Germany
  16. 16Department of Neurosciences, Federico II University, Napoli
  17. 17Department of Neurology, University Clinic Essen, University of Duisburg-Essen, Essen, Germany
  18. 18Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands
  19. 19Departement of Neurology, University Hospital Gui de Chauliac, Montpellier, France
  20. 20Department of Neurology, Goethe University Frankfurt, Frankfurt, Germany
  21. 21Department of Molecular Neuroscience, Institute of Neurology, UCL London, UK
  22. 22Department of Medical Genetics, Szentagothai Research Center, University Pécs, Hungary
  23. 23Department of Neurology, Medical University Innsbruck, Innsbruck, Austria
  24. 24Department of Neurology, St. Josef Hospital, University Hospital of Bochum, Bochum, Germany
  25. 25Service of Neurology, University Hospital “Marqués de Valdecilla (IFIMAV)”, University of Cantabria, Spain
  26. 26Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain
  27. 27Department of Neurology, Philipps University of Marburg, Marburg, Germany
  28. 28IRCCS San Raffaele Pisana, Rome, Italy
  29. 29Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy
  30. 30Department of Neurology, Université Libre de Bruxelles, Brussels, Belgium
  31. 31Department of Neurodegeneration and Restorative Research, Centers of Molecular Physiology of the Brain and Neurological Medicine, University Hospital of Göttingen, Göttingen
  32. 32Laboratoire de Neurogenetique, Ecole Pratique des Hautes Etudes (EPHE), Institut du Cerveau et de la Moelle épinière, Hôpital de la Salpêtrière, Paris, France
  33. 33Department of Neurology, University Hospital of Bonn, Bonn, Germany
  34. 34German Center for Neurodgenerative Diseases (DZNE), Bonn, Germany
  35. 35Institut du Cerveau et de la Moelle Epinière, Paris, France
  1. Correspondence to Dr Sophie Tezenas du Montcel, Unité de Biostatistiques et Information Medicale, Département de Santé Publique, Bâtiment Mazarin 3eme étage, Groupe Hospitalier Pitié-Salpêtrière, 47-83 Bd de l'Hopital, 75651 Paris Cedex 13, France; sophie.tezenas{at}psl.aphp.fr

Abstract

Background The most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset.

Methods We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age.

Results For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age.

Conclusions These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies.

ClinicalTrials.gov, number NCT01037777 and NCT00136630 for the French patients.

  • Movement disorders (other than Parkinsons)

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