Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6.
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.
NCT01037777 and NCT00136630 for the French patients.
UPMC Univ Paris 06, ER4, Modelling in Clinical Research, Paris, France Department of Biostatistics and Medical Informatics, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France.
Sophie
http://orcid.org/0000-0002-2866-4330
S
Tezenas du Montcel
UPMC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France Inserm, U975, Paris, France Cnrs, UMR 7225, Paris, France Département de Génétique et Cytogénétique, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France.
Alexandra
A
Durr
Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology, Warsaw, Poland.
Maria
M
Rakowicz
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
Lorenzo
http://orcid.org/0000-0001-8893-5932
L
Nanetti
UPMC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France Inserm, U975, Paris, France Cnrs, UMR 7225, Paris, France Département de Génétique et Cytogénétique, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France.
Perrine
P
Charles
Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
Anna
A
Sulek
Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS Istituto Neurologico "Carlo Besta", Milan, Italy.
Caterina
C
Mariotti
First Department of Neurology Institute of Psychiatry and Neurology, Warsaw, Poland.
Rafal
R
Rola
Department of Neurology, Hertie-Institute for Clinical Brain Research, University of Tübingen, Germany German Center for Neurodgenerative Diseases (DZNE), Tübingen, Germany.
Ludger
L
Schols
Institute of Medical Genetics and Applied Genomics, University Tübingen, Tübingen, Germany.
Peter
P
Bauer
UPMC Univ Paris 06, ER4, Modelling in Clinical Research, Paris, France.
Isabelle
I
Dufaure-Garé
Department of Neurology, University Hospital of Bonn, Bonn, Germany.
Heike
H
Jacobi
UPMC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France Inserm, U975, Paris, France Cnrs, UMR 7225, Paris, France.
Sylvie
S
Forlani
Department of Neurology, Charité University Medicine, Berlin, Germany.
Tanja
T
Schmitz-Hübsch
Department of Neurosciences, Federico II University, Napoli.
Alessandro
A
Filla
Department of Neurology, University Clinic Essen, University of Duisburg-Essen, Essen, Germany.
Dagmar
D
Timmann
Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands.
Bart P
BP
van de Warrenburg
UPMC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France Inserm, U975, Paris, France Cnrs, UMR 7225, Paris, France Département de Génétique et Cytogénétique, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France Departement of Neurology, University Hospital Gui de Chauliac, Montpellier, France.
Cecila
C
Marelli
Department of Neurology, Goethe University Frankfurt, Frankfurt, Germany.
Jun-Suk
JS
Kang
Department of Molecular Neuroscience, Institute of Neurology, UCL London, UK.
Paola
P
Giunti
Department of Molecular Neuroscience, Institute of Neurology, UCL London, UK.
Arron
A
Cook
Department of Medical Genetics, Szentagothai Research Center, University Pécs, Hungary.
Laszlo
L
Baliko
Béla
B
Melegh
Department of Medical Genetics, Szentagothai Research Center, University Pécs, Hungary.
Melegh
M
Bela
Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
Sylvia
S
Boesch
Department of Neurology, St. Josef Hospital, University Hospital of Bochum, Bochum, Germany.
Sandra
S
Szymanski
Service of Neurology, University Hospital "Marqués de Valdecilla (IFIMAV)", University of Cantabria, Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
José
J
Berciano
Service of Neurology, University Hospital "Marqués de Valdecilla (IFIMAV)", University of Cantabria, Spain Centro de Investigación Biomédica en Red de Enfermedades Neurodegenerativas (CIBERNED), Santander, Spain.
Jon
http://orcid.org/0000-0003-4025-4606
J
Infante
Department of Neurology, Philipps University of Marburg, Marburg, Germany.
Katrin
K
Buerk
IRCCS San Raffaele Pisana, Rome, Italy.
Marcella
M
Masciullo
Department of Medical-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy.
Roberto
http://orcid.org/0000-0003-3285-5401
R
Di Fabio
Department of Neurology, Université Libre de Bruxelles, Brussels, Belgium.
Chantal
C
Depondt
Department of Neurodegeneration and Restorative Research, Centers of Molecular Physiology of the Brain and Neurological Medicine, University Hospital of Göttingen, Göttingen.
Susanne
S
Ratka
UPMC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France Inserm, U975, Paris, France Cnrs, UMR 7225, Paris, France Département de Génétique et Cytogénétique, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France Laboratoire de Neurogenetique, Ecole Pratique des Hautes Etudes (EPHE), Institut du Cerveau et de la Moelle épinière, Hôpital de la Salpêtrière, Paris, France.
Giovanni
G
Stevanin
Department of Neurology, University Hospital of Bonn, Bonn, Germany German Center for Neurodgenerative Diseases (DZNE), Bonn, Germany.
Thomas
T
Klockgether
UPMC Univ Paris 06, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière, UMR-S975, Paris, France Inserm, U975, Paris, France Cnrs, UMR 7225, Paris, France Département de Génétique et Cytogénétique, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France Institut du Cerveau et de la Moelle Epinière, Paris, France.
Alexis
A
Brice
UPMC Univ Paris 06, ER4, Modelling in Clinical Research, Paris, France Department of Biostatistics and Medical Informatics, AP-HP, Hopitaux Universitaires Pitié-Salpétrière Charles-Foix, Paris, France.
Jean-Louis
JL
Golmard
D000328:Adult; D017668:Age of Onset; D000465:Algorithms; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D015233:Models, Statistical; D020754:Spinocerebellar Ataxias / Q000453:epidemiology* / Q000235:genetics
Movement disorders (other than Parkinsons)