Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6.
J Med Genet. 2014-04-29; 51(7): 479-486
DOI: 10.1136/jmedgenet-2013-102200
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1. J Med Genet. 2014 Jul;51(7):479-86. doi: 10.1136/jmedgenet-2013-102200. Epub 2014
Apr 29.
Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6.
Tezenas du Montcel S(1), Durr A(2), Rakowicz M(3), Nanetti L(4), Charles P(2),
Sulek A(5), Mariotti C(4), Rola R(6), Schols L(7), Bauer P(8), Dufaure-Garé I(9),
Jacobi H(10), Forlani S(11), Schmitz-Hübsch T(12), Filla A(13), Timmann D(14),
van de Warrenburg BP(15), Marelli C(16), Kang JS(17), Giunti P(18), Cook A(18),
Baliko L(19), Melegh B, Boesch S(20), Szymanski S(21), Berciano J(22), Infante
J(22), Buerk K(23), Masciullo M(24), Di Fabio R(25), Depondt C(26), Ratka S(27),
Stevanin G(28), Klockgether T(29), Brice A(30), Golmard JL(1).
Author information:
(1)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.
(2)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.
(3)Department of Clinical Neurophysiology, Institute of Psychiatry and Neurology,
Warsaw, Poland.
(4)Unit of Genetics of Neurodegenerative and Metabolic Diseases, Fondazione IRCCS
Istituto Neurologico “Carlo Besta”, Milan, Italy.
(5)Department of Genetics, Institute of Psychiatry and Neurology, Warsaw, Poland.
(6)First Department of Neurology Institute of Psychiatry and Neurology, Warsaw,
Poland.
(7)Department of Neurology, Hertie-Institute for Clinical Brain Research,
University of Tübingen, Germany German Center for Neurodgenerative Diseases
(DZNE), Tübingen, Germany.
(8)Institute of Medical Genetics and Applied Genomics, University Tübingen,
Tübingen, Germany.
(9)UPMC Univ Paris 06, ER4, Modelling in Clinical Research, Paris, France.
(10)Department of Neurology, University Hospital of Bonn, Bonn, Germany.
(11)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.
(12)Department of Neurology, Charité University Medicine, Berlin, Germany.
(13)Department of Neurosciences, Federico II University, Napoli.
(14)Department of Neurology, University Clinic Essen, University of
Duisburg-Essen, Essen, Germany.
(15)Department of Neurology, Radboud University Medical Centre, Donders Institute
for Brain, Cognition, and Behaviour, Nijmegen, The Netherlands.
(16)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.
(17)Department of Neurology, Goethe University Frankfurt, Frankfurt, Germany.
(18)Department of Molecular Neuroscience, Institute of Neurology, UCL London, UK.
(19)Department of Medical Genetics, Szentagothai Research Center, University
Pécs, Hungary.
(20)Department of Neurology, Medical University Innsbruck, Innsbruck, Austria.
(21)Department of Neurology, St. Josef Hospital, University Hospital of Bochum,
Bochum, Germany.
(22)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.
(23)Department of Neurology, Philipps University of Marburg, Marburg, Germany.
(24)IRCCS San Raffaele Pisana, Rome, Italy.
(25)Department of Medical-Surgical Sciences and Biotechnologies, Sapienza
University of Rome, Rome, Italy.
(26)Department of Neurology, Université Libre de Bruxelles, Brussels, Belgium.
(27)Department of Neurodegeneration and Restorative Research, Centers of
Molecular Physiology of the Brain and Neurological Medicine, University Hospital
of Göttingen, Göttingen.
(28)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.
(29)Department of Neurology, University Hospital of Bonn, Bonn, Germany German
Center for Neurodgenerative Diseases (DZNE), Bonn, Germany.
(30)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.
Erratum in
J Med Genet. 2014 Sep;51(9):613. Bela, Melegh [corrected to Melegh, Béla].
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.
CLINICALTRIALSGOV, NUMBER: NCT01037777 and NCT00136630 for the French patients.
Published by the BMJ Publishing Group Limited. For permission to use (where not
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DOI: 10.1136/jmedgenet-2013-102200
PMCID: PMC4078703
PMID: 24780882 [Indexed for MEDLINE]