Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

Sophie Tezenas du Montcel, Alexandra Durr, Maria Rakowicz, Lorenzo Nanetti, Perrine Charles, Anna Sulek, Caterina Mariotti, Rafal Rola, Ludger Schols, Peter Bauer, Isabelle Dufaure-Garé, Heike Jacobi, Sylvie Forlani, Tanja Schmitz-Hübsch, Alessandro Filla, Dagmar Timmann, Bart P. van de Warrenburg, Cecila Marelli, Jun Suk Kang, Paola Giunti & 16 others Arron Cook, L. Balikó, B. Melegh, Sylvia Boesch, Sandra Szymanski, José Berciano, Jon Infante, Katrin Buerk, Marcella Masciullo, Roberto Di Fabio, Chantal Depondt, Susanne Ratka, Giovanni Stevanin, Thomas Klockgether, Alexis Brice, Jean Louis Golmard

Research output: Contribution to journalArticle

20 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)479-486
Number of pages8
JournalJournal of Medical Genetics
Volume51
Issue number7
DOIs
Publication statusPublished - 2014

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Spinocerebellar Ataxias
Age of Onset
Genotype
Alleles
Normal Distribution
Longitudinal Studies
Registries
Parturition
Mutation
Research

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Medicine(all)

Cite this

du Montcel, S. T., Durr, A., Rakowicz, M., Nanetti, L., Charles, P., Sulek, A., ... Golmard, J. L. (2014). Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. Journal of Medical Genetics, 51(7), 479-486. https://doi.org/10.1136/jmedgenet-2013-102200

Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. / du Montcel, Sophie Tezenas; Durr, Alexandra; Rakowicz, Maria; Nanetti, Lorenzo; Charles, Perrine; Sulek, Anna; Mariotti, Caterina; Rola, Rafal; Schols, Ludger; Bauer, Peter; Dufaure-Garé, Isabelle; Jacobi, Heike; Forlani, Sylvie; Schmitz-Hübsch, Tanja; Filla, Alessandro; Timmann, Dagmar; van de Warrenburg, Bart P.; Marelli, Cecila; Kang, Jun Suk; Giunti, Paola; Cook, Arron; Balikó, L.; Melegh, B.; Boesch, Sylvia; Szymanski, Sandra; Berciano, José; Infante, Jon; Buerk, Katrin; Masciullo, Marcella; Di Fabio, Roberto; Depondt, Chantal; Ratka, Susanne; Stevanin, Giovanni; Klockgether, Thomas; Brice, Alexis; Golmard, Jean Louis.

In: Journal of Medical Genetics, Vol. 51, No. 7, 2014, p. 479-486.

Research output: Contribution to journalArticle

du Montcel, ST, Durr, A, Rakowicz, M, Nanetti, L, Charles, P, Sulek, A, Mariotti, C, Rola, R, Schols, L, Bauer, P, Dufaure-Garé, I, Jacobi, H, Forlani, S, Schmitz-Hübsch, T, Filla, A, Timmann, D, van de Warrenburg, BP, Marelli, C, Kang, JS, Giunti, P, Cook, A, Balikó, L, Melegh, B, Boesch, S, Szymanski, S, Berciano, J, Infante, J, Buerk, K, Masciullo, M, Di Fabio, R, Depondt, C, Ratka, S, Stevanin, G, Klockgether, T, Brice, A & Golmard, JL 2014, 'Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6', Journal of Medical Genetics, vol. 51, no. 7, pp. 479-486. https://doi.org/10.1136/jmedgenet-2013-102200
du Montcel, Sophie Tezenas ; Durr, Alexandra ; Rakowicz, Maria ; Nanetti, Lorenzo ; Charles, Perrine ; Sulek, Anna ; Mariotti, Caterina ; Rola, Rafal ; Schols, Ludger ; Bauer, Peter ; Dufaure-Garé, Isabelle ; Jacobi, Heike ; Forlani, Sylvie ; Schmitz-Hübsch, Tanja ; Filla, Alessandro ; Timmann, Dagmar ; van de Warrenburg, Bart P. ; Marelli, Cecila ; Kang, Jun Suk ; Giunti, Paola ; Cook, Arron ; Balikó, L. ; Melegh, B. ; Boesch, Sylvia ; Szymanski, Sandra ; Berciano, José ; Infante, Jon ; Buerk, Katrin ; Masciullo, Marcella ; Di Fabio, Roberto ; Depondt, Chantal ; Ratka, Susanne ; Stevanin, Giovanni ; Klockgether, Thomas ; Brice, Alexis ; Golmard, Jean Louis. / Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6. In: Journal of Medical Genetics. 2014 ; Vol. 51, No. 7. pp. 479-486.
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title = "Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6",
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.",
author = "{du Montcel}, {Sophie Tezenas} and Alexandra Durr and Maria Rakowicz and Lorenzo Nanetti and Perrine Charles and Anna Sulek and Caterina Mariotti and Rafal Rola and Ludger Schols and Peter Bauer and Isabelle Dufaure-Gar{\'e} and Heike Jacobi and Sylvie Forlani and Tanja Schmitz-H{\"u}bsch and Alessandro Filla and Dagmar Timmann and {van de Warrenburg}, {Bart P.} and Cecila Marelli and Kang, {Jun Suk} and Paola Giunti and Arron Cook and L. Balik{\'o} and B. Melegh and Sylvia Boesch and Sandra Szymanski and Jos{\'e} Berciano and Jon Infante and Katrin Buerk and Marcella Masciullo and {Di Fabio}, Roberto and Chantal Depondt and Susanne Ratka and Giovanni Stevanin and Thomas Klockgether and Alexis Brice and Golmard, {Jean Louis}",
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TY - JOUR

T1 - Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

AU - du Montcel, Sophie Tezenas

AU - Durr, Alexandra

AU - Rakowicz, Maria

AU - Nanetti, Lorenzo

AU - Charles, Perrine

AU - Sulek, Anna

AU - Mariotti, Caterina

AU - Rola, Rafal

AU - Schols, Ludger

AU - Bauer, Peter

AU - Dufaure-Garé, Isabelle

AU - Jacobi, Heike

AU - Forlani, Sylvie

AU - Schmitz-Hübsch, Tanja

AU - Filla, Alessandro

AU - Timmann, Dagmar

AU - van de Warrenburg, Bart P.

AU - Marelli, Cecila

AU - Kang, Jun Suk

AU - Giunti, Paola

AU - Cook, Arron

AU - Balikó, L.

AU - Melegh, B.

AU - Boesch, Sylvia

AU - Szymanski, Sandra

AU - Berciano, José

AU - Infante, Jon

AU - Buerk, Katrin

AU - Masciullo, Marcella

AU - Di Fabio, Roberto

AU - Depondt, Chantal

AU - Ratka, Susanne

AU - Stevanin, Giovanni

AU - Klockgether, Thomas

AU - Brice, Alexis

AU - Golmard, Jean Louis

PY - 2014

Y1 - 2014

N2 - 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.

AB - 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.

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U2 - 10.1136/jmedgenet-2013-102200

DO - 10.1136/jmedgenet-2013-102200

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EP - 486

JO - Journal of Medical Genetics

JF - Journal of Medical Genetics

SN - 0022-2593

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