Clinical manifestations of homozygote allele carriers in Huntington disease

Objective Because patients homozygous for Huntington disease (HD) receive the gain-of-function mutation in a double dose, one would expect a more toxic effect in homozygotes than in heterozygotes. Our aim was to investigate the phenotypic differences between homozygotes with both alleles >= 36 CA...

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Autores: Cubo, E, Martinez-Horta, SI, Santalo, FS, Descalls, AM, Calvo, S, Gil-Polo, C, Munoz, I, Llano, K, Mariscal, N, Diaz, D, Gutierrez, A, Aguado, L, Ramos-Arroyo, MA
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
Repositorio:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
OAI Identifier:oai:iibsantpau.fundanetsuite.com:p2745
Acceso en línea:https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2745
Access Level:acceso abierto
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spelling Clinical manifestations of homozygote allele carriers in Huntington diseaseCubo, EMartinez-Horta, SISantalo, FSDescalls, AMCalvo, SGil-Polo, CMunoz, ILlano, KMariscal, NDiaz, DGutierrez, AAguado, LRamos-Arroyo, MAObjective Because patients homozygous for Huntington disease (HD) receive the gain-of-function mutation in a double dose, one would expect a more toxic effect in homozygotes than in heterozygotes. Our aim was to investigate the phenotypic differences between homozygotes with both alleles >= 36 CAG repeats and heterozygotes with 1 allele >= 36 CAG repeats. Methods This was an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). Baseline and longitudinal total functional capacity, motor, cognitive, and behavioral scores of the Unified Huntington's Disease Rating Scale (UHDRS) were compared between homozygotes and heterozygotes. Four-year follow-up data were analyzed using longitudinal mixed-effects models. To estimate the association of age at onset with the length of the shorter and larger allele in homozygotes and heterozygotes, regression analysis was applied. Results Of 10,921 participants with HD (5,777 female [52.9%] and 5,138 male [47.0%]) with a mean age of 55.1 +/- 14.1 years, 28 homozygotes (0.3%) and 10,893 (99.7%) heterozygotes were identified. After correcting for multiple comparisons, homozygotes and heterozygotes had similar age at onset and UHDRS scores and disease progression. In the multivariate linear regression analysis, the longer allele was the most contributing factor to decreased age at HD onset in the homozygotes (p < 0.0001) and heterozygotes (p < 0.0001). Conclusions CAG repeat expansion on both alleles of the HTT gene is infrequent. Age at onset, HD phenotype, and disease progression do not significantly differ between homozygotes and heterozygotes, indicating similar effect on the mutant protein. Classification of evidence This study provides Class II evidence that age at onset, the motor phenotype and rate of motor decline, and symptoms and signs progression is similar in homozygotes compared to heterozygotes.LIPPINCOTT WILLIAMS & WILKINS2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttps://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2745NEUROLOGYISSN: 00283878ISSNe: 1526632Xreponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pauinstname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)Inglésinfo:eu-repo/semantics/openAccessoai:iibsantpau.fundanetsuite.com:p27452026-06-14T12:41:47Z
dc.title.none.fl_str_mv Clinical manifestations of homozygote allele carriers in Huntington disease
title Clinical manifestations of homozygote allele carriers in Huntington disease
spellingShingle Clinical manifestations of homozygote allele carriers in Huntington disease
Cubo, E
title_short Clinical manifestations of homozygote allele carriers in Huntington disease
title_full Clinical manifestations of homozygote allele carriers in Huntington disease
title_fullStr Clinical manifestations of homozygote allele carriers in Huntington disease
title_full_unstemmed Clinical manifestations of homozygote allele carriers in Huntington disease
title_sort Clinical manifestations of homozygote allele carriers in Huntington disease
dc.creator.none.fl_str_mv Cubo, E
Martinez-Horta, SI
Santalo, FS
Descalls, AM
Calvo, S
Gil-Polo, C
Munoz, I
Llano, K
Mariscal, N
Diaz, D
Gutierrez, A
Aguado, L
Ramos-Arroyo, MA
author Cubo, E
author_facet Cubo, E
Martinez-Horta, SI
Santalo, FS
Descalls, AM
Calvo, S
Gil-Polo, C
Munoz, I
Llano, K
Mariscal, N
Diaz, D
Gutierrez, A
Aguado, L
Ramos-Arroyo, MA
author_role author
author2 Martinez-Horta, SI
Santalo, FS
Descalls, AM
Calvo, S
Gil-Polo, C
Munoz, I
Llano, K
Mariscal, N
Diaz, D
Gutierrez, A
Aguado, L
Ramos-Arroyo, MA
author2_role author
author
author
author
author
author
author
author
author
author
author
author
description Objective Because patients homozygous for Huntington disease (HD) receive the gain-of-function mutation in a double dose, one would expect a more toxic effect in homozygotes than in heterozygotes. Our aim was to investigate the phenotypic differences between homozygotes with both alleles >= 36 CAG repeats and heterozygotes with 1 allele >= 36 CAG repeats. Methods This was an international, longitudinal, case-control study (European Huntington's Disease Network Registry database). Baseline and longitudinal total functional capacity, motor, cognitive, and behavioral scores of the Unified Huntington's Disease Rating Scale (UHDRS) were compared between homozygotes and heterozygotes. Four-year follow-up data were analyzed using longitudinal mixed-effects models. To estimate the association of age at onset with the length of the shorter and larger allele in homozygotes and heterozygotes, regression analysis was applied. Results Of 10,921 participants with HD (5,777 female [52.9%] and 5,138 male [47.0%]) with a mean age of 55.1 +/- 14.1 years, 28 homozygotes (0.3%) and 10,893 (99.7%) heterozygotes were identified. After correcting for multiple comparisons, homozygotes and heterozygotes had similar age at onset and UHDRS scores and disease progression. In the multivariate linear regression analysis, the longer allele was the most contributing factor to decreased age at HD onset in the homozygotes (p < 0.0001) and heterozygotes (p < 0.0001). Conclusions CAG repeat expansion on both alleles of the HTT gene is infrequent. Age at onset, HD phenotype, and disease progression do not significantly differ between homozygotes and heterozygotes, indicating similar effect on the mutant protein. Classification of evidence This study provides Class II evidence that age at onset, the motor phenotype and rate of motor decline, and symptoms and signs progression is similar in homozygotes compared to heterozygotes.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2745
url https://iibsantpau.fundanetsuite.com/Publicaciones/ProdCientif/PublicacionFrw.aspx?id=2745
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
publisher.none.fl_str_mv LIPPINCOTT WILLIAMS & WILKINS
dc.source.none.fl_str_mv NEUROLOGY
ISSN: 00283878
ISSNe: 1526632X
reponame:r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
instname:Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
instname_str Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau)
reponame_str r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
collection r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau
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