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April 30, 2019; 92 (18) Null Hypothesis

Clinical manifestations of homozygote allele carriers in Huntington disease

Esther Cubo, Saul-Indra Martinez-Horta, Frederic Sampedro Santalo, Asunción Martínez Descalls, Sara Calvo, Cecilia Gil-Polo, Ignacio Muñoz, Katia Llano, Natividad Mariscal, Dolores Diaz, Aranzazu Gutierrez, Laura Aguado, María A. Ramos-Arroyo, for the European HD Network
First published March 13, 2019, DOI: https://doi.org/10.1212/WNL.0000000000007147
Esther Cubo
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Saul-Indra Martinez-Horta
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Frederic Sampedro Santalo
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Asunción Martínez Descalls
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Sara Calvo
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Cecilia Gil-Polo
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Ignacio Muñoz
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Katia Llano
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Natividad Mariscal
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Dolores Diaz
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Aranzazu Gutierrez
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Laura Aguado
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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María A. Ramos-Arroyo
From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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From the Neurology Department (E.C., C.G.-P., I.M., K.L., N.M., D.D., A.G., L.A.) and Research Unit (S.C.), Hospital Universitario Burgos; Movement Disorders Unit, Neurology Department (S.-I.M.-H., F.S.S.), Hospital de La Santa Creu I Sant Pau, Barcelona; Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED) (S.-I.M.-H., F.S.S.), Madrid; Neurology Department (A.M.D.), Fundación Jiménez Diez, Madrid; and Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona, Spain.
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Clinical manifestations of homozygote allele carriers in Huntington disease
Esther Cubo, Saul-Indra Martinez-Horta, Frederic Sampedro Santalo, Asunción Martínez Descalls, Sara Calvo, Cecilia Gil-Polo, Ignacio Muñoz, Katia Llano, Natividad Mariscal, Dolores Diaz, Aranzazu Gutierrez, Laura Aguado, María A. Ramos-Arroyo, for the European HD Network
Neurology Apr 2019, 92 (18) e2101-e2108; DOI: 10.1212/WNL.0000000000007147

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Abstract

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.

Glossary

BMI=
body mass index;
CI=
confidence interval;
EHDN=
European Huntington's Disease Network;
HD=
Huntington disease;
SNP=
single nucleotide polymorphism;
TFC=
total functional capacity;
TMS=
total motor score;
UHDRS=
Unified Huntington's Disease Rating Scale

Footnotes

  • Coinvestigators are listed at links.lww.com/WNL/A840.

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Class of Evidence: NPub.org/coe

  • Received July 3, 2018.
  • Accepted in final form January 4, 2019.
  • © 2019 American Academy of Neurology
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Disputes & Debates: Rapid online correspondence

  • Author response: Clinical manifestations of homozygote allele carriers in Huntington disease
    • Maria Antonia Ramos Arroyo, Clinical Geneticist, Complejo Hospitalario de Navarra (Pamplona, Spain)
    • Esther Cubo, Neurologist, Hospital Universitario (Burgos, Spain)
    Submitted August 13, 2019
  • Reader response: Clinical manifestations of homozygote allele carriers in Huntington disease
    • Gustavo Da Prat, MD, Neurology, INEBA
    • Jose Luis Etcheverry, MD, Neurology, INEBA
    • Martin Cesarini, MD, Neurology, INEBA
    • Emilia Gatto, MD, Neurology - Chair of the Movement Disorder Department, INEBA
    Submitted May 17, 2019
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