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Article
July 8, 2016

Clinical manifestations of intermediate allele carriers in Huntington disease

August 9, 2016 issue
87 (6) 571-578

Abstract

Objective:

There is controversy about the clinical consequences of intermediate alleles (IAs) in Huntington disease (HD). The main objective of this study was to establish the clinical manifestations of IA carriers for a prospective, international, European HD registry.

Methods:

We assessed a cohort of participants at risk with <36 CAG repeats of the huntingtin (HTT) gene. Outcome measures were the Unified Huntington's Disease Rating Scale (UHDRS) motor, cognitive, and behavior domains, Total Functional Capacity (TFC), and quality of life (Short Form–36 [SF-36]). This cohort was subdivided into IA carriers (27–35 CAG) and controls (<27 CAG) and younger vs older participants. IA carriers and controls were compared for sociodemographic, environmental, and outcome measures. We used regression analysis to estimate the association of age and CAG repeats on the UHDRS scores.

Results:

Of 12,190 participants, 657 (5.38%) with <36 CAG repeats were identified: 76 IA carriers (11.56%) and 581 controls (88.44%). After correcting for multiple comparisons, at baseline, we found no significant differences between IA carriers and controls for total UHDRS motor, SF-36, behavioral, cognitive, or TFC scores. However, older participants with IAs had higher chorea scores compared to controls (p = 0.001). Linear regression analysis showed that aging was the most contributing factor to increased UHDRS motor scores (p = 0.002). On the other hand, 1-year follow-up data analysis showed IA carriers had greater cognitive decline compared to controls (p = 0.002).

Conclusions:

Although aging worsened the UHDRS scores independently of the genetic status, IAs might confer a late-onset abnormal motor and cognitive phenotype. These results might have important implications for genetic counseling.

ClinicalTrials.gov identifier:

NCT01590589.

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Supplementary Material

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Information & Authors

Information

Published In

Neurology®
Volume 87Number 6August 9, 2016
Pages: 571-578
PubMed: 27402890

Publication History

Received: November 17, 2015
Accepted: March 28, 2016
Published online: July 8, 2016
Published in print: August 9, 2016

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Disclosure

E. Cubo has consulting fees for UCB, Allergan, and Abbvie. M. Ramos-Arroyo, S. Martinez-Horta, A. Martinez-Descalls, S. Calvo, and C. Gil-Polo report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Study Funding

European Huntington Disease Registry (data mining project: #530), SACYL (GRS 1021A14).

Authors

Affiliations & Disclosures

Esther Cubo, MD, PhD
From the Neurology Department (E.C., C.G.-P.) and Research Unit (S.C.), Hospital Universitario Burgos; Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona; Movement Disorders Unit, Neurology Department (S.M.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona; and Neurology Department (A.M.-D.), Fundación Jimenez Diez, Madrid, Spain.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
Travel grants: Allergan, Abbvie, UCB
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
European Huntington Disease Registry (data mining Project: # 530), SACYL (GRS 1021A14).
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
María A. Ramos-Arroyo, MD, PhD
From the Neurology Department (E.C., C.G.-P.) and Research Unit (S.C.), Hospital Universitario Burgos; Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona; Movement Disorders Unit, Neurology Department (S.M.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona; and Neurology Department (A.M.-D.), Fundación Jimenez Diez, Madrid, Spain.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
SACYL (GRS 1021A14)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
European Huntington Disease Registry (data mining Project: # 530)
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Saul Martinez-Horta, PhD
From the Neurology Department (E.C., C.G.-P.) and Research Unit (S.C.), Hospital Universitario Burgos; Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona; Movement Disorders Unit, Neurology Department (S.M.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona; and Neurology Department (A.M.-D.), Fundación Jimenez Diez, Madrid, Spain.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Asunción Martínez-Descalls, PhD
From the Neurology Department (E.C., C.G.-P.) and Research Unit (S.C.), Hospital Universitario Burgos; Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona; Movement Disorders Unit, Neurology Department (S.M.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona; and Neurology Department (A.M.-D.), Fundación Jimenez Diez, Madrid, Spain.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
SACYL (GRS 1021A14).
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
European Huntington Disease Registry (data mining Project: # 530)
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Sara Calvo, PhD
From the Neurology Department (E.C., C.G.-P.) and Research Unit (S.C.), Hospital Universitario Burgos; Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona; Movement Disorders Unit, Neurology Department (S.M.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona; and Neurology Department (A.M.-D.), Fundación Jimenez Diez, Madrid, Spain.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
SACYL (GRS 1021A14)
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
European Huntington Disease Registry (data mining Project: # 530)
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE
Cecilia Gil-Polo, MD, PhD On behalf of the European HD Network
From the Neurology Department (E.C., C.G.-P.) and Research Unit (S.C.), Hospital Universitario Burgos; Genetic Department (M.A.R.-A.), Complejo Hospitalario de Navarra, Pamplona; Movement Disorders Unit, Neurology Department (S.M.-H.), Hospital de la Santa Creu i Sant Pau, Barcelona; and Neurology Department (A.M.-D.), Fundación Jimenez Diez, Madrid, Spain.
Disclosure
Scientific Advisory Boards:
1.
NONE
Gifts:
1.
NONE
Funding for Travel or Speaker Honoraria:
1.
NONE
Editorial Boards:
1.
NONE
Patents:
1.
NONE
Publishing Royalties:
1.
NONE
Employment, Commercial Entity:
1.
NONE
Consultancies:
1.
NONE
Speakers' Bureaus:
1.
NONE
Other Activities:
1.
NONE
Clinical Procedures or Imaging Studies:
1.
NONE
Research Support, Commercial Entities:
1.
NONE
Research Support, Government Entities:
1.
NONE
Research Support, Academic Entities:
1.
NONE
Research Support, Foundations and Societies:
1.
NONE
Stock/stock Options/board of Directors Compensation:
1.
NONE
License Fee Payments, Technology or Inventions:
1.
NONE
Royalty Payments, Technology or Inventions:
1.
NONE
Stock/stock Options, Research Sponsor:
1.
NONE
Stock/stock Options, Medical Equipment & Materials:
1.
NONE
Legal Proceedings:
1.
NONE

Notes

Correspondence to Dr. Cubo: [email protected]
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Coinvestigators are listed on the Neurology® Web site at Neurology.org.

Author Contributions

Dr. Cubo: study concept, design, and writing the manuscript. Dr. Ramos-Arroyo: interpretation and critical revision of the manuscript. S. Martinez-Horta: interpretation and critical revision of the manuscript. Dr. Martinez-Descalls: critical revision of the manuscript. S. Calvo: data analysis. Dr. Gil-Polo: interpretation and critical revision of the manuscript.

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