Clinical manifestations of intermediate allele carriers in Huntington disease

Cubo, Esther; Ramos-Arroyo, María A.; Martínez‐Horta, Saül; Martinez-Descalls, Asuncion; Calvo, Sara; Gil‐Polo, Cecilia

doi:10.1212/wnl.0000000000002944

Cited by 46 publications

(31 citation statements)

References 33 publications

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“…In conformity with those findings, there is a growing scientific support of IA patients presenting a classical HD phenotype (Andrich et al, 2008;Cubo et al, 2016;Savitt & Jankovic, 2019;Squitieri & Jankovic, 2012). The probability of IA to manifest HD is of extremely relevance, not only for the pathogenesis comprehension of disease, but also for clinical and genetic counseling, since those individuals are often reassured as having no chance of developing HD (Squitieri & Jankovic, 2012).…”

mentioning

confidence: 77%

Comment on: “Investigation of intermediate CAG alleles of the HTT in the general population of Rio de Janeiro, Brazil, in comparison with a sample of Huntington disease‐affected families.”

Franklin

Meira

Camargo

et al. 2020

Molec Gen & Gen Med

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mentioning

confidence: 77%

Comment on: “Investigation of intermediate CAG alleles of the HTT in the general population of Rio de Janeiro, Brazil, in comparison with a sample of Huntington disease‐affected families.”

Franklin

Meira

Camargo

et al. 2020

Molec Gen & Gen Med

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“…To balance differences in sample sizes, a post hoc secondary analysis was carried out, comparing homozygotes with a subset of heterozygotes, paired by age and CAG larger allele (1:3). In addition, because aging might worsen the UHDRS scores, especially bradykinesia and gait scores, independently of the genetic status, 15 a comparative analysis between homozygotes and heterozygotes was conducted including young and older participants. All homozygote and heterozygote participants were classified as older (>51 years old) or younger participants (≤51 years old), based on the median age of homozygotes at registry entry.…”

Section: Discussionmentioning

confidence: 99%

“…We used the same methodology as that described in a previous study. 15 The European HD Registry is a large, prospective study observing the natural course, clinical spectrum, and management of HD in 140 centers from 17 European countries and 3 other countries. 9,12 More information on the Registry can be found at euro-hd.net/html/ registry.…”

Section: Data Availability Statementmentioning

confidence: 99%

Clinical manifestations of homozygote allele carriers in Huntington disease

Cubo¹,

Martinez-Horta²,

Sampedro³

et al. 2019

Neurology

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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.

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“…Since 2004, we have started a prospective collection of data by contributing to REGISTRY [6] and, more recently, to ENROLL-HD programs. Currently, we have clinical and genetic data from about 60 JHD cases with onset movement disorders ≤ 20 years of age.…”

Section: Patientsmentioning

confidence: 99%