The diagnosis and natural history of Huntington disease

Pagán, Fernando; Torres‐Yaghi, Yasar; Altshuler, Marcelle

doi:10.1016/b978-0-12-801893-4.00005-5

Cited by 12 publications

(8 citation statements)

References 45 publications

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“…22,23 Heterozygote individuals with clinically diagnosed HD experience a steady progressive decline in the cardinal features of the disease. 24,25 In our study, heterozygotes had a similar rate of decline compared to homozygotes in terms of BMI, TFC, TMS, behavior, and cognitive UHDRS scores. In contrast, Squitieri et al 2 observed a faster rate of progression in disability, measured by independence and the physical disability scales, in 8 homozygotes compared to 75 heterozygotes.…”

Section: Discussionsupporting

confidence: 59%

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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Section: Discussionsupporting

confidence: 59%

Clinical manifestations of homozygote allele carriers in Huntington disease

Cubo¹,

Martinez-Horta²,

Sampedro³

et al. 2019

Neurology

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“…For example, while the rate of progression for swallowing difficulties (as well as speech difficulties) appears to be consistent over the course of the disease,[44, 45] the rate of progression for chorea declines in the more advanced stages. [46–49] As such, it is also possible that the different cognitive cutoff scores may be explained by the fact that chorea might be less problematic for individuals with more advanced HD. In fact, it seems especially plausible that differences in the rates of progression for these symptom domains, in conjunction with associated anosognosia (especially in more advanced disease),[50–54] may contribute to the differential performance of these PRO measures.…”

Section: Discussionmentioning

confidence: 99%

Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability?

et al. 2018

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“…An interesting role for SQSTM1 is apparent in Huntington's disease, a neurodegenerative disorder caused by trinucleotide repeat expansion in the Huntingtin gene (Htt) (Pagan et al, 2017). Normal HTT serves as a scaffold protein during selective autophagy (Rui et al, 2015) where it associates with SQSTM1.…”

Section: Huntington's Diseasementioning

confidence: 99%

p62/SQSTM1 – steering the cell through health and disease

Sánchez‐Martín

Komatsu

2018

Journal of Cell Science

232

179

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SQSTM1 (also known as p62) is a multifunctional stress-inducible scaffold protein involved in diverse cellular processes. Its functions are tightly regulated through an extensive pattern of post-translational modifications, and include the isolation of cargos degraded by autophagy, induction of the antioxidant response by the Keap1-Nrf2 system, as well as the regulation of endosomal trafficking, apoptosis and inflammation. Accordingly, malfunction of SQSTM1 is associated with a wide range of diseases, including bone and muscle disorders, neurodegenerative and metabolic diseases, and multiple forms of cancer. In this Review, we summarize current knowledge regarding regulation, post-translational modifications and functions of SQSTM1, as well as how they are dysregulated in various pathogenic contexts.

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The diagnosis and natural history of Huntington disease

Cited by 12 publications

References 45 publications

Clinical manifestations of homozygote allele carriers in Huntington disease

Clinical manifestations of homozygote allele carriers in Huntington disease

Understanding patient-reported outcome measures in Huntington disease: at what point is cognitive impairment related to poor measurement reliability?

p62/SQSTM1 – steering the cell through health and disease

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