Journal of Huntington's Disease - Volume 7, issue 3 - Journals

Cancer: From Wild-Type to Mutant Huntingtin

Authors: Thion, Morgane Sonia | Humbert, Sandrine

Article Type: Review Article

Abstract: Huntingtin (HTT) is a scaffold protein mostly known because it gives rise to the severe and incurable inherited neurological disorder Huntington’s disease (HD) when mutated. The Huntingtin gene (HTT ) carries a polymorphic trinucleotide expansion of CAGs in exon 1 that ranges from 9 to 35 in the non-HD affected population. However, if it exceeds 35 CAG repeats, the altered protein is referred to as mutant HTT and leads to the development of HD. Given the wide spectrum of severe symptoms developed by HD individuals, wild-type and mutant HTT have been mostly studied in the context of this …disorder. However, HTT expression is ubiquitous and several peripheral symptoms in HD have been described, suggesting that HTT is of importance, not only in the central nervous system (CNS), but also in peripheral organs. Accordingly, HTT and mutant HTT may interfere with non-brain-related diseases. Correlative studies have highlighted a decreased cancer incidence in the HD population and both wild-type and mutant HTT have been implicated in tumor progression. In this review, we describe the current evidence linking wild-type and mutant HTT to cancer and discuss how CAG polymorphism, HTT function, and partners may influence carcinogenesis and metastatic progression. Show more

Keywords: Huntington disease, huntingtin, cancer, CAG expansion, breast cancer, adhesion, metastasis

DOI: 10.3233/JHD-180290

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 201-208, 2018

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Reduced Cancer Incidence in Huntington’s Disease: Analysis in the Registry Study

Article Type: Research Article

Abstract: Background: People with Huntington’s disease (HD) have been observed to have lower rates of cancers. Objective: To investigate the relationship between age of onset of HD, CAG repeat length, and cancer diagnosis. Methods: Data were obtained from the European Huntington’s disease network REGISTRY study for 6540 subjects. Population cancer incidence was ascertained from the GLOBOCAN database to obtain standardised incidence ratios of cancers in the REGISTRY subjects. Results: 173/6528 HD REGISTRY subjects had had a cancer diagnosis. The age-standardised incidence rate of all cancers in the REGISTRY HD population was 0.26 (CI 0.22–0.30). Individual …cancers showed a lower age-standardised incidence rate compared with the control population with prostate and colorectal cancers showing the lowest rates. There was no effect of CAG length on the likelihood of cancer, but a cancer diagnosis within the last year was associated with a greatly increased rate of HD onset (Hazard Ratio 18.94, p < 0.001). Conclusions: Cancer is less common than expected in the HD population, confirming previous reports. However, this does not appear to be related to CAG length in HTT. A recent diagnosis of cancer increases the risk of HD onset at any age, likely due to increased investigation following a cancer diagnosis. Show more

Keywords: Huntington’s disease, trinucleotide repeat, cancer, neurodegeneration

DOI: 10.3233/JHD-170263

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 209-222, 2018

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Computational Analysis of Transcriptional Regulation Sites at the HTT Gene Locus

Article Type: Research Article

Abstract: Background: Huntington’s disease is a late onset neurological disorder caused by a trinucleotide CAG repeat expansion mutation in the HTT gene encoding for the protein huntingtin. Despite considerable ongoing research, the wild-type function of huntingtin is not yet fully understood. Objective: To improve knowledge of HTT gene regulation at the transcriptional level and inform future studies aimed at uncovering the HTT gene’s normal function. Methods: The HTT gene region was functionally characterized through an in silico analysis using publicly available data sets. ChIP-seq data sets and the online STRING database were …used to identify putative transcription factor binding sites (TFBSs) and protein-protein interactions within the HTT promoter region. siRNA-mediated knockdown and ChIP-qPCR of STAT1 , a TF identified from the in silico analysis, were used to validate the bioinformatics screen. Results: 16 regions containing potential regulatory genomic markers were identified. TFBSs for 59 transcription factors (TFs) were detected in one or more of the 16 candidate regions. Using these TFs, 15 clusters of protein-protein interactions were identified using STRING. siRNA-mediated knockdown of STAT1 resulted in an increase in HTT expression, and ChIP-qPCR detected enrichment of STAT1 binding at one of the predicted regions. These assays confirmed the utility of the bioinformatic analysis. Conclusions: Putative regulatory regions outside of the immediate HTT promoter region have been identified with specific protein-protein interactions. Future work will focus on in vitro and in vivo studies to examine the effect of modulating identified TFBSs and altering the levels of specific TFs of interest in regulating HTT gene expression. Show more

Keywords: Gene regulation, transcription factors, computational biology, ENCODE, Huntington’s disease

DOI: 10.3233/JHD-170272

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 223-237, 2018

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Suicidal Ideation Assessment in Individuals with Premanifest and Manifest Huntington Disease

Article Type: Research Article

Abstract: Background: Huntington disease (HD) is associated with increased risk of suicide. Objective: This study compares suicide ideation in HD to the general population, assesses factors associated with increased prevalence of suicidal thoughts, and compares clinician-rated to self-reported assessments of suicidal ideation. Methods: We examined 496 participants with premanifest or manifest HD. Clinician-rated suicidal ideation was measured using the Problem Behaviors Assessment – short form. Self-reported ideation was measured using two items from the HDQLIFE Concern with Death and Dying item bank. Independent sample t -tests were conducted to compare the prevalence of suicidal thoughts between our …HD sample and the U.S. population. Logistic regression analyses were used to determine characteristics associated with higher odds of clinically significant suicidal ideation. Kappa agreement coefficients were calculated to evaluate concurrence between clinician-rated and self-reported assessments. Results: Our sample had a significantly higher occurrence of suicidal ideation (19.76%) and suicidal plans (2.1%) than the general population (p < 0.0001). Odds of clinically significant suicidal ideation were 6.8 times higher in females (p = 0.04) on the clinician measure, and Hispanic/Latinos had 10.9 times higher odds than non-Hispanics (p = 0.025) on the self-report measure. Clinician-rated assessment had fair agreement (k = 0.2–0.4) with self-reported assessments, except in early stage HD where there was no overlap in the identification of participants with clinically significant suicidal ideation. Discussion: Assessment for suicidal ideation and clinically significant suicidal thoughts in HD with a multimodal approach that includes clinician-rated and self-report measures is critical at all stages of the disease. Show more

Keywords: Huntington disease, suicidal ideation, suicide, suicide assessment, comparing methods

DOI: 10.3233/JHD-180299

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 239-249, 2018

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Marriage as Protector for Nursing Home Admission in Huntington’s Disease

Authors: Winder, Jessica Y. | Achterberg, Wilco P. | Roos, Raymund A.C.

Article Type: Research Article

Abstract: Background: Huntington’s disease is a progressive, incurable neurodegenerative disorder and it is not possible to delay onset or progression of the disease. Consequently, the disease leads to functional decline and loss of independency and finally to institutionalization. Objective: The aim of this study is to identify factors which are associated with nursing home admission in patients with Huntington’s disease. Methods: The Unified Huntington’s Disease Rating Scale (UHDRS) and the UHDRS-For Advanced Patients (UHDRS-FAP) were administered in 28 nursing home residents and 12 patients receiving day-care. Comparisons between the two groups were performed using Mann-Whitney U tests …and Chi-square tests. The significantly different findings were fitted in individual univariate logistic regression models to determine which components were most predictive of institutionalization. Results: Day-care participants were more often married than nursing home residents (p = 0.006) and were functionally more independent: the Functional Assessment Scale (p = 0.022) of the UHDRS was significantly higher. Not being married was more predictive for nursing home admission than functional capacity in the regression models. Conclusions: Our results suggest that being married is protective for nursing home placement. Possibly, a caregiver living with a patient can assist with activities of daily living which the patient could not have done independently, resulting in being able to live at home longer. Providing support to unmarried patients, who do not have a caregiver living with them, by home care services specialized in Huntington’s disease might increase the chance of the best possible care before institutionalization and postpone nursing home admission. Show more

Keywords: Huntington’s disease, advanced stage, nursing home admission, functional assessment, marriage

DOI: 10.3233/JHD-180305

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 251-257, 2018

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Anorectal Dysfunction in Presymptomatic Mutation Carriers and Patients with Huntington’s Disease

Authors: Kobal, Jan | Matej, Kolenc | Koželj, Matic | Podnar, Simon

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) patients often report anorectal dysfunction; however, in HD research no detailed analysis of these complaints has been published. Objective: To report anorectal dysfunction in a systematically studied cohort of HD subjects. Methods: In 54 HD patients (24 men) and 10 presymptomatic HD mutation carriers (2 men) and in 99 controls (44 men) a history of anal incontinence and constipation was obtained and data was compared accordingly. In HD mutation carriers a clinical neurologic assessment and in some cases anorectal manometry were performed. Results: Defecation urgency was reported by 28% of …our HD mutation carriers, soiling in 18% and fecal incontinence in 28%. Severe anal incontinence (solid stools) was found in 0% men / 10% women, moderate (liquid stools) in 21% / 13%, and mild (flatus only) in 67% / 47% of our HD subjects. Compared to controls, anal incontinence was significantly more common in HD subjects (p < 0.001). Severe chronic constipation was found in 4.2% men / 0.0% women, moderate in 8.3% / 0.0%, and mild in 21% / 27% of HD subjects. Constipation was more common in HD men (p = 0.02) than in HD women (p = 0.144). Anorectal dysfunction was not reported by 54% of our HD subjects. Patients reporting incontinence or constipation were significantly more depressed (r = 0.53, p = 0.001). Upon anorectal manometry reduced resting anal pressure was found in 4 of 6 HD women. Conclusions: Our study demonstrated significant bowel dysfunction in HD patients. We propose these symptoms to be of central autonomic origin, although we cannot exclude effects of medication. These often neglected symptoms in HD subjects require greater attention from physicians. Show more

Keywords: Huntington’s disease, anal incontinence, chronic constipation, central autonomic deregulation

DOI: 10.3233/JHD-170280

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 259-267, 2018

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Vocalisation as a Viable Assessment for Phenotyping Minipigs Transgenic for the Huntington Gene?

Article Type: Research Article

Abstract: Background: Large animal models, such as the transgenic (tg) Huntington disease (HD) minipig, have been proposed to improve translational reliability and assessment of safety, efficacy and tolerability in preclinical studies. Minipigs are characterised by high genetic homology and comparable brain structures to humans. In addition, behavioural assessments successfully applied in humans could be explored in minipigs to establish similar endpoints in preclinical and clinical studies. Recently, analysis of voice and speech production was established to characterise HD patients. Objective: The aim of this study was to investigate whether vocalisation could also serve as a viable marker for phenotyping …minipigs transgenic for Huntington’s disease (tgHD) and whether tgHD minipigs reveal changes in this domain compared to wildtype (wt) minipigs. Methods: While conducting behavioural testing, incidence of vocalisation was assessed for a cohort of 14 tgHD and 18 wt minipigs. Statistical analyses were performed using Fisher’s Exact Test for group comparisons and McNemar’s Test for intra-visit differences between tgHD and wt minipigs. Results: Vocalisation can easily be documented during phenotyping assessments of minipigs. Differences in vocalisation incidences across behavioural conditions were detected between tgHD and wt minipigs. Influence of the genotype on vocalisation was detectable during a period of 1.5 years. Conclusion: Vocalisation may be a viable marker for phenotyping minipigs transgenic for the Huntington gene. Documentation of vocalisation provides a non-invasive opportunity to capture potential disease signs and explore phenotypic development including the age of disease manifestation. Show more

Keywords: Large animal model, transgenic, minipig, vocalisation, phenotyping, preclinical

DOI: 10.3233/JHD-170284

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 269-278, 2018

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Upcoming Meetings Related to Huntington’s Disease

Article Type: Meeting Report

DOI: 10.3233/JHD-189004

Citation: Journal of Huntington's Disease, vol. 7, no. 3, pp. 287-287, 2018

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Journal of Huntington's Disease - Volume 7, issue 3

Cancer: From Wild-Type to Mutant Huntingtin

Reduced Cancer Incidence in Huntington’s Disease: Analysis in the Registry Study

Computational Analysis of Transcriptional Regulation Sites at the HTT Gene Locus

Suicidal Ideation Assessment in Individuals with Premanifest and Manifest Huntington Disease

Marriage as Protector for Nursing Home Admission in Huntington’s Disease

Anorectal Dysfunction in Presymptomatic Mutation Carriers and Patients with Huntington’s Disease

Vocalisation as a Viable Assessment for Phenotyping Minipigs Transgenic for the Huntington Gene?

Upcoming Meetings Related to Huntington’s Disease

North America

Europe

Asia