Journal of Huntington's Disease - Volume 7, issue 2

Authors: Romo, Lindsay | Mohn, Emily S. | Aronin, Neil

Article Type: Review Article

Abstract: Huntington’s disease (HD) is an inherited neurodegenerative disorder caused by a mutation that expands the polyglutamine (CAG) repeat in exon 1 of the huntingtin (HTT ) gene. Wild-type HTT protein interacts with other proteins to protect cells against toxic stimuli, mediate vesicle transport and endocytosis, and modulate synaptic activity. Mutant HTT protein disrupts autophagy, vesicle transport, neurotransmitter signaling, and mitochondrial function. Although many of the activities of wild-type HTT protein and the toxicities of mutant HTT protein are characterized, less is known about the activities of HTT mRNA. Most putative HD therapies aim to target mutant HTT mRNA …before it is translated into the protein. Therefore, it is imperative to learn as much as we can about how cells handle both wild-type and mutant HTT mRNA so that effective therapies can be designed. Here, we review the structure of wild-type and mutant HTT mRNA, with emphasis on their alternatively polyadenylated or spliced isoforms. We then consider the abundance of HTT mRNA isoforms in HD and discuss the potential implications of these findings. Evidence in the review should be used to guide future research aimed at developing mRNA-lowering therapies for HD. Show more

Keywords: Huntington disease, mRNA, 3’UTR, alternative splicing, RNA 3’ End Processing

DOI: 10.3233/JHD-180292

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 101-108, 2018

Authors: Silajdžić, Edina | Björkqvist, Maria

Article Type: Review Article

Abstract: There is an unmet clinical need for objective biomarkers to monitor disease progression and treatment response in Huntington’s disease (HD). The aim of this review is, therefore, to provide practical advice for biomarker discovery and to summarise studies on biofluid markers for HD. A PubMed search was performed to review literature with regard to candidate saliva, urine, blood and cerebrospinal fluid biomarkers for HD. Information has been organised into tables to allow a pragmatic approach to the discussion of the evidence and generation of practical recommendations for future studies. Many of the markers published converge on metabolic and inflammatory pathways, …although changes in other analytes representing antioxidant and growth factor pathways have also been found. The most promising markers reflect neuronal and glial degeneration, particularly neurofilament light chain. International collaboration to standardise assays and study protocols, as well as to recruit sufficiently large cohorts, will facilitate future biomarker discovery and development. Show more

Keywords: Huntington’s disease, biomarker, blood, plasma, serum, cerebrospinal fluid, urine, saliva

DOI: 10.3233/JHD-170273

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 109-135, 2018

Authors: Franich, Nicholas R. | Basso, Manuela | André, Emily A. | Ochaba, Joseph | Kumar, Amit | Thein, Soe | Fote, Gianna | Kachemov, Marketta | Lau, Alice L. | Yeung, Sylvia Y. | Osmand, Alexander | Zeitlin, Scott O. | Ratan, Rajiv R. | Thompson, Leslie M. | Steffan, Joan S.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is a progressive neurodegenerative disorder associated with aging, caused by an expanded polyglutamine (polyQ) repeat within the Huntingtin (HTT) protein. In HD, degeneration of the striatum and atrophy of the cortex are observed while cerebellum is less affected. Objective: To test the hypothesis that HTT protein levels decline with age, which together with HTT mutation could influence disease progression. Methods: Using whole brain cell lysates, a unique method of SDS-PAGE and western analysis was used to quantitate HTT protein, which resolves as a monomer and as a high molecular weight species that …is modulated by the presence of transglutaminase 2. HTT levels were measured in striatum, cortex and cerebellum in congenic homozygous Q140 and HdhQ150 knock-in mice and WT littermate controls. Results: Mutant HTT in both homozygous knock-in HD mouse models and WT HTT in control striatal and cortical tissues significantly declined in a progressive manner over time. Levels of mutant HTT in HD cerebellum remained high during aging. Conclusions: A general decline in mutant HTT levels in striatum and cortex is observed that may contribute to disease progression in homozygous knock-in HD mouse models through reduction of HTT function. In cerebellum, sustained levels of mutant HTT with aging may be protective to this tissue which is less overtly affected in HD. Show more

Keywords: Autophagy, Huntingtin, Huntington’s disease, neurodegeneration

DOI: 10.3233/JHD-170274

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 137-150, 2018

Authors: Schuldenzucker, Verena | Schubert, Robin | Muratori, Lisa M. | Freisfeld, Frauke | Rieke, Lorena | Matheis, Tamara | Schramke, Sarah | Motlik, Jan | Kemper, Nicole | Radespiel, Ute | Reilmann, Ralf

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal-dominant, progressive neurodegenerative disorder with motor, cognitive, behavioral and metabolic symptoms. HD patients exhibit an altered response to stress which is reflected in changes of cortisol levels. Large animal models of HD such as the Libechov minipig are currently explored in preclinical studies to improve translational reliability and assessing behavior is of interest. Objective: This study aimed to investigate whether cortisol metabolism and response to stress are changed in minipigs transgenic for the Huntington gene (tgHD) compared to wildtype (wt) animals suggesting that cortisol may be used as a marker for stress …in minipigs. Methods: Thirty-two Libechov minipigs (14 tgHD and 18 wt) were tested before, during and after a stressor, i.e., a hoof trimming procedure, was applied at baseline and after one year. A total of six saliva samples were collected at each assessment and cortisol was measured. In addition, body temperature and respiratory rate were assessed at three pre-determined points during each hoof trimming procedure. Results: All minipigs showed a rise of cortisol in response to the hoof trimming stressor similarly to cortisol changes induced by stress observed in humans. No relevant differences were detected between tgHD and wt minipigs. Conclusion: Cortisol testing for the assessment of stress compensation, e.g., during hoof trimming, is feasible and well tolerated in wt and tgHD minipigs. To elucidate the time profile of cortisol responses to stressors further studies with assessments at multiple time points and exploration of the diurnal profiles of cortisol in minipigs are recommended. Show more

Keywords: Animal models, minipigs, phenotyping, biomarker, saliva, cortisol, vital signs

DOI: 10.3233/JHD-180285

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 151-161, 2018

Authors: Schultz, Jordan L. | Nopoulos, Peg C. | Gonzalez-Alegre, Pedro

Article Type: Research Article

Abstract: Background: Huntington Disease (HD) and human immunodeficiency virus (HIV) are both associated with neurodegeneration in the cerebral cortex and striatum. The rate of striatal degeneration is a known predictor of symptom onset in HD indicating a potential neurobiological link between HD and HIV. Objective: To determine if the presence of pre-existing HIV infection would trigger a significantly earlier age of symptom onset (ASO) in HD-mutation carriers when compared to non-infected HD subjects. Methods: This was a retrospective analysis of the Enroll-HD database that included participants with a CAG repeat of at least 36. Participants with HD …and a comorbidity of HIV that was diagnosed prior to their reported ASO were identified and compared to participants with HD who did not have HIV. An ANCOVA analysis was performed to investigate the differences in ASO between the HIV and non-HIV groups. Sex, drug use, and CAG repeat number were used as covariates. Results: The average ASO of HD subjects with previous HIV infection (n  = 8) was 9.1 years earlier than non-HIV infected HD subjects (n  = 3259) [F  (1, 3267) =10.05, p  = 0.002]. Despite low numbers of participants in the HIV group, the calculated effect size of this difference was 1.07. Conclusion: The known neurobiological changes caused by HIV seem to hasten the ASO in patients with HD. These results may enhance our understanding of the neuropathology of HD in a way that will help with the identification of novel targets for future therapies. Show more

Keywords: Huntington’s disease, symptom onset, Enroll-HD, human immunodeficiency virus

DOI: 10.3233/JHD-180287

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 163-166, 2018

Authors: Saft, Carsten | von Hein, Sarah Maria | Lücke, Thomas | Thiels, Charlotte | Peball, Marina | Djamshidian, Atbin | Heim, Beatrice | Seppi, Klaus

Article Type: Research Article

Abstract: Background: Motor symptoms in Huntington’s disease (HD) are heterogeneous with dystonia being described as a symptom with a very high prevalence not only in juvenile cases. Objective: Treatment options for dystonia are limited. Cannabinoids have been described as a potential treatment for patients with dystonia of a different origin. Here, we present early onset HD patients with a marked improvement of motor symptoms mainly due to alleviation of dystonia due to treatment with cannabinoids. In addition we review the current literature concerning the use of cannabinoids in HD. Method: The Unified Huntington’s Disease Rating Scale (UHDRS) …motor score, including a chorea and dystonia subscore, was conducted before and after the start of cannabinoids in seven patients without any other changes in medication. Results: The UHDRS motor score and the dystonia subscore (±SD) improved from 70.9 (25.5) to 60.6 (26.9) with a mean change of 10.3 [95% CI 6.0–14.6] and from 12.3 (4.0) to 8.0 (3.6) with a mean change of 4.3 [95% CI 2.3–6.3], respectively (both p  = 0.018). Conclusion: Improvement of motor symptoms, mainly dystonia, led to several relevant improvements from a global clinical perspective such as improvement of care, gait and fine motor skills and weight gain. Moreover, we observed changes in behavior with less irritability and apathy, as well as less hypersalivation in some cases. Show more

Keywords: Cannabinoid, dystonia, chorea, Huntington’s, Huntington, sativex, nabilone, dronabinol

DOI: 10.3233/JHD-170283

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 167-173, 2018

Authors: MacLeod, Rhona | Moldovan, Ramona | Stopford, Cheryl | Ferrer-Duch, Mariangels

Article Type: Research Article

Abstract: Background: Predictive testing for Huntington’s disease (HD) has been available for individuals at risk of HD by direct mutation analysis since 1993. International Predictive test guidelines recommend that support is offered following the result regardless of test outcome. However, there is lack of an evidence base regarding what this support should look like and how it might work in practice. Objective: A service improvement initiative looked at the feasibility of offering a narrative group session co-facilitated by a genetic counsellor and clinical psychologist, to individuals who had tested mutation negative for HD. The narrative session was evaluated from …the perspective of group participants. Methods: Individuals who tested mutation negative at a genetic centre in the North of England over a 5-year period were invited to attend a narrative group session. 52 people were contacted and 9 people agreed to participate. Participants completed standardised questionnaires (PHQ-9 and GAD-7) before and after the session and a detailed written evaluation. Participants’ comments were analysed thematically. Results: Participants were overwhelmingly positive about the narrative session finding it a safe and enjoyable way to explore difficult life experiences. Reported benefits included feeling less isolated, being inspired by other people’s stories and connecting as a group. All 9 participants said they would recommend the narrative session to anyone impacted by HD. Conclusions: The narrative group session was considered an interesting and useful approach to facilitating adaptation following a negative predictive test result for HD. Show more

Keywords: Huntington’s disease, narrative, predictive testing, service evaluation

DOI: 10.3233/JHD-170276

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 175-183, 2018

Authors: Roman, Olivia C. | Stovall, Jeffrey | Claassen, Daniel O.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) patients are at significantly higher risk of suicidal behavior, and associated cognitive and behavioral factors play an important role. Impulsivity is commonly thought to be a risk factor, but does not completely account for all suicide attempts. Objective: To provide clinical evidence that perseverative behavior may precipitate suicide attempts in HD. Methods: Case review of four HD patients who attempted suicide. Results: Each patient demonstrated a clinical history of perseverative behavior, and endorsed perseveration on upsetting thoughts leading up to their suicide attempts. The attempts were planned in response to …these ruminations. Conclusions: The patients in this series experienced uncontrollable distressful thoughts prior to their thoughtfully planned suicide attempts. These patients did not appear to act impulsively in their decision to attempt suicide. Show more

Keywords: Huntington’s disease, perseveration, suicide

DOI: 10.3233/JHD-170249

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 185-187, 2018

Authors: Veenhuizen, Ruth | Nijsten, Hanneke | van Roosmalen, Paul | Lammertsen, Karen | Stor, Tom | de Jager, Lia | de Man, Jesseke | van der Doelen, Rina | Landa, Karin | Grond, Vera | Heffels, Joyce | Groenewoud, Rinske | Rovers, Luce | Bakker, Christian | Leiwakabessy, Saskia | van der Wedden, Dirk | van Blitterswijk, Jacqueline | van den Bosch, Dieuwke

Article Type: Article Commentary

Abstract: Huntington’s disease (HD) patients and families deserve expert treatment and care throughout their lives, but uniformity in functional diagnosis and treatment was lacking. In the aim of reaching this uniformity on day-to-day treatment and care offered by multidisciplinary outreach teams from Dutch long term care facilities for ambulatory HD patients, a consensus trajectory was started to harmonise our care programme with international standards and within the country. The consensus statements, given as supplementary material, should lead to expert treatment and care for HD families throughout the Netherlands and this manuscript should contribute and revitalise a global discussion on standards of …treatment and care. Show more

Keywords: Huntington’s disease, caregivers, standard of care, consensus, case managers, ambulatory care, outreach clinic

DOI: 10.3233/JHD-180298

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 189-191, 2018

Authors: Diago, Elena Bellosta | Martínez-Horta, Saül | Lasaosa, Sonia Santos | Alebesque, Alejandro Viloria | Pérez-Pérez, Jesús | Kulisevsky, Jaime | del Val, Javier López

Article Type: Research Article

Abstract: Background: Sleep disturbances are an early and prominent feature of Huntington’s disease (HD). Objective: The current study investigated the relation between sleep quality impairment and cognitive and psychiatric symptoms in patients with HD. Methods: Sleep quality, daytime sleepiness, and neurocognitive symptoms were assessed in 38 mutation carriers (23 premanifest and 15 early stage) and 38 age-and sex-matched controls using standardized questionnaires (the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, the cognitive section of the Unified Huntington’s Disease Rating Scale, the Hospital Anxiety and Depression Scale, and the Irritability Scale). Results: Compared to controls, HD …patients had worse sleep quality (p  = 0.016), which was associated with more severe cognitive impairment and higher anxiety, depression and irritability scores. These findings suggest that HD patients may have a delayed sleep phase, as indicated by the increased sleep onset latency (p  = 0.019) and later wake-up time (0.013), which was associated with worse cognitive performance and greater depressive and anxiety symptoms. Conclusions: Our data provide further evidence for an association between sleep quality in HD and cognitive performance and psychiatric symptoms Show more

Keywords: Anxiety, circadian rhythm, depression, hypothalamus, suprachiasmatic nucleus

DOI: 10.3233/JHD-180291

Citation: Journal of Huntington's Disease, vol. 7, no. 2, pp. 193-198, 2018