Journal of Huntington's Disease - Volume 9, issue 3

Authors: Howland, David | Ellederova, Zdenka | Aronin, Neil | Fernau, Deborah | Gallagher, Jill | Taylor, Amanda | Hennebold, Jon | Weiss, Alison R. | Gray-Edwards, Heather | McBride, Jodi

Article Type: Review Article

Abstract: Genetically modified rodent models of Huntington’s disease (HD) have been especially valuable to our understanding of HD pathology and the mechanisms by which the mutant HTT gene alters physiology. However, due to inherent differences in genetics, neuroanatomy, neurocircuitry and neurophysiology, animal models do not always faithfully or fully recapitulate human disease features or adequately predict a clinical response to treatment. Therefore, conducting translational studies of candidate HD therapeutics only in a single species (i.e. mouse disease models) may not be sufficient. Large animal models of HD have been shown to be valuable to the HD research community and the …expectation is that the need for translational studies that span rodent and large animal models will grow. Here, we review the large animal models of HD that have been created to date, with specific commentary on differences between the models, the strengths and disadvantages of each, and how we can advance useful models to study disease pathophysiology, biomarker development and evaluation of promising therapeutics. Show more

Keywords: Minipigs, sheep, nonhuman primates, therapeutics

DOI: 10.3233/JHD-200425

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 201-216, 2020

Authors: van der Plas, Ellen | Schultz, Jordan L. | Nopoulos, Peg C.

Article Type: Review Article

Abstract: The current dogma of HD pathoetiology posits it is a degenerative disease affecting primarily the striatum, caused by a gain of function (toxicity) of the mutant mHTT that kills neurons. However, a growing body of evidence supports an alternative theory in which loss of function may also influence the pathology.This theory is predicated on the notion that HTT is known to be a vital gene for brain development. mHTT is expressed throughout life and could conceivably have deleterious effects on brain development. The end event in the disease is, of course, neurodegeneration; however the process by which …that occurs may be rooted in the pathophysiology of aberrant development. To date, there have been multiple studies evaluating molecular and cellular mechanisms of abnormal development in HD, as well as studies investigating abnormal brain development in HD animal models. However, direct study of how mHTT could affect neurodevelopment in humans has not been approached until recent years. The current review will focus on the most recent findings of a unique study of children at-risk for HD, the Kids-HD study. This study evaluates brain structure and function in children ages 6–18 years old who are at risk for HD (have a parent or grand-parent with HD). Show more

Keywords: Brain development, Huntington’s disease, children at risk for HD, MRI

DOI: 10.3233/JHD-200394

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 217-229, 2020

Authors: Zarotti, Nicolò | Dale, Maria | Eccles, Fiona | Simpson, Jane

Article Type: Review Article

Abstract: Background: Although Huntington’s disease (HD) can cause a wide range of psychological difficulties, no review has ever been carried out on the range of psychological interventions adopted with this population. Objective: To scope the literature on psychological interventions for psychological difficulties in people affected by HD. Methods: A systematic scoping review was performed across MEDLINE, PsycINFO, CINAHL, Academic Search Ultimate, and Cochrane Library up to 1 March 2020. Results: From an initial return of 1579 citations, a total of nine papers were considered eligible for review. These included a qualitative investigation, three case studies, …two case series, two uncontrolled pretest-posttest designs, and only one randomised control trial (RCT). Despite the wide range of psychological difficulties which can be experienced by people affected by the HD gene expansion, the adopted interventions only accounted for five main psychological outcomes (anxiety, apathy, depression, irritability, and coping). Further discussion and suggestions for future research are provided for each outcome. Conclusion: The current literature on psychological interventions in people affected by HD is extremely limited both in terms of methods and addressed clinical outcomes. Consequently, no conclusions can be offered yet as to which psychological therapy may help this population. As further more comprehensive research is urgently needed for this group, the ultimate aim of the present review is to act as a call to arms for HD researchers worldwide to help shed light on the most effective way to translate psychological theory into practice for the benefit of people affected by HD. Show more

Keywords: Huntington’s disease, psychotherapy, clinical psychology, psychological interventions

DOI: 10.3233/JHD-200418

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 231-243, 2020

Authors: Tereshchenko, Alexander | van der Plas, Ellen | Mathews, Katherine D. | Epping, Eric | Conrad, Amy L. | Langbehn, Douglas R. | Nopoulos, Peg

Article Type: Research Article

Abstract: Background: The gene (Huntingtin or HTT ) causing Huntington’s disease (HD) is vital for development and is expressed throughout the brain and body lifelong. The mutant form (mHTT ) may influence growth and development. Objective: To determine the impact of mHTT on human measures of growth, including height, weight, and body mass index (BMI), between child and adolescent carriers of mHTT and control peers. Methods: Children ages 6–18 years of age (n  = 186) at risk for HD were enrolled in the KidsHD study. For research purposes only, genetic testing was performed to classify participants …as Gene-Expanded (GE = 78) or as Gene Non-Expanded (GNE = 108). Outcome measures included height, weight, and body mass index (BMI). Mixed models were used to determine if non-linear age trends differed between groups for BMI, height, and weight. Results: Differences were seen in the trajectory of BMI in which the GE group reached a plateau in late adolescence with no further increase, compared with a nearly linear increase in the GNE group. There was a significant sex interaction pattern where GE males were taller than GNE males in adolescence, in the presence of similar weight. In contrast, GE females weighed significantly less than their GNE counterparts in adolescence, in the presence of similar height. Conclusion: Measures of growth are abnormal in child and adolescent carriers of mHTT , decades before HD onset. Although further studies are needed for replication, the current findings suggest that developmental aberrations may be systemic and a vital part of disease pathology. Show more

Keywords: Body mass index, weight, height, children at-risk for Huntington’s disease

DOI: 10.3233/JHD-200407

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 245-251, 2020

Authors: Delfino, Laura | Mason, Robert P. | Kyriacou, Charalambos P. | Giorgini, Flaviano | Rosato, Ezio

Article Type: Research Article

Abstract: Background: Altered cellular vesicle trafficking has been linked to the pathogenesis of Huntington’s disease (HD), a fatal, inherited neurodegenerative disorder caused by mutation of the huntingtin (HTT) protein. The Rab GTPase family of proteins plays a key role in regulation of vesicle trafficking, with distinct Rabs helping specify membrane identity and mediating cellular processes including budding, motility and tethering of vesicles to their targets. In recent years several Rab GTPases—notably, Rab5 and Rab11—have been linked to the pathogenesis of neurodegenerative disorders, including HD. Objective: We investigated whether Rab8, which regulates post-Golgi vesicle trafficking, is able to improve HD-relevant …phenotypes in a well-characterised model. Methods: We overexpressed Rab8 in a Drosophila model of HD testing cellular, behavioural, and molecular phenotypes. Results: We found that Rab8 overexpression ameliorated several disease-related phenotypes in fruit flies expressing a mutant HTT fragment throughout the nervous system, including neurodegeneration of photoreceptor neurons, reduced eclosion of the adult fly from the pupal case and shortened lifespan. Rab8 overexpression also normalised aberrant circadian locomotor behaviour in flies expressing mutant HTT in a specific population of neurons that regulate the circadian clock. Intriguingly, expression of Rab8 increased the accumulation of SDS-insoluble aggregated species of mutant HTT. Conclusion: Collectively, our findings demonstrate that increased Rab8 levels protect against mutant HTT toxicity and potentiate its aggregation, likely reducing the accumulation of downstream toxic soluble species. Show more

Keywords: Huntington’s disease, Drosophila melanogaster , neurodegeneration, Rab8, HTT

DOI: 10.3233/JHD-200411

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 253-263, 2020

Authors: Stuttgen, Kelsey | Bollinger, Juli | McCague, Allison | Dvoskin, Rachel | Mathews, Debra

Article Type: Research Article

Abstract: Background: Communicating genetic information within families can provide individuals with the emotional support, alert family members to their own potential risk, and strengthen relationships. However, these communications have the potential to cause emotional distress to individuals and family members if family members are informed of a risk they do not wish to know or discuss. Communication about the decision to pursue testing and test results are especially sensitive in Huntington’s disease (HD), where individuals often feel strongly about either knowing or not knowing their genetic status. Objective: To examine family communication patterns of genetic risk, the decision to …pursue testing, and test results not just years, but decades after testing for HD, and examine how family communication of genetic risk information affects family relationships over the long-term. Methods: In this qualitative study, 39 semi-structured interviews were conducted with probands who went through genetic testing for HD. Clinic notes from these individuals were also analyzed. Results: Family communication patterns varied based on relation (e.g., significant others, child, extended family) and were influenced by a variety of factors. Sharing with spouses and children had a positive influence on the relationship in most cases. Sharing with extended family members had varying effects on relationships. Negative effects were more likely when family members were in denial, had not pursued testing for themselves, or did not support testing. Conclusion: Communication to significant others and children, should be discussed with and supported in individuals seeking testing for HD, but for extended family members, potential effects on the relationship, emotional distress, and benefits should be discussed and weighed. Show more

Keywords: Communication, genetic testing, family relations, Huntington’s disease

DOI: 10.3233/JHD-200402

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 265-274, 2020

Authors: Anil, Megha | Mason, Sarah L. | Barker, Roger A.

Article Type: Research Article

Abstract: Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder that typically manifests between the ages of 30 and 50 years. However, the disease can present at any age, and phenotypic differences between younger and later-onset patients have received limited attention. Objective: To compare clinical features of late- (>70 years of age) and younger-onset (<30 years of age) HD patients. Methods: Patients presenting to our regional NHS HD clinic with new-onset manifest HD diagnosed over the age of 70 years (LoHD) (n  = 18) were compared with a younger cohort who developed disease under the age of …30 years (YoHD) (n  = 12). Rate of progression over time on standard cognitive and motor measures was compared. Results: At first clinic presentation, both groups had the same total UHDRS scores. However, the LoHD group had higher chorea scores (F (1,28) = 6.52, p  = 0.016), while the YoHD group had more dystonia (F (1,28) = 8.69, p  = 0.006) and eye movement abnormalities (F (1,28) = 16.991, p  < 0.001). The YoHD group also had a greater rate of motor progression, especially for bulbar measures (F (1, 28) = 6.96, p  = 0.013) and bradykinesia (F (1, 28) = 7.99, p  = 0.009). No differences were found in the rate of cognitive change (F (1,21) = 1.727, p  = 0.203) nor functional capacity (F (1,28) = 1.388, p  = 0.249) between the groups. Conclusion: Phenotypic differences between YoHD and LoHD patients were found in terms of initial presentation and rate of motor progression. This has implications for therapeutic trials involving HD patients of different ages, given their different clinical features and progression. Show more

Keywords: Huntington’s disease, disease progression, age of onset, neurodegenerative disorders

DOI: 10.3233/JHD-200404

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 275-282, 2020

Authors: Kaur, Jaslovleen | Parveen, Shaista | Shamim, Uzma | Sharma, Pooja | Suroliya, Varun | Sonkar, Akhilesh Kumar | Ahmad, Istaq | Garg, Jyoti | Anand, Kuljeet Singh | Laskar, Sanghamitra | Chowdhury, Debashish | Kushwaha, Suman | Goyal, Vinay | Srivastava, Achal K. | Singh, Gagandeep | Faruq, Mohd

Article Type: Research Article

Abstract: Background: The diagnostic workup for choreiform movement disorders including Huntington’s disease (HD) and those mimicking HD like phenotype is complex. Objective: The aim of the present study was to genetically define HD and HD-like presentations in an Indian cohort. We also describe HTT -CAG expansion manifesting as neuroferritinopathy-like disorder in four families from Punjab in India. Materials and methods: 159 patients clinically diagnosed as HD and HD-like presentations from various tertiary neurology clinics were referred to our centre (CSIR-IGIB) for genetic investigations. As a first tier test, CAG-TNR for HTT was performed and subsequently HD-negative …samples were screened for JPH3 (HDL2), TBP (SCA17), ATN1 (DRPLA), PPP2R2B (SCA12) and GGGGCC expansion in C9orf72 gene. Four families presenting as neuroferritinopathy-like disorder were also investigated for HTT-CAG expansion. Results: 94 of 159 (59%) patients were found to have expanded HTT- CAG repeats. Pathogenic repeat expansion in JPH3 , TBP, ATN1 and C9orf72 were not found in HD negative cases. Two patients were positive for SCA12-CAG expansion in pathogenic length, whereas 5 cases harboured TBP-CAG repeats falling in reduced penetrance range of 41– 48 repeats for SCA17. Four unrelated families, presented with atypical chorea and brain MRI findings suggestive of basal ganglia abnormalities mimicking neuroferritinopathy were found to harbour HTT -CAG expansion. Conclusion: We present SCA12 as a new reported phenocopy of HD which should be considered for diagnostic workout along with SCA17 for HD-like syndromes. This study also illustrates the necessity, to consider evolving HD like phenotype, as a clinical diagnosis for cases with initial manifestations depicting neuroferritinopathy. Show more

Keywords: Huntington’s disease, trinucleotide repeats, SCA12, neuroferritinopathy-like

DOI: 10.3233/JHD-200398

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 283-289, 2020

Authors: Isaacs, David | Gibson, Jessie S. | Stovall, Jeffrey | Claassen, Daniel O.

Article Type: Research Article

Abstract: Background: Psychiatric symptoms are widely prevalent in Huntington’s disease (HD) and exert greater impact on quality of life than motor manifestations. Despite this, psychiatric symptoms are frequently underrecognized and undertreated. Lack of awareness, or anosognosia, has been observed at all stages of HD and may contribute to diminished patient self-reporting of psychiatric symptoms. Objective: We sought to evaluate the impact of anosognosia on performance of commonly used clinical rating scales for psychiatric manifestations of HD. Methods: We recruited 50 HD patients to undergo a formal psychiatrist evaluation, the Problem Behavior Assessment-Short Form (PBA-s), and validated self-report …rating scales for depression, anxiety, and anger. Motor impairment, cognitive function, and total functional capacity were assessed as part of clinical exam. Patient awareness of motor, cognitive, emotional, and functional capacities was quantified using the Anosognosia Rating Scale. Convergent validity, discriminant validity, classification accuracy, and anosognosia effect was determined for each psychiatric symptom rating scale. Results: Anosognosia was identified in one-third of patients, and these patients underrated the severity of depression and anxiety when completing self-report instruments. Anosognosia did not clearly influence self-reported anger, but this result may have been confounded by the sub-optimal discriminant validity of anger rating scales. Conclusion: Anosognosia undermines reliability of self-reported depression and anxiety in HD. Self-report rating scales for depression and anxiety may have a role in screening, but results must be corroborated by provider and caregiver input when anosognosia is present. HD clinical trials utilizing patient-reported outcomes as study endpoints should routinely evaluate participants for anosognosia. Show more

Keywords: Anger, agnosia, anxiety, depression, Huntington’s disease, mood disorders

DOI: 10.3233/JHD-200410

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 291-302, 2020

Authors: Casella, Chiara | Bourbon-Teles, Jose | Bells, Sonya | Coulthard, Elizabeth | Parker, Greg D. | Rosser, Anne | Jones, Derek K. | Metzler-Baddeley, Claudia

Article Type: Research Article

Abstract: Background: Impaired myelination may contribute to Huntington’s disease (HD) pathogenesis. Objective: This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. Methods: Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model …of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics. Results: MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD. Conclusion: Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression. Show more

Keywords: Huntington’s disease, drumming training, white matter, myelin, diffusion MRI

DOI: 10.3233/JHD-200424

Citation: Journal of Huntington's Disease, vol. 9, no. 3, pp. 303-320, 2020