Journal of Huntington's Disease

Exercise is beneficial for persons with Huntington's disease (HD). Inpatient rehabilitation settings are well-suited for implementing exercise programs. Exercise parameters, such as duration and intensity, need to be further investigated. The objective of our study was to evaluate the effects of an exercise program at moderate intensity performed five times a week for persons with mid-stage HD during a four-week inpatient rehabilitation program.

In a single-blind randomized monocentric controlled trial, two groups followed a four-week inpatient rehabilitation program including: occupational therapy, psychomotor therapy, psychosocial workshop, mobility sessions, dietary management, nursing, socio-educational activities, physician consultations and personalized consultations. In addition, the intervention group specifically participated in five one-hour exercise sessions per week at moderate intensity (flat ground walking, sand walking, resistance training, adaptive cycling and water activities), whereas the control group engaged in specific activities without physical activity. The primary outcome was the UHDRS-modified Motor Score (mMS). Functional, cognitive and psychological assessments were also completed.

Thirty-two patients were recruited. The UHDRS-mMS did not significantly differ at post-intervention. In the intervention group (n = 16), within-group improvements were observed for HAD-Anxiety, PBA-apathy, PBA-depression, PBA-psychosis; both within and between-group for 6-min walk test, Stroop Word Reading, and PBA-executive function; and between-group only for Borg. The control group (n = 16) improved within-group on PBA components: depression, apathy and irritability.

Inpatient rehabilitation program had positive effects on psychological symptoms, while exercise produced additional positive effects beyond exercise tolerance, anxiety, STROOP Word Reading and executive function. Inpatient rehabilitation programs may require longer-term post-rehabilitation support.

NCT04917133

To gain insight into factors contributing to the quality of care in nursing homes specialized in Huntington's disease from the perspectives of formal and informal caregivers.

A qualitative descriptive focus group study.

Formal and informal caregivers from three specialized nursing homes in the Netherlands were separated into six focus groups. All data was analyzed using reflexive thematic analysis.

From both groups, three main themes were explored: (1) care approaches and principles, (2) attention to specific care domains, and (3) preconditions for delivering care. Formal caregivers highlighted the importance of balancing residents’ autonomy and restrictions, the need to work systematically, and adopting a resident-centered approach. Furthermore, attention to palliative care, nutritional care, and emotional support are needed. Informal caregivers emphasized the need for providing structure, supportive conversations, and the importance of the nursing home environment itself. Attention to the transition phase immediately after admission to the nursing home, as well as guidance on future care planning, is important. There is a need for care teams that consist of knowledgeable, familiar caregivers within a care organization that (im)materially supports its staff.

Maintaining autonomy despite disease-related restrictions, providing structure, applying palliative care principles, and offering emotional support are essential components of quality of care, as emphasized by both formal and informal caregivers. Achieving this requires systematic nursing practices performed by a team of knowledgeable caregivers. Although informal caregivers’ descriptions are more superficial, key elements in them are similar to those of formal caregivers.

This study explored how to provide good care for people with Huntington's disease living in specialized nursing homes. We wanted to understand what both professional caregivers (such as nurses and care staff) and family members consider important for high-quality care.

We held group discussions with professional caregivers and family members from three Dutch nursing homes that specialize in Huntington's disease. We analyzed what they shared about their experiences and views.

Professional caregivers mentioned the importance of putting the resident at the center of care and working in a systematic way. They also spoke about the need for supporting autonomy while taking into account necessary restrictions. In addition, caregivers highlighted the need for emotional support, and attention to specific areas such as palliative care and nutrition. Family members emphasized the need for daily structure, supportive conversations, and a pleasant nursing home environment. They also said that support is needed right after a resident moves in, and that guidance and planning for the future are crucial. Both groups emphasized the importance of a skilled and familiar care team with sufficient knowledge of the disease.

Providing good care for people with Huntington's disease requires a combination of supporting independence, offering structure, providing emotional and palliative care, and working as a consistent and knowledgeable team. While professionals and family members bring different perspectives, they largely agreed on what matters most in Huntington's disease care.

Reliable detection of huntingtin (HTT) is essential for understanding Huntington's disease (HD) biology and for evaluating therapeutic strategies. However, high-quality monoclonal antibodies (mAbs) against the HTT C-terminal domain remain limited.

We sought to generate and validate novel monoclonal antibodies targeting the HTT C-terminal HEAT-containing domain to better detect HTT independently of potential effects of polyglutamine length that can impact some N-terminally targeted antibodies.

We immunized mice with a highly purified, well-characterized recombinant protein corresponding to the HTT C-terminal domain. We generated monoclonal antibody-producing hybridoma cell lines and characterized the antibodies in common immuno-applications using parental and HTT-knockout cell lines, and in patient-derived fibroblasts.

Three novel, independent hybridoma lines producing anti-HTT monoclonal antibodies were derived. Using CRISPR-edited HTT knockout cell lines and in patient-derived cells, we identified one clone, anti-HTT [2F8], that was specific and effective across Western blot, immunofluorescence, and ELISA assays. All antibodies bound full-length HTT irrespective of HAP40 interaction or polyQ length in vitro and in cells and showed no cross-reactivity to the N-terminal HEAT domain.

These C-terminal HTT mAbs are thus valuable additional tools for studying endogenous HTT function in both normal and disease contexts.

To compare the sensitivity of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) for detecting cognitive change in Huntington's disease (HD) subjects stratified by baseline performance quartiles and the Huntington's Disease Integrated Staging System (HD-ISS).

Participants (age 25–65; CAG 40–50) from an observational cohort completed MMSE and MoCA at baseline, with follow-up visits at least six months after baseline, and observations truncated at five years.

We analyzed the full cohort (n = 246) and an HD-ISS–staged subset (n = 132). Longitudinal change was evaluated using mixed-effects models, adjusted for baseline age, gender, education, CAG, and age × CAG interaction. Baseline discrimination between HD-ISS stages was assessed with ROC curves and AUC comparisons.

Annual decline was nearly identical for MMSE and MoCA (–0.334 vs. −0.331). Adjusted quartile analyses revealed differential sensitivity: MoCA showed greater decline in lower and higher performance levels (Quartiles 1, 3, and 4), while MMSE was most sensitive at mid-range (Quartile 2). In HD-ISS analyses, MMSE demonstrated more consistent decline across stages, particularly Stages 1 and 3, indicating sensitivity to early and moderate disease phases. Baseline ROC analyses favored MoCA for stage discrimination (Stage 0 vs. all: AUC 0.789 vs. 0.686, p = 0.011).

The MMSE and MoCA exhibit complementary strengths. MoCA demonstrates superior sensitivity for baseline staging and early disease detection, while MMSE better captures longitudinal decline. These findings suggest that combined use of both instruments may provide a more complete assessment of cognitive progression in HD.

Weight loss and eating difficulties are common in Huntington's disease (HD), but professionals’ perspectives remain underexplored.

To investigate professionals and service users’ perspectives on weight loss and eating difficulties, and explore how these issues are prioritized, managed, and experienced.

Semi-structured interviews (n = 19; 10 professionals, 9 service users) in the UK. Reflexive thematic analysis identified key themes regarding the causes, management, and impact of eating problems in HD.

Six themes emerged: (1) Common tactics for weight gain and their limitations, (2) Variability in professional knowledge and access to care, (3) Cognitive and psychopathological contributors to weight loss, (4) Physical and practical barriers to eating, (5) Social and emotional impacts of feeding difficulties, and (6) Perceptions of weight loss and disease progression. Within these themes we found that, amongst other findings, high-energy diets and supplements are widely used but often poorly tolerated long-term. Access to specialist care is inconsistent, leading to a “geographical lottery”. Cognitive and psychological symptoms, including apathy and executive dysfunction, significantly affect eating behaviors. Physical symptoms such as chorea and dysphagia further complicate intake. Social withdrawal due to embarrassment is common. Weight loss is often under-recognized or under-prioritized by patients.

Causes of weight loss are complex and need multidisciplinary holistic management, which is not always available. Management of complex psychosocial factors is as important as managing physical symptoms. Proactive, personalized interventions can improve both longevity and quality of life for people with HD.

People with Huntington's disease (HD) are encouraged to consider end-of-life planning early on to mitigate future challenges. Initial evidence shows that undertaking planning discussions around this subject presents various barriers; however, a comprehensive evidence synthesis has not been completed to date. Accordingly, we here synthesise evidence regarding experiences of end-of-life planning discussions (EOLPD) among people with HD, their families and familial caregivers, and healthcare professionals supporting them.

Five databases were systematically searched for peer-reviewed articles addressing the research question. After screening, eight articles meeting the inclusion criteria were identified, and a narrative synthesis undertaken to develop key themes.

Four themes were developed. “The value of EOLPD” details the perceived effectiveness of such discussions. “To talk or not to talk” reflect motivations to seek out or avoid EOLPD. “A clear vision of the future” encapsulates how EOLPD may provide comfort for some but fear and anxiety for others. The final theme highlights the importance of those engaging in EOLPD accessing “The right people at the right time”.

End-of-life planning in HD remains inconsistently implemented and often process-focused, with a need for more holistic and patient-centred discussions. Further research is necessary to explore needs, expectations and experiences among HD families, and to support healthcare professionals to successfully lead on introducing these discussions. Additionally, much of the literature addressed euthanasia rather than natural death, highlighting a need for more research in the context of natural death.

Huntington's Disease-like 2 (HDL2) presents complexities in diagnosis due to its similarity to Huntington's Disease (HD). Limited research highlights gaps in knowledge about management and genetic counselling for the condition. HDL2 is rare but an important differential diagnosis for individuals with HD-like symptoms who have tested negative for HD.

This review aimed to synthesise published clinical and genetic data on HDL2, identify knowledge gaps, and serve as a resource for healthcare professionals supporting individuals affected by or at risk of HDL2.

A mixed method integrative systematic review of four databases (Medline, Embase, Scopus, and PsycINFO) generated 323 peer-reviewed articles, of which 36 were included. Data about clinical features, genetic testing and counselling, and patient experiences were interpreted via narrative synthesis.

The majority of included studies explored the clinical features, genetic testing results and medical histories of individuals with HDL2. A total of 109 people with HDL2 were reported. Limited data was obtained about genetic counselling, management and support, and experiences of those with HDL2 and their families. Findings related to seven categories: DNA repeat length and impact on phenotype, age of onset and disease duration, family history, African ancestry, neurological characteristics, clinical characteristics, and experiences and support.

This review highlights the importance of understanding the reduced penetrance range and early psychiatric symptoms in HDL2 for accurate genetic counselling and interpretation of test results. Adapting existing protocols for HD and qualitatively collecting patient experiences can inform the development of a HDL2 genetic testing and counselling protocol.

Gene silencing is widely recognized as a promising therapeutic approach for dominant monogenic disorders. Current silencing strategies, many of which are transient, utilize RNA interference. Gene silencing may also be achieved through directed epigenetic editing using a CRISPR/dCas9 effector fused to DNA methyltransferase 3A (dCas9-DNMT3A). We used this system to direct DNA methylation to HTT, the causal gene underlying the autosomal dominant neurodegenerative disorder Huntington's disease, to assess the translational potential of this strategy for treating a genetic neurological disease.

To characterize the regulatory effect of targeted dCas9-DNMT3A-mediated DNA methylation at HTT.

We exploited DNA methylation profiles of high and low HTT-expressing tissues and targeted hypomethylated regions of HTT associated with high levels of HTT expression.

De novo DNA methylation of loci within defined upstream, promoter, intragenic and downstream regions of HTT resulted in robust, acute silencing of HTT. The best long-term silencing of HTT, which persisted up to 30 days, was observed when targeted DNA methylation was directed to the 5’UTR and promoter regions of HTT.

HTT gene silencing may be achieved via targeted de novo DNA methylation within hypomethylated regulatory regions at the HTT locus. DNA methylation editing may be an attractive therapeutic approach for Huntington disease due to its potential for long-term silencing and reversibility.

Huntington's disease (HD) is a neurodegenerative disorder caused characterized by motor, cognitive, and psychiatric/behavioral impairments. Among these symptoms, irritability is particularly burdensome due to its frequency and significant impact on the daily lives of both patients and caregivers. Currently, no FDA-approved medication specifically targets this symptom.

To assess the efficacy of dextromethorphan/quinidine (DM/Q) 20/10 mg (NUEDEXTA^®) in managing irritability in HD.

Double-blind, placebo-controlled, randomized, crossover clinical trial. Participants underwent a 13-week study: six weeks of DM/Q treatment, one-week washout, and six weeks of placebo. The DM/Q 20/10 mg regimen started with a once-daily dose, increased to twice daily after the first week, and tapered back to once daily in the sixth week. Participants were evaluated during three in-person visits: at baseline and at the end of each treatment phase. Assessments included motor and cognitive exams, the Irritability Scale, and the Problem Behavior Assessment–short version (PBA-s) (ClinicalTrials.gov NCT03854019).

Twenty participants were enrolled, with 18 completing the study (mean age = 43.94 ± 10.70 years, 11 females and 7 males). Both DM/Q and placebo reduced mean Irritability Scale scores (32% and 27.5%, respectively) and the irritability subscale of the PBA-s (42% and 33%, respectively), with no statistically significant differences between groups. Additionally, DM/Q showed no significant advantage over placebo in motor, behavioral, or cognitive outcomes.

DM/Q did not demonstrate significant benefits in managing irritability compared to placebo. Further research with larger sample sizes and alternative therapeutic strategies is needed to effectively address this symptom in HD.

This study extends prior clinimetric evaluations by examining the factor structure, internal consistency, and distributional properties of the Problem Behaviors Assessment – Short Form (PBA-s) in a large sample of people with Huntington's disease (pwHD) at various stages of progression using the Huntington's Disease Integrated Staging System (HD-ISS) framework.

Baseline PBA-s item total scores were analyzed from 14,371 Enroll-HD participants. Using HD-ISS criteria, participants were categorized as Stage 0/1 (n = 3262; 23%), Stage 2 (n = 1722; 12%), or Stage 3 (n = 9387; 65%).

Missing responses were low across items and stages. Item total score distributions demonstrated significant skew in Stages 0/1 and 2. Within Stage 3, skewness was less prevalent but still present in most distributions. In all groups, the PBA-s demonstrated moderate internal consistency, though five items exhibited weak item-total correlations. Resultant factor structures differed from those previously reported and varied by HD-ISS stage. In Stages 0/1 and 2, a three-factor model representing internalizing, externalizing, and cognitive control problems accounted for 39–42% of the total variance. In Stage 3, a five-factor solution explained 56% of the overall variance and consisted of internalizing, externalizing, cognitive control problems, suicidality, and cognitive dysfunction.

While the PBA-s demonstrates adequate internal consistency, our results revealed high rates of non-endorsement (i.e., item total scores = 0) and a variable factor structure with disease progression. Thus, the PBA-s may not distinguish mild changes in behavioral symptoms that might occur in early HD-ISS stages of disease.

In Huntington's disease (HD), certain brain cells called spiny projection neurons (SPNs) are especially vulnerable. One reason is that the gene involved in HD (called HTT) can gain extra DNA repeats, known as CAG repeats, over a person's lifetime. When these repeats grow very large—over about 150—they cause major changes in how SPNs work, eventually leading to cell damage and death.

To study this, we created a mathematical tool called the HD-Phase-Model. This model can identify SPNs with very large CAG repeat expansions just by looking at their gene activity patterns, without needing to directly measure repeat length. After confirming that the model worked correctly on known data, we applied it to several independent datasets from different brain regions. The model consistently detected SPNs showing the same harmful gene activity patterns linked to very large CAG expansions. Importantly, these patterns were specific to HD and were not found in brain cells from people with Alzheimer's or Parkinson's disease.

Overall, our work shows that patterns of gene activity can be used to predict which SPNs have extreme CAG expansions. This provides a new way to study how these expansions drive HD-specific brain cell damage.

Graphical abstract

This is a visual representation of the abstract.

Huntington's disease (HD) is a hereditary neurodegenerative disorder, with pathological changes detectable by MRI before symptom onset. Quantitative MRI (qMRI) provides tissue-specific parameters and holds potential for capturing disease-related biomarkers. However, conventional analysis methods often rely on single-modality imaging or mean features, constraining their ability to capture HD's complex microstructural evolution.

To assess the feasibility of multi-modal MRI combined with the MOLED sequence in HD patients and explore its value in early disease detection and staging.

22 HD patients (14 Pre-HD and 8 M-HD) and 27 healthy controls were enrolled. MOLED-derived T2 and T2* maps, along with structural MRI, were acquired using two 3.0 T scanners to assess inter-scanner consistency. The MOLED sequence incorporates ultrafast acquisition techniques to minimize motion artifacts and improve image quality. Histogram-based features (e.g., variance, skewness, and maximum) and volumes were extracted from eight deep brain regions. Multiple machine learning models were employed for classification analysis.

The MOLED demonstrated good image consistency and reproducibility across scanners. Significant group differences were observed in the volumes of several basal ganglia regions and in variance-based features across multiple modalities. Machine learning models combining clinical and mapping features achieved the highest classification performance (maximum F1-macro = 0.846, Sensitivity-macro = 0.838).

MOLED provides stable and complementary quantitative information for multi-modal MRI. Integrating multimodal multi-feature with machine learning enables a more comprehensive depiction of HD-related microstructural heterogeneity and disease progression.