Huntington's Disease Families Research Articles

A practical guide for diagnostic investigations and special considerations in patients with Huntington's disease in Korea.

The Korean Huntington's Disease Society (KHDS) has recently published a practical guide for clinical approach to patients with Huntington's disease (HD) in Korea in April issue of Journal of Movement Disorders this year.1 This article is the second practical guide particularly focused on 1) essential points of genetic counseling for families of HD covering issues of testing minors and prenatal/preimplantation testing; and 2) premanifest HD and useful laboratory investigations for assessing disease severity and progression. The latter part of this article deals with special issues of juvenile and very late-onset HD, and common comorbidities in HD patients. 3) Finally, the management principles of HD patients are briefly explained. The contents were drafted by the guideline task force members of the KHDS. We intended to include published literature containing South Korean data in this paper. We believe this article will be a pocket guide to physicians as well as movement disorders specialists in Korea in planning diagnostic work-up for and management of HD patients and families.

Through their eyes: A retrospective mixed-methods study on the experiences and support needs of children growing up with a parent with Huntington’s disease

Background Growing up with a parent with Huntington's disease (HD) profoundly impacts children. However, this impact and children's needs are often misunderstood, even by professional services. Even when resources are available, children often feel that their needs are unmet, raising concerns about the adequacy of available guidance and support. Objective This study aims to offer an in-depth understanding of the multifaceted impact of growing up with a parent with HD, examining the needs for professional guidance on emotional and social aspects, and identifying specific areas where support can be improved to better aid them. Methods This retrospective study utilized an exploratory sequential mixed methods design, combining qualitative focus groups ( n = 13) and a quantitative survey ( n = 23). Qualitative data were analyzed using an inductive thematic analysis with a descriptive phenomenological approach. Quantitative data were analyzed using descriptive statistics. Results The impact of HD on children extends across various domains, affecting self-development, social interactions, and family dynamics. Support received at home varied, with limited access to professional help. Support needs primarily revolved around emotional support and access to comprehensive information. Key support providers, such as parents, peers, mentors, healthcare providers and coaches with expertise in HD, play crucial roles in addressing these needs. Conclusions The study underscores challenges faced by children in HD families. By centering our efforts on the emotional well-being of these children, offering tailored information, involving their social network, providing community-based support, and strengthening parental support systems, we can improve the support required by children in these families.

An exploration of the genetics of the mutant Huntingtin (mHtt) gene in a cohort of patients with chorea from different ethnic groups in sub-Saharan Africa.

Africans are underrepresented in Huntington's disease (HD) research. A European ancestor was postulated to have introduced the mutant Huntingtin (mHtt) gene to the continent; however, recent work has shown the existence of a unique Htt haplotype in South-Africa specific to indigenous Africans. We aimed to investigate the CAG trinucleotide repeats expansion in the Htt gene in a geographically diverse cohort of patients with chorea and unaffected controls from sub-Saharan Africa. We evaluated 99 participants: 43 patients with chorea, 21 asymptomatic first-degree relatives of subjects with chorea, and 35 healthy controls for the presence of the mHtt. Participants were recruited from 5 African countries. Additional data were collected from patients positive for the mHtt gene; these included demographics, the presence of psychiatric and (or) cognitive symptoms, family history, spoken languages, and ethnic origin. Additionally, their pedigrees were examined to estimate the number of people at risk of developing HD and to trace back the earliest account of the disease in each region. HD cases were identified in all countries. Overall, 53.4% of patients with chorea were carriers for the mHTT; median tract size was 45 CAG repeats. Of the asymptomatic relatives, 28.6% (6/21) were carriers for the mHTT; median tract size was 40 CAG. No homozygous carries were identified. Median CAG tract size in controls was 17 CAG repeats. Men and women were equally affected by HD. All patients with HD-bar three who were juvenile onset of <21 years-were defined as adult onset (median age of onset was 40 years). HD transmission followed an autosomal dominant pattern in 84.2% (16/19) of HD families. In familial cases, maternal transmission was higher 52.6% (10/19) than paternal transmission 36.8% (7/19). The number of asymptomatic individuals at risk of developing HD was estimated at ten times more than the symptomatic patients. HD could be traced back to the early 1900s in most African sites. HD cases spread over seven ethnic groups belonging to two distinct linguistic lineages separated from each other approximately 54-16kya ago: Nilo-Sahara and Niger-Congo. This is the first study examining HD in multiple sites in sub-Saharan Africa. We demonstrated that HD is found in multiple ethnic groups residing in five sub-Saharan African countries including the first genetically confirmed HD cases from Guinea and Kenya. The prevalence of HD in the African continent, its associated socio-economic impact, and genetic origins need further exploration and reappraisal.

Caregiver Burden of Patients With Huntington's Disease in South Korea.

This is the first prospective cohort study of Huntington's disease (HD) in Korea. This study aimed to investigate the caregiver burden in relation to the characteristics of patients and caregivers. From August 2020 to February 2022, we enrolled patients with HD from 13 university hospitals in Korea. We used the 12-item Zarit Burden Interview (ZBI-12) to evaluate the caregiver burden. We evaluated the clinical associations of the ZBI-12 scores by linear regression analysis and investigated the differences between the low- and high-burden groups. Sixty-five patients with HD and 45 caregivers were enrolled in this cohort study. The average age at onset of motor symptoms was 49.3 ± 12.3 years, with an average cytosine-adenine-guanine (CAG)n of 42.9 ± 4.0 (38-65). The median ZBI-12 score among our caregivers was 17.6 ± 14.2. A higher caregiver burden was associated with a more severe Shoulson-Fahn stage (p = 0.038) of the patients. A higher ZBI-12 score was also associated with lower independence scale (B = -0.154, p = 0.006) and functional capacity (B = -1.082, p = 0.002) scores of patients. The caregiving duration was longer in the high- than in the low-burden group. Caregivers' demographics, blood relation, and marital and social status did not affect the burden significantly. HD patients' neurological status exerts an enormous impact on the caregiver burden regardless of the demographic or social status of the caregiver. This study emphasizes the need to establish an optimal support system for families dealing with HD in Korea. A future longitudinal analysis could help us understand how disease progression aggravates the caregiver burden throughout the entire disease course.

Supporting Huntington's Disease Families Through the Ups and Downs of Clinical Trials.

Recent years have been turbulent ones for the Huntington's disease (HD) community. Three clinical trials for HD, including the first Phase 3 trial of a potentially disease modifying genetic therapy for HD, were all brought to a halt in March of 2021. 2022 brought more study roadblocks and an additional trial termination. As HD science progresses and larger scale trials become more frequent in the community, HD families are faced with the difficult reality that clinical research rarely results in a new drug hitting the market. To better understand how the HD community can be prepared for the ups and downs that accompany an expanding clinical research pipeline, the Huntington's Disease Society of America (HDSA) spoke with members of the Huntington's Disease Coalition for Patient Engagement (HD-COPE). This group of global advocates led by HDSA and the Huntington's Society of Canada (HSC) collaborates with pharmaceutical companies to ensure that HD voices are represented in the planning of clinical trials. These conversations allowed HDSA to summarize how the HD community can be best supported through the clinical research process in three key areas: engagement, support, and education.

Mental health symptoms among those affected by Huntington's disease: A cross-sectional study.

Although cognitive and motor symptoms of Huntington's disease (HD) are associated with disease progression, the underlying causes of psychological symptoms are not as clearly understood. Recent evidence suggests that some mental health difficulties experienced by people with HD are shared by noncarriers within HD families. Accordingly, there is a need to evaluate potential systemic contributors to HD mental distress, to support meaningful interventions for psychological symptoms in people with HD and affected families. We used short-form Problem Behaviors Assessment mental health symptom data from the international Enroll-HD data set to characterize mental health symptoms across eight HD groups: Stages 1-5, premanifest and genotype-negative individuals, and family controls (n=8567) using chi-square analysis with post hoc comparisons. We identified that people with later-stage HD (Stages 2-5) had significantly higher apathy, obsessive-compulsiveness, and (from Stage 3) disorientation than the remaining groups at a medium effect size, and that these findings largely held across three measure administrations over time. These findings highlight the critical symptoms in manifest HD from Stage 2 onward, but also demonstrate that crucial symptoms such as depression, anxiety, and irritability are present across HD-affected groups (including noncarriers of the gene expansion). The outcomes highlight a need for specific clinical management of later-stage HD psychological symptoms, and for systemic support across affected families.

Understanding the Relationship Between Perseveration, Comorbid Behavioral Symptoms, Motor Decline, Functional Decline, and Self-report Accuracy in Huntington Disease Can Help Inform Clinical Practice.

Perseveration is one of the most debilitating symptoms of Huntington disease (HD). To study perseveration and its relationship to comorbid behavioral symptoms, motor decline, functional decline, and subject self-report accuracy by analyzing cross-sectional data tracking individuals who have or are at risk for HD and healthy controls (HC). We studied 96 individuals from HD families and 35 HC who were either family controls or gene negative. We used χ2 tests to compare patient demographic and survey outcomes data and to analyze the presence of obsessions and compulsions (OC), depression, and apathy relative to the presence of perseveration. Individuals with HD and perseveration had a higher presence of OC, depression, and apathy compared with individuals with HD of the same stages without perseveration (19%, 47.6%, and 47.6% vs 15%, 40%, and 25%, respectively). In addition, individuals in HD Stages 1-3 with higher motor scores (showing a later stage of disease) displayed a significantly higher rate of perseveration than the HC (P = 0.0476; P = 0.0499, respectively). The presence of an informant resulted in a significantly higher rate of perseveration reporting for individuals in HD Stages 1 and 2 (41.2% and 53.8% with informant vs 23.5% and 11.1% without informant, respectively). Perseveration was seen across all motor and functional stages for the individuals with HD, without significant differences between the different stages. Additionally, informants were beneficial to obtaining accurate patient reports of perseveration. These findings should prove useful for physician evaluation and treatment considerations.

Layers of Loss: A Scoping Review and Taxonomy of HD Caregivers' Spiritual Suffering, Grief/Loss and Coping Strategies.

Huntington's disease (HD), an incurable, multi-generational, autosomal dominant disorder, creating unique challenges and a myriad of spiritually-related stressors in those affected and their familial caregivers. Spiritual suffering, experiences of grief/loss, and coping strategies have not been systematically studied in HD caregivers. To comprehensively define spiritual suffering, grief/loss, and coping strategies used by HD caregivers. A PRISMA-ScR scoping literature review was conducted. Data from included research articles were organized thematically using induction and open coding. A grounded, deductive approach was used to delineate a demarcated taxonomy of themes, which encompasses all three over-arching domains. Four reviewers, employing a modified Delphi approach, ascertained which themes were demonstrated by research participants in each study. 36 of 583 articles met the review criteria; none were published in the palliative care literature. Investigations primarily focused on intrapersonal (self-image) distress and existential angst; only rarely looked deeper into divine/transpersonal suffering, disrupted religious relationships, or meaning distress. HD caregivers experience profound grief/loss, expressed as disenfranchised grief that is associated with the ambiguous loss of their loved one, loss of family structure, social connectedness, and personal losses. Half of the studies reported maladaptive HD caregiver coping strategies-characterized by dysfunctional escape schemes; in contrast, transcendent/creative strategies were often unexplored. HD caregivers experience prolonged grief and other forms of spiritual suffering as they progressively lose their loved ones and disruption to their own lives. With an improved assessment tool, teams with spiritual and palliative care experts will better be able to support HD family caregivers.

Striving for a Realistic and Unapologetic View of Huntington's Disease.

This article describes how the author, a Huntington's disease (HD) gene expansion carrier and long-time advocate, has helped give voice to the HD community through his blog, At Risk for Huntington's Disease. Since 2005, the 321 articles have helped document the new and harrowing experience of living in the gray zone between a genetic test result and disease onset. At Risk for HD has explored major challenges for the HD community, has become a key reference for HD families, and has chronicled the quest to defeat the disease. This article analyzes the blog's thematic impact.

Spanish HTT gene study reveals haplotype and allelic diversity with possible implications for germline expansion dynamics in Huntington disease.

We aimed to determine the genetic diversity and molecular characteristics of the Huntington disease (HD) gene (HTT) in Spain. We performed an extended haplotype and exon one deep sequencing analysis of the HTT gene in a nationwide cohort of population-based controls (n = 520) and families with symptomatic individuals referred for HD genetic testing. This group included 331 HD cases and 140 carriers of intermediate alleles. Clinical and family history data were obtained when available. Spanish normal alleles are enriched in C haplotypes (40.1%), whereas A1 (39.8%) and A2 (31.6%) prevail among intermediate and expanded alleles, respectively. Alleles ≥ 50 CAG repeats are primarily associated with haplotypes A2 (38.9%) and C (32%), which are also present in 50% and 21.4%, respectively, of HD families with large intergenerational expansions. Non-canonical variants of exon one sequence are less frequent, but much more diverse, in alleles of ≥27 CAG repeats. The deletion of CAACAG, one of the six rare variants not observed among smaller normal alleles, is associated with haplotype C and appears to correlate with larger intergenerational expansions and early onset of symptoms. Spanish HD haplotypes are characterized by a high genetic diversity, potentially admixed with other non-Caucasian populations, with a higher representation of A2 and C haplotypes than most European populations. Differences in haplotype distributions across the CAG length range support differential germline expansion dynamics, with A2 and C showing the largest intergenerational expansions. This haplotype-dependent germline instability may be driven by specific cis-elements, such as the CAACAG deletion.

Haplotype-specific insertion-deletion variations for allele-specific targeting in Huntington's disease

Huntington's disease (HD) is a dominantly inherited neurodegenerative disease caused by an expanded CAG repeat in huntingtin (HTT). Given an important role for HTT in development and significant neurodegeneration at the time of clinical manifestation in HD, early treatment of allele-specific drugs represents a promising strategy. The feasibility of an allele-specific antisense oligonucleotide (ASO) targeting single-nucleotide polymorphisms (SNPs) has been demonstrated in models of HD. Here, we constructed a map of haplotype-specific insertion-deletion variations (indels) to develop alternative mutant-HTT-specific strategies. We mapped indels annotated in the 1000 Genomes Project data on common HTT haplotypes, revealing candidate indels for mutant-specific HTT targeting. Subsequent sequencing of an HD family confirmed candidate sites and revealed additional allele-specific indels. Interestingly, the most common normal HTT haplotype carries indels of big allele length differences at many sites, further uncovering promising haplotype-specific targets. When patient-derived cells carrying the most common HTT diplotype were treated with ASOs targeting the mutant alleles of candidate indels (rs772629195 or rs72239206), complete mutant specificity was observed. In summary, our map of haplotype-specific indels permits the identification of allele-specific targets in HD subjects, potentially contributing to the development of safe HTT-lowering therapeutics that are suitable for early treatment in HD.

Huntington's Disease Gene Hunters: An Expanding Tale.

Huntington's Disease Gene Hunters: An Expanding Tale.

Another Perspective on Huntington's Disease: Disease Burden in Family Members and Pre-Manifest HD When Compared to Genotype-Negative Participants from ENROLL-HD.

Background: In addition to the effects on patients suffering from motor-manifest Huntington’s disease (HD), this fatal disease is devasting to people who are at risk, premanifest mutation-carriers, and especially to whole families. There is a huge burden on people in the environment of affected HD patients, and a need for further research to identify at-risk caregivers. The aim of our research was to investigate a large cohort of family members, in comparison with genotype negative and premanifest HD in order to evaluate particular cohorts more closely. Methods: We used the ENROLL-HD global registry study to compare motoric, cognitive, functional, and psychiatric manifestation in family members, premanifest HD, and genotype negative participant as controls. Cross-sectional data were analyzed using ANCOVA-analyses in IBM SPSS Statistics V.28. Results: Of N = 21,116 participants from the global registry study, n = 5174 participants had a premanifest motor-phenotype, n = 2358 were identified as family controls, and n = 2640 with a negative HD genotype. Analysis of variance revealed more motoric, cognitive, and psychiatric impairments in premanifest HD (all p < 0.001). Self-reported psychiatric assessments revealed a significantly higher score for depression in family controls (p < 0.001) when compared to genotype negative (p < 0.001) and premanifest HD patients (p < 0.05). Family controls had significantly less cognitive capacities within the cognitive test battery when compared to genotype negative participants. Conclusions: Within the largest cohort of HD patients and families, several impairments of motoric, functional, cognitive, and psychiatric components can be confirmed in a large cohort of premanifest HD, potentially due to prodromal HD pathology. HD family controls suffered from higher self-reported depression and less cognitive capacities, which were potentially due to loaded or stressful situations. This research aims to sensitize investigators to be aware of caregiver burdens caused by HD and encourage support with socio-medical care and targeted psychological interventions. In particular, further surveys and variables are necessary in order to implement them within the database so as to identify at-risk caregivers.

Neurobiological and Psychosocial Correlates of Communication Between Huntington's Disease Patients and Their Offspring.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that presents significant challenges to family communication. The investigators examined observations of communication between parents with HD and their offspring talking about the challenges of HD and explored potential correlates of their communication. The sample included parents with HD and their adolescent and young-adult offspring (N=64). Parent communication and chorea were independently coded from video recordings. Parents and offspring completed working memory assessments and self-reports of neuropsychiatric symptoms, stress, and coping. Evidence was found for the association of observed parent-offspring communication with disease markers, psychosocial characteristics, and neurocognitive function. For parents, disease markers and working memory were correlates of communication, whereas offspring's psychiatric symptoms, stress, and coping were associated with their communication. These findings have potential implications for clinical interventions to enhance communication and quality of life for HD families.

Huntington's disease: nearly four decades of human molecular genetics.

Huntington's disease (HD) is a devastating neurogenetic disorder whose familial nature and progressive course were first described in the 19th century but for which no disease-modifying treatment is yet available. Through the active participation of HD families, this disorder has acted as a flagship for the application of human molecular genetic strategies to identify disease genes, understand pathogenesis and identify rational targets for development of therapies.

Generation of two induced pluripotent stem cell lines SPPHi001-A and SPPHi002-A from a Huntington's disease family of Southwestern China.

The Huntington's disease (HD) is still a devastating neurological disease without a specific cure. In this report, the peripheral blood mononuclear cells (PBMCs) from two members of a HD family from Southwestern China were reprogrammed into hiPSC lines by an episomal and non-integrating Sendai virus delivery method. The induced HD-hiPSC lines, SPPHi001-A and SPPHi002-A, were expanded and validated for their stem cell-like pluripotency, normal karyotyping, and capability of in vitro differentiation into three germ-layers. These newly generated HD hiPSC lines from Chinese HD patients enable us to further elucidate the mechanism of HD and discover its specific treatment.

Frequency of the loss of CAA interruption in the HTT CAG tract and implications for Huntington disease in the reduced penetrance range

PurposeIn some Huntington disease (HD) patients, the “loss of interruption” (LOI) variant eliminates an interrupting codon in the HTT CAG-repeat tract, which causes earlier age of onset (AOO). The magnitude of this effect is uncertain, since previous studies included few LOI carriers, and the variant also causes CAG size misestimation. We developed a rapid LOI detection screen, enabling unbiased frequency estimation among manifest HD patients. Additionally, we combined published data with clinical data from newly identified patients to accurately characterize the LOI’s effect on AOO. MethodsWe developed a LOI detection polymerase chain reaction (PCR) assay, and screened patients to estimate the frequency of the LOI variant and its effect on AOO. ResultsMean onset for LOI carriers (n=49) is 20.4 years earlier than expected based on diagnosed CAG size. After correcting for CAG size underestimation, the variant is still associated with onset 9.5 years earlier. The LOI is present in 1.02% of symptomatic HD patients, and in 32.2% of symptomatic reduced penetrance (RP) range patients (36–39 CAGs). ConclusionThe LOI causes significantly earlier onset, greater than expected by CAG length, particularly in persons with 36–39 CAG repeats. Detection of this variant has implications for HD families, especially for those in the RP range.

Management of information within Portuguese families with Huntington disease: a transgenerational process for putting the puzzle together.

Huntington disease (HD) is a rare progressive neurological disease, with no cure, inherited in an autosomal dominant fashion, significantly impacting family relations, health and well-being. So far, no studies have reported how Portuguese families deal with information about HD, from a transgenerational perspective. This qualitative study aims to fill in that gap, and focuses on how families acquire knowledge about HD and management of information within the family and in their social relationships. The study adopted semi-structured interviews with 10 participants from HD families. Interviews were transcribed and analysed thematically. Findings suggested that management of information in the family started with the search for a diagnosis in an affected family member. Diagnosis led to a process of “making sense of HD in the family”, which activated a transgenerational process to understand HD in the family context, marked by improved awareness and different ways family members manage it (closedness and openness). These results should be relevant for health-care professionals, bringing further insight into the process of acquiring knowledge about HD, and highlighting the relevance of continued efforts for enhanced pre- and post-test counselling and ongoing support to the HD families.

Addressing the Value of Multidisciplinary Clinical Care in Huntington's Disease: A Snapshot of a New Huntington's Disease Center.

Clinical care for Huntington's disease (HD) is often provided in experienced centers that provide multidisciplinary care. However, the value of these centers and their uptake by HD families remain unknown. To describe the services provided by a new HD center, including estimates of capture of the population served. Retrospective review of a HD Center launched in 2015, including quantitative and qualitative data on clinic visits, demographic and clinical data. We observed a rapid and ongoing growth on the annual number of clinic encounters, with high demand for in-clinic multidisciplinary care. Using census data and estimates of HD prevalence, we determined that we served about 20% of local patients with HD. Most HD patients received pharmacological treatment for psychiatric symptoms, and over half were treated for chorea. About 25% of new HD diagnoses were on patients without family history of HD. Finally, the demand for predictive testing in at risk individuals significantly increased following the press release reporting the successful completion of the Ionis-HTTRx (RG 6042) trial. This report indicates a high demand for multidisciplinary care by HD families, supporting its value, providing a snapshot of the organization and function of a single center. Furthermore, it demonstrates how dissemination of news related to research advances influence clinical behavior. Reporting similar information from other HD centers to would provide us with a more global view of the status of HD care across multiple geographical areas.

Quality of Care for Huntington’s Disease in the United States: Findings from a National Survey of Patients and Caregivers

Little is known about the quality of care for people living with Huntington's disease (HD) in the United States. To document the current HD care experience and identify gaps in care provision in the United States. Web-based surveys for persons self-identifying as being affected by HD (PAHD, which included individuals with, or at risk for HD) or as caregivers/family members, were developed and refined with targeted input from focus groups comprised of caregivers and family members. The surveys were disseminated via social media and patient advocacy partners from April-May 2017. Total valid responses numbered 797, including 585 caregiver/family respondents and 212 PAHD responses. Respondents reported care provision from HD specialty centers, primary care, movement disorder clinics, and other settings. One in five respondents reported that the person with HD was not currently receiving medical or community care. Respondents generally reported a good level of care, with HD specialists providing the highest rated healthcare experience. Caregiver/family respondents reported helping with a range of activities including budget/finances (60.5%), housekeeping (57.1%) and daily help (53.2%). Most respondents (97.9%) reported searching online, including general information about HD (86.4%), using HD social media channels (61.3%) and looking up clinical trials (59.8%). Respondents emphasized a need for support in financial planning and accessing care, and also for more HD education in the medical community. There is need for more support for HD patients and families. People desire more credible, accessible information. Improving resources available to patients and families should be a goal for HD organizations, along with measurement of patient outcomes.