Generation of two human iPSC lines from dermal fibroblasts of adult- and juvenile-onset Huntington's disease patients and two healthy donors.

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease caused by a mutation in the HTT gene. To generate human-induced pluripotent stem cells (hiPSCs), we used dermal fibroblasts from 1 healthy adult control (K-Pic2), 1 HD manifest patient (M-T2), 1 healthy juvenile control (jK-N1), and 1 juvenile HD patient (jHD-V1). HD stage of patients was assessed by neurological tests and donors were without comorbidities and were non-smokers. Characterization showed that the obtained hiPSCs have the same number of CAG repeats as the parental fibroblast lines, express pluripotency markers and have the ability to differentiate into all 3 germ layers.

Establishing normative data for the evaluation of cognitive performance in Huntington's disease considering the impact of gender, age, language, and education.

BACKGROUND: A declining cognitive performance is a hallmark of Huntington's disease (HD). The neuropsychological battery of the Unified HD Rating Scale (UHDRS'99) is commonly used for assessing cognition. However, there is a need to identify and minimize the impact of confounding factors, such as language, gender, age, and education level on cognitive decline. OBJECTIVES: Aim is to provide appropriate, normative data to allow clinicians to identify disease-associated cognitive decline in diverse HD populations by compensating for the impact of confounding factors METHODS: Sample data, N = 3267 (60.5% females; mean age of 46.9 years (SD = 14.61, range 18-86) of healthy controls were used to create a normative dataset. For each neuropsychological test, a Bayesian generalized additive model with age, education, gender, and language as predictors was constructed to appropriately stratify the normative dataset. RESULTS: With advancing age, there was a non-linear decline in cognitive performance. In addition, performance was dependent on educational levels and language in all tests. Gender had a more limited impact. Standardized scores have been calculated to ease the interpretation of an individual's test outcome. A web-based online tool has been created to provide free access to normative data. CONCLUSION: For defined neuropsychological tests, the impact of gender, age, education, and language as factors confounding disease-associated cognitive decline can be minimized at the level of a single patient examination.

Speech biomarkers in Huntington's disease: A cross-sectional study in pre-symptomatic, prodromal and early manifest stages.

BACKGROUND AND PURPOSE: Motor speech alterations are a prominent feature of clinically manifest Huntington's disease (HD). Objective acoustic analysis of speech can quantify speech alterations. It is currently unknown, however, at what stage of HD speech alterations can be reliably detected. We aimed to explore the patterns and extent of speech alterations using objective acoustic analysis in HD and to assess correlations with both rater-assessed phenotypical features and biological determinants of HD. METHODS: Speech samples were acquired from 44 premanifest (29 pre-symptomatic and 15 prodromal) and 25 manifest HD gene expansion carriers, and 25 matched healthy controls. A quantitative automated acoustic analysis of 10 speech dimensions was performed. RESULTS: Automated speech analysis allowed us to differentiate between participants with HD and controls, with areas under the curve of 0.74 for pre-symptomatic, 0.92 for prodromal, and 0.97 for manifest stages. In addition to irregular alternating motion rates and prolonged pauses seen only in manifest HD, both prodromal and manifest HD displayed slowed articulation rate, slowed alternating motion rates, increased loudness variability, and unstable steady-state position of articulators. In participants with premanifest HD, speech alteration severity was associated with cognitive slowing (r = -0.52, p < 0.001) and the extent of bradykinesia (r = 0.43, p = 0.004). Speech alterations correlated with a measure of exposure to mutant gene products (CAG-age-product score; r = 0.60, p < 0.001). CONCLUSION: Speech abnormalities in HD are associated with other motor and cognitive deficits and are measurable already in premanifest stages of HD. Therefore, automated speech analysis might represent a quantitative HD biomarker with potential for assessing disease progression.

Quality of life, health-related quality of life, and associated factors in Huntington's disease: a systematic review.

BACKGROUND: Huntington's disease (HD) is a genetic, neurodegenerative disease. Due to the progressive nature of HD and the absence of a cure, (health-related) quality of life ((HR)QoL) is an important topic. Several studies have investigated (HR)QoL in HD, yet a clear synthesis of the existing literature is lacking to date. We performed a systematic review on self-reported (HR)QoL, and factors and intervention effects associated with (HR)QoL in premanifest and manifest HD gene expansion carriers (pHDGECs and mHDGECs, respectively). METHODS: PubMed, EMBASE, Web of Science, and PsycINFO were searched systematically from September 17th, 2021, up to August 11th, 2022. Methodological and conceptual quality of the included studies was assessed with two appraisal tools. RESULTS: 30 out of 70 eligible articles were included. mHDGECs experienced lower (HR)QoL compared to pHDGECs and controls, whereas mixed findings were reported when compared to other neurological diseases. Several factors were associated with (HR)QoL that might contribute to lower (HR)QoL in mHDGECs, including depressive symptoms, physical and psychological symptoms, lower functional capacity, lower support, and unmet needs. Multidisciplinary rehabilitation programs and a respiratory muscle training were beneficial for (HR)QoL in mHDGECs. DISCUSSION: (HR)QoL is experienced differently across the course of the disease. Although (HR)QoL is key for understanding the impact of HD and the effect of symptomatic treatment, there is a need to improve the methodological and conceptual shortcomings that were found in most studies, especially regarding the conceptual clarity when reporting on QoL and HRQoL. Suggestions for strengthening these shortcomings are provided in this review.

Psychosocial Impact of Huntington's Disease and Incentives to Improve Care for Affected Families in the Underserved Region of the Slovak Republic.

INTRODUCTION: Huntington's disease (HD) is often on the margin of standard medical practice due to its low prevalence, the lack of causal treatment, and the typically long premanifest window prior to the onset of the symptoms, which contrasts with the long-lasting burden that the disease causes in affected families. METHODS: To capture these socio-psychological aspects of HD and map the experiences of affected individuals, persons at risk of HD, and caregivers, we created a questionnaire using a qualitative research approach. The questionnaire containing 16 questions was conducted online for a period of three months through patient associations in Slovakia and their infrastructures. RESULTS: In total, we received 30 responses. The survey results, in particular, indicate insufficient counselling by physicians with explicitly missing information about the possibility of preimplantation genetic diagnostic. There was also a necessity to improve comprehensive social and health care in the later stages of the disease, raise awareness of the disease in the general health community, and provide more information on ongoing clinical trials. CONCLUSION: The psychosocial effects, as well as the burden, can be mitigated by comprehensive genetic counselling as well as reproductive and financial guidelines and subsequent therapeutic programs to actively support patients, caregivers, children, and adolescents growing up in affected families, preferably with the help of local HD community association. LIMITATIONS: We have used online data collection to reach a wider HD community, but at the same time, we are aware that the quality of the data we would obtain through face-to-face interviews would be considerably better. Therefore, future studies need to be conducted to obtain more detailed information.

Generation of three human iPSC lines from patients with Huntington's disease with different CAG lengths and human control iPSC line from a healthy donor.

Huntington's disease (HD) is a progressive neurodegenerative disorder with autosomal-dominant heritability that affect the central nervous system and peripheral tissues. The human-induced pluripotent stem cells (hiPSC) lines were generated from dermal fibroblasts of patients without comorbidities, non-smokers, at the pre-manifest (IIMCBi004-A), early-manifest (IIMCBi005-A), and manifest (IIMCBi006-A) HD stage assessed by neurological tests, as well as from a healthy donor (IIMCBi003-A). Characterization showed that the obtained hiPSC lines contained different CAG repeats consistent with the number of CAG repeats in original fibroblasts. Moreover, hiPSCs expressed pluripotency markers and were able to differentiate into three-germ layers in vitro.

[Disease-modifying treatment approaches in Huntington disease : Past and future]. / Krankheitsmodifizierende Therapieansätze bei der Huntington-Krankheit : Blicke zurück und Blicke voraus.

Huntington disease (HD) is the most frequent monogenetic neurodegenerative disease and can be unequivocally diagnosed even in the preclinical stage, at least in all individuals in whom the CAG expansion mutation in the huntingtin gene (HTT) is in the range of full penetrance. Therefore, important preconditions for an intervention early in the disease process are met, rendering modification of the course of the disease in a clinically meaningful way possible. In this respect, HD can be viewed as a model disorder for exploring neuroprotective treatment approaches. In the past emphasis was placed on the compensation of a suspected neurotransmitter deficit (GABA) analogous to Parkinson's disease and on classical neuroprotective strategies to influence hypothetical common pathways in neurodegenerative diseases (e.g., excitotoxicity, mitochondrial dysfunction, oxidative stress). With the discovery of the causative HTT mutation in 1993, therapeutic research increasingly focused on intervening as proximally as possible in the chain of pathophysiological events. Currently, an important point of intervention is the HTT mRNA with the aim of reducing the continued production of mutant huntingtin gene products and thus relieving the body of their detrimental actions. To this end, various treatment modalities (single-stranded DNA and RNA, divalent RNA and zinc finger repressor complexes, orally available splice modulators) were developed and are currently in clinical trials (phases I-III) or in late stages of preclinical development. In addition, there is the notion that it may be possible to modify the length of the somatically unstable CAG mutation, i.e. its increase in the brain during the lifetime, thereby slowing the progression of HD.

Enroll-HD: An Integrated Clinical Research Platform and Worldwide Observational Study for Huntington's Disease.

Established in July 2012, Enroll-HD is both an integrated clinical research platform and a worldwide observational study designed to meet the clinical research requirements necessary to develop therapeutics for Huntington's disease (HD). The platform offers participants a low-burden entry into HD research, providing a large, well-characterized, research-engaged cohort with associated clinical data and biosamples that facilitates recruitment into interventional trials and other research studies. Additional studies that use Enroll-HD data and/or biosamples are built into the platform to further research on biomarkers and outcome measures. Enroll-HD is now operating worldwide in 21 countries at 159 clinical sites across four continents-Europe, North America, Latin America, and Australasia-and has recruited almost 25,000 participants, generating a large, rich clinical database with associated biosamples to expedite HD research; any researcher at a verifiable research organization can access the clinical datasets and biosamples from Enroll-HD and nested studies. Important operational features of Enroll-HD include a strong emphasis on standardization, data quality, and protecting participant identity, a single worldwide study protocol, a flexible EDC system capable of integrating multiple studies, a comprehensive monitoring infrastructure, an online portal to train and certify site personnel, and standardized study documents including informed consent forms and contractual agreements.

Study Protocol for the Development of a European eHealth Platform to Improve Quality of Life in Individuals With Huntington's Disease and Their Partners (HD-eHelp Study): A User-Centered Design Approach.

Background: Huntington's disease (HD) is an autosomal dominant neurodegenerative disease that affects the quality of life (QoL) of HD gene expansion carriers (HDGECs) and their partners. Although HD expertise centers have been emerging across Europe, there are still some important barriers to care provision for those affected by this rare disease, including transportation costs, geographic distance of centers, and availability/accessibility of these services in general. eHealth seems promising in overcoming these barriers, yet research on eHealth in HD is limited and fails to use telehealth services specifically designed to fit the perspectives and expectations of HDGECs and their families. In the European HD-eHelp study, we aim to capture the needs and wishes of HDGECs, partners of HDGECs, and health care providers (HCPs) in order to develop a multinational eHealth platform targeting QoL of both HDGECs and partners at home. Methods: We will employ a participatory user-centered design (UCD) approach, which focusses on an in-depth understanding of the end-users' needs and their contexts. Premanifest and manifest adult HDGECs (n = 76), partners of HDGECs (n = 76), and HCPs (n = 76) will be involved as end-users in all three phases of the research and design process: (1) Exploration and mapping of the end-users' needs, experiences and wishes; (2) Development of concepts in collaboration with end-users to ensure desirability; (3) Detailing of final prototype with quick review rounds by end-users to create a positive user-experience. This study will be conducted in the Netherlands, Germany, Czech Republic, Italy, and Ireland to develop and test a multilingual platform that is suitable in different healthcare systems and cultural contexts. Discussion: Following the principles of UCD, an innovative European eHealth platform will be developed that addresses the needs and wishes of HDGECs, partners and HCPs. This allows for high-quality, tailored care to be moved partially into the participants' home, thereby circumventing some barriers in current HD care provision. By actively involving end-users in all design decisions, the platform will be tailored to the end-users' unique requirements, which can be considered pivotal in eHealth services for a disease as complex and rare as HD.

Validation Study of a German Cognitive Battery for Huntington's Disease: Relationship Between Cognitive Performance, Functional Decline, and Disease Burden.

OBJECTIVE: Cognitive decline is a key characteristic of Huntington's disease (HD). This study aimed to investigate the diagnostic accuracy of a cognitive battery with six tests used by most HD research centers to assess cognitive impairment in HD. METHOD: In total, 106 HD patients in different disease stages with more (HD-CD, N = 30) and less cognitive impairments (HD-NC, N = 70) and 100 healthy controls (NC) were matched by age, sex, and education and were examined using a standardized protocol including cognitive, motor, and functional assessments. RESULTS: One-way between-groups analysis of variance showed that controls performed significantly better than HD patients and that HD-NC significantly outperformed HD-CD patients in all cognitive tests (NC > HD-NC > HD-CD), with all Games-Howell post-hoc tests p < .001. Analyses using area under the receiver-operating characteristic curve (AUC) disclosed the diagnostic accuracy of all tests included in the battery to discriminate between NC and HD patients with AUC ranging from 0.809 to 0.862 (all p < .001) and between HD-CD and HD-NC patients with AUC ranging from 0.833 to 0.899 (all p < .001). In both analysis, Stroop Color Naming Test showed the highest discriminative potential. Additional analyses showed that cognitive deficits in all domains progressed with disease duration. Moreover, cognitive performance correlated with the severity of motor and functional impairment (all p < .001) and with the Disease Burden Score regardless of disease duration and age. CONCLUSION: Our results indicate that the cognitive battery is a suitable tool for assessing cognitive impairment in HD.

Identification of two compound heterozygous VPS13A large deletions in chorea-acanthocytosis only by protein and quantitative DNA analysis.

BACKGROUND: Chorea-acanthocytosis (ChAc; OMIM #200150) is a rare autosomal recessive condition with onset in early adulthood that is caused by mutations in the vacuolar protein sorting 13A (VPS13A) gene encoding chorein. Several diagnostic genomic DNA (gDNA) sequencing approaches are widely used. However, their limitations appear not to be acknowledged thoroughly enough. METHODS: Clinically, we deployed magnetic resonance imaging, blood smear analysis, and clinical chemistry for the index patient's characterization. The molecular analysis of the index patient next to his parents covered genomic DNA (gDNA) sequencing approaches, RNA/cDNA sequencing, and chorein specific Western blot. RESULTS: We report a 33-year-old male patient without functional protein due to compound heterozygosity for two VPS13A large deletions of 1168 and 1823 base pairs (bp) affecting, respectively, exons 8 and 9, and exon 13. To our knowledge, this represents the first ChAc case with two compound heterozygous large deletions identified so far. Of note, standard genomic DNA (gDNA) Sanger sequencing approaches alone yielded false negative findings. CONCLUSION: Our case demonstrates the need to carry out detection of chorein in patients suspected of having ChAc as a helpful and potentially decisive tool to establish diagnosis. Furthermore, the course of the molecular analysis in this case discloses diagnostic pitfalls in detecting some variations, such as deletions, using only standard genomic DNA (gDNA) Sanger sequencing approaches and exemplifies alternative methods, such as RNA/cDNA sequencing or qRT-PCR analysis, necessary to avoid false negative results.