Onset Of Huntington's Disease Research Articles

Investigation of the Influence of TBP CAG/CAA Repeats in Conjunction with HTT CAG Repeats on Huntington's Disease Age at Onset in a Brazilian Sample.

Huntington's disease (HD) is a genetic neurodegenerative progressive and fatal disease characterized by motor disorder, cognitive impairment, and behavioral problems, caused by expanded repeats of CAG trinucleotides in the HTT gene. The aim of this study was to investigate the influence of TBP gene CAG/CAA repeats in conjunction with HTT gene CAG repeats, on the age at HD onset in Brazilian individuals. Individuals diagnosed as molecularly negative for HD presented 29-39 TBP CAG/CAA. Their most frequent allele had 36 repeats. In individuals diagnosed as molecularly positive for HD, a range of 25-40 TBP CAG/ CAA was found. The most frequent TBP allele had 38 repeats. We also conducted TBP direct Sanger sequencing of some samples which demonstrated other four TBP structures different from the basic TBP structure and others reported in the literature. The HTT expanded CAG and TBP CAG/CAA repeat sizes jointly explained 66% of the age at onset (AO) in our HD patients. The strongest variable in the model associated with AO was the number of expanded HTT CAG repeats. The difference between the association of HD AO with HTT expanded CAG together with TBP CAG/CAA and the association of HD AO with HTT expanded CAG was 0.001 (∆R2). Therefore, we found a weak association (0.1%) of TBP CAG/CAA repeats on HD AO, if any.

Effect of Ayurvedic interventions as add-on therapy in Huntington's disease: A case report

Huntington's disease (HD) is a rare autosomal dominant neurodegenerative disorder. It is caused due to trinucleotide cytosine-adenine-guanine (CAG) repeat expansion on chromosome 4. The greater the CAG repeat size, the earlier the onset of the disease. It is characterized by motor, cognitive, and psychiatric symptoms. The onset of Juvenile HD occurs before the age of 21 and is rarer compared to adult-onset HD. A 30-year-old female, diagnosed with HD by molecular genetic analysis and magnetic resonance imaging, presented to Ayurveda hospital with chief complaints of abnormal involuntary movements in both the limbs bilaterally, difficulty in walking without support, difficulty in speech, swallowing, episodes of anger outbursts, and hard stools. The Ayurvedic treatment protocol was planned with a course of Nasya (~medication through nasal route), Basti (~medicated enema), and Abhyanga (~therapeutic oleation). Shashtika Shali Pinda Sweda (~sudation by application of poultice with rice), Shiropichu (~therapeutic procedure of placing tampon with oil over head region), and Karnapurana (~filling of ear with medicated liquid) along with internal medications which had Balya (~strength promoting), Brimhana (~restorative measures), Agni balavardhana (~enhancing digestive fire), Rechana (~cleansing), Rasayana (~rejuvenation therapy), and Vatahara (~Vata pacifying) actions were also adopted. By the completion of treatment, improvement was noticed in terms of reduced involuntary movements, better balance while standing, and reduced frequency of falls. Assessment by Abnormal Involuntary Movements Scale showed a reduction from score 30 to 18 after treatment, inferring that Ayurvedic therapies can help in betterment of patients affected with HD.

Longer CAG repeat length is associated with shorter survival after disease onset in Huntington disease

It is well known that the length of the CAG trinucleotide expansion of the huntingtin gene is associated with many aspects of Huntington disease progression. These include age of clinical onset and rate of initial progression of disease severity. The relationship between CAG length and survival in Huntington disease is less studied. To address this, we obtained the complete Registry HD database from the European Huntington Disease Network and reanalyzed the time from reported age of disease onset until death. We conducted semiparametric proportional hazards modeling of 8,422 participants who had experienced onset of clinical Huntington disease, either retrospectively or prospectively. Of these, 826 had a recorded age of death. To avoid biased model estimates, retrospective onset ages were represented by left truncation at study entry. After controlling for onset age, which tends to be younger in those with longer CAG repeat lengths, we found that CAG length had a substantial and highly significant influence upon survival time after disease onset. For a fixed age of onset, longer CAG expansions were predictive of shorter survival. This is consistent with other known relationships between CAG length and disease severity. We also show that older onset age predicts shorter lifespan after controlling for CAG length and that the influence of CAG on survival length is substantially greater in women. We demonstrate that apparent contradictions between these and previous analyses of the same data are primarily due to the question of whether to control for clinical onset age in the analysis of time until death.

Huntington's Disease Gene Hunters: An Expanding Tale.

Huntington's Disease Gene Hunters: An Expanding Tale.

Clinical progression over 2 years of 220 patients with late onset Huntington's disease

Late onset Huntington's disease (LoHD) occurring in tardive adulthood (≥ 60 years) is recently gaining attention. We examined LoHD patients' clinical, cognitive and behavioral data over 2 years to investigate disease progression.

DIAPHRAGMATIC CHOREA IN A PATIENT WITH HUNTINGTON'S DISEASE: A CASE REPORT

TOPIC: Pulmonary Physiology TYPE: Fellow Case Reports INTRODUCTION: Respiratory muscle weakness is known to occur in neurodegenerative disorders, including Huntington's disease (HD), and causes 25% of deaths in this population. Though diaphragmatic dystonia has been described in some neurodegenerative diseases, it has not been in HD. In general, little published data exists on overall respiratory function and diaphragmatic movement in HD. CASE PRESENTATION: We describe a 58-year-old male with HD, presenting with progressive dyspnea over 1 year and an accompanying choking sensation upon awakening. Cardiac evaluation with echocardiogram and dobutamine stress test revealed only left ventricular hypertrophy. Family history includes HD in his mother, diagnosed at autopsy age 72;an older brother with HD onset at 53 that died at 62;a maternal aunt with onset in her 50s that died in her 70s. His maternal grandmother and 2 other family members also had involuntary movements believed to be chorea. Most died from respiratory complications. Physical exam showed adequate air entry bilaterally, with clear breath sounds and decreased chest wall expansion. No abdominal paradox or diaphragm dysfunction was appreciated in supine or seated position. On walking oximetry, he became tachypneic and dyspneic after 2 minutes of walking, prompting him to stop. His saturation on room air did not drop below 96%. Heart rate increased to 110 beats per minute. Laboratory panel revealed hemoglobin 13.8 g/dl. A venous blood gas revealed pH 7.38 and pCO2 of 49.A dynamic digital chest radiography (DDR) was performed during two tidal breaths and a forced inspiratory and expiratory maneuver. This revealed decreased bilateral lung inflation. Diaphragmatic contours were elevated bilaterally with a mildly reduced excursion. During the breathing cycle multiple independent diaphragmatic contractions were appreciated on forced inspiration and exhalation resulting in paradoxical motion and dyssynchrony. There was exaggerated use of accessory muscles in the shoulder girdle as a compensatory mechanism. Spasms in the upper airway were also noted throughout the test. Because of covid restrictions, the patient is awaiting pulmonary function tests. DISCUSSION: DDR uniquely provides the opportunity to interrogate respiratory physiology and identify diaphragmatic abnormalities, such as coordination impairments and dyssynchrony compared to static chest radiography;with lower levels of radiation as used in video fluoroscopy. As previously described1, we suggest that the understanding of dyspnea in patients with neurologic disease is enhanced using DDR. CONCLUSIONS: We report the first case of diaphragmatic chorea in a patient with HD using DDR. Future studies are needed to better understand this newly recognized phenomenon of diaphragmatic discoordination and its association with shortness of breath. REFERENCE #1: O'Sullivan M, Singh A, Prime D, Moore J, Zink S. A Whole New Chest X-Ray. ATS 2019 ePoster Viewing Site. Published May 2019. Accessed April 28, 2021. https://cslide-us.ctimeetingtech.com/ats2019_eposter/attendee/eposter/poster/6529 DISCLOSURES: No relevant relationships by Norma Braun, source=Web Response No relevant relationships by Jose Concepcion, source=Web Response No relevant relationships by Natasha Garg, source=Web Response No relevant relationships by Mary O Sullivan, source=Web Response No relevant relationships by Valeria Santibanez, source=Web Response

Sleep disturbances by disease type and stage in Huntington's disease

IntroductionSleep disturbances are a common symptom in patients with Huntington's disease (HD). However, it is unclear when in the disease course of HD sleep disturbances become more frequent compared to the general population. This study investigated the frequency and odds of developing sleep disturbances between adults with HD or at-risk for HD and non-HD controls. MethodsParticipants from the Enroll-HD study were split by both disease type and disease severity using CAG length, diagnostic confidence level, and total functional capacity score. Multivariate logistic regression was used to calculate odds ratios adjusted for age, sex, tobacco and alcohol use, depression and psychosis scores, and cognition to compare HD groups to non-HD controls. Cox proportional hazards models and Kaplan Meier curves were used to determine differences in probabilities of developing sleep disturbances and how sleep disturbances are related to age at motor onset. ResultsThere were significant differences between HD participants and non-HD controls in both the disease type and disease stage analyses (p < 0.001). The odds of a sleep disturbance increased with worsening disease stage and was highest in those with juvenile HD. The development of a sleep disorder in manifest HD participants was observed to be around the time of disease onset. ConclusionsSleep disturbances are more frequent in HD patients than those without HD. There are also differences based on disease type and stage. This is supplemented by the finding that the onset of sleep disturbances occurs near the time of motor onset of HD.

Mutant Huntingtin Impairs Pancreatic β-cells by Recruiting IRS-2 and Disturbing the PI3K/AKT/FoxO1 Signaling Pathway in Huntington's Disease.

Patients with Huntington's disease (HD) have an increased incidence of diabetes. However, the molecular mechanisms of pancreatic β-cell dysfunction have not been entirely clarified. Revealing the pathogenesis of diabetes can provide a novel understanding of the onset and progression of HD, as well as potential clues for the development of new therapeutics. Here, we demonstrated that the mouse pancreatic insulinoma cell line NIT-1 expressing N-terminal mutant huntingtin (mHTT) containing 160 polyglutamine (160Q cells) displayed lower cell proliferative ability than the cells expressing N-terminal wild-type HTT containing 20 polyglutamine (20Q cells). In addition, 160Q cells were more prone to apoptosis and exhibited deficient glucose-stimulated insulin expression and secretion. Furthermore, insulin signaling molecule insulin receptor substrate 2 (IRS-2) expression decreased and was recruited into mHTT aggregates. Consequently, glucose stimulation failed to activate the downstream molecule phosphatidylinositol-3 kinase (PI3K) in 160Q cells, leading to reduced phosphorylation levels of serine-threonine protein kinase AKT and forkhead box protein O1 (FoxO1). These data indicate that activation of the glucose-stimulated PI3K/AKT/FoxO1 signaling pathway is significantly blocked in pancreatic β-cells in HD. Importantly, insulin treatment inhibited the aggregation of mHTT and significantly improved the activation of PI3K/AKT/FoxO1 signaling in 160Q cells. These results suggest that the inhibition of the PI3K/AKT/FoxO1 pathway might be due to the recruitment of IRS-2 into mHTT aggregates in HD β-cells, ultimately contributing to the impairment of pancreatic β-cells. In conclusion, our work provides new insight into the underlying mechanisms of the high incidence of diabetes and abnormal glucose homeostasis in HD.

Mild Cognitive Impairment as an Early Landmark in Huntington's Disease.

As one of the clinical triad in Huntington's disease (HD), cognitive impairment has not been widely accepted as a disease stage indicator in HD literature. This work aims to study cognitive impairment thoroughly for prodromal HD individuals with the data from a 12-year observational study to determine whether Mild Cognitive Impairment (MCI) in HD gene-mutation carriers is a defensible indicator of early disease. Prodromal HD gene-mutation carriers evaluated annually at one of 32 worldwide sites from September 2002 to April 2014 were evaluated for MCI in six cognitive domains. Linear mixed-effects models were used to determine age-, education-, and retest-adjusted cut-off values in cognitive assessment for MCI, and then the concurrent and predictive validity of MCI was assessed. Accelerated failure time (AFT) models were used to determine the timing of MCI (single-, two-, and multiple-domain), and dementia, which was defined as MCI plus functional loss. Seven hundred and sixty-eight prodromal HD participants had completed all six cognitive tasks, had MRI, and underwent longitudinal assessments. Over half (i.e., 54%) of the participants had MCI at study entry, and half of these had single-domain MCI. Compared to participants with intact cognitive performances, prodromal HD with MCI had higher genetic burden, worsened motor impairment, greater brain atrophy, and a higher likelihood of estimated HD onset. Prospective longitudinal study of those without MCI at baseline showed that 48% had MCI in subsequent visits and data visualization suggested that single-domain MCI, two-domain MCI, and dementia represent appropriate cognitive impairment staging for HD gene-mutation carriers. Findings suggest that MCI represents an early landmark of HD and may be a sensitive enrichment variable or endpoint for prodromal clinical trials of disease modifying therapeutics.

Effect of Body Weight on Age at Onset in Huntington Disease: A Mendelian Randomization Study.

ObjectiveWeight loss is associated with clinical progression in Huntington disease (HD), but whether body weight causally affects disease onset or progression is unknown. Therefore, we aimed to assess whether genetically determined variations in body weight are causally related to age at onset in HD.MethodsUsing data from different recent genome-wide association studies, we performed a 2-sample mendelian randomization (MR) analysis to assess whether genetic markers of body mass index (BMI) are causally related to residual age at onset in HD, i.e., the difference between observed and expected age at onset based on mutation size. Our study had a statistical power of 90% to detect a causal effect of ≥3.8 months per BMI unit change at a type I error rate of 0.05.ResultsInverse-variance weighted MR estimates showed that a higher genetically determined BMI was not causally related to residual age at onset in HD (β = −0.44 years per unit increase in BMI, confidence interval: −1.33 to 0.46, p = 0.34). All other complementary (nonparametric) MR regression methods yielded similar results.ConclusionsAlthough maintaining a healthy and stable body weight remains important in patients with HD, promoting weight gain with the aim of delaying disease onset or slowing down disease progression should be discouraged. Our findings point toward the existence of underlying pathologic processes that dictate both the rate of clinical progression and weight loss in HD, which need further elucidation as targeting these pathways, rather than body weight per se, could be of therapeutic value.

Robust Optimization and Data Classification for Characterization of Huntington Disease Onset via Duality Methods

The features that characterize the onset of Huntington disease (HD) are poorly understood yet have significant implications for research and clinical practice. Motivated by the need to address this issue, and the fact that there may be inaccuracies in clinical HD data, we apply robust optimization and duality techniques to study support vector machine (SVM) classifiers in the face of uncertainty in feature data. We present readily numerically solvable semi-definite program reformulations via conic duality for a broad class of robust SVM classification problems under a general spectrahedron uncertainty set that covers the most commonly used uncertainty sets of robust optimization models, such as boxes, balls, and ellipsoids. In the case of the box-uncertainty model, we also provide a new simple quadratic program reformulation, via Lagrangian duality, leading to a very efficient iterative scheme for robust classifiers. Computational results on a range of datasets indicate that these robust classification methods allow for greater classification accuracies than conventional support vector machines in addition to selecting groups of highly correlated features. The conic duality-based robust SVMs were also successfully applied to a new, large HD dataset, achieving classification accuracies of over 95% and providing important information about the features that characterize HD onset.

It Is Time to Define Huntington's Disease Onset more Clearly.

It Is Time to Define Huntington's Disease Onset more Clearly.

Central Cognitive Processing Speed Is an Early Marker of Huntington's Disease Onset.

Several studies have suggested that cognitive processing speed may be useful for assessing early cognitive change in premanifest Huntington's disease (HD); however, current measures lack the ability to control for the effects of motor dysfunction commonly found in HD. The Computerized Test of Information Processing (CTiP) is a rapidly administered computerized tool that allows for the examination of central cognitive processing speed by using motor-corrected scores to account for motor dysfunction. To examine central cognitive processing speed as an early marker of HD onset using the CTiP. The CTiP and other measures were administered to 102 HD gene carriers and 55 healthy adults (HA). Gene carriers included presymptomatic HD (pre-HD; n = 33), prodromal HD (pro-HD; ie, individuals close to disease onset; n = 23), and mild-moderate HD (HD; n = 46). The HD group performed significantly slower than all other groups (HA, pre-HD, and pro-HD) on most subtests (Ps < .05). Moreover, the pro-HD group performed significantly slower than the HA group on both motor-corrected subtests (Ps < 0.05). Effect sizes associated with significant group differences between the pro-HD and HA groups on motor-corrected CTiP subtests (d = 0.73 and 0.84) were similar to effect sizes associated with group differences on the Symbol Digit Modalities Test (d = .82) and other traditional cognitive assessments (Montreal Cognitive Assessment, d = .75; Mini-Mental State Examination, d = .84). The CTiP may be a useful marker of deficits in central cognitive processing speed in individuals close to manifest onset of HD.

The Role of the Cerebellum in Huntington's Disease: a Systematic Review.

Huntington's disease (HD) is a rare neurological disorder characterized by progressive motor, cognitive, and psychiatric disturbances. Although striatum degeneration might justify most of the motor symptoms, there is an emerging evidence of involvement of extra-striatal structures, such as the cerebellum. To elucidate the cerebellar involvement and its afferences with motor, psychiatric, and cognitive symptoms in HD. A systematic search in the literature was performed in MEDLINE, LILACS, and Google Scholar databases. The research was broadened to include the screening of reference lists of review articles for additional studies. Studies available in the English language, dating from 1993 through May 2020, were included. Clinical presentation of patients with HD may not be considered as the result of an isolated primary striatal dysfunction. There is evidence that cerebellar involvement is an early event in HD and may occur independently of striatal degeneration. Also, the loss of the compensation role of the cerebellum in HD may be an explanation for the clinical onset of HD. Although more studies are needed to elucidate this association, the current literature supports that the cerebellum may integrate the natural history of neurodegeneration in HD.

The Interaction of Aging and Cellular Stress Contributes to Pathogenesis in Mouse and Human Huntington Disease Neurons.

Huntington disease (HD) is a fatal, inherited neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene. While mutant HTT is present ubiquitously throughout life, HD onset typically occurs in mid-life. Oxidative damage accumulates in the aging brain and is a feature of HD. We sought to interrogate the roles and interaction of age and oxidative stress in HD using primary Hu97/18 mouse neurons, neurons differentiated from HD patient induced pluripotent stem cells (iPSCs), and the brains of HD mice. We find that primary neurons must be matured in culture for canonical stress responses to occur. Furthermore, when aging is accelerated in mature HD neurons, mutant HTT accumulates and sensitivity to oxidative stress is selectively enhanced. Furthermore, we observe HD-specific phenotypes in neurons and mouse brains that have undergone accelerated aging, including a selective increase in DNA damage. These findings suggest a role for aging in HD pathogenesis and an interaction between the biological age of HD neurons and sensitivity to exogenous stress.

Fiberoptic endoscopic evaluation of swallowing in early-to-advanced stage Huntington\u2019s disease

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor disturbances, cognitive decline, and behaviour changes. A well-recognized feature of advanced HD is dysphagia, which leads to malnutrition and aspiration pneumonia, the latter being the primary cause of death in HD. Previous studies have underscored the importance of dysphagia in HD patients with moderate-to-advanced stage disease, but it is unclear whether dysphagia affects patients already at an early stage of disease and whether genetic or clinical factors can predict its severity. We performed fiberoptic endoscopic evaluation of swallowing (FEES) in 61 patients with various stages of HD. Dysphagia was found in 35% of early-stage, 94% of moderate-stage, and 100% of advanced-stage HD. Silent aspiration was found in 7.7% of early-stage, 11.8% of moderate-stage, and 27.8% of advanced-stage HD. A strong correlation was observed between disease progression and dysphagia severity: worse dysphagia was associated with worsening of motor symptoms. Dysphagia severity as assessed by FEES correlated with Huntington’s Disease Dysphagia Scale scores (a self-report questionnaire specific for evaluating swallowing in HD). The present findings add to our understanding of dysphagia onset and progression in HD. A better understanding of dysphagia onset and progression in HD may inform guidelines for standard clinical care in dysphagia, its recognition, and management.

Huntington’s Disease: Les Jeux Sont Faits?

In a meticulous study, Humbert, Durr, and colleagues showed evidence for aberrant neurodevelopment in both Huntington's disease (HD) and mouse models of HD. We consider the implications of prenatal pathological changes for the onset and progression of HD and their relatedness to current therapeutic plans.

Gene expression profiles complement the analysis of genomic modifiers of the clinical onset of Huntington disease.

Huntington disease (HD) is a neurodegenerative disorder that is caused by a CAG repeat expansion in HTT. The length of this repeat, however, only explains a proportion of the variability in age of onset in patients. Genome-wide association studies have identified modifiers that contribute toward a proportion of the observed variance. By incorporating tissue-specific transcriptomic information with these results, additional modifiers can be identified. We performed a transcriptome-wide association study assessing heritable differences in genetically determined expression in diverse tissues, with genome-wide data from over 4000 patients. Functional validation of prioritized genes was undertaken in isogenic HD stem cells and patient brains. Enrichment analyses were performed with biologically relevant gene sets to identify the core pathways. HD-associated gene coexpression modules were assessed for associations with neurological phenotypes in an independent cohort and to guide drug repurposing analyses. Transcriptomic analyses identified genes that were associated with age of HD onset and displayed colocalization with gene expression signals in brain tissue (FAN1, GPR161, PMS2, SUMF2), with supporting evidence from functional experiments. This included genes involved in DNA repair, as well as novel-candidate modifier genes that have been associated with other neurological conditions. Further, cortical coexpression modules were also associated with cognitive decline and HD-related traits in a longitudinal cohort. In summary, the combination of population-scale gene expression information with HD patient genomic data identified novel modifier genes for the disorder. Further, these analyses expanded the pathways potentially involved in modifying HD onset and prioritized candidate therapeutics for future study.

Behavioral Deficits in Juvenile Onset Huntington's Disease.

Reports of behavioral disturbance in Juvenile-Onset Huntington’s Disease (JOHD) have been based primarily on qualitative caregiver reports or retrospective medical record reviews. This study aims to quantify differences in behavior in patients with JOHD using informant- and self-report questionnaires. Informants of 21 children/young adults (12 female) with JOHD and 115 children/young adults (64 female) with a family history of Huntington’s Disease, but who did not inherit the disease themselves (Gene-Non-Expanded; GNE) completed the Behavior Rating Inventory of Executive Function (BRIEF) and the Pediatric Behavior Scale (PBS). Mixed linear regression models (age/sex adjusted) were conducted to assess group differences on these measures. The JOHD group had significantly higher scores, indicating more problems, than the GNE group on all BRIEF subscales, and measures of Aggression/Opposition and Hyperactivity/Inattention of the PBS (all p < 0.05). There were no group differences in Depression/Anxiety. Inhibit, Plan/Organize, Initiate, and Aggression/Opposition had significant negative correlations with Cytosine-Adenine-Guanine (CAG) repeat length (all p < 0.05) meaning that individuals with higher CAG repeats scored lower on these measures. There was greater discrepancy between higher informant-vs. lower self-reported scores in the JOHD group, supporting the notion of lack of insight for the JOHD-affected group. These results provide quantitative evidence of behavioral characteristics of JOHD.

Understanding HD Psychosis: An Analysis from the ENROLL-HD Database.

Background:Psychosis is considered rare in Huntington’s Disease, with an estimated prevalence of 3–11%. However, it has a profound impact on quality of life and disease burden. This study uses the Enroll-HD database to determine the prevalence, onset, and severity of psychosis in Huntington’s Disease and to determine demographic and disease characteristics associated with psychosis.Methods:Data were obtained from Enroll-HD. Adults with manifest Huntington’s Disease were included. Descriptive statistics were calculated. Simple logistic regression was used to calculate the odds ratio with 95% confidence interval for association with each characteristic.Results:7,966 manifest Huntington’s Disease participants were analyzed, and 12.95% had a history of psychosis. Mean age of psychosis onset (48.34 years, SD 13.26) mirrored Huntington’s Disease onset. Family history of psychosis in a first degree relative was documented in 23.6% of participants with psychosis. Variables significantly (p < 0.05) associated with presence of psychosis in manifest HD included lower education level, unemployment, single marital status, depression, decreased verbal fluency score, and decreased total functional capacity & functional assessment score.Discussion:Psychosis in Huntington’s Disease is more prevalent than many prior studies have reported. It is associated with several demographic & psychiatric features, decreased cognitive capacity, and worse functional outcomes.Highlights:Psychosis in HD is more prevalent than prior studies have reported. It is associated with a range of demographic and psychiatric variables, worse cognition, and worse functional outcomes suggesting several features that may be used to predict onset of psychosis and improve understanding and management of psychosis in HD.