Huntington's Disease Patients Research Articles

What Is the Evidence for Using Anti-Epileptic Drugs to Treat Agitation and Irritability in Huntington's Disease?

AimsBackground: Huntington's disease (HD), due to the pathological expansion of CAG trinucleotide repeats within the Huntington's gene on chromosome 4p (1), is an autosomal dominant progressive neurodegenerative disease with motor, cognitive and neuropsychiatric symptoms that includes irritability and agitation in an estimated 38–73% of HD patients (2) which is characterized by impatience and a tendency to become angry in response to minimal provocation. Expert consensus recommends implementation of environmental and behavioural strategies then commencing treatment with SSRI's, Neuroleptics or Anti-Epileptic Drugs (AED) (3). No previous papers, to our knowledge, have examined the newest antiepileptic agents or have identified the most efficacious antiepileptics for this use. Aim: We present a review of the literature describing antiepileptic treatments for agitation and irritability in HD focusing on identification of the most efficacious antiepileptics and the role of newer antiepileptic agents for this use.MethodsA search in the main database sources (EMBASE, MEDLINE, Allied and Complementary medicine) was performed in order to obtain a comprehensive evaluation of available antiepileptic psychopharmacological treatments in HD for agitation and irritability.ResultsAntiepileptic (AED) agents described in consensus statements and case studies have included sodium valproate, carbamazepine and lamotrigine, which work by inhibition of voltage gated Na and Ca channels, and are often combined with antipsychotic agents for improvement of pathological mood swings and irritability. However, none of the papers identified were Level III or better.ConclusionNo specific mood stabilizing antiepileptic psychopharmacological treatment of the Psychiatric symptoms of irritability and agitation in HD was identified. Overall, the use of AED have weak evidence base with no quantifiable outcome measures, such as such as the Disruptive or Aggressive Behavior behavioural subscale of the Unified Huntington's Disease Rating Scale or the Neuropsychiatric Inventory, indicating improvement of symptoms identified. Surveys and expert opinions were based on their personal knowledge of the HD populations and the selection of the experts surveyed was not systematic which could influence the practice pattern results. The review indicates a pressing need for treatment studies to determine which psychopharmacological and behavioral treatments are most efficacious.

Divergent Effects of the Nonselective Adenosine Receptor Antagonist Caffeine in Pre-Manifest and Motor-Manifest Huntington's Disease.

There is a controversy about potentially positive or negative effects of caffeine consumption on onset and disease progression of neurodegenerative diseases such as Huntington’s Disease (HD). On the molecular level, the psychoactive drug caffeine targets in particular adenosine receptors (AR) as a nonselective antagonist. The aim of this study was to evaluate clinical effects of caffeine consumption in patients suffering from premanifest and motor-manifest HD. Data of the global observational study ENROLL-HD were used, in order to analyze the course of HD regarding symptoms onset, motor, functional, cognitive and psychiatric parameters, using cross-sectional and longitudinal data of up to three years. We split premanifest and manifest participants into two subgroups: consumers of >3 cups of caffeine (coffee, cola or black tea) per day (>375 mL) vs. subjects without caffeine consumption. Data were analyzed using ANCOVA-analyses for cross-sectional and repeated measures analysis of variance for longitudinal parameters in IBM SPSS Statistics V.28. Within n = 21,045 participants, we identified n = 1901 premanifest and n = 4072 manifest HD patients consuming >3 cups of caffeine/day vs. n = 841 premanifest and n = 2243 manifest subjects without consumption. Manifest HD patients consuming >3 cups exhibited a significantly better performance in a series of neuropsychological tests. They also showed at the median a later onset of symptoms (all p < 0.001), and, during follow-up, less motor, functional and cognitive impairments in the majority of tests (all p < 0.050). In contrast, there were no beneficial caffeine-related effects on neuropsychological performance in premanifest HD mutation carriers. They showed even worse cognitive performances in stroop color naming (SCNT) and stroop color reading (SWRT) tests (all p < 0.050) and revealed more anxiety, depression and irritability subscores in comparison to premanifest participants without caffeine consumption. Similarly, higher self-reported anxiety and irritability were observed in genotype negative/control group high dose caffeine drinkers, associated with a slightly better performance in some cognitive tasks (all p < 0.050). The analysis of the impact of caffeine consumption in the largest real-world cohort of HD mutation carriers revealed beneficial effects on neuropsychological performance as well as manifestation and course of disease in manifest HD patients while premanifest HD mutation carrier showed no neuropsychological improvements, but worse cognitive performances in some tasks and exhibited more severe signs of psychiatric impairment. Our data point to state-related psychomotor-stimulant effects of caffeine in HD that might be related to regulatory effects at cerebral adenosine receptors. Further studies are required to validate findings, exclude potential other unknown biasing factors such as physical activity, pharmacological interventions, gender differences or chronic habitual influences and test for dosage related effects.

Huntingtin Co-Isolates with Small Extracellular Vesicles from Blood Plasma of TgHD and KI-HD Pig Models of Huntington's Disease and Human Blood Plasma.

(1) Background: Huntington’s disease (HD) is rare incurable hereditary neurodegenerative disorder caused by CAG repeat expansion in the gene coding for the protein huntingtin (HTT). Mutated huntingtin (mHTT) undergoes fragmentation and accumulation, affecting cellular functions and leading to neuronal cell death. Porcine models of HD are used in preclinical testing of currently emerging disease modifying therapies. Such therapies are aimed at reducing mHTT expression, postpone the disease onset, slow down the progression, and point out the need of biomarkers to monitor disease development and therapy efficacy. Recently, extracellular vesicles (EVs), particularly exosomes, gained attention as possible carriers of disease biomarkers. We aimed to characterize HTT and mHTT forms/fragments in blood plasma derived EVs in transgenic (TgHD) and knock-in (KI-HD) porcine models, as well as in HD patients’ plasma. (2) Methods: Small EVs were isolated by ultracentrifugation and HTT forms were visualized by western blotting. (3) Results: The full length 360 kDa HTT co-isolated with EVs from both the pig model and HD patient plasma. In addition, a ~70 kDa mutant HTT fragment was specific for TgHD pigs. Elevated total huntingtin levels in EVs from plasma of HD groups compared to controls were observed in both pig models and HD patients, however only in TgHD were they significant (p = 0.02). (4) Conclusions: Our study represents a valuable initial step towards the characterization of EV content in the search for HD biomarkers.

Phospholipid Profiles Are Selectively Altered in the Putamen and White Frontal Cortex of Huntington's Disease.

Huntington’s disease (HD) is a genetic, neurodegenerative illness that onsets in late adulthood as a series of progressive and terminal cognitive, motor, and psychiatric deficits. The disease is caused by a polyQ mutation in the Huntingtin gene (HTT), producing a polyglutamine expansion in the Huntingtin protein (HTT). HTT interacts with phospholipids in vitro; however, its interactions are changed when the protein is mutated in HD. Emerging evidence suggests that the susceptibility of brain regions to pathological stimuli is influenced by lipid composition. This study aimed to identify where and how phospholipids are changed in human HD brain tissue. Phospholipids were extracted using a modified MTBE method from the post-mortem brain of 13 advanced-stage HD patients and 13 age- and sex-matched controls. Targeted precursor ion scanning mass spectrometry was used to detect phospholipid species. In the white cortex of HD patients, there was a significantly lower abundance of phosphatidylcholine (PC) and phosphatidylserine (PS), but no difference in phosphatidylethanolamine (PE). In HD putamen, ester-linked 22:6 was lower in all phospholipid classes promoting a decrease in the relative abundance of ester polyunsaturated fatty acids in PE. No differences in phospholipid composition were identified in the caudate, grey cortex or cerebellum. Ether-linked PE fatty acids appear protected in the HD brain, as no changes were identified. The nature of phospholipid alterations in the HD brain is dependent on the lipid (subclass, species, and bond type) and the location.

Decreased CSF oxytocin relates to measures of social cognitive impairment in Huntington's disease patients

ObjectiveHuntington's disease (HD) is an inherited neurodegenerative disease with motor, cognitive and psychiatric symptoms. Non-motor symptoms like depression and altered social cognition are proposed to be caused by dysfunction of the hypothalamus. We measured the hypothalamic neuropeptide oxytocin in plasma and cerebrospinal fluid (CSF) in a cohort of HD gene expansion carriers (HDGECs), compared the levels to healthy HD family controls and correlated oxytocin levels to disease progression and social cognition. MethodsWe recruited 113 HDGECs and 33 controls. Psychiatric and cognitive symptoms were evaluated, and social cognition was assessed with the Emotion Hexagon test, Reading the Mind in the Eyes and The Awareness of Social Inference Test. The levels of oxytocin in CSF and blood were analyzed by radioimmunoassay. ResultsWe found the level of oxytocin in CSF to be significantly lower by 33.5% in HDGECs compared to controls (p = 0.016). When dividing the HDGECs into groups with or without cognitive impairment, we found the oxytocin level to be significantly lower by 30.3% in the HDGECs with cognitive symptoms (p = 0.046). We found a statistically significant correlation between the level of oxytocin and scores on social cognition (Reading the Mind in the Eyes p = 0.0019; Emotion Hexagon test: p = 0.0062; The Awareness of Social Inference Test: p = 0.002). ConclusionsThis is the first study to measure oxytocin in the CSF of HDGECs. We find that HDGECs have a significantly lower level of oxytocin compared to controls, and that the level of oxytocin may represent an objective and comparable measure that could be used as a state biomarker for impairment of social cognition. We suggest treatment trials to evaluate a potential effect of oxytocin on social cognition in HD.

Effects of Exercise on Skeletal Muscle Pathophysiology in Huntington's Disease.

Huntington’s disease (HD) is a rare, hereditary, and progressive neurodegenerative disease, characterized by involuntary choreatic movements with cognitive and behavioral disturbances. In order to mitigate impairments in motor function, physical exercise was integrated in HD rehabilitative interventions, showing to be a powerful tool to ameliorate the quality of life of HD-affected patients. This review aims to describe the effects of physical exercise on HD-related skeletal muscle disorders in both murine and human models. We performed a literature search using PubMed, Scopus, and Web of Science databases on the role of physical activity in mouse models of HD and human patients. Fifteen publications fulfilled the criteria and were included in the review. Studies performed on mouse models showed a controversial role played by exercise, whereas in HD-affected patients, physical activity appeared to have positive effects on gait, motor function, UHDMRS scale, cognitive function, quality of life, postural stability, total body mass, fatty acid oxidative capacity, and VO2 max. Physical activity seems to be feasible, safe, and effective for HD patients. However, further studies with longer follow-up and larger cohorts of patients will be needed to draw firm conclusions on the positive effects of exercise for HD patients.

Hospital Admissions of Huntington's Disease Patients in a Huntington's Disease Centre Between 2011 and 2016: A Retrospective Analysis.

BackgroundHuntington's Disease (HD) is a relentlessly progressive genetic neurodegenerative disorder with characteristic motor, psychiatric, and behavioral abnormalities that inevitably results in severe disability and death. Many patients have multiple hospital admissions during the disease course, but there is limited information which problems lead to hospitalization.ObjectivesTo assess acute reasons for hospital admissions, discharge routes, and clinical characteristics of HD patients in a retrospective analysis.MethodsWe reviewed all medical records of patients with an established diagnosis of Huntington's Disease and hospital admissions between 2011 and 2016 in our local hospital‐based database.ResultsThere were 135 hospital admissions in 53 HD patients during the review period, representing a median of two admissions per patient. Median duration of hospitalization was seven days. The most frequent reason for admission was a worsening of HD motor symptoms (n = 77, 57.0%) such as chorea, parkinsonism, gait problems, falls, and dysphagia. Psychiatric symptoms related to HD were the second most common reason for admission (n = 58, 43.0%). Infections (including aspiration pneumonia) and traumas/surgical procedures were only responsible for 6.7% and 5.9% of admissions, respectively. Emergency admissions were not common (42.2%), and the majority of patients were able to return to their previous residency upon discharge (85.2%, home or nursing home). Recurrent admissions were associated with worse motor function and functional capacity.ConclusionsWorsening of motor and psychiatric symptoms associated with Huntington's Disease were the most common reasons for hospital admissions. Therefore, our data highlight the importance of optimal symptom control in HD patients.

Hyperactive Striatal Dopamine Signaling Observed in Huntington’s Disease Mouse Models Prior to Motor Symptom Onset Can be Attenuated via Activation of M4 Receptors

Almost all Huntington’s Disease (HD) patients die within 10‐30 years after symptom onset and currently there are no available treatments to slow, stop, or reverse its progression. HD is a neurodegenerative disease that causes a biphasic signaling pattern in the striatum in which there is hyperactive signaling during the early stages, followed by hypoactive signaling later on. Among the many neurotransmitters shown to follow the biphasic signaling pattern found in HD, dopamine (DA) and its inputs from the mid‐brain to the striatum are thought to be critical for motor and action planning. However, there is currently a lack of studies that directly examine DA signaling in animal models before symptom onset, leaving room for investigation in a critical area of the disease. Here we use a combination of techniques to assess dopamine signaling and its regulation during pre‐symptomatic disease stages. We hypothesized that we would observe increased dopamine transients in YAC128 positive mice when compared to littermate controls at this time point, and that activation of the M4 receptor with the M4 selective positive allosteric modulator (PAM) VU’154 would normalize transient amplitude in YAC128 mice. Using fast scanning cyclic voltammetry (FSCV), we recorded dopamine signaling in pre‐symptomatic YAC128 mice via ex vivo preparations. We also used, fiber photometry to record dopamine signaling in vivo, in the same mouse strain. We found that indeed, DA transient amplitudes are increased in pre‐symptomatic YAC128 mice when compared to littermate controls in both ex vivo and in vivo settings. Additionally, we report that activation of the M4 receptor is able to normalize the enhanced DA signaling in HD mice. These findings are some of the first to directly show increased DA signaling in the basal ganglia in early stage HD rodent models and support previous evidence that M4 ­­­­­­­is potentially an exciting target for normalizing aberrant neurotransmission in HD.

Classification of Huntington's Disease Stage with Features Derived from Structural and Diffusion-Weighted Imaging.

The purpose of this study was to classify Huntington’s disease (HD) stage using support vector machines and measures derived from T1- and diffusion-weighted imaging. The effects of feature selection approach and combination of imaging modalities are assessed. Fourteen premanifest-HD individuals (Pre-HD; on average > 20 years from estimated disease onset), eleven early-manifest HD (Early-HD) patients, and eighteen healthy controls (HC) participated in the study. We compared three feature selection approaches: (i) whole-brain segmented grey matter (GM; voxel-based measure) or fractional anisotropy (FA) values; (ii) GM or FA values from subcortical regions-of-interest (caudate, putamen, pallidum); and (iii) automated selection of GM or FA values with the algorithm Relief-F. We assessed single- and multi-kernel approaches to classify combined GM and FA measures. Significant classifications were achieved between Early-HD and Pre-HD or HC individuals (accuracy: generally, 85% to 95%), and between Pre-HD and controls for the feature FA of the caudate ROI (74% accuracy). The combination of GM and FA measures did not result in higher performances. We demonstrate evidence on the high sensitivity of FA for the classification of the earliest Pre-HD stages, and successful distinction between HD stages.

Epidemiology of Huntington’s Disease in the United States Medicare and Medicaid Populations

Introduction: Huntington’s disease (HD) is a rare, genetic, and ultimately fatal neurodegenerative disease, with a devastating impact on individuals and families across generations. Few estimates of HD epidemiology in the United States (US) exist. Methods: This study employed a retrospective cross-sectional design to examine the epidemiology of HD in the US Medicare and Medicaid beneficiary populations using 2016-2017 claims data from the Medicare 100% Research Identifiable Files (RIFs) and 2014 claims data from the Medicaid Analytic eXtract (MAX) files for 17 states. Medicare beneficiaries ≥65 years with a diagnosis of HD (≥1 claim with ICD-10-CM code G10) in 2017 and Medicaid beneficiaries <65 years with a diagnosis of HD (≥1 claim with ICD-9-CM code 333.4) in 2014 were identified. The study outcomes included the 2017 prevalence proportion and incidence rate of HD in the Medicare population and the 2014 prevalence proportion of HD in the Medicaid population. Results: In the Medicare population, 1,941 prevalent and 819 incident cases of HD were identified in 2017, corresponding to a prevalence proportion of 13.1 per 100,000 persons and incidence rate of 6.1 per 100,000 person-years. In the Medicaid population, 353 prevalent cases of HD were identified in 2014, corresponding to a prevalence proportion of 15.2 per 100,000 persons. Conclusion: This study suggests that prevalence and incidence of HD in the US may be higher than previously estimated. This has important implications in raising awareness of HD among providers and payers and ensuring availability of and access to services for HD patients and care partners in the Medicare and Medicaid populations.

Altered Cholesterol Homeostasis in Huntington's Disease.

Huntington’s disease (HD) is an autosomal dominant genetic disorder caused by an expansion of the CAG repeat in the first exon of Huntingtin’s gene. The associated neurodegeneration mainly affects the striatum and the cortex at early stages and progressively spreads to other brain structures. Targeting HD at its earlier stages is under intense investigation. Numerous drugs were tested, with a rate of success of only 3.5% approved molecules used as symptomatic treatment. The restoration of cholesterol metabolism, which is central to the brain homeostasis and strongly altered in HD, could be an interesting disease-modifying strategy. Cholesterol is an essential membrane component in the central nervous system (CNS); alterations of its homeostasis have deleterious consequences on neuronal functions. The levels of several sterols, upstream of cholesterol, are markedly decreased within the striatum of HD mouse model. Transcription of cholesterol biosynthetic genes is reduced in HD cell and mouse models as well as post-mortem striatal and cortical tissues from HD patients. Since the dynamic of brain cholesterol metabolism is complex, it is essential to establish the best method to target it in HD. Cholesterol, which does not cross the blood-brain-barrier, is locally synthesized and renewed within the brain. All cell types in the CNS synthesize cholesterol during development but as they progress through adulthood, neurons down-regulate their cholesterol synthesis and turn to astrocytes for their full supply. Cellular levels of cholesterol reflect the dynamic balance between synthesis, uptake and export, all integrated into the context of the cross talk between neurons and glial cells. In this review, we describe the latest advances regarding the role of cholesterol deregulation in neuronal functions and how this could be a determinant factor in neuronal degeneration and HD progression. The pathways and major mechanisms by which cholesterol and sterols are regulated in the CNS will be described. From this overview, we discuss the main clinical strategies for manipulating cholesterol metabolism in the CNS, and how to reinstate a proper balance in HD.

Neural Network Aided Detection of Huntington Disease.

Huntington Disease (HD) is a degenerative neurological disease that causes a significant impact on the quality of life of the patient and eventually death. In this paper we present an approach to create a biomarker using as an input DNA CpG methylation data to identify HD patients. DNA CpG methylation is a well-known epigenetic marker for disease state. Technological advances have made it possible to quickly analyze hundreds of thousands of CpGs. This large amount of information might introduce noise as potentially not all DNA CpG methylation levels will be related to the presence of the illness. In this paper, we were able to reduce the number of CpGs considered from hundreds of thousands to 237 using a non-linear approach. It will be shown that using only these 237 CpGs and non-linear techniques such as artificial neural networks makes it possible to accurately differentiate between control and HD patients. An underlying assumption in this paper is that there are no indications suggesting that the process is linear and therefore non-linear techniques, such as artificial neural networks, are a valid tool to analyze this complex disease. The proposed approach is able to accurately distinguish between control and HD patients using DNA CpG methylation data as an input and non-linear forecasting techniques. It should be noted that the dataset analyzed is relatively small. However, the results seem relatively consistent and the analysis can be repeated with larger data-sets as they become available.

Development of mAb-based polyglutamine-dependent and polyglutamine length-independent huntingtin quantification assays with cross-site validation.

Huntington’s disease (HD) is caused by an expansion of the CAG trinucleotide repeat domain in the huntingtin gene that results in expression of a mutant huntingtin protein (mHTT) containing an expanded polyglutamine tract in the amino terminus. A number of therapeutic approaches that aim to reduce mHTT expression either locally in the CNS or systemically are in clinical development. We have previously described sensitive and selective assays that measure human HTT proteins either in a polyglutamine-independent (detecting both mutant expanded and non-expanded proteins) or in a polyglutamine length-dependent manner (detecting the disease-causing polyglutamine repeats) on the electrochemiluminescence Meso Scale Discovery detection platform. These original assays relied upon polyclonal antibodies. To ensure an accessible and sustainable resource for the HD field, we developed similar assays employing monoclonal antibodies. We demonstrate that these assays have equivalent sensitivity compared to our previous assays through the evaluation of cellular and animal model systems, as well as HD patient biosamples. We also demonstrate cross-site validation of these assays, allowing direct comparison of studies performed in geographically distinct laboratories.

The Many Faces of Huntington's Chorea Treatment: The Impact of Sudden Withdrawal of Tiapride after 40 Years of Use and a Systematic Review.

Huntington’s Disease (HD) is a rare, neurodegenerative disorder characterized by chorea, cognitive decline, and behavioral changes. Despite wide clinical use since the mid-1980s, tiapride was recently withdrawn from the Dutch market without rationale. Although alternatives are available, many patients experienced dysregulation after this unwanted change. We provide insight into the impact of sudden tiapride withdrawal by reviewing medical records of HD patients who were using tiapride at the time of withdrawal. In addition, we performed a systematic search in five databases on tiapride efficacy and its safety profile in HD. Original research and expert opinions were included. In our patient group on tiapride, 50% required tiapride import from abroad. Regarding the review, 12 articles on original datasets and three expert opinions were included. The majority of studies showed an improvement in chorea while patients were on tiapride. Due to limited sample sizes, not all studies performed statistical tests on their results. Fifty percent of clinical experts prefer tiapride as initial chorea monotherapy, especially when comorbid behavioral symptoms are present. Side effects are often rare and mild. No safety concerns were reported. In conclusion, tiapride is almost irreplaceable for some patients and is an effective and safe chorea treatment in HD.

Montreal Cognitive Assessment (MoCA) performance in Huntington's disease patients correlates with cortical and caudate atrophy.

Huntington’s Disease (HD) is an autosomal neurodegenerative disease characterized by motor, cognitive, and psychiatric symptoms. Cognitive impairment develops gradually in HD patients, progressing later into a severe cognitive dysfunction. The Montreal Cognitive Assessment (MoCA) is a brief screening test commonly employed to detect mild cognitive impairment, which has also been useful to assess cognitive decline in HD patients. However, the relationship between MoCA performance and brain structural integrity in HD patients remains unclear. Therefore, to explore this relationship we analyzed if cortical thinning and subcortical nuclei volume differences correlated with HD patients’ MoCA performance. Twenty-two HD patients and twenty-two healthy subjects participated in this study. T1-weighted images were acquired to analyze cortical thickness and subcortical nuclei volumes. Group comparison analysis showed a significantly lower score in the MoCA global performance of HD patients. Also, the MoCA total score correlated with cortical thinning of fronto-parietal and temporo-occipital cortices, as well as with bilateral caudate volume differences in HD patients. These results provide new insights into the effectiveness of using the MoCA test to detect cognitive impairment and the brain atrophy pattern associated with the cognitive status of prodromal/early HD patients.

Current and Possible Future Therapeutic Options for Huntington's Disease.

Huntington’s disease (HD) is an autosomal neurodegenerative disease that is characterized by an excessive number of CAG trinucleotide repeats within the huntingtin gene (HTT). HD patients can present with a variety of symptoms including chorea, behavioural and psychiatric abnormalities and cognitive decline. Each patient has a unique combination of symptoms, and although these can be managed using a range of medications and non-drug treatments there is currently no cure for the disease. Current therapies prescribed for HD can be categorized by the symptom they treat. These categories include chorea medication, antipsychotic medication, antidepressants, mood stabilizing medication as well as non-drug therapies. Fortunately, there are also many new HD therapeutics currently undergoing clinical trials that target the disease at its origin; lowering the levels of mutant huntingtin protein (mHTT). Currently, much attention is being directed to antisense oligonucleotide (ASO) therapies, which bind to pre-RNA or mRNA and can alter protein expression via RNA degradation, blocking translation or splice modulation. Other potential therapies in clinical development include RNA interference (RNAi) therapies, RNA targeting small molecule therapies, stem cell therapies, antibody therapies, non-RNA targeting small molecule therapies and neuroinflammation targeted therapies. Potential therapies in pre-clinical development include Zinc-Finger Protein (ZFP) therapies, transcription activator-like effector nuclease (TALEN) therapies and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated system (Cas) therapies. This comprehensive review aims to discuss the efficacy of current HD treatments and explore the clinical trial progress of emerging potential HD therapeutics.

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.

Smoking, alcohol consumption, and age at onset of Huntington's disease: a Mendelian randomization study

BackgroundSmoking and alcohol consumption have been associated with earlier age at onset (AAO) of Huntington's disease (HD) in observational studies. We conducted this Mendelian randomization (MR) study to evaluate whether these associations are causal. MethodsWe selected genetic instruments for lifetime smoking (n = 462,690) and alcohol consumption (n = 941,280) based on two large genome-wide association studies (GWAS). The summary-level data for residual AAO of HD were derived from a GWAS meta-analysis carried out by the Genetic Modifiers of Huntington's disease Consortium (n = 9,064 HD patients). We conducted univariable and multivariable MR analyses to evaluate the independent impact of smoking and alcohol consumption on AAO of HD. ResultsGenetically predicted lifetime smoking was causally related to an earlier AAO of HD in the univariable MR analyses (β = −2.16 years per standard deviation (SD) increase in lifetime smoking index, 95% confidence interval (CI) = −3.70 to −0.63, P = 0.006). This association persisted significant in the multivariable MR analyses after adjusting for alcohol consumption (β = −2.04 years per SD increase in lifetime smoking index, 95% CI = −3.85 to −0.22, P = 0.028). However, no significant association was found between alcohol consumption and AAO of HD. ConclusionsThis study suggests that genetically predicted smoking is causally related to an earlier AAO of HD.

Benefit of cognitive behavioral therapy for post-traumatic stress disorder and obsessive-compulsive disorders in Huntington’s disease: a case report

ABSTRACT We describe the management of post-traumatic stress disorder (PTSD) and obsessive-compulsive disorders (OCD), through Cognitive Behavioral Therapy (CBT) in a Huntington’s disease (HD) patient.Even with a psychopharmacological treatment to manage PTSD and OCD, psychiatric disorders remained in the HD patient. We proposed CBT essentially based on progressive exposure. The symptomatology disappeared shortly after starting the psychotherapeutical treatment and was maintained over time. We discuss the benefits of CBT on this patient considering the therapeutical alliance and the cognitive disorders.This clinical case gives positive impetus for future research concerning the non-pharmacological management of psychiatric comorbidities in Huntington’s disease.

An orally available, brain penetrant, small molecule lowers huntingtin levels by enhancing pseudoexon inclusion

Huntington’s Disease (HD) is a progressive neurodegenerative disorder caused by CAG trinucleotide repeat expansions in exon 1 of the huntingtin (HTT) gene. The mutant HTT (mHTT) protein causes neuronal dysfunction, causing progressive motor, cognitive and behavioral abnormalities. Current treatments for HD only alleviate symptoms, but cerebral spinal fluid (CSF) or central nervous system (CNS) delivery of antisense oligonucleotides (ASOs) or virus vectors expressing RNA-induced silencing (RNAi) moieties designed to induce mHTT mRNA lowering have progressed to clinical trials. Here, we present an alternative disease modifying therapy the orally available, brain penetrant small molecule branaplam. By promoting inclusion of a pseudoexon in the primary transcript, branaplam lowers mHTT protein levels in HD patient cells, in an HD mouse model and in blood samples from Spinal Muscular Atrophy (SMA) Type I patients dosed orally for SMA (NCT02268552). Our work paves the way for evaluating branaplam’s utility as an HD therapy, leveraging small molecule splicing modulators to reduce expression of dominant disease genes by driving pseudoexon inclusion.