Huntington's Chorea Research Articles

Exploring the Role of Deutetrabenazine in the Treatment of Chorea Linked with Huntington's Disease.

This review investigates the efficacy of deutetrabenazine in the management of chorea related to HD. Motor, psychological, and cognitive symptoms characterize HD, a neurodegenerative disease. One prominent movement disorder associated with HD is chorea, which results in uncontrollably jerky movements of the muscles. HD has no known cure; instead, symptom management with a variety of medication options is the main goal. Effective management is essential because chorea has a significant impact on patients' quality of life. Dutetrabenazine is the first deuterated medication to receive approval from the US Food and Drug Administration (FDA) for the therapeutic treatment of chorea in Huntington's disease (HD). Treating chorea associated with HD may benefit from the use of deutetrabenazine. The novel compound deutetrabenazine contains deuterium. It inhibits CYP2D6 metabolism, prolongs the half-lives of active metabolites, and may cause persistent systemic exposure while maintaining significant pharmacological action. Deutetrabenazine decreases the release of monoamines, including dopamine, in the synaptic cleft by inhibiting the VMAT2 vesicular monoamine transporter. For chorea, this mechanism has a therapeutic effect. For the treatment of choreiform movement and tardive dyskinesia in HD, the FDA approved deutetrabenazine in 2017. Here we highlight, Deutetrabenazine as a promising new treatment for Huntington's disease chorea, for patients with chorea, deutetrabenazine offers hope for an enhanced quality of life. To completely understand its effectiveness and potential advantages, additional research is necessary, including direct comparison studies, as a result of the mixed study results.

The Microbiota-Gut-Brain Axis and Neurological Disorders: A Comprehensive Review.

Microbes have inhabited the earth for hundreds of millions of years longer than humans. The microbiota-gut-brain axis (MGBA) represents a bidirectional communication pathway. These communications occur between the central nervous system (CNS), the enteric nervous system (ENS), and the emotional and cognitive centres of the brain. The field of research on the gut-brain axis has grown significantly during the past two decades. Signalling occurs between the gut microbiota and the brain through the neural, endocrine, immune, and humoral pathways. A substantial body of evidence indicates that the MGBA plays a pivotal role in various neurological diseases. These include Alzheimer's disease (AD), autism spectrum disorder (ASD), Rett syndrome, attention deficit hyperactivity disorder (ADHD), non-Alzheimer's neurodegeneration and dementias, fronto-temporal lobe dementia (FTLD), Wilson-Konovalov disease (WD), multisystem atrophy (MSA), Huntington's chorea (HC), Parkinson's disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), temporal lobe epilepsy (TLE), depression, and schizophrenia (SCZ). Furthermore, the bidirectional correlation between therapeutics and the gut-brain axis will be discussed. Conversely, the mood of delivery, exercise, psychotropic agents, stress, and neurologic drugs can influence the MGBA. By understanding the MGBA, it may be possible to facilitate research into microbial-based interventions and therapeutic strategies for neurological diseases.

The Role of Mitochondria in the Development of Nervous System Diseases and Mental Disorders

The review analyzed articles from the Pub- Med database mainly from the last 10 years, indicating the role of mitochondria in the development of diseases of the central nervous system and mental disorders. Mu- tations in mitochondrial/nuclear DNA genes, oxidative stress, impaired redox mechanisms, and regulation of mitochondrial dynamics have been found to cause mito- chondrial dysfunction. At the same time, the permeabil- ity of mitochondrial membranes changes, the influx of calcium ions increases, as a result of which the mem- brane potential shifts, oxidation processes become more intense, a large number of reactive oxygen species are formed, oxidative phosphorylation is disrupted, and the process of neuronal apoptosis starts. Mitochondrial dys- function is a common pathogenetic mechanism of Alz- heimer's and Parkinson's diseases, amyotrophic lateral sclerosis, Huntington's chorea, epilepsy, schizophrenia, etc. Discoveries and advances in molecular genetics have increased our understanding of the early pathology of mitochondrial disorders, enabled disease modeling, and provided entirely new perspectives on molecular pathogenesis. It is necessary that this research continues and then, in the near future, it will help develop the search for possible ways to treat the diseases that people suffer from.

Applications of magnetic resonance spectroscopy in diagnosis of neurodegenerative diseases: A systematic review

BackgroundMagnetic resonance spectroscopy (MRS) is an imaging technique used to measure metabolic changes in the tissue. Due to the lack of evidence, MRS is not a priority in diagnosing neurodegenerative diseases because it is a relatively specialized technique that requires specialized equipment and expertise to perform and interpret. This systematic review aimed to present a comprehensive collection of MRS results in the most common neurodegenerative diseases. MethodsA systematic search of four electronic databases (PubMed, Scopus, Web of Science, and ScienceDirect) was conducted for studies published from 2017 to 2022. Articles that provided specific biomarker levels were selected, and studies that assessed the diseases via treatment, featured MRS applying nuclei other than 1H, or compared different animal models were excluded. ResultsA total of 25 articles, plus 3 articles for extra information in the introduction, were included in this review. Six of the most common neurodegenerative diseases, i.e., Alzheimer's and Parkinson's disease, Huntington chorea, ataxia, multiple sclerosis (MS), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP) were examined via MRS. The changes and ratios of N-acetylaspartate (NAA) could be seen in all of these disorders, which could lead to early diagnosis. However, there are other biomarkers, such as Cr and Chon, which can give convincing results. DiscussionThis observational study is the first synthesis of the latest evidence proving metabolic changes during neurodegenerative diseases using MRS as a diagnosis method. The findings indicate decreased N-acetylaspartate (NAA) and NAA/Cr ratios in Alzheimer's disease (AD), Parkinson's disease (PD), ataxias, and MS, reflecting neuronal loss or dysfunction. Increased choline and myo-inositol were noted in some studies, suggesting cell membrane turnover and neuroinflammation. Findings were less consistent for other metabolites like glutamate and gamma-aminobutyric acid. However, there were limitations due to the lack of studies on the same volumes of interest (VOIs) and the small number of participants.

Structural mechanisms for VMAT2 inhibition by tetrabenazine.

The vesicular monoamine transporter 2 (VMAT2) is a proton-dependent antiporter responsible for loading monoamine neurotransmitters into synaptic vesicles. Dysregulation of VMAT2 can lead to several neuropsychiatric disorders including Parkinson's disease and schizophrenia. Furthermore, drugs such as amphetamine and MDMA are known to act on VMAT2, exemplifying its role in the mechanisms of actions for drugs of abuse. Despite VMAT2's importance, there remains a critical lack of mechanistic understanding, largely driven by a lack of structural information. Here, we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of VMAT2 complexed with tetrabenazine (TBZ), a non-competitive inhibitor used in the treatment of Huntington's chorea. We find TBZ interacts with residues in a central binding site, locking VMAT2 in an occluded conformation and providing a mechanistic basis for non-competitive inhibition. We further identify residues critical for cytosolic and lumenal gating, including a cluster of hydrophobic residues which are involved in a lumenal gating strategy. Our structure also highlights three distinct polar networks that may determine VMAT2 conformational dynamics and play a role in proton transduction. The structure elucidates mechanisms of VMAT2 inhibition and transport, providing insights into VMAT2 architecture, function, and the design of small-molecule therapeutics.

GluN2B subunit selective N-methyl-D-aspartate receptor ligands: Democratizing recent progress to assist the development of novel neurotherapeutics.

N-methyl-D-aspartate receptors (NMDARs) play essential roles in vital aspects of brain functions. NMDARs mediate clinical features of neurological diseases and thus, represent a potential therapeutic target for their treatments. Many findings implicated the GluN2B subunit of NMDARs in various neurological disorders including epilepsy, ischemic brain damage, and neurodegenerative disorders such as Parkinson's disease, Alzheimer's disease, Huntington's chorea, and amyotrophic lateral sclerosis. Although a large amount of information is growing consistently on the importance of GluN2B subunit, however, limited recent data is available on how subunit-selective ligands impact NMDAR functions, which blunts the ability to render the diagnosis or craft novel treatments tailored to patients. To bridge this gap, we have focused on and summarized recently reported GluN2B selective ligands as emerging subunit-selective antagonists and modulators of NMDAR. Herein, we have also presented an overview of the structure-function relationship for potential GluN2B/NMDAR ligands with their binding sites and connection to CNS functionalities. Understanding of design rules and roles of GluN2B selective compounds will provide the link to medicinal chemists and neuroscientists to explore novel neurotherapeutic strategies against dysfunctions of glutamatergic neurotransmission.

EE34 Cost-Effectiveness Analysis of Valbenazine Compared with Deutetrabenazine for the Management of Huntington Chorea

To evaluate clinical and economic outcomes associated with valbenazine compared with deutetrabenazine in patients with Huntington Chorea.

Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trial

Valbenazine is a highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor approved for treatment of tardive dyskinesia. To address the ongoing need for improved symptomatic treatments for individuals with Huntington's disease, valbenazine was evaluated for the treatment of chorea associated with Huntington's disease. KINECT-HD (NCT04102579) was a phase 3, randomised, double-blind, placebo-controlled trial, performed in 46 Huntington Study Group sites in the USA and Canada. The study included adults with genetically confirmed Huntington's disease and chorea (Unified Huntington's Disease Rating Scale [UHDRS] Total Maximal Chorea [TMC] score of 8 or higher) who were randomly assigned (1:1) via an interactive web response system (with no stratification or minimisation) to oral placebo or valbenazine (≤80 mg, as tolerated) for 12 weeks of double-blinded treatment. The primary endpoint was a least-squares mean change in UHDRS TMC score from the screening and baseline period (based on the average of screening and baseline values for each participant) to the maintenance period (based on the average of week 10 and 12 values for each participant) in the full-analysis set using a mixed-effects model for repeated measures. Safety assessments included treatment-emergent adverse events, vital signs, electrocardiograms, laboratory tests, clinical tests for parkinsonism, and psychiatric assessments. The double-blind placebo-controlled period of KINECT-HD has been completed, and an open-label extension period is ongoing. KINECT-HD was performed from Nov 13, 2019, to Oct 26, 2021. Of 128 randomly assigned participants, 125 were included in the full-analysis set (64 assigned to valbenazine, 61 assigned to placebo) and 127 were included in the safety-analysis set (64 assigned to valbenazine, 63 assigned to placebo). The full-analysis set included 68 women and 57 men. Least-squares mean changes from the screening and baseline period to the maintenance period in the UHDRS TMC score were -4·6 for valbenazine and -1·4 for placebo (least-squares mean difference -3·2, 95% CI -4·4 to -2·0; p<0·0001). The most commonly reported treatment-emergent adverse event was somnolence (ten [16%] with valbenazine, two [3%] with placebo). Serious treatment-emergent adverse events were reported in two participants in the placebo group (colon cancer and psychosis) and one participant in the valbenazine group (angioedema because of allergic reaction to shellfish). No clinically important ch anges in vital signs, electrocardiograms, or laboratory tests were found. No suicidal behaviour or worsening of suicidal ideation was reported in participants treated with valbenazine. In individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. Neurocrine Biosciences.

Valbenazine as treatment for Huntington's disease chorea

Chorea, the prototypical movement disorder in Huntington's disease, is a syndrome characterised by abrupt involuntary movements resulting from a continuous flow of random muscle contractions. 1 Cardoso F Seppi K Mair KJ Wenning GK Poewe W Seminar on choreas. Lancet Neurol. 2006; 5: 589-602 Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar Symptomatic treatment of chorea in patients with Huntington's disease should be considered when it causes functional disability, discomfort, or social embarrassment. 1 Cardoso F Seppi K Mair KJ Wenning GK Poewe W Seminar on choreas. Lancet Neurol. 2006; 5: 589-602 Summary Full Text Full Text PDF PubMed Scopus (220) Google Scholar One mainstay of pharmacological treatment is to reduce dopaminergic neurotransmission via inhibition of vesicular monoamine transporter type 2 (VMAT2), leading to presynaptic dopamine depletion. 2 Bashir H Jankovic J Treatment options for chorea. Expert Rev Neurother. 2018; 18: 51-63 Crossref PubMed Scopus (31) Google Scholar , 3 Koch J Shi WX Dashtipour K VMAT2 inhibitors for the treatment of hyperkinetic movement disorders. Pharmacol Ther. 2020; 212107580 Crossref Scopus (5) Google Scholar Safety and efficacy of valbenazine for the treatment of chorea associated with Huntington's disease (KINECT-HD): a phase 3, randomised, double-blind, placebo-controlled trialIn individuals with Huntington's disease, valbenazine resulted in improvement in chorea compared with placebo and was well tolerated. Continued research is needed to confirm the long-term safety and effectiveness of this medication throughout the disease course in individuals with Huntington's disease-related chorea. Full-Text PDF

Caring for Partners of a Dismal Dance: Listening for Spiritual Suffering in Family Caregivers of Patients with Huntington's Chorea (FR265)

Caring for Partners of a Dismal Dance: Listening for Spiritual Suffering in Family Caregivers of Patients with Huntington's Chorea (FR265)

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.

Improving Mood and Cognitive Symptoms in Huntington's Disease With Cariprazine Treatment.

In Huntington's disease (HD), the main clinical symptoms include depression, apathy, cognitive deficits, motor deficiencies and involuntary movements. Cognitive, mood and behavioral changes may precede motor symptoms by up to 15 years. The treatment of these diverse symptoms is challenging. Tetrabenazine and deutetrabenazine are the only medications specifically approved for Huntington's chorea, but they do not affect the non-motor symptoms. For these, antidepressants, antipsychotics, and benzodiazepines have demonstrated benefit in some cases and can be used off-label. These drugs, due to sedative side effects, may negatively influence cognition. Sixteen patients having HD received a 12-week off-label cariprazine (CAR) treatment (1.5–3 mg/day). Cognitive performance and behavioral changes were measured by the Addenbrooke Cognitive Examination (ACE) test, the Cognitive and Behavioral part of the Unified Huntington's Disease Rating Scale (UHDRS), and the Beck Depression Inventory (BDI). Mixed model for repeated measures was fitted to the data, with terms of visit, baseline (BL) and their interaction. Cariprazine treatment resulted in the following changes from BL to week 12, respectively: the mean score of BDI decreased from 17.7 ± 10.7 to 10.0 ± 10.7 (p <0.0097), while the Behavioral Assessment score of the UHDRS decreased from 54.9 ± 11.3 to 32.5 ± 15.4 (p < 0.0001); ACE score increased from 75.1 ± 11.0 to 89.0 ± 9.3 (p < 0.0001); Cognitive Verbal Fluency score from 6.2 ± 2.5 to 7.7 ± 2.7 (p < 0.0103); Symbol Digit Test from 9.2 ± 6.9 to 12.3 ± 8.9 (p < 0.0009). Mild akathisia was the most frequent side effect, presenting in 2 out of 16 patients (12.5%). We conclude that CAR had a positive effect on depressive mood, apathy and cognitive functions in patients with early stage of HD. Based on the neurobiological basis of these symptoms, CAR can improve the dopamine imbalance of the prefrontal cortex. This draws attention to the transdiagnostic approach which supports the further understanding of the similar symptomatology of different neuropsychiatric disorders and helps to identify new indications of pharmaceutical compounds.

Experience of joint management of patient with Huntington's chorea by neurological and dental specialists with use of tetrabenazine

Huntington's chorea is a hereditary disease causing progressive degeneration of the central nervous system with the damage to extrapyramidal structures: basal nuclei, striatum, subthalamic nucleus with increased activity of the central dopaminergic pathways, with the development of neurological, psychiatric, and emotional/personality disorders [1, 17]. The inheritance pattern of the disorder is autosomal dominance. The prevalence of Huntington's disease ranges from 3 to 17 cases per 100,000 population, averaging 5–7 cases per 100,000 population in Russia [2]. The development of the disease is associated with the expansion of CAG (cytosine-adenine-guanine) trinucleotide repeats in the frst exon of the HTT gene encoding the huntingtin protein. This expansion of trinucleotides (long sections of glutamine residues) leads to the selective loss of neurons that connect the striatum and the globus pallidus. This leads to a loss of inhibitory activity and an increase in the excitation impulse, which leads to uncontrolled movements.Unfortunately, medical treatment does not slow down the progression of this disease (a lethal outcome occurs within 15–20 years). Improvement of the quality of life of people with Huntington's chorea, with the provision of medical services at an appropriate level, remains an urgent issue. This direction is especially relevant in providing dental care to patients with Huntington's chorea. Due to the pronounced hyperkinetic syndrome and compulsive movements in the muscles of the arms, trunk, neck and face, it is almost impossible to provide dental care for these patients. Currently, general anesthesia is used to enable dental intervention, but patients note that with frequent use of anesthesia, the patient's condition deteriorates, with an increase in hyperkinetic symptoms. Tetrabenazine is known to reduce the severity of hyperkinetic symptoms and is used in many countries [5].However, in our country many specialists are not familiar with it. During the follow-up of a patient with Huntington's chorea, with the selection of a therapeutic dose of tetrabenazine, it was possible to provide three stages of dental care for the patient without the use of general anesthesia. The material presented in the article can provide useful information on the use of tetrabenazine in patients with Huntington's chorea.

A case of chronic progressive chorea

Patient T., whom I have the honor to present to the Society, suffers from the form of the disease that, according to a typical picture, can be defined as chorea chronica progressiva. The first to emerge from chronic progressive chorea as a separate nosological unit was the American neuropathologist Huntington, in honor of whom chronic chorea was called Huntingtons chorea for a long time, in contrast to chorea minor, first described by Sydenham; the latter is a more common form of Witta's dog and carries on itself all the signs of an acute infectious disease.

Discovery of Dihydro-1,4-Benzoxazine Carboxamides as Potent and Highly Selective Inhibitors of Sirtuin-1.

Sirtuins are signaling hubs orchestrating the cellular response to various stressors with roles in all major civilization diseases. Sirtuins remove acyl groups from lysine residues of proteins, thereby controlling their activity, turnover, and localization. The seven human sirtuins, SirT1-7, are closely related in structure, hindering the development of specific inhibitors. Screening 170,000 compounds, we identify and optimize SirT1-specific benzoxazine inhibitors, Sosbo, which rival the efficiency and surpass the selectivity of selisistat (EX527). The compounds inhibit the deacetylation of p53 in cultured cells, demonstrating their ability to permeate biological membranes. Kinetic analysis of inhibition and docking studies reveal that the inhibitors bind to a complex of SirT1 and nicotinamide adenine dinucleotide, similar to selisistat. These new SirT1 inhibitors are valuable alternatives to selisistat in biochemical and cell biological studies. Their greater selectivity may allow the development of better targeted drugs to combat SirT1 activity in diseases such as cancer, Huntington's chorea, or anorexia.

A Brief Review on the Role of Vesicular Monoamine Transporter2 Inhibitors in Hyperkinetic Movement Disorders.

Hyperkinetic movement disorders are a common group of movement abnormalities in children, characterized with repetitive unintended involuntary movements. Major hyperkinetic movements include tremor, tic, dystonia, myoclonus, and chorea. Although a number of drugs have been proven to be beneficial for these abnormalities, some patients may become resistant to conventional treatments. Vesicular monoamine transporter2 (VMAT2) inhibitors (Tetrabenazine, Deutetrabenazine, and Valbenazine) are new agents introduced in the last decade for treating some of movement disorders, in particular tardive dyskinesia, Huntington chorea, and Tourette syndrome. In this brief review, we discussed the role of these drugs in managing hyperkinetic movement disorders.

Obstruction and ischaemia due to caecal volvulus in Huntington's chorea

Obstruction and ischaemia due to caecal volvulus in Huntington's chorea

F. С. Facklam. Beitrag zur Lehre vom Wesen der Huntington’schen Chorea. Archiv für Psych. 1898; pg. 137—204

The author analyzes in detail Huntington's chorea based on rich literature and 8 own observations. In one case, the author was also able to study the central nervous system, peripheral nerves and individual muscles, and interesting results were obtained.

PND2 A Meta-Analysis of Efficacy and Safety of Vesicular Monoamine Transporter Type 2 Inhibitors for Treatment of Huntington Chorea

PND2 A Meta-Analysis of Efficacy and Safety of Vesicular Monoamine Transporter Type 2 Inhibitors for Treatment of Huntington Chorea

Clinical and Neurochemical Effects of Transcranial Magnetic Stimulation (TMS) in Multiple Sclerosis: A Study Protocol for a Randomized Clinical Trial.

Background: Transcranial Magnetic Stimulation (TMS) is a technique based on the principles of electromagnetic induction. It applies pulses of magnetic radiation that penetrate the brain tissue, and it is a non-invasive, painless, and practically innocuous procedure. Previous studies advocate the therapeutic capacity of TMS in several neurodegenerative and psychiatric processes, both in animal models and in human studies. Its uses in Parkinson's disease, Alzheimer's disease and in Huntington's chorea have shown improvement in the symptomatology and in the molecular profile, and even in the cellular density of the brain. Consequently, the extrapolation of these TMS results in the aforementioned neurodegenerative disease to other entities with etiopathogenic and clinical analogy would raise the relevance and feasibility of its use in multiple sclerosis (MS). The overall objective will be to demonstrate the effectiveness of the TMS in terms of safety and clinical improvement, as well as to observe the molecular changes in relation to the treatment.Methods and Design: Phase II clinical trial, unicentric, controlled, randomized, single blind. A total of 90 patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) who meet all the inclusion criteria and do not present any of the exclusion criteria that are established and from which clinically evaluable results can be obtained. The patients included will be assigned under the 1:1:1 randomization formula, constituting three groups for the present study: 30 patients treated with natalizumab + white (placebo) + 30 patients treated with natalizumab + TMS (1 Hz) + 30 patients treated with natalizumab + TMS (5 Hz).Discussion: Results of this study will inform on the efficiency of the TMS for the treatment of MS. The expected results are that TMS is a useful therapeutic resource to improve clinical status (main parameters) and neurochemical profile (surrogate parameters); both types of parameters will be checked.Ethics and Dissemination: The study is approved by the Local Ethics Committee and registered in https://clinicaltrials.gov (NCT04062331). Dissemination will include submission to a peer-reviewed journal, patients, associations of sick people and family members, healthcare magazines and congress presentations.Trial Registration: ClinicalTrials.gov ID: NCT04062331 (registration date: 19th/ August/2019).Version Identifier: EMTr-EMRR, ver-3, 21/11/2017.