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Alabama Medicine : Journal of the... 1990
Review
Topics: Diagnosis, Differential; Humans; Huntington Disease; Magnetic Resonance Imaging; Prevalence; Tomography, Emission-Computed, Single-Photon
PubMed: 2146862
DOI: No ID Found -
International Journal of Molecular... Aug 2021Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in... (Review)
Review
Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG expansion in the HD gene. The disease is characterized by neurodegeneration, particularly in the striatum and cortex. The first symptoms usually appear in mid-life and include cognitive deficits and motor disturbances that progress over time. Despite being a genetic disorder with a known cause, several mechanisms are thought to contribute to neurodegeneration in HD, and numerous pre-clinical and clinical studies have been conducted and are currently underway to test the efficacy of therapeutic approaches targeting some of these mechanisms with varying degrees of success. Although current clinical trials may lead to the identification or refinement of treatments that are likely to improve the quality of life of those living with HD, major efforts continue to be invested at the pre-clinical level, with numerous studies testing novel approaches that show promise as disease-modifying strategies. This review offers a detailed overview of the currently approved treatment options for HD and the clinical trials for this neurodegenerative disorder that are underway and concludes by discussing potential disease-modifying treatments that have shown promise in pre-clinical studies, including increasing neurotropic support, modulating autophagy, epigenetic and genetic manipulations, and the use of nanocarriers and stem cells.
Topics: Animals; Autophagy; Clinical Trials as Topic; Disease Management; Disease Models, Animal; Humans; Huntington Disease
PubMed: 34445070
DOI: 10.3390/ijms22168363 -
Brain Research Feb 2017Huntington׳s Disease (HD) is a fatal neurodegenerative disorder caused by expanded polyglutamine repeats in the Huntingtin (HTT) gene. While the gene was identified... (Review)
Review
Huntington׳s Disease (HD) is a fatal neurodegenerative disorder caused by expanded polyglutamine repeats in the Huntingtin (HTT) gene. While the gene was identified over two decades ago, it remains poorly understood why mutant HTT (mtHTT) is initially toxic to striatal medium spiny neurons (MSNs). Models of HD using non-neuronal human patient cells and rodents exhibit some characteristic HD phenotypes. While these current models have contributed to the field, they are limited in disease manifestation and may vary in their response to treatments. As such, human HD patient MSNs for disease modeling could greatly expand the current understanding of HD and facilitate the search for a successful treatment. It is now possible to use pluripotent stem cells, which can generate any tissue type in the body, to study and potentially treat HD. This review covers disease modeling in vitro and, via chimeric animal generation, in vivo using human HD patient MSNs differentiated from embryonic stem cells or induced pluripotent stem cells. This includes an overview of the differentiation of pluripotent cells into MSNs, the established phenotypes found in cell-based models and transplantation studies using these cells. This review not only outlines the advancements in the rapidly progressing field of HD modeling using neurons derived from human pluripotent cells, but also it highlights several remaining controversial issues such as the 'ideal' series of pluripotent lines, the optimal cell types to use and the study of a primarily adult-onset disease in a developmental model. This article is part of a Special Issue entitled SI: Exploiting human neurons.
Topics: Animals; Humans; Huntington Disease; Induced Pluripotent Stem Cells; Neurons
PubMed: 26459990
DOI: 10.1016/j.brainres.2015.10.001 -
Advances in Experimental Medicine and... 2018Huntington's disease (HD) is the most common monogenic neurodegenerative disease and the commonest genetic dementia in the developed world. With autosomal dominant... (Review)
Review
Huntington's disease (HD) is the most common monogenic neurodegenerative disease and the commonest genetic dementia in the developed world. With autosomal dominant inheritance, typically mid-life onset, and unrelenting progressive motor, cognitive and psychiatric symptoms over 15-20 years, its impact on patients and their families is devastating. The causative genetic mutation is an expanded CAG trinucleotide repeat in the gene encoding the Huntingtin protein, which leads to a prolonged polyglutamine stretch at the N-terminus of the protein. Since the discovery of the gene over 20 years ago much progress has been made in HD research, and although there are currently no disease-modifying treatments available, there are a number of exciting potential therapeutic developments in the pipeline. In this chapter we discuss the epidemiology, genetics and pathogenesis of HD as well as the clinical presentation and management of HD, which is currently focused on symptomatic treatment. The principles of genetic testing for HD are also explained. Recent developments in therapeutics research, including gene silencing and targeted small molecule approaches are also discussed, as well as the search for HD biomarkers that will assist the validation of these potentially new treatments.
Topics: Humans; Huntingtin Protein; Huntington Disease; Peptides; Trinucleotide Repeat Expansion
PubMed: 29427096
DOI: 10.1007/978-3-319-71779-1_1 -
Current Neurology and Neuroscience... Apr 2017Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, ending in... (Review)
Review
Huntington's disease (HD) is an autosomal dominantly inherited neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, ending in death. Despite the discovery of the underlying genetic mutation more than 20 years ago, treatment remains focused on symptomatic management. Chorea, the most recognizable symptom, responds to medication that reduces dopaminergic neurotransmission. Psychiatric symptoms such as depression and anxiety may also respond well to symptomatic therapies. Unfortunately, many other symptoms do not respond to current treatments. Furthermore, high-quality evidence for treatment of HD in general remains limited. To date, there has been minimal success with identifying a disease-modifying therapy based upon molecular models. However, one of the emerging gene silencing techniques may provide a breakthrough in treating this devastating disease.
Topics: Animals; Anxiety; Behavior; Chorea; Cognition Disorders; Depression; Humans; Huntington Disease
PubMed: 28324302
DOI: 10.1007/s11910-017-0739-9 -
Handbook of Clinical Neurology 2017In this chapter, we review the evolution of our understanding of the genetic aspects of HD, and the applications of our understanding in the management of Huntington's... (Review)
Review
In this chapter, we review the evolution of our understanding of the genetic aspects of HD, and the applications of our understanding in the management of Huntington's disease patients and families over the last 150 years. Important aspects of the clinical genetics and epidemiology of Huntington's disease are discussed, such as the definition of "normal" and "abnormal" numbers of CAG (cytosine-adenine-guanine) repeats in the critical spot within the huntingtin gene, meiotic instability of CAG repeat numbers, common Huntington's disease genetic haplotypes, compound heterozygosity for an abnormal gene, and somatic mosaicism for CAG repeat expansions. We touch only briefly on the creation of multiple animal models for Huntington's disease that have profoundly impacted our understanding of the disease and permitted the development of potential disease-modifying treatments, and end with what is, at the time of writing, the dawn of a new era: the advent of gene-based therapies (gene silencing, gene editing) for Huntington's disease.
Topics: Animals; Humans; Huntington Disease; Trinucleotide Repeat Expansion
PubMed: 28947123
DOI: 10.1016/B978-0-12-801893-4.00001-8 -
CNS Neuroscience & Therapeutics Apr 2018
Topics: Animals; Humans; Huntington Disease
PubMed: 29582586
DOI: 10.1111/cns.12841 -
Nature Reviews. Neurology Apr 2014Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic... (Review)
Review
Huntington disease (HD) can be seen as a model neurodegenerative disorder, in that it is caused by a single genetic mutation and is amenable to predictive genetic testing, with estimation of years to predicted onset, enabling the entire range of disease natural history to be studied. Structural neuroimaging biomarkers show that progressive regional brain atrophy begins many years before the emergence of diagnosable signs and symptoms of HD, and continues steadily during the symptomatic or 'manifest' period. The continued development of functional, neurochemical and other biomarkers raises hopes that these biomarkers might be useful for future trials of disease-modifying therapeutics to delay the onset and slow the progression of HD. Such advances could herald a new era of personalized preventive therapeutics. We describe the natural history of HD, including the timing of emergence of motor, cognitive and emotional impairments, and the techniques that are used to assess these features. Building on this information, we review recent progress in the development of biomarkers for HD, and potential future roles of these biomarkers in clinical trials.
Topics: Biomarkers; Brain; Humans; Huntington Disease; Magnetic Resonance Imaging; Neuroimaging; Radionuclide Imaging
PubMed: 24614516
DOI: 10.1038/nrneurol.2014.24 -
Journal of Genetics Jul 2018Huntington's disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes... (Review)
Review
Huntington's disease (HD) is caused due to an abnormal expansion of polyglutamine repeats in the first exon of huntingtin gene. The mutation in huntingtin causes abnormalities in the functioning of protein, leading to deleterious effects ultimately to the demise of specific neuronal cells.The disease is inherited in an autosomal dominant manner and leads to a plethora of neuropsychiatric behaviour and neuronal cell death mainly in striatal and cortical regions of the brain, eventually leading to death of the individual. The discovery of the mutant gene led to a surge in molecular diagnostics of the disease and in making different transgenic models in different organisms to understand the function of wild-type and mutant proteins. Despite difficult challenges, there has been a significant increase in understanding the functioning of the protein in normal and other gain-of-function interactions in mutant form. However, there have been no significant improvements in treatments of the patients suffering from this ailment and most of the treatment is still symptomatic. HD warrants more attention towards better understanding and treatment as more advancement in molecular diagnostics and therapeutic interventions are available. Several different transgenic models are available in different organisms, ranging from fruit flies to primate monkeys, for studies on understanding the pathogenicity of the mutant gene. It is the right time to assess the advancement in the field and try new strategies for neuroprotection using key pathways as target. The present review highlights the key ingredients of pathology in the HD and discusses important studies for drug trials and future goals for therapeutic interventions.
Topics: Animals; Humans; Huntington Disease; Mutation; Neuroprotection; Prevalence
PubMed: 30027901
DOI: No ID Found -
Human Molecular Genetics Oct 2021Huntington's disease (HD) is a devastating neurogenetic disorder whose familial nature and progressive course were first described in the 19th century but for which no... (Review)
Review
Huntington's disease (HD) is a devastating neurogenetic disorder whose familial nature and progressive course were first described in the 19th century but for which no disease-modifying treatment is yet available. Through the active participation of HD families, this disorder has acted as a flagship for the application of human molecular genetic strategies to identify disease genes, understand pathogenesis and identify rational targets for development of therapies.
Topics: Alleles; Animals; Biomarkers; Disease Management; Disease Susceptibility; Genetic Association Studies; Genetic Linkage; Genetic Predisposition to Disease; Humans; Huntington Disease; Models, Biological
PubMed: 34169318
DOI: 10.1093/hmg/ddab170