scholarly journals Molecular mediators, environmental modulators and experience-dependent synaptic dysfunction in Huntington's disease.

2004 ◽  
Vol 51 (2) ◽  
pp. 415-430 ◽  
Author(s):  
Anthony J Hannan
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Environmental Enrichment ◽  
Molecular Mechanisms ◽  
Psychiatric Symptoms ◽  
Brain Regions ◽  
Cag Repeat ◽  
Autosomal Dominant Disorder ◽  
Gene Environment

Huntington's disease (HD) is an autosomal dominant disorder in which there is progressive neurodegeneration producing motor, cognitive and psychiatric symptoms. HD is caused by a trinucleotide (CAG) repeat mutation, encoding an expanded polyglutamine tract in the huntingtin protein. At least eight other neurodegenerative diseases are caused by CAG/glutamine repeat expansions in different genes. Recent evidence suggests that environmental factors can modify the onset and progression of Huntington's disease and possibly other neurodegenerative disorders. This review outlines possible molecular and cellular mechanisms mediating the polyglutamine-induced toxic 'gain of function' and associated gene-environment interactions in HD. Key aspects of pathogenesis shared with other neurodegenerative diseases may include abnormal protein-protein interactions, selective disruption of gene expression and 'pathological plasticity' of synapses in specific brain regions. Recent discoveries regarding molecular mechanisms of pathogenesis are guiding the development of new therapeutic approaches. Knowledge of gene-environment interactions, for example, could lead to development of 'enviromimetics' which mimic the beneficial effects of specific environmental stimuli. The effects of environmental enrichment on brain and behaviour will also be discussed, together with the general implications for neuroscience research involving animal models.

“organic Personality Disorder” as Part of Early Neuropsychiatric Manifestations in Huntington’s Disease - a Case Report

2009 ◽  
Vol 24 (S1) ◽  
pp. 1-1
Author(s):  
J. Maia
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Psychiatric Symptoms ◽  
Age Of Onset ◽  
Neuropsychiatric Symptoms ◽  
Personality Change ◽  
Psychotic Symptoms ◽  
Autosomal Dominant Disorder ◽  
Neuropsychiatric Manifestations ◽  
Psychiatric Manifestations

Huntington's Disease (HD) is an inherited autosomal dominant disorder characterized by motor, cognitive and psychiatric symptomatology, being considered a paradigmatic neuropsychiatric disorder that includes all three components of the "Triadic Syndromes": dyskinesia, dementia and depression.Firstly described in 1872 as an "Hereditary Chorea" by George Huntington only in 1993 was its responsible gene identified. A person who inherits the HD gene will sooner or later develop the disease. the age of onset, early signs and rate of disease progression vary greatly from person to person.Neuropsychiatric symptoms are an integral part of HD and have been considered the earliest markers of the disease, presenting sometimes more than 10 years before a formal diagnosis is done. Patients may experience dysphoria, mood swings, agitation, irritability, hostile outbursts, psychotic symptoms and deep bouts of depression with suicidal ideation. Personality change is reported in 48% of the cases, with the paranoid subtype being described as the most prevalent. the clinical case presented illustrates a case of HD which started with insidious psychiatric symptoms and an important personality change.Despite a wide number of medications being prescribed to help control emotional, movement and behaviour problems, there is still no treatment to stop or reverse the course of the disease. Furthermore, psychiatric manifestations are often amenable to treatment, and relief of these symptoms may provide significant improvement in patient's and caregivers quality of life.A greater awarness of psychiatric manifestations of HD is essential to an earlier diagnosis and an optimized therapeutic approach.

scholarly journals Huntington’s Disease in a Patient Misdiagnosed as Conversion Disorder

2018 ◽  
Vol 2018 ◽  
pp. 1-4
Author(s):  
João Machado Nogueira ◽  
Ana Margarida Franco ◽  
Susana Mendes ◽  
Anabela Valadas ◽  
Cristina Semedo ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Psychiatric Symptoms ◽  
Age Of Onset ◽  
Late Onset ◽  
Psychiatric Patients ◽  
Conversion Disorder ◽  
Cag Repeat ◽  
Clinical Assessments ◽  
Clinical Presentations

Huntington’s disease (HD) is an inherited, progressive, and neurodegenerative neuropsychiatric disorder caused by the expansion of cytosine-adenine-guanine (CAG) trinucleotide in Interested Transcript (IT) 15 gene on chromosome 4. This pathology typically presents in individuals aged between 30 and 50 years and the age of onset is inversely correlated with the length of the CAG repeat expansion. It is characterized by chorea, cognitive deficits, and psychiatric symptoms. Usually the psychiatric disorders precede motor and cognitive impairment, Major Depressive Disorder and anxiety disorders being the most common presentations. We present a clinical case of a 65-year-old woman admitted to our Psychiatric Acute Unit. During the 6 years preceding the admission, the patient had clinical assessments made several times by different specialties that focused only on isolated symptoms, disregarding the syndrome as a whole. In the course of her last admission, the patient was referred to our Neuropsychiatric Team, which made the provisional diagnosis of late-onset Huntington’s disease, later confirmed by genetic testing. This clinical vignette highlights the importance of a multidisciplinary approach to atypical clinical presentations and raises awareness for the relevance of investigating carefully motor symptoms in psychiatric patients.

Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease

2010 ◽  
Vol 90 (3) ◽  
pp. 905-981 ◽  
Author(s):  
Chiara Zuccato ◽  
Marta Valenza ◽  
Elena Cattaneo
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Mechanisms ◽  
Neurodegenerative Disorder ◽  
Disease Process ◽  
Primary Source ◽  
Cag Repeat ◽  
Mutant Protein ◽  
Loss Of Function ◽  
Causative Gene

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the gene encoding for huntingtin protein. A lot has been learned about this disease since its first description in 1872 and the identification of its causative gene and mutation in 1993. We now know that the disease is characterized by several molecular and cellular abnormalities whose precise timing and relative roles in pathogenesis have yet to be understood. HD is triggered by the mutant protein, and both gain-of-function (of the mutant protein) and loss-of-function (of the normal protein) mechanisms are involved. Here we review the data that describe the emergence of the ancient huntingtin gene and of the polyglutamine trait during the last 800 million years of evolution. We focus on the known functions of wild-type huntingtin that are fundamental for the survival and functioning of the brain neurons that predominantly degenerate in HD. We summarize data indicating how the loss of these beneficial activities reduces the ability of these neurons to survive. We also review the different mechanisms by which the mutation in huntingtin causes toxicity. This may arise both from cell-autonomous processes and dysfunction of neuronal circuitries. We then focus on novel therapeutical targets and pathways and on the attractive option to counteract HD at its primary source, i.e., by blocking the production of the mutant protein. Strategies and technologies used to screen for candidate HD biomarkers and their potential application are presented. Furthermore, we discuss the opportunities offered by intracerebral cell transplantation and the likely need for these multiple routes into therapies to converge at some point as, ideally, one would wish to stop the disease process and, at the same time, possibly replace the damaged neurons.

scholarly journals Psychiatric morbidity and poor follow-up underlie suboptimal functional and survival outcomes in Huntington's disease

2020 ◽  
Author(s):  
Nikhil Ratna ◽  
Nitish L Kamble ◽  
Sowmya D V ◽  
Meera Purushottam ◽  
Pramod K Pal ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Tertiary Care ◽  
Psychiatric Morbidity ◽  
Cag Repeat ◽  
Duration Of Illness ◽  
Low Middle Income Countries

Abstract BACKGROUND: Huntington’s disease (HD), an inherited, often late-onset, neurodegenerative disorder, is considered to be a rare, orphan disease. Research into its genetic correlates and services for those affected are inadequate in most low-middle income countries, including India. The apparent ‘incurability’ often deters symptomatic and rehabilitative care, resulting in poor quality of life and sub-optimal outcomes. There are no studies assessing disease burden and outcomes from India. METHODS: We attempted to evaluate individuals diagnosed to have HD at our tertiary-care center between 2013 and 2016 for clinical symptoms, functionality, mortality, follow up status through a structured interview, clinical data from medical records and UHDRS-TFC scoring. RESULTS: Of the 144 patients, 25% were untraceable, and another 17 (11.8%) had already died. Mean age at death and duration of illness at the time of death, were 53 years and 7 years respectively, perhaps due to suicides and other comorbidities at an early age. The patients who could be contacted (n=81) were assessed for morbidity and total functional capacity (TFC). Mean CAG repeat length and TFC score were 44.2 and 7.5 respectively. Most individuals (66%) were in TFC stage I and II and could perhaps benefit from several interventions. The TFC score correlated inversely with duration of illness (p<0.0001). The majority were being taken care of at home, irrespective of the physical and mental disability. There was a high prevalence of psychiatric morbidity (91%) including suicidal tendency (22%). Three of the 17 who died had committed suicide, and several other families reported suicidal history in other family members. Only about half the patients (57%) maintained a regular clinical follow-up. CONCLUSIONS: This study demonstrates the poor follow-up rates, significant suicidality and other psychiatric symptoms, sub-optimal survival durations and functional outcomes highlighting the need for holistic care for the majority who appear to be amenable to interventions.

Dementia due to Huntington’s disease

2020 ◽  
pp. 448-453
Author(s):  
Russell L. Margolis
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Psychiatric Symptoms ◽  
Cag Repeat ◽  
Causative Mutation ◽  
Clinical Onset ◽  
Key Features ◽  
Neurobiological Research ◽  
Clinical Triad ◽  
Near Future

Huntington’s disease (HD), first described in 1872, is perhaps the prototypical hereditary dementia and movement disorder. Key features include autosomal dominant inheritance, typically mid-life clinical onset, and a clinical triad of abnormal voluntary and involuntary movements, subcortical dementia, and psychiatric symptoms. The disease progresses inevitably, with death typically 15–20 years after onset. Neurodegeneration is most prominent in the striatum and cerebral cortex. The discovery of the causative mutation, an expanded CAG repeat in the gene huntingtin, has led to the development of reliable genetic testing for affected and at-risk individuals and an explosion of neurobiological research into HD pathogenesis. While present treatment of HD is limited to managing symptoms, there is considerable optimism that treatments to prevent, slow, or stop disease progression may be feasible in the near future.

The molecular biology of Huntington's disease

2001 ◽  
Vol 31 (1) ◽  
pp. 3-14 ◽  
Author(s):  
L. W. HO ◽  
J. CARMICHAEL ◽  
J. SWARTZ ◽  
A. WYTTENBACH ◽  
J. RANKIN ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Neurodegenerative Disorder ◽  
Psychiatric Symptoms ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Intranuclear Inclusions ◽  
Progressive Dementia ◽  
Cellular Models

Background. Huntington's disease (HD) is a fatal neurodegenerative disorder with an autosomal dominant mode of inheritance. It leads to progressive dementia, psychiatric symptoms and an incapacitating choreiform movement disorder, culminating in premature death. HD is caused by an increased CAG repeat number in a gene coding for a protein with unknown function, called huntingtin. The trinucleotide CAG codes for the amino acid glutamine and the expanded CAG repeats are translated into a series of uninterrupted glutamine residues (a polyglutamine tract).Methods. This review describes the epidemiology, clinical symptomatology, neuropathological features and genetics of HD. The main aim is to examine important findings from animal and cellular models and evaluate how they have enriched our understanding of the pathogenesis of HD and other diseases caused by expanded polyglutamine tracts.Results. Selective death of striatal and cortical neurons occurs. It is likely that the HD mutation confers a deleterious gain of function on the protein. Neuronal intranuclear inclusions containing huntingtin and ubiquitin develop in patients and transgenic mouse models of HD. Other proposed mechanisms contributing to neuropathology include excitotoxicity, oxidative stress, impaired energy metabolism, abnormal protein interactions and apoptosis.Conclusions. Although many interesting findings have accumulated from studies of HD and other polyglutamine diseases, there remain many unresolved issues pertaining to the exact roles of intranuclear inclusions and protein aggregates, the mechanisms of selective neuronal death and delayed onset of illness. Further knowledge in these areas will inspire the development of novel therapeutic strategies.

scholarly journals Impaired Brain Energy Metabolism in the BACHD Mouse Model of Huntington's Disease: Critical Role of Astrocyte–Neuron Interactions

2014 ◽  
Vol 34 (9) ◽  
pp. 1500-1510 ◽  
Author(s):  
Lydie Boussicault ◽  
Anne-Sophie Hérard ◽  
Noel Calingasan ◽  
Fanny Petit ◽  
Carole Malgorn ◽  
...  
Keyword(s):  
Energy Metabolism ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Cag Repeat ◽  
Metabolic Alterations ◽  
Culture Models ◽  
Repeat Expansions

Huntington's disease (HD) is caused by cytosine-adenine-guanine (CAG) repeat expansions in the huntingtin (Htt) gene. Although early energy metabolic alterations in HD are likely to contribute to later neurodegenerative processes, the cellular and molecular mechanisms responsible for these metabolic alterations are not well characterized. Using the BACHD mice that express the full-length mutant huntingtin (mHtt) protein with 97 glutamine repeats, we first demonstrated localized in vivo changes in brain glucose use reminiscent of what is observed in premanifest HD carriers. Using biochemical, molecular, and functional analyses on different primary cell culture models from BACHD mice, we observed that mHtt does not directly affect metabolic activity in a cell autonomous manner. However, coculture of neurons with astrocytes from wild-type or BACHD mice identified mutant astrocytes as a source of adverse non-cell autonomous effects on neuron energy metabolism possibly by increasing oxidative stress. These results suggest that astrocyte-to-neuron signaling is involved in early energy metabolic alterations in HD.

scholarly journals A Rationale for Hypoxic and Chemical Conditioning in Huntington’s Disease

2021 ◽  
Vol 22 (2) ◽  
pp. 582
Author(s):  
Johannes Burtscher ◽  
Vittorio Maglione ◽  
Alba Di Pardo ◽  
Grégoire P. Millet ◽  
Christoph Schwarzer ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Drug Targets ◽  
Ion Homeostasis ◽  
Brain Regions ◽  
Molecular Pathways ◽  
Cellular Functions ◽  
Cellular Environment ◽  
Δ Opioid Receptor

Neurodegenerative diseases are characterized by adverse cellular environments and pathological alterations causing neurodegeneration in distinct brain regions. This development is triggered or facilitated by conditions such as hypoxia, ischemia or inflammation and is associated with disruptions of fundamental cellular functions, including metabolic and ion homeostasis. Targeting intracellular downstream consequences to specifically reverse these pathological changes proved difficult to translate to clinical settings. Here, we discuss the potential of more holistic approaches with the purpose to re-establish a healthy cellular environment and to promote cellular resilience. We review the involvement of important molecular pathways (e.g., the sphingosine, δ-opioid receptor or N-Methyl-D-aspartate (NMDA) receptor pathways) in neuroprotective hypoxic conditioning effects and how these pathways can be targeted for chemical conditioning. Despite the present scarcity of knowledge on the efficacy of such approaches in neurodegeneration, the specific characteristics of Huntington’s disease may make it particularly amenable for such conditioning techniques. Not only do classical features of neurodegenerative diseases like mitochondrial dysfunction, oxidative stress and inflammation support this assumption, but also specific Huntington’s disease characteristics: a relatively young age of neurodegeneration, molecular overlap of related pathologies with hypoxic adaptations and sensitivity to brain hypoxia. The aim of this review is to discuss several molecular pathways in relation to hypoxic adaptations that have potential as drug targets in neurodegenerative diseases. We will extract the relevance for Huntington’s disease from this knowledge base.

scholarly journals Endophenotypical drift in Huntington’s disease: a 5-year follow-up study

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Marie N. N. Hellem ◽  
Rebecca K. Hendel ◽  
Tua Vinther-Jensen ◽  
Ida U. Larsen ◽  
Troels T. Nielsen ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Burden ◽  
Psychiatric Symptoms ◽  
Cag Repeat ◽  
Symptom Trajectories ◽  
Younger Age ◽  
Cardinal Symptoms ◽  
State Examination

Abstract Background Huntington’s disease (HD) is clinically characterized by progressing motor, cognitive and psychiatric symptoms presenting as varying phenotypes within these three major symptom domains. The disease is caused by an expanded CAG repeat tract in the huntingtin gene and the pathomechanism leading to these endophenotypes is assumed to be neurodegenerative. In 2012/2013 we recruited 107 HD gene expansion carriers (HDGECs) and examined the frequency of the three cardinal symptoms and in 2017/2018 we followed up 74 HDGECs from the same cohort to describe the symptom trajectories and individual drift between the endophenotypes as well as potential predictors of progression and remission. Results We found higher age to reduce the probability of improving on psychiatric symptoms; increasing disease burden score ((CAG-35.5) * age) to increase the risk of developing cognitive impairment; increasing disease burden score and shorter education to increase the risk of motor onset while lower disease burden score and higher Mini Mental State Examination increased the probability of remaining asymptomatic. We found 23.5% (N = 8) to improve from their psychiatric symptoms. Conclusions There is no clear pattern in the development of or drift between endophenotypes. In contrast to motor and cognitive symptoms we find that psychiatric symptoms may resolve and thereby not entirely be caused by neurodegeneration. The probability of improving from psychiatric symptoms is higher in younger age and advocates for a potential importance of early treatment.

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