scholarly journals Huntington’s disease: diagnosis and management

2021 ◽  
pp. practneurol-2021-003074
Author(s):  
Thomas B Stoker ◽  
Sarah L Mason ◽  
Julia C Greenland ◽  
Simon T Holden ◽  
Helen Santini ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Asymptomatic Carrier ◽  
Neuropsychiatric Symptoms ◽  
Disease Diagnosis ◽  
Cag Repeat ◽  
Disease Modifying Therapies ◽  
Trial Evidence ◽  
Multidisciplinary Clinics ◽  
Progressive Cognitive Impairment

Huntington’s disease (HD) is an inherited neurodegenerative disease characterised by neuropsychiatric symptoms, a movement disorder (most commonly choreiform) and progressive cognitive impairment. The diagnosis is usually confirmed through identification of an increased CAG repeat length in the huntingtin gene in a patient with clinical features of the condition. Though diagnosis is usually straightforward, unusual presentations can occur, and it can be difficult to know when someone has transitioned from being an asymptomatic carrier into the disease state. This has become increasingly important recently, with several putative disease-modifying therapies entering trials. A growing number of conditions can mimic HD, including rare genetic causes, which must be considered in the event of a negative HD genetic test. Patients are best managed in specialist multidisciplinary clinics, including when considering genetic testing. Current treatments are symptomatic, and largely directed at the chorea and neurobehavioural problems, although supporting trial evidence for these is often limited.

scholarly journals Is There a Relation Between Caregiver Burden and Cognitive Dysfunction in Huntington’s Disease?

2020 ◽  
Author(s):  
M. M. Schumacher-Kuiper ◽  
A. M. van Loon ◽  
C. F. W. Peeters ◽  
M. R. Ekkel ◽  
C. M. P. M. Hertogh ◽  
...  
Keyword(s):  
Network Analysis ◽  
Huntington's Disease ◽  
Cognitive Functioning ◽  
Huntington’S Disease ◽  
Caregiver Burden ◽  
Neuropsychiatric Symptoms ◽  
Repeat Length ◽  
Cag Repeat ◽  
Cross Sectional ◽  
Indirect Relationship

Abstract Caring for a family member with Huntington’s disease (HD) can be seriously burdensome. Cognitive and neuropsychiatric symptoms that are part of HD can impact the quality of life of caregivers. Therefore, we investigated the relationship between caregiver burden, cognitive impairment and patient characteristics. A retrospective cross-sectional study was performed on 33 adult HD-outpatient-caregiver dyads. We assessed caregiver burden and cognitive functioning of the included patient on the same day with the MCSI and MoCA respectively. For statistical analysis, we performed a network analysis and used descriptive statistics to describe our study sample. Caregivers scored on average 13.5 out of 26 points on the MCSI. The scores on the MoCA of the HD patients varied from 9 to 30 and was on average 22. Our network analysis demonstrated an indirect relationship between cognitive functioning and caregiver burden, in which CAG repeat length and the time since HD has been diagnosed are the primary mediators. We found a negative association between CAG repeat length and cognitive functioning. Furthermore, a relationship was found between higher caregiver burden and psychotropic drug use. We observed an indirect relationship between cognitive functioning and caregiver burden using network analysis. This analysis produces comprehensible results with the variables of interest. This study sheds new light on the components that make up caregiver burden in HD.

scholarly journals Differential Diagnosis of Chorea—HIV Infection Delays Diagnosis of Huntington’s Disease by Years

2021 ◽  
Vol 11 (6) ◽  
pp. 710
Author(s):  
Jannis Achenbach ◽  
Simon Faissner ◽  
Carsten Saft
Keyword(s):  
Hiv Infection ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Disease Onset ◽  
Diagnostic Delay ◽  
Depression Scale ◽  
Cag Repeat ◽  
Psychiatric Disease ◽  
Disease Manifestation ◽  
Cross Sectional

Background: There is a broad range of potential differential diagnoses for chorea. Besides rare, inherited neurodegenerative diseases such as Huntington’s disease (HD) chorea can accompany basal ganglia disorders due to vasculitis or infections, e.g., with the human immunodeficiency virus (HIV). The clinical picture is complicated by the rare occurrence of HIV infection and HD. Methods: First, we present a case suffering simultaneously from HIV and HD (HIV/HD) focusing on clinical manifestation and disease onset. We investigated cross-sectional data regarding molecular genetic, motoric, cognitive, functional, and psychiatric disease manifestation of HIV/HD in comparison to motor-manifest HD patients without HIV infection (nonHIV/HD) in the largest cohort of HD patients worldwide using the registry study ENROLL-HD. Data were analyzed using ANCOVA analyses controlling for covariates of age and CAG repeat length between groups in IBM SPSS Statistics V.25. Results: The HD diagnosis in our case report was delayed by approximately nine years due to the false assumption that the HIV infection might have been the cause of chorea. Out of n = 21,116 participants in ENROLL-HD, we identified n = 10,125 motor-manifest HD patients. n = 23 male participants were classified as suffering from HIV infection as a comorbidity, compared to n = 4898 male non-HIV/HD patients. Except for age, with HIV/HD being significantly younger (p < 0.050), we observed no group differences regarding sociodemographic, genetic, educational, motoric, functional, and cognitive parameters. Male HIV/HD patients reported about a 5.3-year-earlier onset of HD symptoms noticed by themselves compared to non-HIV/HD (p < 0.050). Moreover, patients in the HIV/HD group had a longer diagnostic delay of 1.8 years between onset of symptoms and HD diagnosis and a longer time regarding assessment of first symptoms by the rater and judgement of the patient (all p < 0.050). Unexpectedly, HIV/HD patients showed less irritability in the Hospital Anxiety and Depression Scale (all p < 0.05). Conclusions: The HD diagnosis in HIV-infected male patients is secured with a diagnostic delay between first symptoms noticed by the patient and final diagnosis. Treating physicians therefore should be sensitized to think of potential alternative diagnoses in HIV-infected patients also afflicted by movement disorders, especially if there is evidence of subcortical atrophy and a history of hyperkinesia, even without a clear HD-family history. Those patients should be transferred for early genetic testing to avoid further unnecessary diagnostics and improve sociomedical care.

scholarly journals The Contribution of Somatic Expansion of the CAG Repeat to Symptomatic Development in Huntington’s Disease: A Historical Perspective

2021 ◽  
Vol 10 (1) ◽  
pp. 7-33
Author(s):  
Darren G. Monckton
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Human Genetics ◽  
Age At Onset ◽  
Cag Repeat ◽  
Model Systems ◽  
Causative Mutation ◽  
Inverse Association ◽  
Independent Manner ◽  
Dna Mismatch

The discovery in the early 1990s of the expansion of unstable simple sequence repeats as the causative mutation for a number of inherited human disorders, including Huntington’s disease (HD), opened up a new era of human genetics and provided explanations for some old problems. In particular, an inverse association between the number of repeats inherited and age at onset, and unprecedented levels of germline instability, biased toward further expansion, provided an explanation for the wide symptomatic variability and anticipation observed in HD and many of these disorders. The repeats were also revealed to be somatically unstable in a process that is expansion-biased, age-dependent and tissue-specific, features that are now increasingly recognised as contributory to the age-dependence, progressive nature and tissue specificity of the symptoms of HD, and at least some related disorders. With much of the data deriving from affected individuals, and model systems, somatic expansions have been revealed to arise in a cell division-independent manner in critical target tissues via a mechanism involving key components of the DNA mismatch repair pathway. These insights have opened new approaches to thinking about how the disease could be treated by suppressing somatic expansion and revealed novel protein targets for intervention. Exciting times lie ahead in turning these insights into novel therapies for HD and related disorders.

“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.

Plasma Cytokine Levels in Relation to Neuropsychiatric Symptoms and Cognitive Dysfunction in Huntington’s disease

2016 ◽  
Vol 5 (4) ◽  
pp. 369-377 ◽  
Author(s):  
Jos A. Bouwens ◽  
Erik van Duijn ◽  
Christa M. Cobbaert ◽  
Raymund A.C. Roos ◽  
Roos C. van der Mast ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cognitive Dysfunction ◽  
Neuropsychiatric Symptoms ◽  
Plasma Cytokine ◽  
Cytokine Levels

scholarly journals Targeting CAG repeat RNAs reduces Huntington’s disease phenotype independently of huntingtin levels

2016 ◽  
Vol 126 (11) ◽  
pp. 4319-4330 ◽  
Author(s):  
Laura Rué ◽  
Mónica Bañez-Coronel ◽  
Jordi Creus-Muncunill ◽  
Albert Giralt ◽  
Rafael Alcalá-Vida ◽  
...  
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Cag Repeat ◽  
Disease Phenotype

scholarly journals Skeletal muscle regeneration is altered in the R6/2 mouse model of Huntington's disease

2022 ◽  
Author(s):  
Sanzana Hoque ◽  
Marie Sjogren ◽  
Valerie Allamand ◽  
Kinga Gawlik ◽  
Naomi Franke ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Muscle Damage ◽  
Satellite Cell ◽  
Mouse Models ◽  
Satellite Cells ◽  
Muscle Fibers ◽  
Cag Repeat ◽  
Skeletal Muscle Regeneration

Huntington's disease (HD) is caused by CAG repeat expansion in the huntingtin (HTT) gene. Skeletal muscle wasting alongside central pathology is a well-recognized phenomenon seen in patients with HD and HD mouse models. HD muscle atrophy progresses with disease and affects prognosis and quality of life. Satellite cells, progenitors of mature skeletal muscle fibers, are essential for proliferation, differentiation, and repair of muscle tissue in response to muscle injury or exercise. In this study, we aim to investigate the effect of mutant HTT on the differentiation and regeneration capacity of HD muscle by employing in vitro mononuclear skeletal muscle cell isolation and in vivo acute muscle damage model in R6/2 mice. We found that, similar to R6/2 adult mice, neonatal R6/2 mice also exhibit a significant reduction in myofiber width and morphological changes in gastrocnemius and soleus muscles compared to WT mice. Cardiotoxin (CTX)-induced acute muscle damage in R6/2 and WT mice showed that the Pax7+ satellite cell pool was dampened in R6/2 mice at 4 weeks post-injection, and R6/2 mice exhibited an altered inflammatory profile in response to acute damage. Our results suggest that, in addition to the mutant HTT degenerative effects in mature muscle fibers, expression of mutant HTT in satellite cells might alter developmental and regenerative processes to contribute to the progressive muscle mass loss in HD. Taken together, the results presented here encourage further studies evaluating the underlying mechanisms of satellite cell dysfunction in HD mouse models.

scholarly journals Juvenile Huntington’s Disease and Other PolyQ Diseases, Update on Neurodevelopmental Character and Comparative Bioinformatic Review of Transcriptomic and Proteomic Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Karolina Świtońska-Kurkowska ◽  
Bart Krist ◽  
Joanna Delimata ◽  
Maciej Figiel
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Mouse Models ◽  
Muscular Atrophy ◽  
Expression Patterns ◽  
Cag Repeat ◽  
Human Cognition ◽  
Expression Data ◽  
Neuronal Stem Cell ◽  
Polyq Diseases

Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington’s disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. In addition, we extended our bioinformatic transcriptomic analysis by proteomics data. We identified a group of 13 commonly downregulated genes and proteins in HD mouse models. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.

scholarly journals Innovative Therapeutic Approaches for Huntington’s Disease: From Nucleic Acids to GPCR-Targeting Small Molecules

2021 ◽  
Vol 15 ◽  
Author(s):  
Hidetoshi Komatsu
Keyword(s):  
Nucleic Acid ◽  
Huntington's Disease ◽  
Huntington’S Disease ◽  
High Throughput Screening ◽  
Neurodegenerative Disorder ◽  
Direct Injection ◽  
Cag Repeat ◽  
Great Promise ◽  
Nucleic Acid Delivery ◽  
Small Interfering Rnas

Huntington’s disease (HD) is a fatal neurodegenerative disorder due to an extraordinarily expanded CAG repeat in the huntingtin gene that confers a gain-of-toxic function in the mutant protein. There is currently no effective cure that attenuates progression and severity of the disease. Since HD is an inherited monogenic disorder, lowering the mutant huntingtin (mHTT) represents a promising therapeutic strategy. Huntingtin lowering strategies mostly focus on nucleic acid approaches, such as small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs). While these approaches seem to be effective, the drug delivery to the brain poses a great challenge and requires direct injection into the central nervous system (CNS) that results in substantial burden for patients. This review discusses the topics on Huntingtin lowering strategies with clinical trials in patients already underway and introduce an innovative approach that has the potential to deter the disease progression through the inhibition of GPR52, a striatal-enriched class A orphan G protein-coupled receptor (GPCR) that represents a promising therapeutic target for psychiatric disorders. Chemically simple, potent, and selective GPR52 antagonists have been discovered through high-throughput screening and subsequent structure-activity relationship studies. These small molecule antagonists not only diminish both soluble and aggregated mHTT in the striatum, but also ameliorate HD-like defects in HD mice. This therapeutic approach offers great promise as a novel strategy for HD therapy, while nucleic acid delivery still faces considerable challenges.

scholarly journals The MID1 Protein: A Promising Therapeutic Target in Huntington’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Annika Heinz ◽  
Judith Schilling ◽  
Willeke van Roon-Mom ◽  
Sybille Krauß
Keyword(s):  
Huntington's Disease ◽  
Huntington’S Disease ◽  
Protein A ◽  
Cag Repeat ◽  
Cag Repeats ◽  
Progressive Movement ◽  
Promising Therapeutic Target ◽  
Promising Therapeutic Approach ◽  
Exon 1 ◽  
Polyglutamine Protein

Huntington’s disease (HD) is caused by an expansion mutation of a CAG repeat in exon 1 of the huntingtin (HTT) gene, that encodes an expanded polyglutamine tract in the HTT protein. HD is characterized by progressive psychiatric and cognitive symptoms associated with a progressive movement disorder. HTT is ubiquitously expressed, but the pathological changes caused by the mutation are most prominent in the central nervous system. Since the mutation was discovered, research has mainly focused on the mutant HTT protein. But what if the polyglutamine protein is not the only cause of the neurotoxicity? Recent studies show that the mutant RNA transcript is also involved in cellular dysfunction. Here we discuss the abnormal interaction of the mutant HTT transcript with a protein complex containing the MID1 protein. MID1 aberrantly binds to CAG repeats and this binding increases with CAG repeat length. Since MID1 is a translation regulator, association of the MID1 complex stimulates translation of mutant HTT mRNA, resulting in an overproduction of polyglutamine protein. Thus, blocking the interaction between MID1 and mutant HTT mRNA is a promising therapeutic approach. Additionally, we show that MID1 expression in the brain of both HD patients and HD mice is aberrantly increased. This finding further supports the concept of blocking the interaction between MID1 and mutant HTT mRNA to counteract mutant HTT translation as a valuable therapeutic strategy. In line, recent studies in which either compounds affecting the assembly of the MID1 complex or molecules targeting HTT RNA, show promising results.

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