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Clévio Nóbrega - Polyglutamine Disorders

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Book:
Polyglutamine Disorders
Author:
Clvio Nbrega / Lus Pereira de Almeida
Publisher:
Springer
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Books / Romance novel
Year:
2018
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Polyglutamine Disorders: summary, description and annotation

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This book provides a cutting-edge review of polyglutamine disorders. It primarily focuses on two main aspects: (1) the mechanisms underlying the pathologies development and progression, and (2) the therapeutic strategies that are currently being explored to stop or delay disease progression.

Polyglutamine (polyQ) disorders are a group of inherited neurodegenerative diseases with a fatal outcome that are caused by an abnormal expansion of a coding trinucleotide repeat (CAG), which is then translated in an abnormal protein with an elongated glutamine tract (Q). To date, nine polyQ disorders have been identified and described: dentatorubral-pallidoluysian atrophy (DRPLA); Huntingtons disease (HD); spinalbulbar muscular atrophy (SBMA); and six spinocerebellar ataxias (SCA 1, 2, 3, 6, 7, and 17).

The genetic basis of polyQ disorders is well established and described, and despite important advances that have opened up the possibility of generating genetic models of the disease, the mechanisms that cause neuronal degeneration are still largely unknown and there is currently no treatment available for these disorders. Further, it is believed that the different polyQ may share some mechanisms and pathways contributing to neurodegeneration and disease progression.

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Springer International Publishing AG 2018

Clvio Nbrega and Lus Pereira de Almeida (eds.) Polyglutamine Disorders Advances in Experimental Medicine and Biology 1049

1. Clinical Features of Huntingtons Disease

Rhia Ghosh 1 and Sarah J. Tabrizi 1

(1)

UCL Huntingtons Disease Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, London, WC1N 3BG, UK

Sarah J. Tabrizi

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Abstract

Huntingtons 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 1520 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.

Keywords

Huntingtons disease Genetics Symptoms Management Therapeutics Biomarkers

1.1 Introduction

Huntingtons disease (HD) is one of the most common causes of dominantly inherited neurodegenerative disease []. The condition was first described in the USA by George Huntingtin in 1872, himself a newly qualified doctor at the time, and his original descriptions of the disease remain true today.

As yet there are still no disease modifying treatments available, but an intensive international research effort is underway with many clinical trials currently on-going. In this chapter we will first cover the epidemiology, genetics , and pathogenesis of HD and then discuss clinical aspects of the disease and the latest developments in HD therapeutics research.

1.2 Epidemiology

The prevalence of HD had been thought to be 410/100,000 in Western populations [].

The disease is thought to have migrated from North-West Europe to other parts of the world, and there is global variation in prevalence , with naturally low rates in Japan, Hong Kong and Taiwan [].

1.3 Genetics of Huntingtons Disease

HD is a single-gene disorder with autosomal dominant transmission and so the presence of the mutation on either allele leads to the disease. Therefore an affected parent has a 50% chance of passing it on to their child. The mutation is an expanded CAG triplet repeat near the start of exon 1 of the Huntingtin gene ( HTT ), which lies on the short arm of chromosome 4. On translation , this leads to the presence of a polyglutamine (polyQ) stretch at the N-terminus of Huntingtin protein (HTT).

The wild-type gene carries 1035 CAG repeats , with a mean value of 18 CAG repeats across the population (although this mean value is greater in populations with higher disease prevalence ) []. HTT with 2735 CAG repeats is referred to as an intermediate allele.

Intermediate alleles in the general population are thought to arise from stepwise expansion of the CAG repeat over many generations. People who inherit intermediate length alleles have long been thought to be unaffected, but a behavioural phenotype has now been identified in this group [].

This intrinsic instability of the CAG repeat during meiosis especially affects the disease gene, leading to expansions (and sometimes contractions) in repeat length inherited by successive generations [].

As with all genetic conditions a detailed family history is essential to help make a correct diagnosis. However 68% of patients with newly diagnosed HD have no family history []. As mentioned above, de novo mutations may arise from intermediate length alleles, leading to sporadic cases. Seemingly sporadic cases may occur following non-paternity, misdiagnosis in prior generations, or when deaths of family members occur from other causes before development of neurological symptoms thus masking the presence of the HD gene.

1.3.1 Effect of CAG Repeat Length on Disease Phenotype

Disease onset is defined clinically as the presence of unequivocal extrapyramidal motor signs suggestive of HD. In typical mid-life onset HD with CAG repeat 4055, the length of the CAG repeat accounts for ~56% of the variability in age at motor onset [].

Taking into account the CAG repeat length as well as the number of disease free years already lived, a conditional probability model was developed by Langbehn et al. which is able to estimate the chance of on-going disease free survival over a number of years []. However, models based on population data cannot be applied in a one-to-one clinical setting and it is not possible to accurately predict an individuals age of onset of disease from their CAG repeat length.

Patients often experience psychiatric and cognitive symptoms , as well as very subtle motor disturbances for many years before their official disease onset. CAG repeat length correlates much less strongly with age of onset of psychiatric symptoms , but does show some correlation with rate of disease progression []. The duration of disease from diagnosis to death is independent of CAG repeat length.

1.4 Pathogenesis of Huntingtons Disease

Huntingtin is a large 350 kDa protein comprised of multiple repeated units of 50 amino acids, termed HEAT repeats, which assemble into a superhelical structure with a hydrophobic core. Compared to the wild-type protein, the mutant protein contains an expanded polyglutamine stretch starting at residue 18 [.

Table 1.1

Pathogenic mechanisms in Huntingtons disease

Mechanism	Role of mutant Huntingtin
Proteolysis and generation of mHTT fragments	Multiple lines of evidence support the toxic fragment hypothesis that proteolytic cleavage of mutant HTT liberates toxic N-terminal fragments containing the expanded polyQ tract, which contribute to cell death through accumulation and additional activation of further proteolytic caspases []
Inclusion formation	Intranuclear inclusions of mutant HTT are a pathognomic feature of HD. Inclusions also form in the cytoplasm, dendrites and axon terminals, though to a lesser extent. Inclusions are heterogeneous population comprising different forms of mHTT []
Post-translational modification of mHTT	HTT undergoes extensive post-translational modification at multiple sites through phosphorylation , SUMOylation , acetylation, ubiquitination and palmitoylation. All these modifications can exert an effect on mHTT pathogenicity, but their full significance, interdependence and exact role in any pathogenic mechanism remains largely unknown []
Loss of neurotrophin (BDNF) support	There is loss of brain-derived neurotrophic factor (BDNF) support from cortico-striatal projections, as mHTT is known to interfere with both the expression and trafficking of BDNF that promotes survival of striatal neurons []

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