We searched PubMed (January, 2000, to June, 2010) with the terms “Huntington's disease” or “Huntingtin” and “Reviews”, and then “HD” or “Htt” with “genetics”, “treatment”, “imaging”, “biomarkers”, and specific targets, as identified in initial searches, plus our own files. We only reviewed articles in English.
ReviewHuntington's disease: from molecular pathogenesis to clinical treatment
Introduction
Huntington's disease can be regarded as a model neurodegenerative disorder. It is monogenic, fully penetrant, and—similar to other neurodegenerative diseases—a disorder of protein misfolding. The gene for Huntington's disease, huntingtin (HTT), was discovered1 17 years ago, and much has been learned about the disease's pathogenesis since then.
Huntington's disease is caused by a CAG triplet repeat expansion in HTT, which encodes an expanded polyglutamine stretch in the huntingtin (HTT) protein.1 The disease is inherited in an autosomal dominant manner with age-dependent penetrance, and repeat CAG lengths of 40 or more are associated with nearly full penetrance by age 65 years.2 Individuals at risk of inheriting the expanded CAG nucleotide can be identified before clinical onset by predictive genetic testing. Longer CAG repeats predict earlier onset, accounting for up to 50–70% of variance in age of onset, with the remainder likely to be due to modifying genes and the environment.3 By contrast, length of the CAG repeat seems to contribute less to the rate of progression,4 and understanding the determinants of rate of progression could provide means for intervention.
Prevalence of Huntington's disease is 4–10 per 100 000 in the western world, with many more people at risk of the disease. Mean age of onset is 40 years, with death occurring 15–20 years from onset (figure 1). Clinical features of Huntington's disease include progressive motor dysfunction, cognitive decline, and psychiatric disturbance,5, 6 probably caused by both neuronal dysfunction and neuronal cell death. Formal diagnosis of Huntington's disease is made on the basis of characteristic extrapyramidal motor signs of chorea, dystonia, bradykinesia, or incoordination in an individual at risk.7 Although chorea is usually prominent early in the course of the disease, later progressive bradykinesia, incoordination, and rigidity (so-called motor impairment) are more disabling functionally.8 Many patients have substantial cognitive or behavioural disturbances before onset of diagnostic motor signs.9
Most drugs currently used for symptomatic management of Huntington's disease (table)10 are derived from anecdotal clinical experience.11, 12, 13 In a randomised controlled trial, tetrabenazine reduced chorea.14 Behavioural and social interventions are often as effective as drug treatments for behavioural difficulties.15
Identification of new targets, strategies for drug discovery, and therapeutic approaches are now reaching an important turning point. Methods leading to successful development and testing of rational neuroprotective (disease-modifying) treatments are on the horizon.
Furthermore, identification of biomarkers in individuals positive for the Huntington's disease expansion mutation, who may have subtle cognitive motor or emotional signs and symptoms, but prior to sufficient motor signs for a formal diagnosis (prodromal disease), suggests that preventive treatment could be possible.
Our Review covers the pathogenesis of Huntington's disease relevant to current and potential future therapeutic targets and the translation of this work to clinical trials. We highlight relevant areas of progress and principles, questions, and challenges ahead in trying to develop and test such treatments in patients, particularly before functional impairment happens, when neuronal dysfunction and other neurobiological abnormalities are most likely to be still reversible.
Section snippets
Principles of pathogenesis
HTT is a very large protein predicted to consist mainly of repeated units of about 50 amino acids, termed HEAT repeats (figure 2). These repeats are composed of two antiparallel α-helices with a helical hairpin configuration,16 which assemble into a superhelical structure with a continuous hydrophobic core. HTT has many interaction partners, particularly at its N-terminus,17 suggesting that it serves as a scaffold to coordinate complexes of other proteins. HTT also undergoes extensive
Selected mechanisms, targets, and experimental treatments
The directionality and sequence of pathogenic events in Huntington's disease is still poorly understood. Ideally, therapeutic interventions would target early steps in a pathogenic chain of events. With our currently limited knowledge, it is difficult to identify the crucial steps (after those that include HTT) in the pathogenic pathways. Furthermore, some cellular effects, which might appear relatively far downstream, such as alterations in cellular metabolism (figure 3), could feed back to
Development of outcomes and biomarkers for disease-modifying therapies
Over the past 10 years, many clinical trials in Huntington's disease have been done.146 Up to now, no drug has proven efficacious in a randomised placebo-controlled trial of disease-modifying therapy. Clinical trials are challenging, because Huntington's disease progresses slowly and there is clinical heterogeneity. The clinical rating scales used to assess progression, such as the unified Huntington's disease rating scale,7 similar to all clinical rating scales, are subject to inter-rater and
Conclusions and questions for future study
In almost 20 years since the gene mutation for Huntington's disease was identified, important advances have been made, but much is still unknown, and fundamental questions remain.
Of all the protein interactions of mutant HTT, which are most important for pathogenesis? Which of the post-translational modifications of HTT will yield the best therapeutic targets? To what extent does loss of HTT function contribute to pathogenesis or modify the effects of gain of function? Therapeutic strategies
Search strategy and selection criteria
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Tracking mutant huntingtin aggregation kinetics in cells reveals three major populations that include an invariant oligomer pool
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A new model for prediction of the age of onset and penetrance for Huntington's disease based on CAG length
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Venezuelan kindreds reveal that genetic and environmental factors modulate Huntington's disease age of onset
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