Bates, GP; Dorsey, R; Gusella, JF; Hayden, MR; Kay, C; Leavitt, BR; Nance, M; ... Tabrizi, SJ; + view all Bates, GP; Dorsey, R; Gusella, JF; Hayden, MR; Kay, C; Leavitt, BR; Nance, M; Ross, CA; Scahill, RI; Wetzel, R; Wild, EJ; Tabrizi, SJ; - view fewer (2015) Huntington's disease. Nature Reviews Disease Primers , 1 , Article 15005. 10.1038/nrdp.2015.5.

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Abstract

Huntington’s disease is devastating to patients and their families — with autosomal dominant inheritance, onset typically in the prime of adult life, progressive course and combination of motor, cognitive and behavioural features. The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene which encodes the protein huntingtin. In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confers toxic gains of function and predispose the protein to fragmentation, resulting in neuronal dysfunction and death. In this Primer, we review the epidemiology of Huntington’s disease, noting that prevalence is higher than previously thought, geographically variable and increasing. We describe the relationship between CAG repeat length and clinical phenotype and the concept of genetic modifiers of the disease. We discuss normal huntingtin protein function, evidence for differential toxicity of mutant huntingtin variants, theories of huntingtin aggregation and the many different mechanisms of Huntington’s disease pathogenesis. We describe the genetic and clinical diagnosis of the condition, its clinical assessment and the multidisciplinary management of symptoms, given the absence of effective disease-modifying therapies. We review past and present clinical trials and therapeutic strategies under investigation, including impending trials of targeted huntingtin-lowering drugs and the progress in development of biomarkers that will support the next generation of trials.

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