Huntington disease is devastating to patients and their families — with autosomal dominant inheritance, onset typically in the prime of adult life, progressive course, and a combination of motor, cognitive and behavioural features. The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene that encodes the protein huntingtin. In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confer 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 disease, noting that prevalence is higher than previously thought, geographically variable and increasing. We describe the relationship between CAG repeat length and clinical phenotype, as well as 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 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. For an illustrated summary of this Primer, visit: http://go.nature.com/hPMENh
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The authors thank R. Korn for his assistance in preparing and editing the Current clinical trials section. They thank J. Behagg for his assistance in preparing the manuscript.
S.J.T. has served on advisory boards or had consultancies with GlaxoSmithKline, Ixico Technologies, Isis Pharmaceuticals, Novartis, Roche, Sanofi-Aventis, Siena Biotech Takeda Pharmaceuticals International and TEVA Pharmaceuticals. All honoraria paid for these consultancies and advisory boards go to University College London, UK, S.J.T.'s employer. R.D. has received compensation for consulting activities from Clintrex, Lundbeck, mc10, Shire and the US National Institute of Neurological Disorders and Stroke; research support from Auspex Pharmaceuticals, Biogen, Davis Phinney Foundation, Great Lakes Neurotechnologies, Huntington Study Group, Lundbeck, The Michael J. Fox Foundation, US National Science Foundation, Patient-Centered Outcomes Research Institute, Prana Biotechnology and Sage Bionetworks; and has stock options in Grand Rounds. R.D. is an uncompensated advisor to SBR Health and Vidyo. M.R.H. is president of Global R&D and Chief Scientific Officer at Teva. B.R.L. is the Co-Chair of the Huntington Study Group; has acted as a consultant for Novartis, Pfizer, Siena Biotech, Teva and Isis; and has received relevant research grant support from CHDI, Teva, the Canadian Institutes of Health Research and the Michael Smith Foundation. M.N. has served on paid advisory boards for Lundbeck Inc. and Auspex Pharmaceuticals, and receives research grant funding from Teva Pharmaceuticals and NeuroSearch. C.A.R. currently acts as a consultant for Raptor Pharma; has consulted for Isis, Pfizer, Delbiopharm and Lundbeck; and receives research funding from Johnson & Johnson/Janssen Pharma. The other authors declare no competing interests.
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Bates, G., Dorsey, R., Gusella, J. et al. Huntington disease. Nat Rev Dis Primers 1, 15005 (2015). https://doi.org/10.1038/nrdp.2015.5
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