title: Huntington disease.
abstract: 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.
authors.affiliation: Department of Medical and Molecular Genetics, King's College London, London, UK.
authors.forename: Gillian P
authors.initials: GP
authors.lastname: Bates
authors.affiliation: Department of Neurology, University of Rochester Medical Center, Rochester, New York, USA.
authors.forename: Ray
authors.initials: R
authors.lastname: Dorsey
authors.affiliation: Molecular Neurogenetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, and Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: James F
authors.initials: JF
authors.lastname: Gusella
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hayden
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Chris
authors.initials: C
authors.lastname: Kay
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Department of Medical Genetics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Blair R
authors.initials: BR
authors.lastname: Leavitt
authors.affiliation: Struthers Parkinson's Center, Golden Valley, Minneapolis, Minnesota, USA; and Hennepin County Medical Center, Minneapolis, Minnesota, USA.
authors.forename: Martha
authors.initials: M
authors.lastname: Nance
authors.affiliation: Division of Neurobiology, Department of Psychiatry and Departments of Neurology, Pharmacology and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ross
authors.affiliation: Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Rachael I
authors.initials: RI
authors.lastname: Scahill
authors.affiliation: Department of Structural Biology and Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Wetzel
authors.affiliation: Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Wild
authors.affiliation: Department of Neurodegenerative Disease, University College London Institute of Neurology, Queen Square, London WC1N 3BG, UK.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Tabrizi
mesh_terms: D000328:Adult; D006801:Humans; D000071058:Huntingtin Protein / Q000235:genetics; D006816:Huntington Disease / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D009419:Nerve Tissue Proteins / Q000235:genetics; D010455:Peptides / Q000235:genetics; D010641:Phenotype; D015995:Prevalence; D019680:Trinucleotide Repeat Expansion
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D010455:Peptides; C097188:polyglutamine