Seminar 218 www.thelancet.com Vol 369 January 20, 2007 The hereditary nature of chorea was noted in the 19th century by several doctors, 1–4 but George Huntington’s vivid description led to the eponymous designation of the disorder as Huntington’s disease. 5 Over the next few decades, the worldwide distribution of the disorder and its juvenile form were recorded. The discovery of the causal HD gene (table 1) has stimulated research, and work is now focusing on molecular mechanisms of disease. Clinical findings in Huntington’s disease Individuals with Huntington’s disease can become symptomatic at any time between the ages of 1 and 80 years; before then, they are are healthy and have no detectable clinical abnormalities. 9 This healthy period merges imperceptibly with a prediagnostic phase, when patients show subtle changes of personality, cognition, and motor control. Both the healthy and prediagnostic stages are sometimes called presymptomatic, but in fact the prediagnostic phase is associated with findings, even though patients can be unaware of them. 10 Diagnosis takes place when findings become sufficiently developed and specific. 11 In the prediagnostic phase, individuals might become irritable or disinhibited and unreliable at work; multitasking becomes difficult and forgetfulness and anxiety mount. Family members note restlessness or fidgeting, sometimes keeping their partners awake at night. 4 Eventually, this stage merges with the diagnostic phase (see webmovie), during which time affected individuals show distinct chorea, incoordination, motor impersistence, and slowed saccadic eye movements. 12,13 Cognitive dysfunction in Huntington’s disease, often spares long-term memory but impairs executive functions, such as organising, planning, checking, or adapting alternatives, and delays the acquisition of new motor skills. 4,14 These features worsen over time; speech deteriorates faster than comprehension. Unlike cog- nition, psychiatric and behavioural symptoms arise with some frequency but do not show stepwise progression with disease severity. Depression is typical and suicide is estimated to be about five to ten times that of the general population (about 5–10%). 14–17 Manic and psychotic symptoms can develop. 4 Suicidal ideation is a frequent finding in patients with Huntington’s disease. In a cross-sectional study, about 9% of asymptomatic at-risk individuals contemplated suicide at least occasionally, 11 perhaps a result of being raised by an affected parent and awareness of the disease. In the prediagnostic phase, the proportion rose to 22%, but in patients who had been recently diagnosed, suicidal ideation was lower. The frequency increased again in later stages of the illness. 11 The correlation of suicidal ideation with suicide has not been studied in people with Huntington’s disease, but suicide attempts are not Huntington’s disease Francis O Walker Huntington’s disease is an autosomal-dominant, progressive neurodegenerative disorder with a distinct phenotype, including chorea and dystonia, incoordination, cognitive decline, and behavioural difficulties. Typically, onset of symptoms is in middle-age after affected individuals have had children, but the disorder can manifest at any time between infancy and senescence. The mutant protein in Huntington’s disease—huntingtin—results from an expanded CAG repeat leading to a polyglutamine strand of variable length at the N-terminus. Evidence suggests that this tail confers a toxic gain of function. The precise pathophysiological mechanisms of Huntington’s disease are poorly understood, but research in transgenic animal models of the disorder is providing insight into causative factors and potential treatments. Lancet 2007; 369: 218–28 Department of Neurology, Wake Forest University, Medical Center Blvd, Winston Salem, NC 27157, USA (Prof F O Walker MD) fwalker@wfubmc.edu Search strategy and selection criteria I searched Pub Med from 1965-2005 for the term “Huntington’s Disease” cross referenced with the terms “apoptosis”, “axonal transport”, “mitochondria”, “animal model”, “proteosome”, “transcription”, “juvenile”, “suicide”, “neurotransmitters”, “age of onset”, “identical twins”, “neurodegeneration”, and “imaging”. I translated all non-English language publications that resulted from this search strategy. I mainly selected articles from the past five years, but did not exclude commonly referenced and highly regarded older publications. I also searched the reference lists of articles identified by this search strategy and selected those that I judged relevant. Several review articles and book chapters were included because they provide comprehensive overviews beyond the scope of this Seminar. The reference list was further modified during the peer-review process based on comments from the reviewers. Year Event Publications (n)* 1374 Epidemic dancing mania described .. 1500 Paracelsus suggests CNS origin for chorea .. 1686 Thomas Sydenham describes post-infectious chorea .. 1832 John Elliotson identifies inherited form of chorea 1 .. 1872 George Huntington characterises Huntington’s disease 5 .. 1953 DNA structure elucidated 5 1955 Huntington’s disease described in Lake Maracaibo region of Venezuela 13 1967 World Federation of Neurology meeting on Huntington’s disease 38 1976 First animal model (kainic acid) of Huntington’s disease described 6 100 1983 Gene marker for Huntington’s disease discovered 138 1993 HD gene identified; 7 Huntington study group formed for clinical trials 172 1996 Transgenic mouse developed 8 242 2000 Drugs screened for effectiveness in transgenic animal models 344 *Approximate number of publications on Huntington’s disease cited for that year in the Current List of Medical Literature (before 1966) and in PubMed (1967 onwards). Table 1: History of Huntington’s disease See Online for webmovie