CLINICAL REVIEW For the full versions of these articles see bmj.com Huntington’s disease Marianne J U Novak,1 2 Sarah J Tabrizi1 3 1National Hospital for Neurology Huntington’s disease is a devastating inherited and Neurosurgery, London neurodegenerative disease characterised by progressive motor, WC1N 3BG cognitive, and psychiatric symptoms. Patients may present 2Wellcome Trust Centre for Neuroimaging, UCL Institute of with any of these symptoms, and familiarity with the pheno- Neurology, London WC1N 3BG type is therefore important. Chorea and loss of balance are 3Department of Neurodegenerative early symptoms that patients notice, although families often Disease, UCL Institute of Neurology notice cognitive or personality changes before this. Correspondence to: S Tabrizi [email protected] The disease occurs in all racial groups but is most common in people of northern European origin. Its prevalence in the Cite this as: BMJ 2010;340:c3109 Western hemisphere is 7-10/100 000.w1 The mean age of onset doi: 10.1136/bmj.c3109 of symptoms is 40 years, but juvenile onset (<20 years) and older onset (>70 years) forms are well recognised. The Hunt- ington’s Disease Association (HDA) has records of 6161 adults with symptomatic Huntington’s disease and 541 children with juvenile Huntington’s disease (in England and Wales) at the Fig 1 | Statistical parametric map showing grey matter volume loss in patient groups compared with controls. Pre-A and time of writing. This is a conservative estimate of prevalence pre-B are premanifest Huntington’s disease gene carriers with because it includes only those people in contact with the HDA, estimated time to clinical disease onset greater than and less and it suggests that the true prevalence of the disease is higher than 10.8 years, respectively. (This was estimated using CAG than previously thought.1 repeat length and age in a formula that has been well validated Although relatively uncommon, Huntington’s disease can and used extensively in research into Huntington’s diseasew10). be devastating for patients and their families. People who are at Stage 1 and stage 2 are patients with early manifest disease who risk of developing the disease because of a family history face have no functional impairment and mild functional impairment, difficult decisions about genetic testing. We review the features respectively. The figure shows progressive grey matter volume loss in the caudate and putamen (striatum) initially, followed of Huntington’s disease, recent advances in management, and by the cerebral cortex. Results are adjusted for age, sex, study advances in the practice and ethics of genetic testing that may site, and total intracranial volume and are corrected for multiple be relevant to a wide spectrum of health professionals. comparisons using family-wise error at P<0.05. Reproduced from Tabrizi et al,7 with permission from the Elsevier Publishing Group What are the clinical features of Huntington’s disease? The disease was originally named Huntington’s chorea after changes are initially seen most prominently in the striatum George Huntington, who wrote the first detailed description (part of the basal ganglia) and later become more widespread, in 1872. More recently, however, the name has changed to as shown in fig 1. Huntington’s disease to reflect the fact that chorea is not the Huntington’s disease progresses over 15-20 years. Char- only important manifestation of the disease. Many non-motor acteristic symptoms reflect a triad of motor, cognitive, and symptoms may be more disabling and distressing than the psychiatric manifestations of the disease (box 1). The onset motor symptoms.2-4 One study assessed the effect of cognitive of disease is currently defined as the point at which charac- and motor symptoms on the ability of 67 people with early teristic motor signs develop8; this is when a patient moves Huntington’s disease to carry out activities of daily living, and from being a “premanifest gene carrier” to having “manifest” found that cognitive impairment was associated with reduced disease. This distinction is somewhat arbitrary because most bmj.com archive functional ability independent of motor impairment.2 patients develop cognitive or psychiatric symptoms (or both) Ж Book review: Saturday Imaging and postmortem studies have shown that the during the prodromal (“premanifest”) period, often many (BMJ 2005;330:368) d isease is characterised by cerebral atrophy.5 6 Atrophic years before any motor signs are seen.7 9 w2 SUMMARY POINTS SOURCES AND SELECTION CRITERIA Huntington’s disease causes motor, cognitive, and psychiatric impairment This review is based on our experience of leading (SJT) Predictive and diagnostic genetic testing are available through specialist centres and working in (MJUN) the multidisciplinary Huntington’s disease clinic at the National Hospital for Neurology Genetic testing for the disease has many implications for patients and families and Neurosurgery, supported by an up to date literature The disease currently has no cure, but many therapeutic options exist to improve symptoms review performed using PubMed and a review of the Optimal care usually requires input from a multidisciplinary team Cochrane database. 34 BMJ | 3 JULY 2010 | VOLUME 341 CLINICAL REVIEW Box 1 | Common symptoms of Huntington’s disease Psychiatric symptoms Depression is one of the most common psychiatric symptoms Motor symptoms Chorea, dystonia, loss of postural reflexes, bradykinesia, rigidity and occurs as part of the disease, rather than merely as a response to diagnosis. A recent survey of 2835 patients with Cognitive symptoms Disorganisation as a result of difficulties with planning, initiating, and organising thoughts, the disease found that 40% had symptoms of depression, activities, and communication; perseveration; impulsivity; perceptual distortions; lack of and 50% reported having sought treatment for depression 10 insight; distractibility; difficulty in learning new information in the past. Other reported psychiatric symptoms include w3-w5 Psychiatric obsessive-compulsive symptoms and psychosis. Depression, obsessive-compulsive disorders, anxiety, irritability, apathy, hypersexuality It is important to recognise psychiatric symptoms in (uncommon), psychosis (uncommon) Huntington’s disease so that symptomatic treatment can Metabolic be offered. This may be difficult later in the disease because Weight loss, sleep disturbance diagnoses may be obscured by other features of the disease; Others depression, for example, may be difficult to detect in a patient Dysphasia (combination of motor and language difficulties), dysphagia (combination of who has altered facial expressions and tone of voice. Con- motor problems, impulsivity, and distractibility) versely, metabolic symptoms such as weight loss and sleep disturbance may be wrongly attributed to depression. Motor symptoms The motor symptoms of Huntington’s disease can be Suicide risk divided into two categories: added involuntary move- Patients with Huntington’s disease are more likely than mem- ments such as chorea, and impaired voluntary move- bers of the general population to commit suicide according ments, which cause limb incoordination and impaired to a meta-analysis of studies that reported mortality associ- hand function. These symptoms are worsened by loss ated with mental disorders (standardised mortality ratio of of postural reflexes. The pattern of symptoms tends to 290).w6 A survey of 4171 carriers of the Huntington’s gene change over time, with chorea declining and dystonia, with premanifest and manifest disease found that 17.5% rigidity, and bradykinesia becoming more marked. had suicidal thoughts at or around the time of assessment and 10% of those surveyed had made at least one suicide Cognitive symptoms attempt in the past.11 Suicidal ideation was highest in gene Cognitive impairment includes slowing of thought carriers who were nearing the threshold of being diagnosed processing and deterioration of executive functions with manifest disease (those with soft motor signs of Hunt- (high level cognitive processes that control other aspects ington’s disease), and in those who were beginning to lose of cognitive function). Typically, patients report difficulty their functional ability and independence (those with stage with multitasking, concentration, and short term memory. 2 disease). Risk factors for suicide in Huntington’s disease Thinking style becomes more concrete and less efficient, include depression and impulsivity.4 Some people with the and the planning, initiation, and organisation of time, disease also have suicidal thoughts in the absence of depres- thoughts, and activities become harder. People with sionw7: for some, thoughts of suicide seem to be a rational Huntington’s disease are often impulsive and develop response to their imminent loss of independence. psychomotor perseveration. Visuospatial perception can also deteriorate.4 9 Metabolic symptoms Huntington’s disease causes metabolic symptoms, which Linkage markers on chromosome 4 include catabolic weight loss, endocrine dysfunction, and sleep disturbance.12 Parent with Unaffected A B C D Huntington's parent disease Advanced disease By the time patients have endstage disease they are pro- Either A or B Neither C nor D foundly disabled. Communication may be severely limited carries mutant carries mutant and muteness is common, which can result in agitation HTT gene HTT gene and frustration. Huntington’s disease does not cause global Partner