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Huntington disease: Clinical features and diagnosis

Oksana Suchowersky, MD, FRCPC, FCCMG
Section Editor
Howard I Hurtig, MD
Deputy Editor
John F Dashe, MD, PhD


Huntington disease (HD) is an inherited progressive neurodegenerative disorder characterized by choreiform movements, psychiatric problems, and dementia. It is caused by a cytosine-adenine-guanine (CAG) trinucleotide repeat expansion in the huntingtin (HTT) gene on chromosome 4p and inherited in an autosomal-dominant pattern [1]. The pathophysiology of HD is not fully understood, although it is thought to be related to toxicity of the mutant huntingtin protein.

As there is no known cure, treatment is symptomatic and remains supportive. Genetic mouse models are expanding our understanding of the disease and may lead to disease modifying therapy in the future.

This topic will review the clinical features and diagnosis of HD. Other aspects of HD are discussed separately. (See "Huntington disease: Genetics and pathogenesis" and "Huntington disease: Management".)


The genetics and pathogenesis of HD are reviewed here briefly and discussed in detail separately. (See "Huntington disease: Genetics and pathogenesis".)

Huntington disease is an autosomal dominant disorder caused by an expansion of the CAG trinucleotide in the huntingtin gene (also known as the HD gene) that encodes the protein huntingtin, resulting in an expanded polyglutamine tract. Huntingtin is present in a large number of tissues throughout the body. However, pathology mainly involves the central nervous system, with atrophy of the caudate and putamen (the neostriatum) being most prominent. At the cellular level, protein aggregates are seen both in the cytoplasm and nucleus. The pathophysiology of neuron loss is incompletely understood. The huntingtin protein is thought to become toxic with the CAG expansion ("gain of function") but continues to serve a function that is critical to survival in early development.


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Literature review current through: Dec 2016. | This topic last updated: Wed Oct 19 00:00:00 GMT+00:00 2016.
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  1. Richards RI. Dynamic mutations: a decade of unstable expanded repeats in human genetic disease. Hum Mol Genet 2001; 10:2187.
  2. Pringsheim T, Wiltshire K, Day L, et al. The incidence and prevalence of Huntington's disease: a systematic review and meta-analysis. Mov Disord 2012; 27:1083.
  3. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers 2015; 1:15005.
  4. Brinkman RR, Mezei MM, Theilmann J, et al. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet 1997; 60:1202.
  5. Maat-Kievit A, Losekoot M, Zwinderman K, et al. Predictability of age at onset in Huntington disease in the Dutch population. Medicine (Baltimore) 2002; 81:251.
  6. Seneca S, Fagnart D, Keymolen K, et al. Early onset Huntington disease: a neuronal degeneration syndrome. Eur J Pediatr 2004; 163:717.
  7. Jähnel M. [The case of a 86-years old woman first diagnosed with Huntington's disease]. Psychiatr Prax 2004; 31 Suppl 1:S134.
  8. McCusker EA, Gunn DG, Epping EA, et al. Unawareness of motor phenoconversion in Huntington disease. Neurology 2013; 81:1141.
  9. Blekher TM, Yee RD, Kirkwood SC, et al. Oculomotor control in asymptomatic and recently diagnosed individuals with the genetic marker for Huntington's disease. Vision Res 2004; 44:2729.
  10. Lasker AG, Zee DS. Ocular motor abnormalities in Huntington's disease. Vision Res 1997; 37:3639.
  11. Blekher T, Johnson SA, Marshall J, et al. Saccades in presymptomatic and early stages of Huntington disease. Neurology 2006; 67:394.
  12. Starr A. A disorder of rapid eye movements in Huntington's chorea. Brain 1967; 90:545.
  13. Leigh RJ, Newman SA, Folstein SE, et al. Abnormal ocular motor control in Huntington's disease. Neurology 1983; 33:1268.
  14. Kirkwood SC, Su JL, Conneally P, Foroud T. Progression of symptoms in the early and middle stages of Huntington disease. Arch Neurol 2001; 58:273.
  15. Di Maio L, Squitieri F, Napolitano G, et al. Onset symptoms in 510 patients with Huntington's disease. J Med Genet 1993; 30:289.
  16. van Duijn E, Kingma EM, Timman R, et al. Cross-sectional study on prevalences of psychiatric disorders in mutation carriers of Huntington's disease compared with mutation-negative first-degree relatives. J Clin Psychiatry 2008; 69:1804.
  17. van Duijn E, Kingma EM, van der Mast RC. Psychopathology in verified Huntington's disease gene carriers. J Neuropsychiatry Clin Neurosci 2007; 19:441.
  18. Shiwach R. Psychopathology in Huntington's disease patients. Acta Psychiatr Scand 1994; 90:241.
  19. Paulsen JS, Ready RE, Hamilton JM, et al. Neuropsychiatric aspects of Huntington's disease. J Neurol Neurosurg Psychiatry 2001; 71:310.
  20. Zappacosta B, Monza D, Meoni C, et al. Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or CAG repeat length in Huntington's disease. Arch Neurol 1996; 53:493.
  21. Tsuang D, Almqvist EW, Lipe H, et al. Familial aggregation of psychotic symptoms in Huntington's disease. Am J Psychiatry 2000; 157:1955.
  22. Di Maio L, Squitieri F, Napolitano G, et al. Suicide risk in Huntington's disease. J Med Genet 1993; 30:293.
  23. Wetzel HH, Gehl CR, Dellefave-Castillo L, et al. Suicidal ideation in Huntington disease: the role of comorbidity. Psychiatry Res 2011; 188:372.
  24. Hubers AA, Reedeker N, Giltay EJ, et al. Suicidality in Huntington's disease. J Affect Disord 2012; 136:550.
  25. Snowden J, Craufurd D, Griffiths H, et al. Longitudinal evaluation of cognitive disorder in Huntington's disease. J Int Neuropsychol Soc 2001; 7:33.
  26. Pillon B, Deweer B, Agid Y, Dubois B. Explicit memory in Alzheimer's, Huntington's, and Parkinson's diseases. Arch Neurol 1993; 50:374.
  27. Duff K, Paulsen J, Mills J, et al. Mild cognitive impairment in prediagnosed Huntington disease. Neurology 2010; 75:500.
  28. Hamilton JM, Wolfson T, Peavy GM, et al. Rate and correlates of weight change in Huntington's disease. J Neurol Neurosurg Psychiatry 2004; 75:209.
  29. Aziz NA, van der Burg JM, Landwehrmeyer GB, et al. Weight loss in Huntington disease increases with higher CAG repeat number. Neurology 2008; 71:1506.
  30. Sanberg PR, Fibiger HC, Mark RF. Body weight and dietary factors in Huntington's disease patients compared with matched controls. Med J Aust 1981; 1:407.
  31. Lodi R, Schapira AH, Manners D, et al. Abnormal in vivo skeletal muscle energy metabolism in Huntington's disease and dentatorubropallidoluysian atrophy. Ann Neurol 2000; 48:72.
  32. Squitieri F, Berardelli A, Nargi E, et al. Atypical movement disorders in the early stages of Huntington's disease: clinical and genetic analysis. Clin Genet 2000; 58:50.
  33. Carella F, Scaioli V, Ciano C, et al. Adult onset myoclonic Huntington's disease. Mov Disord 1993; 8:201.
  34. Kereshi S, Schlagenhauff RE, Richardson KS. Myoclonic and major seizures in early adult Huntington's chorea: case-report and electro-clinical findings. Clin Electroencephalogr 1980; 11:44.
  35. Dorsey ER, Beck CA, Darwin K, et al. Natural history of Huntington disease. JAMA Neurol 2013; 70:1520.
  36. Kirkwood SC, Siemers E, Stout JC, et al. Longitudinal cognitive and motor changes among presymptomatic Huntington disease gene carriers. Arch Neurol 1999; 56:563.
  37. Huntington Study Group PHAROS Investigators. At risk for Huntington disease: The PHAROS (Prospective Huntington At Risk Observational Study) cohort enrolled. Arch Neurol 2006; 63:991.
  38. Paulsen JS, Hayden M, Stout JC, et al. Preparing for preventive clinical trials: the Predict-HD study. Arch Neurol 2006; 63:883.
  39. Langbehn DR, Paulsen JS, Huntington Study Group. Predictors of diagnosis in Huntington disease. Neurology 2007; 68:1710.
  40. Paulsen JS, Langbehn DR, Stout JC, et al. Detection of Huntington's disease decades before diagnosis: the Predict-HD study. J Neurol Neurosurg Psychiatry 2008; 79:874.
  41. Tabrizi SJ, Langbehn DR, Leavitt BR, et al. Biological and clinical manifestations of Huntington's disease in the longitudinal TRACK-HD study: cross-sectional analysis of baseline data. Lancet Neurol 2009; 8:791.
  42. Biglan KM, Ross CA, Langbehn DR, et al. Motor abnormalities in premanifest persons with Huntington's disease: the PREDICT-HD study. Mov Disord 2009; 24:1763.
  43. Bechtel N, Scahill RI, Rosas HD, et al. Tapping linked to function and structure in premanifest and symptomatic Huntington disease. Neurology 2010; 75:2150.
  44. Tabrizi SJ, Scahill RI, Durr A, et al. Biological and clinical changes in premanifest and early stage Huntington's disease in the TRACK-HD study: the 12-month longitudinal analysis. Lancet Neurol 2011; 10:31.
  45. Weir DW, Sturrock A, Leavitt BR. Development of biomarkers for Huntington's disease. Lancet Neurol 2011; 10:573.
  46. Tabrizi SJ, Scahill RI, Owen G, et al. Predictors of phenotypic progression and disease onset in premanifest and early-stage Huntington's disease in the TRACK-HD study: analysis of 36-month observational data. Lancet Neurol 2013; 12:637.
  47. Aylward EH, Sparks BF, Field KM, et al. Onset and rate of striatal atrophy in preclinical Huntington disease. Neurology 2004; 63:66.
  48. Feigin A, Leenders KL, Moeller JR, et al. Metabolic network abnormalities in early Huntington's disease: an [(18)F]FDG PET study. J Nucl Med 2001; 42:1591.
  49. Lee JK, Mathews K, Schlaggar B, et al. Measures of growth in children at risk for Huntington disease. Neurology 2012; 79:668.
  50. Bamford KA, Caine ED, Kido DK, et al. A prospective evaluation of cognitive decline in early Huntington's disease: functional and radiographic correlates. Neurology 1995; 45:1867.
  51. Young AB, Penney JB, Starosta-Rubinstein S, et al. PET scan investigations of Huntington's disease: cerebral metabolic correlates of neurological features and functional decline. Ann Neurol 1986; 20:296.
  52. Clark VP, Lai S, Deckel AW. Altered functional MRI responses in Huntington's disease. Neuroreport 2002; 13:703.
  53. Rosas HD, Liu AK, Hersch S, et al. Regional and progressive thinning of the cortical ribbon in Huntington's disease. Neurology 2002; 58:695.
  54. Rosas HD, Hevelone ND, Zaleta AK, et al. Regional cortical thinning in preclinical Huntington disease and its relationship to cognition. Neurology 2005; 65:745.
  55. Rosas HD, Salat DH, Lee SY, et al. Cerebral cortex and the clinical expression of Huntington's disease: complexity and heterogeneity. Brain 2008; 131:1057.
  56. Siesling S, Vegter-van de Vlis M, Losekoot M, et al. Family history and DNA analysis in patients with suspected Huntington's disease. J Neurol Neurosurg Psychiatry 2000; 69:54.
  57. Almqvist EW, Elterman DS, MacLeod PM, Hayden MR. High incidence rate and absent family histories in one quarter of patients newly diagnosed with Huntington disease in British Columbia. Clin Genet 2001; 60:198.
  58. Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of the Huntington's disease mutation. The sensitivity and specificity of measuring CAG repeats. N Engl J Med 1994; 330:1401.
  59. Andrew SE, Goldberg YP, Kremer B, et al. Huntington disease without CAG expansion: phenocopies or errors in assignment? Am J Hum Genet 1994; 54:852.
  60. Mariani LL, Tesson C, Charles P, et al. Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach. JAMA Neurol 2016; 73:1105.
  61. Wild EJ, Tabrizi SJ. Huntington's disease phenocopy syndromes. Curr Opin Neurol 2007; 20:681.
  62. Hensman Moss DJ, Poulter M, Beck J, et al. C9orf72 expansions are the most common genetic cause of Huntington disease phenocopies. Neurology 2014; 82:292.
  63. Wild EJ, Mudanohwo EE, Sweeney MG, et al. Huntington's disease phenocopies are clinically and genetically heterogeneous. Mov Disord 2008; 23:716.
  64. Almqvist EW, Bloch M, Brinkman R, et al. A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease. Am J Hum Genet 1999; 64:1293.
  65. Simpson SA, Harper PS, United Kingdom Huntington's Disease Prediction Consortium. Prenatal testing for Huntington's disease: experience within the UK 1994-1998. J Med Genet 2001; 38:333.
  66. Friedman JH, Trieschmann ME, Myers RH, Fernandez HH. Monozygotic twins discordant for Huntington disease after 7 years. Arch Neurol 2005; 62:995.
  67. Martino D, Stamelou M, Bhatia KP. The differential diagnosis of Huntington's disease-like syndromes: 'red flags' for the clinician. J Neurol Neurosurg Psychiatry 2013; 84:650.
  68. Margolis RL, Holmes SE, Rosenblatt A, et al. Huntington's Disease-like 2 (HDL2) in North America and Japan. Ann Neurol 2004; 56:670.
  69. Rudnicki DD, Holmes SE, Lin MW, et al. Huntington's disease--like 2 is associated with CUG repeat-containing RNA foci. Ann Neurol 2007; 61:272.
  70. Santos C, Wanderley H, Vedolin L, et al. Huntington disease-like 2: the first patient with apparent European ancestry. Clin Genet 2008; 73:480.
  71. Bauer P, Laccone F, Rolfs A, et al. Trinucleotide repeat expansion in SCA17/TBP in white patients with Huntington's disease-like phenotype. J Med Genet 2004; 41:230.
  72. Curtis AR, Fey C, Morris CM, et al. Mutation in the gene encoding ferritin light polypeptide causes dominant adult-onset basal ganglia disease. Nat Genet 2001; 28:350.
  73. Walker FO. Huntington's disease. Lancet 2007; 369:218.