, Volume 1, Issue 2, pp 255–262 | Cite as

Huntington’s disease genetics



Huntington’s disease (HD) is a dominantly transmitted neurodegenerative disorder with wide variation in onset age but with an average age at onset of 40 years. Children ofHD gene carriers have a 50% chance of inheriting the disease. The characteristic symptoms of HD are involuntary choreiform movements, cognitive impairment, mood disorders, and behavioral changes which are chronic and progressive over the course of the illness. HD is a “trinucleotide repeat” disorder, which is caused by an increase in the number of CAG repeats in theHD gene. Repeats of 40 or larger are associated with disease expression, whereas repeats of 26 and smaller are normal. Intermediate numbers of repeats, between 27 and 35, are not associated with disease expression but may expand in paternal transmission, resulting in the disease in descendents. Repeats of 36–39 are associated with reduced penetrance whereby some develop HD and others do not. The identification of the genetic defect in HD permits direct genetic testing for the presence of the gene alteration responsible for the disease. Tests may be performed in three circumstances: (1) confirmation of diagnosis, (2) predictive testing of persons at genetic risk for inheriting HD, and (3) prenatal testing. Testing is widely available and much experience has been gained with protocols that assist the individual in making an informed choice about test options, and minimize the occurrence of adverse emotional outcomes.

Key Words

Huntington’s disease genetics trinucleotide repeat genetic testing genetic modifiers 


  1. 1.
    Myers RH, Marans K, MacDonald ME. Huntington’s disease. In: Genetic instabilities and hereditary neurological diseases (Warren ST, Wells RT, eds), pp 301–323. New York: Academic Press, 1998.Google Scholar
  2. 2.
    Gusella JF, Wexler NS, Conneally PM, Naylor SL, Anderson MA, Tanzi RE et al. A polymorphic DNA marker genetically linked to Huntington’s disease.Nature 306: 234–238, 1983.PubMedCrossRefGoogle Scholar
  3. 3.
    The Huntington’ s Disease Research Collaborative Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes.Cell 72: 971–983, 1993.CrossRefGoogle Scholar
  4. 4.
    Duyao MP, Ambrose CM, Myers RH, Novelletto A, Persichetti F, Frontali M et al. Trinucleotide repeat length: instability and age of onset in Huntington’s disease.Nat Genet 4: 387–392, 1993.PubMedCrossRefGoogle Scholar
  5. 5.
    Chong SS, Almqvist E, Telenius H, LaTray L, Nichol K, Bourdelat-Parks B et al. Contribution of DNA sequence and CAG size to mutation frequencies of intermediate alleles for Huntington disease: evidence from single sperm analyses.Hum Mol Genet 6: 301–309, 1997.PubMedCrossRefGoogle Scholar
  6. 6.
    Maat-Kievit A, Losekoot M, Van Den Boer-Van Den Berg H, Van Ommen GJ, Niermeijer M, Breuning M et al. New problems in testing for Huntington’s disease: the issue of intermediate and reduced penetrance alleles.J Med Genet 38: E12, 2001.PubMedCrossRefGoogle Scholar
  7. 7.
    Merritt AD, Conneally PM, Rahman NF, Drew AL. Juvenile Huntington’s chorea. In: Progress in neurogenetics. (Barbeau A, Brunette TR, eds), pp 645–650. Amsterdam: Excerpta Medica Foundation, 1969.Google Scholar
  8. 8.
    Zühlke C, Olaf R, Bockel B, Lange H, Thies U. Mitotic stability and meiotic variability of the (CAG)n repeat in the Huntington disease gene.Hum Mol Genet 2: 2063–2067, 1993.PubMedCrossRefGoogle Scholar
  9. 9.
    Ranen NG, Stine CO, Abbott MH, Sherr M, Codori AM, Franz ML et al. Anticipation and instability of IT-15 (CAG)n repeats in parent-offspring pairs with Huntington’s disease.Am J Hum Genet 57: 593–602, 1995.PubMedGoogle Scholar
  10. 10.
    Djoussé L, Knowlton B, Hayden M, Almqvist EW, Brinkman R, Ross C et al. Interaction of normal and expanded CAG repeat sizes influences age at onset of Huntington disease.Am J Med Genet 119a: 279–282, 2003.PubMedCrossRefGoogle Scholar
  11. 11.
    Rosenblatt A, Brinkman RR, Liang KY, Almqvist EW, Margolis RL, Huang CY et al. Familial influence on age of onset among siblings with Huntington disease.Am J Med Genet 105: 399–403, 2001.PubMedCrossRefGoogle Scholar
  12. 12.
    Li J-L, Hayden M, Almqvist EW, Brinkman R, Durr A, Dode C et al. A genome scan for modifiers of age at onset in Huntington’s disease: the HD MAPS Study.Am J Hum Genet 73: 682–687, 2003.PubMedCrossRefGoogle Scholar
  13. 13.
    Bates G. Huntingtin aggregation and toxicity in Huntington’s disease.Lancet 361: 1642–1644, 2003.PubMedCrossRefGoogle Scholar
  14. 14.
    Beal MF. Coenzyme Q10 as a possible treatment for neurodegenerative diseases.Free Radic Res 36: 455–460, 2002.PubMedCrossRefGoogle Scholar
  15. 15.
    Ross CA. Polyglutamine pathogenesis: emergence of unifying mechanisms for Huntington’s disease and related disorders.Neuron 35: 819–822, 2002.PubMedCrossRefGoogle Scholar
  16. 16.
    Almqvist EW, Bloch M, Brinkman R, Craufurd D, Hayden MR. A worldwide assessment of the frequency of suicide, suicide attempts, or psychiatric hospitalization after predictive testing for Huntington disease.Am J Hum Genet 64: 1293–1304, 1999.PubMedCrossRefGoogle Scholar
  17. 17.
    Taylor CA, Myers RH. Long-term psychological impact of Huntington’s disease linkage testing.Am J Med Genet 70: 365–370, 1997.PubMedCrossRefGoogle Scholar
  18. 18.
    Nance MA, Myers RH, and US Huntington Disease Genetic Testing Group. Trends in predictive and prenatal testing for Huntington disease, 1993–1999.Am J Hum Genet 65: A406, 1999.Google Scholar
  19. 19.
    Farrer LA. Suicide and attempted suicide in Huntington disease: implications for preclinical testing of persons at risk.Am J Med Genet 24: 305–311, 1986.PubMedCrossRefGoogle Scholar
  20. 20.
    Schoenfeld M, Myers RH, Cupples LA, Berkman B, Sax DS, Clark E. Increased rate of suicide among patients with Huntington’s disease.J Neurol Neurosurg Psychiatry 47: 1283–1287, 1984.PubMedCrossRefGoogle Scholar
  21. 21.
    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 60: 198–205, 2001.PubMedCrossRefGoogle Scholar
  22. 22.
    Hayden MR. Huntington’s chorea. New York: Springer, 1981.Google Scholar
  23. 23.
    Visintainer CL, Matthias-Hagen V, Nance MA. U.S. Huntington Disease Genetic Testing Group. Anonymous predictive testing for Huntington’s disease in the United States.Genet Testing 5: 213–218, 2001.CrossRefGoogle Scholar
  24. 24.
    Tyler A, Morris M, Lazarou L, Meredith L, Myring J, Harper P. Presymptomatic testing for Huntington’s disease in Wales 1987–1990.Br J Psychiatry 161: 481–488, 1992.PubMedCrossRefGoogle Scholar
  25. 25.
    Hersch SM, Jones R, Koroshetz WJ, Quaid K. The neurogenetics genie: testing for the Huntington’s disease mutation.Neurology 44: 1369–1373, 1990.Google Scholar
  26. 26.
    Guidelines for the molecular genetics predictive testing Huntington’s disease.Neurology 44:1533–1536, 1994.Google Scholar
  27. 27.
    Bui TH, Harper JC. Preimplantation genetic diagnosis.Clin Obstet Gynecol 45: 640–648, 2002.PubMedCrossRefGoogle Scholar
  28. 28.
    Pickering S, Polidoropoulos N, Caller J, Scriven P, Ogilvie CM, Braude P. Preimplantation Genetic Diagnosis Study Group. Strategies and outcomes of the first 100 cycles of preimplantation genetic diagnosis at the Guy’s and St. Thomas’ Center.Fertil Steril 79: 81–90, 2003.PubMedCrossRefGoogle Scholar
  29. 29.
    Stern HJ, Harton GL, Sisson ME, Jones SL, Fallon LA, Thorsell LP et al. Non-disclosing preimplantation genetic diagnosis for Huntington disease.Prenat Diagn 22: 503–507, 2002.PubMedCrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc 2004

Authors and Affiliations

  1. 1.Department of NeurologyBoston University School of MedicineBoston

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