Huntington’s disease

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Huntington’s disease is one of the most common hereditary neurodegenerative diseases, which remains practically incurable, inevitably leading to the disability of patients and premature death. A fairly wide prevalence in the world, the special severity of the course, the almost complete penetrance of the mutant gene, the peculiarity of clinical and genetic correlations in Huntington’s disease have attracted researchers specializing in neuroscience for many years. The study of the molecular neurobiology of Huntington’s disease over the past decades has largely contributed to significant progress in molecular biology, genetics, and many other biomedical disciplines. At the same time, Huntington’s disease has become a “model” disease in resolving issues of genetic counseling and prognostic testing in modern medical genetics. The review provides brief facts on the history of the study of the disease, including mapping and identification of the mutant gene. The issues of etiology and pathogenesis, molecular genetics of the disease, epidemiology, diagnostics, and differential diagnostics are discussed in detail. The spectrum of clinical manifestations of Huntington’s disease, its various forms, and course features are presented. From a modern perspective, the problem of developing valid biomarkers of both the manifest and the asymptomatic stages of the disease, as well as the course of the pathological process, are highlighted. The main issues of primary and secondary prevention of Huntington’s disease, bioethical principles of conducting genetic counseling for families burdened by this disease are outlined. The approaches to the symptomatic treatment of Huntington’s disease are described, a review of the main promising experimental therapeutic methods that can potentially slow down or stop the progression of the disease, as well as prevent its manifestation in asymptomatic carriers of the mutant gene, are presented. An important contribution of patient organizations to addressing issues affecting the interests of burdened families, scientific and clinical research on the disease was noted. Literature was searched and analyzed using the databases of Scopus, Web of Science, Pubmed (MedLine), eLibrary.

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About the authors

Sergey A. Klyushnikov

Research Center of Neurology

Author for correspondence.
ORCID iD: 0000-0002-8752-7045

Russian Federation, Moscow

M.D., Ph.D., leading researcher of the 5th department of neurology of the Research Center of Neurology


  1. Huntington G. On Chorea. Med. Surg. Rep. 1872; 26: 317-21.
  2. Gusella J.F., Wexler N.S., Conneally P.M., Naylor S.L., Anderson M.A., Tanzi R.E., et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983; 306(5940): 234-38. DOI:
  3. Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993; 72(6): 971-83. DOI:
  4. Illarioshkin S.N., Klyushnikov S.A., Seliverstov Yu.A. Huntington’s Disease [Bolezn’ Gentingtona]. Moscow: Atmosfera; 2018. (in Russian)
  5. Baig S.S., Strong M., Quarrell O.W.J. The global prevalence of Huntington’s disease: a systematic review and discussion. Neurodegener. Dis. Manag. 2016; 6(4): 331-43. DOI:
  6. Seliverstov Yu.A., Dranitsyna M.A., Kravchenko M.A., Klyushnikov S.A., Illarioshkin S.N. Epidemiology of Huntington’s disease in Russian Federation. In: Illarioshkina S.N., Levina O.S., eds. Parkinson’s Disease and Movement Disorders: Physician’s Guide. Based on the Materials of the IV National Congress on Parkinson’s Disease and Movement Disorders (with International Participation) [Bolezn’ Parkinsona i rasstroystva dvizhenii: Rukovodstvo dlya vrachey. Po materialam IV Natsional’nogo kongressa po bolezni Parkinsona i rasstroystvam dvizhenii (s mezhdunarodnym uchastiem)]. Moscow; 2017: 244-6. (in Russian)
  7. Folstein S.E. Huntington’s disease: a disorder of families. Baltimore: Johns Hopkins University Press; 1989.
  8. Agostinho L.A., dos Santos S.R., Alvarenga R.M.P., Paiva C.L.A. A systematic review of the intergenerational aspects and the diverse genetic profiles of Huntington’s disease. Genet. Mol. Res. 2013; 12(2): 1974-81. DOI:
  9. Illarioshkin S.N. Diseases caused by the expansion of tandem microsatellite repeats. In: Gintera E.K., Puzyreva V.P., eds. Hereditary Diseases: National Guide [Nasledstvennye bolezni: natsional’noe rukovodstvo]. Moscow: Geotar-Media; 2016: 259-90. (in Russian)
  10. OMIM Entry. HUNTINGTIN; HTT. Available at:
  11. Illarioshkin S.N., Ivanova-Smolenskaya I.A., Markova E.D. Novel Mutational Mechanism in Man: Expansion of Trinucleotide Repeats. Genetika. 1995; 31(11): 1478-89. (in Russian)
  12. Bates G.P., Dorsey R., Gusella J.F., Hayden M.R., Kay C., Leavitt B.R., et al. Huntington disease. Nat. Rev. Dis. Primers. 2015; 1: 15005. DOI:
  13. Klintschar M., Dauber E.M., Ricci U., Cerri N., Immel U.D., Kleiber M., et al. Haplotype studies support slippage as the mechanism of germline mutations in short tandem repeats. Electrophoresis. 2004; 25(20): 3344-8. DOI:
  14. Xu Z., Tito A., Rui Y.N., Zhang S. Studying polyglutamine diseases in Drosophila. Exp. Neurol. 2015; 274(Pt. A): 25-41. DOI:
  15. Illarioshkin S.N. Conformational Brain Diseases [Konformatsionnye bolezni mozga]. Moscow: Yanus-K; 2003. (in Russian)
  16. Myers R.H. Huntington’s disease genetics. NeuroRx. 2004; 1(2): 255-62. DOI:
  17. Panegyres P.K., Shu C.C., Chen H.Y., Paulsen J.S. Factors influencing the clinical expression of intermediate CAG repeat length mutations of the Huntington’s disease gene. J. Neurol. 2015; 262(2): 277-84. DOI:
  18. Milunsky J.M., Maher T.A., Loose B.A., Darras B.T., Ito M. XL PCR for the detection of large trinucleotide expansions in juvenile Huntington’s disease. Clin. Genet. 2003; 64(1): 70-3. DOI:
  19. Semaka A., Kay C., Doty C., Collins J.A., Bijlsma E.K., Richards F., et al. CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. J. Med. Genet. 2013; 50(10): 696-703. DOI:
  20. Nahhas F., Garbern J., Feely S., Feldman G.L. An intergenerational contraction of a fully penetrant Huntington disease allele to a reduced penetrance allele: interpretation of results and significance for risk assessment and genetic counseling. Am. J. Med. Genet. 2009; 149A(4): 732-6. DOI:
  21. Duyao M., Ambrose C., Myers R., Novelletto A., Persichetti F., Frontali M., et al. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat. Genet. 1993; 4(4): 387-92. DOI:
  22. Illarioshkin S.N., Igarashi S., Onodera O., Markova E.D., Nikolskaya N.N., Tanaka H., et al. Trinucleotide repeat length and rate of progression of Huntington’s disease. Ann. Neurol. 1994; 36(4): 630-5. DOI:
  23. Ponzi A., Barton S.J., Bunner K.D., Rangel Barajas C., Zhang E.S., Miller B.R., et al. Striatal network modeling in Huntington’s Disease. PLoS Comput. Biol. 2020; 16(4): e1007648. DOI:
  24. Tabrizi S.J., Scahill R.I., Owen G., Durr A., Leavitt B.R., Roos R.A., 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(7): 637-49. DOI:
  25. Risacher S.L., Saykin A.J. Neuroimaging biomarkers in neurodege¬nerative diseases and dementia. Semin. Neurol. 2013; 33(4): 386-416. DOI:
  26. Illarioshkin S.N., Klyushnikov S.A., Vigont V.A., Seliverstov Yu.A., Kaznacheeva E.V. Molecular pathogenesis in Huntington’s disease. Biokhimiya. 2018; 83(9): 1299-310. DOI: (in Russian)
  27. Tabrizi S.J., Ghosh R., Leavitt B.R. Huntingtin lowering strategies for disease modification in Huntington’s disease. Neuron. 2019; 102(4): 899. DOI:
  28. La Rosa P., Petrillo S., Bertini E.S., Piemonte F. Oxidative stress in DNA repeat expansion disorders: a focus on NRF2 signaling involvement. Biomolecules. 2020; 10(5): 702. DOI:
  29. Palpagama T.H., Waldvogel H.J., Faull R.L.M., Kwakowsky A. The role of microglia and astrocytes in Huntington’s disease. Front. Mol. Neurosci. 2019; 12: 258. DOI:
  30. Pavese N., Gerhard A., Tai Y.F., Ho A.K., Turkheimer F., Barker R.A., et al. Microglial activation correlates with severity in Huntington disease: a clinical and PET study. Neurology. 2006; 66(11): 1638-43. DOI:
  31. Crotti A., Glass C.K. The choreography of neuroinflammation in Huntington’s disease. Trends Immunol. 2015; 36(6): 364-73. DOI:
  32. Stanga S., Caretto A., Boido M., Vercelli A. Mitochondrial dysfunctions: a red thread across neurodegenerative diseases. Int. J. Mol. Sci. 2020; 21(10): E3719. DOI:
  33. Zhang Q., Lei Y.H., Zhou J.P., Hou Y.Y., Wan Z., Wang H.L., et al. Role of PGC-1α in mitochondrial quality control in neurodegenerative diseases. Neurochem. Res. 2019; 44(9): 2031‐43. DOI:
  34. Hickey M.A., Chesselet M.F. Apoptosis in Huntington’s disease. Prog. Neuropsychopharmacol. Biol. Psychiatry. 2003; 27(2): 255‐65. DOI:
  35. Areal L.B., Pereira L.P., Ribeiro F.M., Olmo I.G., Muniz M.R., do Carmo Rodrigues M., et al. Role of dynein axonemal heavy chain 6 gene expression as a possible biomarker for Huntington’s disease: a translational study. J. Mol. Neurosci. 2017; 63(3-4): 342‐48. DOI:
  36. Metzger S., Rong J., Nguyen H.P., Cape A., Tomiuk J., Soehn A.S., et al. Huntingtin-associated protein-1 is a modifier of the age-at-onset of Huntington’s disease. Hum. Mol. Genet. 2008; 17(8): 1137‐46. DOI:
  37. Couly S., Paucard A., Bonneaud N., Maurice T., Benigno L., Jourdan C., et al. Improvement of BDNF signalling by P42 peptide in Huntington’s disease. Hum. Mol. Genet. 2018; 27(17): 3012‐28. DOI:
  38. Quarrell O.W., Nance M.A., Nopoulos P., Paulsen J.S., Smith J.A., Squitieri F. Managing juvenile Huntington’s disease. Neurodegener. Dis. Manag. 2013; 3(3). DOI:
  39. Peltsch A., Hoffman A., Armstrong I., Pari G., Munoz D.P. Saccadic impairments in Huntington’s disease. Exp. Brain Res. 2008; 186(3): 457-69. DOI:
  40. Klyushnikov S.A., Yudina E.N., Illarioshkin S.N., Ivanova-Smolenskaya I.A. Mental disorders in Huntington’s disease. Nevrologiya, neyropsikhiatriya, psikhosomatika. 2012; 4(2S): 46-51. DOI: (in Russian)
  41. Goh A.M., Wibawa P., Loi S.M., Walterfang M., Velakoulis D., Looi J.C. Huntington’s disease: neuropsychiatric manifestations of Huntington’s disease. Australas Psychiatry. 2018; 26(4): 366‐75. DOI:
  42. Brandt J., Folstein S.E., Folstein M.F. Differential cognitive impairment in Alzheimer’s disease and Huntington’s disease. Ann. Neurol. 1988; 23(6): 555-61. DOI:
  43. Klyushnikov S.A. Diagnosis of Huntington’s chorea at the preclinical stage and in atypical variants of the disease (clinical and molecular genetic comparisons): Diss. Moscow; 1998. (in Russian)
  44. Paulsen J.S., Miller A.C., Hayes T., Shaw E. Cognitive and behavioral changes in Huntington disease before diagnosis. Handb. Clin. Neurol. 2017; 144: 69‐91. DOI:
  45. Rosenblatt A. Neuropsychiatry of Huntington’s disease. Dialogues Clin. Neurosci. 2007; 9(2): 191-7.
  46. Zarotti N., Simpson J., Fletcher I., Squitieri F., Migliore S. Exploring emotion regulation and emotion recognition in people with pre¬symptomatic Huntington’s disease: The role of emotional awareness. Neuropsychologia. 2018; 112: 1‐9. DOI:
  47. Oosterloo M., Craufurd D., Nijsten H., van Duijn E. Obsessive-compulsive and perseverative behaviors in Huntington’s disease. J. Huntingtons Dis. 2019; 8(1): 1‐7. DOI:
  48. Aziz N.A., Pijl H., Frölich M., Schröder-van der Elst J.P., van der Bent C., Roelfsema F., et al. Growth hormone and ghrelin secretion are associated with clinical severity in Huntington’s disease. Eur. J. Neurol. 2010; 17(2): 280-8. DOI:
  49. van der Burg J.M., Björkqvist M., Brundin P. Beyond the brain: widespread pathology in Huntington’s disease. Lancet Neurol. 2009; 8(8): 765-74. DOI:
  50. Unified Huntington’s disease rating scale: reliability and consistency. Huntington Study Group. Mov. Disord. 1996; 11(2): 136‐42. DOI:
  51. Penney J.B. Jr., Vonsattel J.P., MacDonald M.E., Gusella J.F., Myers R.H. CAG repeat number governs the development rate of pathology in Huntington’s disease. Ann. Neurol. 1997; 41(5): 689-92. DOI:
  52. Yudina E.N., Konovalov R.N., Abramycheva N.Yu., Klyushnikov S.A., Illarioshkin S.N. Experience of using MRI morphometry in Huntington’s disease. Annaly klinicheskoy i eksperimental’noy nevrologii. 2013; 7(4): 16-9. (in Russian)
  53. Yudina E.N. Morphofunctional brain changes in Huntington’s disease: Diss. Moscow; 2014. (in Russian)
  54. Seliverstova E.V., Seliverstov Yu.A., Konovalov R.N., Illarioshkin S.N. Resting-state fMRI: new possibilities for studying physiology and pathology of the brain. Annaly klinicheskoy i eksperimental’noy nevrologii. 2013; 7(4): 39-44. (in Russian)
  55. Seliverstov Yu.A. Clinical and neuroimaging analysis of functional changes in the brain in Huntington’s disease: Diss. Moscow; 2015. (in Russian)
  56. La Spada A.R., Weydt P., Pineda V.V. Huntington’s disease pathogenesis: mechanisms and pathways. In: Lo D.C., Hughes R.E., eds. Neurobiology of Huntington’s disease: applications to drug discovery. Chapter 2. Boca Raton, FL: CRC Press/Taylor & Francis; 2011.
  57. Banati R.B. Visualising microglial activation in vivo. Glia. 2002; 40(2): 206-17. DOI:
  58. Wilson H., De Micco R., Niccolini F., Politis M. Molecular imaging markers to track Huntington’s disease pathology. Front. Neurol. 2017; 8: 11. DOI:
  59. Ponomareva N., Klyushnikov S., Abramycheva N., Malina D., Scheglova N., Fokin V., et al. Alpha-theta border EEG abnormalities in preclinical Huntington’s disease. J. Neurol. Sci. 2014; 344(1-2): 114-20. DOI:
  60. Constantinescu R., Romer M., Oakes D., Rosengren L., Kieburtz K. Levels of the light subunit of neurofilament triplet protein in cerebrospinal fluid in Huntington’s disease. Parkinsonism Relat. Disord. 2009; 15(3): 245-8. DOI:
  61. Byrne L.M., Rodrigues F.B., Johnson E.B., Wijeratne P.A., De Vita E., Alexander D.C., et al. Evaluation of mutant huntingtin and neurofilament proteins as potential markers in Huntington’s disease. Sci. Transl. Med. 2018; 10(458): eaat7108. DOI:
  62. Wild E.J., Tabrizi S.J. Huntington’s disease phenocopy syndromes. Curr. Opin. Neurol. 2007; 20(6): 681-7. DOI:
  63. Schneider S.A., Bird T. Huntington’s disease, Huntington’s disease look-alikes, and benign hereditary chorea: what’s new? Mov. Disord. Clin. Pract. 2016; 3(4): 342-54. DOI:
  64. Seliverstov Yu.A., Klyushnikov S.A. Differential diagnosis of chorea. Nervnye bolezni. 2015; (1): 6-15. (in Russian)
  65. Klyushnikov S.A., Ivanova-Smolenskaya I.A., Nikol’skaya N.N., Illarioshkin S.N., Markova E.D., Bodareva E.A. Ethical issues of genetic counseling using Huntington’s chorea. Rossiyskiy meditsinskiy zhurnal. 2000; (2): 32-6. (in Russian)
  66. Poon L.H., Kang G.A., Lee A.J. Role of tetrabenazine for Huntington’s disease-associated chorea. Ann. Pharmacother. 2010; 44(6): 1080‐9. DOI:
  67. Dean M., Sung V.W. Review of deutetrabenazine: a novel treatment for chorea associated with Huntington’s disease. Drug Des. Devel. Ther. 2018; 12: 313-9. DOI:
  68. Wyant K.J., Ridder A.J., Dayalu P. Huntington’s disease-update on treatments. Curr. Neurol. Neurosci. Rep. 2017; 17(4): 33. DOI:
  69. Brusa L., Orlacchio A., Moschella V., Iani C., Bernardi G., Mercuri N.B. Treatment of the symptoms of Huntington’s disease: preliminary results comparing aripiprazole and tetrabenazine. Mov. Disord. 2009; 24(1): 126-9. DOI:
  70. Seliverstov Y., Borzov A., Niyazov R., Belyaev M., Illarioshkin S. Tetrabenazine and olanzapine in management of Huntington disease: comparative retrospective analysis of data from the worldwide observational study Enroll-HD (P2.008). Neurology. 2017; 88(16 Suppl.).
  71. Deroover J., Baro F., Bourguignon R.P., Smets P. Tiapride versus placebo: a double-blind comparative study in the management of Huntington’s chorea. Curr. Med. Res. Opin. 1984; 9(5): 329-38. DOI:
  72. Seliverstov Yu.A., Klyushnikov S.A. Modern approaches to medical correction of chorea in Huntington’s disease. Nervnye bolezni. 2014; (3): 24-8. (in Russian)
  73. Klyushnikov S.A., Illarioshkin S.N., Seliverstov Yu.A. Amantadine in Huntington’s disease: pros and cons. Nervnye bolezni. 2019; (2): 25-30. DOI: (in Russian)
  74. Zittel S., Tadic V., Moll C.K.E., Bäumer T., Fellbrich A., Gulberti A., et al. Prospective evaluation of Globus pallidus internus deep brain stimulation in Huntington’s disease. Parkinsonism Relat. Disord. 2018; 51: 96‐100. DOI:
  75. Jabłońska M., Grzelakowska K., Wiśniewski B., Mazur E., Leis K., Gałązka P. Pridopidine in the treatment of Huntington’s disease. Rev. Neurosci. 2020; 31(4): 441‐51. DOI:
  76. Koch J., Shi W.X., Dashtipour K. VMAT2 inhibitors for the treatment of hyperkinetic movement disorders. Pharmacol. Ther. 2020; 212: 107580. DOI:
  77. Zeitler B., Froelich S., Marlen K., Shivak D.A., Yu Q., Li D., et al. Allele-selective transcriptional repression of mutant HTT for the treatment of Huntington’s disease. Nat. Med. 2019; 25(7): 1131‐42. DOI:
  78. Nekrasov E.D., Lebedeva O.S., Vasina E.M., Bogomazova A.N., Chestkov I.V., Kiselev S.L., et al. A platform for studies of Huntington’s disease on the basis of induced pluripotent stem cells. Annaly klinicheskoy i eksperimental’noy nevrologii. 2012; (4): 30-5. (in Russian)
  79. Nekrasov E.D., Vigont V.A., Klyushnikov S.A., Lebedeva O.S., Vassina E.M., Bogomazova A.N., et al. Manifestation of Huntington’s disease pathology in human induced pluripotent stem cell-derived neurons. Mol. Neurodegener. 2016; 11: 27. DOI:
  80. Wu J., Tang Y., Zhang C.L. Targeting N-terminal Huntingtin with a dual-sgRNA strategy by CRISPR/Cas9. Biomed. Res. Int. 2019; 2019: 1039623. DOI:
  81. Marxreiter F., Stemick J., Kohl Z. Huntingtin lowering strategies. Int. J. Mol. Sci. 2020; 21(6): 2146. DOI:
  82. Tabrizi S.J., Leavitt B.R., Landwehrmeyer G.B., Wild E.J., Saft C., Barker R.A., et al. Targeting Huntingtin expression in patients with Huntington’s disease. N. Engl. J. Med. 2019; 380(24): 2307‐16. DOI:
  83. Ionis Pharmaceuticals, Inc. Tominersen. Available at:



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