Diagnosing Huntington’s disease

Making the Huntington’s disease diagnosis

A clinical diagnosis of Huntington's disease (HD) is usually made on the basis of family history and the presence of unequivocal motor symptoms. While HD typically progresses in a similar manner, each person with HD has a unique onset and severity of symptoms.26 Subtle changes in cognition, mood and behaviour appear years before diagnosis or onset of unequivocal motor signs and are called ‘prodromal’ symptoms.6,21,23

A genetic test using DNA taken from a blood sample is the most effective and accurate method of diagnosing HD.27

Find out more about genetic testing with the National Institute of Neurological Disorders and Stroke (NINDS).
 

Providing hope during diagnosis

How you communicate a HD diagnosis can have a bigger impact than you may realise. Hear about Ed’s diagnosis experience.

Genetic testing options

Genetic testing for HD is typically carried out in one of three scenarios:26,28-30

  • Predictive testing: genetic testing performed in an asymptomatic individual at genetic risk for inheriting HD wishing to determine if they carry the HD‑causing gene mutation. Learn about predictive genetic testing:
  • Confirmatory testing: genetic test performed in symptomatic individuals, with or without a family history of HD, to confirm an HD diagnosis
  • Prenatal testing: a genetic test that can assist in family planning 


The decision to undergo genetic testing is very personal

It is important for individuals with HD to be fully supported before, during and after their genetic testing journey. Involving a team of HD specialists, including genetic counsellors and social workers, will help individuals navigate these complex choices. Various organisations around the world have provided more information on genetic testing that can help during this process.26,28

A personal choice

While each child of a parent with HD has a 50/50 chance of inheriting the disease, genetic testing for HD is potentially useful in three scenarios.7,26,28 Watch Jeanette and Jackie’s story.

References

1. Huntington G. On chorea. J Neuropsychiatry Clin Neurosci. 2003; 15(1):109–113.

2. Moscovich M, Munhoz RP, Becker N, et al. Américo Negrette and Huntington’s disease. Arq Neuropsiquiatr. 2011; 69(4):711–713.

3. Rodrigues FB, Byrne LM, Wild EJ. Biofluid biomarkers in Huntington’s Disease. Methods Mol Biol. 2018; 1780:329–396.

4. Huntington’s Disease Collaborative Research Group. A novel gene containing trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell. 1993; 72:971–983.

5. Ghosh R & Tabrizi SJ. Huntington disease. In Handbook of Clinical Neurology, vol. 147 2018; pp. 255–278. Edited by Geschwind DH, Paulson HL & Klein C. Elsevier BV.

6. Bates GP, Dorsey R, Gusella JF, et al. Huntington disease. Nat Rev Dis Primers. 2015; 1:15005.

7. Roos RA. Huntington’s disease: a clinical review. Orphanet J Rare Dis. 2010; 5:40. doi:10.1186/1750-1172-5-40.

8. Ross C, Aylward E, Wild E, et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nat Rev Neurol. 2014; 10:204–216.

9. Rawlins M, Wexler N, Wexler A, et al. The Prevalence of Huntington’s Disease. Neuroepidemiology. 2016; 46:144–153.

10. Evans S, Douglas I, Rawlins M, Wexler N, Tabrizi S, Smeeth L. Prevalence of adult Huntington's disease in the UK based on diagnoses recorded in general practice records. J Neurol Neurosurg Psychiatry. 2013; 84:1156–1160.

11. Squitieri F, Griguoli A, Capelli G, Porcellini A, D'Alessio B. Epidemiology of Huntington disease: first post-HTT gene analysis of prevalence in Italy. Clin Genet. 2016; 89:367–370.

12. Fisher E & Hayden M. Multisource Ascertainment of Huntington Disease in Canada: Prevalence and Population at Risk. Mov Disord. 2014; 29:105–114.

13. Rawlins M. Huntington's disease out of the closet? Lancet. 2010; 376:1372–1373.

14. Keum J, Shin A, Gillis T, et al. The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease. Am J Hum Genet. 2016; 98:287–298.

15. Paulsen JS, Long JD, Ross CA, et al. Prediction of manifest Huntington's disease with clinical and imaging measures: a prospective observational study. Lancet Neurol. 2014; 13:1193–1201.

16. 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;12:637–649.

17. Paulsen J. Cognitive Impairment in Huntington Disease: Diagnosis and Treatment. Curr Neurol Neurosci Rep. 2011; 11:474–483.

18. Rosenblatt A. Neuropsychiatry of Huntington's disease. Dialogues Clin Neurosci. 2007; 9:191–197.

19. Paulsen J, Long J, Johnson H, et al. Clinical and Biomarker Changes in Premanifest Huntington Disease Show Trial Feasibility: A Decade of the PREDICT-HD Study. Front Aging Neurosci. 2014; 6:78.

20. Anderson KE, van Duijn E, Craufurd D, et al. Clinical management of neuropsychiatric symptoms of Huntington disease: expert-based consensus guidelines on agitation, anxiety, apathy, psychosis and sleep disorders. J Huntingtons Dis. 2018; 7(3):355–366.

21. Reilmann R, Leavitt BR, Ross CA. Diagnostic criteria for Huntington's disease based on natural history. Mov Disord. 2014; 29:1335–1341.

22. Ross CA, Reilmann R, Cardoso F, et al. Movement Disorder Society Task Force Viewpoint: Huntington's Disease Diagnostic Categories. Mov Disord Clin Pract. 2019; 23;6:541–546.

23. 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; 79:874–880.

24. Potter NT, Spector EB, Prior TW. Technical Standards and Guidelines for Huntington Disease Testing. Genet Med. 2004; 6:61–65.

25. The American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group. Laboratory Guidelines for Huntington Disease Genetic Testing. Am J Hum Genet. 1998; 62:1243–1247.

26. Nance M, Paulsen JS, Rosenblatt A, etal. Physician’s Guide to the Management of Huntington’s Disease. 3rd ed 2011. New York, NY: Huntington's Disease Society of America.

27. National Institute of Neurological Disorders and Stroke, National Institutes of Health. Huntington’s Disease: Hope Through Research. National Institutes of Health website: https://catalog.ninds.nih.gov/pubstatic//17-NS-19/17-NS-19.pdf (Accessed May 2020).

28. Frank S, Adkison CR, Bennet R, et al. Genetic testing protocol for Huntington’s disease. Huntington’s Disease Society of America website: http://hdsa.org/wp-content/uploads/2015/02/HDSA-Gen-Testing-Protocol-for-HD.pdf (Accessed May 2020).

29. Myers RH. Huntington's disease genetics. NeuroRx. 2004;1(2):255–262.

30. Craufurd D, MacLeod R, Frontali M, et al. Diagnostic genetic testing for Huntington's disease. Pract Neurol. 2015;15(1):80–84.

31. Kendrick LM, Hudgell D, Hellman A, Weaver MS. Attending to total pain in juvenile Huntington disease: a case report informed by narrative review of the literature. J Palliat Care. 2019; 34:205–207.

32. European Huntington’s Disease Network physiotherapy clinical guidelines. European Huntington’s Disease Network website: http://www.ehdn.org/wp-content/uploads/2016/08/English_version.pdf (Accessed May 2020).

33. Saudou F & Humbert S. The Biology of Huntingtin. Neuron. 2016; 89:910–926.

34. Wild EJ, Boggio R, Langbehn D, et al. Quantification of mutant huntingtin protein in cerebrospinal fluid from Huntington's disease patients. J Clin Invest. 2015; 125(5):1979–1986.

35. Frank S. Treatment of Huntington’s disease. Neurotherapeutics. 2014; 11(1):153–160.

36. Gusella JF, Wexler NS, Conneally PM, et al. A polymorphic DNA marker genetically linked to Huntington’s disease. Nature. 1983; 306:234–238.

37. Rinaldi C & Wood MJA. Antisense oligonucleotides: the next frontier for treatment of neurological disorders. Nat Rev Neurol. 2018; 14:9–21.

38. Lane RM, Smith A, Baumann T, et al. Translating Antisense Technology into a Treatment for Huntington's Disease. Methods Mol Biol. 2018; 1780:497–523.

39. Liang XH, Sun H, Nichols JG, Crooke ST. RNase H1-Dependent Antisense Oligonucleotides Are Robustly Active in Directing RNA Cleavage in Both the Cytoplasm and the Nucleus. Mol Ther. 2017; 25:2075–2092.

40. Wild EJ & Tabrizi SJ. Therapies targeting DNA and RNA in Huntington's disease. Lancet Neurol. 2017; 16:837–847.

41. Food and Drug Administration (FDA). Cellular & Gene Therapy Products. FDA website: https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products (Accessed May 2020).

42. Wang D & Gao G. State-of-the-art human gene therapy: part II. Gene therapy strategies and clinical applications. Discov Med. 2014; 18:151–161.

43. Tabrizi SJ, Ghosh R, Leavitt BR. Huntingtin Lowering Strategies for Disease Modification in Huntington's Disease. Neuron. 2019; 101(5):801–819.

44. O'Brien J, Hayder H, Zayed Y & Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne). 2018;9:402.

45. Cassandri M, Smirnov A, Novelli F, et al. Zinc-finger proteins in health and disease. Cell Death Discovery. 2017;3:17071. 

46. Naso MF, Tomkowicz B, Perry III WL & Strohl WR. Adeno-Associated Virus (AAV) as a Vector for Gene Therapy. BioDrugs. 2017; 31(4):317–334.

47. Scitable by Nature Education: Intron/introns. Nature website: https://www.nature.com/scitable/definition/intron-introns-67/ (Accessed May 2020).

48. Pandya-Jones A. Pre-mRNA Splicing During Transcription in the Mammalian System. Wiley Interdiscip Rev RNA. 2011; 2(5):700–717.

49. Sivaramakrishnan M, McCarthy KD, Campagne S, et al. Binding to SMN2 pre-mRNA-protein complex elicits specificity for small molecule splicing modifiers. Nat Commun. 2017; 8:1476.

50. Poirier A, Weetall M, Heinig K, et al. Risdiplam distributes and increases SMN protein in both the central nervous system and peripheral organs. Pharmacol Res Perspect. 2018; 6:e00447.

51. PTC Therapeutics and CHDI Foundation Announce a Collaboration on a Small-Molecule Therapeutic for Huntington's Disease. PTC Therapeutics website: http://ir.ptcbio.com/news-releases/news-release-details/ptc-therapeutics-and-chdi-foundation-announce-collaboration (Accessed May 2020).

52. Food and Drug Administration (FDA). Route of Administration. FDA website: https://www.fda.gov/drugs/data-standards-manual-monographs/route-administration (Accessed June 2020).

53. Ikezu, T. The Use of Viral Vectors to Enhance Cognition. Cognitive Enhancement. 2015;111–137.