About Huntington’s disease

Today, we know more about Huntington's disease than ever before

Huntington's disease (HD) is a rare, monogenic neurodegenerative disease characterised by a triad of cognitive, behavioural and motor symptoms leading to functional decline and progressive loss of independence.5-8 It typically strikes in the prime of life, between 30 and 50 years of age,7 and impacts families across generations, with each child of a parent with HD having a 50/50 chance of developing the disease.5 There is currently no proven approach to slowing or stopping the relentless progression of this ultimately fatal disease.6

The more we learn about the mutant huntingtin (mHTT) protein responsible for causing HD, and how we may be able to lower its levels, the closer we get to unlocking the mysteries of this condition.

HD average prevalance rate

HD is the most common monogenic neurological disorder in the developed world. HD has an average prevalence rate of ~10 in 100,000, which has increased worldwide between 9–20% each decade.9-13

Watch to learn more about HD

HD is characterised by a triad of cognitive, behavioural and motor symptoms

HD leads to functional decline and loss of independence,7,8 and results in death on average 15 years after the onset of motor symptoms.14

Cognitive disturbances in HD can occur years before diagnosis and onset of motor symptoms, and deteriorate steadily as the disease progresses. Behavioural manifestations in HD are particularly diverse and can also occur many years before a clinical diagnosis of HD is made.15-18 Motor symptoms in HD are initially subtle and progress in a non-linear trajectory over the course of the disease.8,19

Cognitive* Language difficulties, decreased attention, difficulty retrieving information, deficits in learning and memory, emotional recognition problems, lack of awareness, reduced mental flexibility, cognitive slowing, and problems with planning.5–8 [5/Ghosh R & Tabrizi SJ. 2018; 6/Bates GP et al. 2015; 7/Roos RA. 2010; 8/Ross C et al. 2014] Behavioural* Apathy, depression, impaired judgment, irritability, sleep problems, impulsivity, suicidality, aggression and psychosis.5,7,8,20 [5/Ghosh R & Tabrizi SJ. 2018; 7/Roos RA. 2010; 8/Ross C et al. 2014; 20/Anderson KE et al. 2018] Motor* Chorea, bradykinesia, impaired speech, impaired walking, dystonia, akinesia, rigidity, decreased saccades, dysphagia, poor balance/risk of falls and tics.5,7,8 [5/Ghosh R & Tabrizi SJ. 2018; 7/Roos RA. 2010; 8/Ross C et al. 2014]

Since individuals experience these symptoms in their own unique way, HD can often be difficult to diagnose. This means it can also be challenging for patient care and a multidisciplinary approach may help improve disease management.

*This is not a comprehensive list of HD symptoms. Symptoms and signs differ for each individual with HD.7

HD is a continuum which can be described in three stages

Clinical diagnosis of HD is typically defined by the onset of unequivocal motor symptoms and occurs when people are in the prime of life, typically between the ages of 30 and 50 years.7,8,21,22 HD phasing terminology continues to evolve; however, the disease generally progresses through the presymptomatic, prodromal and manifest stages.5,7,22

The presymptomatic, prodromal, and manifest stages of HD

1. Presymptomatic

Individuals who carry the HD-causing gene mutation but have not yet developed any symptoms.5,6,8

2. Prodromal

Individuals experience subtle changes in cognition, mood and behaviour that appear years before diagnosis or onset of unequivocal motor signs.6,8,21,23 Brain changes, including striatal atrophy, are apparent.6

3. Manifest

Individuals with HD have unequivocal motor symptoms and are clinically diagnosed with HD.6,8

 

The significance of expanded cytosine–adenine–guanine repeats

Researchers identified that the number of cytosine–adenine–guanine (CAG) trinucleotide repeat expansions in the huntingtin gene (HTT) has been shown to correlate with the age of disease onset.4,5 It is known that a CAG repeat length of ≥40 results in definite HD,6,7,24-26 CAG repeat length inversely correlates with age of onset,5-7 and other genetic and environmental factors may also affect disease progression.5,8

The number of CAG repeats is key to pathogenesis24,25,27

The risk of HD can be defined by the number of CAG repeats that an individual has

A blood test can be performed to determine the CAG repeat length.4,27 More information can be found on the NIH website.

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, et al. 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, et al. 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, et al. 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.