#5 | February 2024

Huntington’s disease

Huntington’s disease (HD) is a monogenic neurodegenerative disorder that displays an autosomal-dominant pattern of inheritance. It is characterised by motor, psychiatric and cognitive symptoms that progress over 15–20 years.

Generally the disease develops in adult life, with an average age of onset of 40 years, though cases of HD have been diagnosed in patients as young as 2 years old, ranging up to 87 years [1]. The progression of the disease leads to more dependency on others in daily life and finally death. The most common cause of death is pneumonia [2].

Epidemiology

The global population prevalence of HD appears to show a more than ten-fold variation across regions with rates being much higher in caucasian population groups [3]. Interestingly, one population group in Venezuela reportedly had a very high prevalence of HD with 700 cases per 100,000 [1] and Australia has a prevalence of 12.1 per 100,000 with most affected people living in Tasmania, tracing back to a founder mutation [4].

Pathophysiology

The mutation responsible for HD is located on chromosome 4. It is an abnormal expansion of three DNA bases – cytosine-adenine-guanine (CAG) in the HTT gene that encodes for huntingtin (HTT). This protein appears to play an important role in neurons in the brain [5].

60% of the variation in the age of onset of symptoms is driven by the number of CAG repeats, with the remaining variation attributed to environmental factors and other genes that modify the mechanism of HD [6][7]. A longer repeat results in an earlier age of onset and faster progression [8]. Anticipitation also influences the age of onset in an individual in relation to the affected parent/s.

Figure 1: Normal versus mutant HTT gene

Anticipation

The neuropathology of HD is characterised by the dysfunction and death of specific neurons within the brain [11]. Although alterations of the CNS are the most prominent clinical features of HD, patients also suffer from metabolic and immune disturbances, skeletal-muscle wasting, weight loss, cardiac failure, testicular atrophy, and osteoporosis [12].

“The phenomenon whereby the signs and symptoms of some genetic conditions tend to become more severe and appear at an earlier age as the disorder is passed from one generation to the next.” [10]

Diagnosis

The diagnosis of HD is easily made in patients with typical symptoms and a positive family history. Predictive genetic testing can confirm if an individual has an affected gene and can quantify the number of CAG repeats in each of the HTT alleles. The detection of an expansion of 36 or more CAG trinucleotide repeats in HTT shows incomplete penetrance however when the repeats reach 41 or more the disease is fully penetrant [6] (Table 1).

Unaffected individuals normally have less than 26 CAG repeats and do not develop HD. Affected individuals with fewer than 40 repeats may never develop noticeable symptoms, whilst those with more than 60 repeats often develop the disease before age 20 [9].

Table 1: Classification of the trinucleotide repeat, and resulting disease status, dependent on the number of CAG repeats [6][13]

Repeat count
Classification
Disease status
Risk to offspring

≤26

Normal

Will not be affected
None
27–35
Intermediate
Will not be affected
Elevated but <50%
36–39
Reduced Penetrance
May or may not be affected
50%
40+
Full Penetrance
Will be affected
50%

Isaacs C et al. Cancer risks and management of BRCA1/2 carriers without cancer. Available at uptodate.com. Accessed 31/07/2023

Figure 2: Distribution of Disease Duration by CAG-Repeat Length [14]

Keum J.W et al. The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease. The American Journal of Human Genetics. 2016; 98:287-298

A: Models for age at death and age at onset

In one major study, CAG-repeat was not found to have significant capacity in explaining disease duration, however along with gender, was strongly correlated with age at death. Furthermore, the disease duration from diagnosis to death was similar regardless of expanded CAG-repeat size [14] (Figure 2).

Clinical course

Figure 3: Natural history of Huntington disease (HD) [11]

Ross C.A, Aylward E.H, Wild E.J et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nature Reviews. Neurology, 2014; 10(4): 204-216

At risk individuals may remain asymptomatic for several years. The ‘prodromal’ phase marks the early suggestive signs of HD. Transitioning to the ‘manifest’ HD phase is a highly distressing time for patients as it marks the official start of their disease and ultimate decline in health (Figure 3 and 4).

Figure 4: Progression of symptoms and signs through HD phases [11]

* (involuntary movement disorder consisting of non-repetitive, non-periodic jerking of limbs, face, or trunks)

Derived from Ross C.A, Aylward E.H, Wild E.J et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nature Reviews. Neurology, 2014; 10(4): 204-216

Treatment

While no existing drugs can actually stop or reverse the neurological degeneration that HD causes, most if not all patients can benefit from the management of certain symptoms associated with the condition (Table 2). A holistic approach including psychotherapy, speech, physical and occupational therapy is necessary to help a patient adapt to changes in their abilities during the course of the disease [15].

Table 2: Supportive treatment options in HD [15]

Derived from Dabrowska M, Juzwa W, Krzyzosiak WJ and Olejniczak M (2018) Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases. Front. Neurosci. 12:75. doi: 10.3389/fnins.2018.0007.

Prognosis

Patients usually die 20 years after onset and in many cases death results from fatal aspiration pneumonia [16]. On average males and females with HD died 10.8 and 15.1 years earlier than unaffected individuals [17].

Causes of death

In 73.5% of individuals with HD, the underlying cause of death was HD (predominantly from respiratory diseases), followed by cardiovascular diseases (10.2%), cancer (4.3%) and other respiratory diseases 3.8%.

Some studies have shown that certain causes of accidental death cannot be differentiated from suicide. In a study of the Danish population with HD (including unaffected siblings who were potential gene carriers), suicides accounted for approximately 5% of deaths among subjects and unaffected siblings – two fold that of the general Danish population [18].

Accidents as a primary cause of death occurred in approximately 4% of HD subjects. The types of accidents observed in HD subjects were largely related to aspiration, whilst in siblings, traffic accidents were a predominant cause. It is worth noting that these traffic accidents were quite striking, with a high proportion involving single drivers respectively crashing with vehicles in the opposite lane; other traffic accidents; and carbon monoxide poisoning [19].

Conclusion

Huntington’s Disease is an incurable genetic condition carrying a poor prognosis with high mortality and morbidity. It has a fairly predictable clinical course and expected survival duration. Affected individuals could potentially be offered cover depending on the age of onset of their first degree relative and the number of CAG repeats. Evidence suggests a positive genetic test result leads to a doubling of suicide risk, as compared to population level suicide which should be considered when offering terms.

Author

Dr Monique Esterhuizen

Chief Medical Officer and Head of Medical & Health Services

Hannover Life Re of Australasia

References

  1. Ghosh R, Tabrizi SJ. Huntington disease. Handbook of Clinical Neurology 2018; 147 (17): 255-278.
  2. Roos RA. Huntington's disease: a clinical review. Orphanet J Rare Dis. 2010;5:40.
  3. Rawlins M, D, Wexler N, S, Wexler A, R, Tabrizi S, J, Douglas I, Evans S, J, W, Smeeth L: The Prevalence of Huntington's Disease. Neuroepidemiology. 2016;46:144-153.
  4. Why is HD so prevalent in Tasmania? - Huntington's Disease Association Tasmania. Available from:huntingtonstasmania.org.au. Viewed on 9 February 2024.
  5. Genetics Home Reference. Huntington Disease. 2013, updated 2019. Available from: https://ghr.nlm.nih.gov/condition/huntington-disease. Viewed on 20 November 2018.
  6. Walker, FO. Huntington's disease. The Lancet. 2007:369(9557), pp. 218-228.
  7. Wexler, N. L. J. P. J. e. a., 2004. Venezuelan kindreds reveal that genetics and environmental factors moderate Huntington's diease age of onset. Proceedings of the Natural Academy of Sciences of the United States of America, Volume 101, pp. 3498-3503.
  8. Harper, P. S., 1999. Huntington's disease: a clinical, genetic and molecular model for polyglutamine repeat disorders. Philosophical Transactions of the Royal Society of London Society B: Biological Sciences, 354(1386), pp. 395-961.
  9. Andrew et al. The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington's disease. Nature Genetics, 1993;Vol 4, pp. 398-403.
  10. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US); What do geneticists mean by anticipation? [updated 2021 Apr 19]. [cited 2024 Feb 1]. Available from: https://medlineplus.gov/genetics/understanding/inheritance/anticipation/. Viewed on 9 February 2024.
  11. Ross C.A, Aylward E.H, Wild E.J et al. Huntington disease: natural history, biomarkers and prospects for therapeutics. Nature Reviews. Neurology, 2014; 10(4): 204-216.
  12. Jorien MM van der Burg, Maria Björkqvist, Patrik Brundin, Beyond the brain: widespread pathology in Huntington's disease, The Lancet Neurology. 2009; 8(8): 765-774. Available from: https://doi.org/10.1016/S1474-4422(09)70178-4. Accessed on 9 February 2024.
  13. Pages 765-774,C.E.M de Die-Smulders et al. Reproductive options for prospective parents in families with Huntington's disease:clinical, psychological and ethical reflections. Human Reproductive Update, 2013. 19(3), pp. 304-315.
  14. Keum J.W et al. The HTT CAG-Expansion Mutation Determines Age at Death but Not Disease Duration in Huntington Disease. The American Journal of Human Genetics. 2016; 98:287-298.
  15. Dabrowska M, Juzwa W, Krzyzosiak WJ and Olejniczak M (2018) Precise Excision of the CAG Tract from the Huntingtin Gene by Cas9 Nickases. Front. Neurosci. 12:75. doi: 10.3389/fnins.2018.0007.
  16. Saudou F, Humbert S. The Biology of Huntingtin. Neuron. 2016;89(5):910-26.
  17. Solberg OK, Filkuková P, Frich JC, Feragen KJB. Age at Death and Causes of Death in Patients with Huntington Disease in Norway in 1986-2015. J Huntingtons Dis. 2018;7(1):77–86.
  18. Sørensen SA, Fenger K. Causes of death in patients with Huntington's disease and in unaffected first degree relatives. J Med Genet. 1992;29(12):911–914.

Image: Westend61/Andrew Brookes/1023297208; Julee Ashmead/stock.adobe.com

If you need further information or would like to send us feedback, please feel free to get in touch.

Contact forms

The information provided in this document does in no way whatsoever constitute legal, accounting, tax or other professional advice. While Hannover Rück SE has endeavoured to include in this document information it believes to be reliable, complete and up-to-date, the company does not make any representation or warranty, express or implied, as to the accuracy, completeness or updated status of such information. Therefore, in no case whatsoever will Hannover Rück SE and its affiliated companies or directors, officers or employees be liable to anyone for any decision made or action taken in conjunction with the information in this document or for any related damages.

Hannover Re is the registered service mark of Hannover Rück SE.

Hannover Rück SE © 2024

Imprint | Disclaimer | Data privacy | www.hannover-re.com