Huntington Disease (HD)

Huntington disease (HD) is an inherited neurological disorder caused by an expansion of cytosine-adenine-guanine (CAG) repeats in the huntingtin (HTT) gene.¹ Individuals who have HD present with chorea, dementia, and behavioral and psychiatric disturbances.² The symptoms of HD usually start between the ages of 35 and 45 years, but they may also appear before or after this age range.² 

Progression and Life Expectancy in HD

The progression of HD manifests as a combination of motor, cognitive, and psychiatric symptoms; however, evidence of progression varies significantly among patients.² Cognitive and psychiatric issues can precede chorea by up to 15 years.³ As the chorea progresses, patients find it more difficult to perform their daily activities and eventually require the help of a caregiver. Over time, motor disability becomes severe, and affected individuals become fully dependent on their caregiver.⁴

After the onset of HD, median survival is from 15 to 18 years. In approximately 25% of cases, the onset is delayed, with symptoms appearing at the age of 50 or even later.⁴ Common causes of death include pneumonia and suicide, and the average age at death is 54 to 55 years.^5,6,7

Read more about HD clinical features

Factors Affecting HD Prognosis and Life Expectancy

Prognosis Associated With Genetic Factors

Because this is a disease inherited in an autosomal dominant pattern, variations in genetics play a significant role in individual disease progression and life expectancy.⁴

Number of CAG Repeats and Age of Onset

The number of CAG repeats and age at onset (as determined by the first motor manifestation of HD) are inversely correlated.^2,4 The 70% variation in age at onset is due to variations in the length of the CAG repeats.⁴ The average number of CAG repeats is 16 to 20 in the general population. This increases to 36 in HD; the presence of 27 to 35 repeats does not cause disease but is associated with genetic instability.² The number of CAG repeats has a significant effect on the progression of cognitive, motor, and neurological disturbances.⁴

Typically, patients with the juvenile form of HD have more than 60 CAG repeats.⁴ A higher number of CAG repeats has been linked to earlier development of symptoms, faster progression of disease, institutionalization at a younger age, and shorter survival.^2,3 Despite the inverse correlation between the number of CAG repeats and age at death, the duration of disease is independent of the length of the mutation.¹ And at this point, no correlation between the number of CAG repeats and the progression of behavioral symptoms has been observed.⁴

Genetic Anticipation

Genetic anticipation is commonly observed in HD. This is a phenomenon in which the disease manifests at an earlier age and/or becomes more severe as it is passed from one generation to the next. It only occurs when the gene passes along the paternal line of inheritance. Attaining a patient’s history is essential to determining prognosis.^4,8

Read more about HD genetics

Prognosis Associated With Complications

Besides the factors of genetics, the complications of HD shorten the patient’s lifespan. The consequences of immobility, such as pneumonia and cardiac disease, are the usual causes of death. Patients with choreatic movements of greater amplitude are prone to injuries such as fractures and head trauma. Dystonia and swallowing difficulties also cause complications and shorten the lifespan.⁴ 

Read more about HD complications

References

1. Keum JW, 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(2):287-298. doi:10.1016/j.ajhg.2015.12.018
2. TK, Hu J, Pringsheim T. Risk factors for the onset and progression of Huntington disease. Neurotoxicology. 2017;61:79-99. doi:10.1016/j.neuro.2017.01.005
3. Loi SM, Tsoukra P, Sun E, et al. Survival in Huntington’s disease and other young-onset dementias. Int J Geriatr Psychiatry. 2023;38(4):e5913. doi: 10.1002/gps.5913
4. Ajitkumar A, De Jesus O. Huntington disease. StatPearls [Internet]. Updated February 12, 2023. Accessed August 10, 2023.
5. Roos RA. Huntington’s disease: a clinical review. Orphanet J Rare Dis. 2010;5:40. doi:10.1186/1750-1172-5-40
6. Ghosh R, Tabrizi SJ. Huntington disease. Handb Clin Neurol. 2018;147:255-278. doi:10.1016/B978-0-444-63233-3.00017-8
7. Caron NS, Wright GEB, Hayden MR. Huntington Disease. In: GeneReviews® Updated June 11, 2020. Accessed August 12, 2023.
8. Nold CS. Huntington disease. JAAPA. 2017;30(3):46-47. doi:10.1097/01.JAA.0000512243.43624.33

Reviewed by Harshi Dhingra, MD, on 8/12/2023.

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Diana Diez Gaspar, PharmD, PhD

Diana earned her PhD and PharmD with distinction in the field of Medicinal and Pharmaceutical Chemistry at the Universidade do Porto. She is an accomplished oncology scientist with 10+ years of experience in developing and managing R&D projects and research staff directed to the development of small proteins fit for medical use.