What is Huntington’s disease?
Huntington’s disease is a rare, hereditary, degenerative disorder of the brain.1 It is characterized by a combination of motor, behavioral, and cognitive disturbances.2,3
Motor symptoms are a mixture of chorea, bradykinesia, and dystonia,2,3 which affect posture, balance, and gait.2 The onset of motor symptoms can occur at any age, but the mean age at onset is typically between ~45 years.2,4
Huntington’s disease is characterized by gradual impairment of comprehension, reasoning, judgement, and memory.2,3 Cognitive symptoms include slower thinking and difficulty concentrating, organizing, planning, making decisions, and answering questions.2,3
The most common psychiatric symptoms of Huntington’s disease are apathy, anxiety, depression, irritability, outbursts of anger, impulsiveness, obsessive-compulsive behaviors, sleep disturbances, and social withdrawal.2,3
Most people start developing symptoms during adulthood, between the ages of 30 and 50; it can also begin in childhood or early adulthood, known as juvenile Huntington’s disease (JHD).5
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What causes Huntington’s disease?
Huntington’s disease is caused by a cytosine, adenine, and guanine (CAG) expansion in the HTT gene that encodes the protein called huntingtin.3 As a result of this expansion, the gene is translated into an altered form of the protein that leads to malfunction and death of neurons, resulting in Huntington’s disease symptoms.3,5,6
Disease severity is determined by the number of CAG repeats, with a large number of triplets indicating earlier onset.2,5 Unaffected individuals have around 20 CAG repeats in the HTT gene, but people with Huntington’s disease have 40 or more.6
The huntingtin protein structure and function
The normal wild-type HTT protein is a large (~348 kDa with a normal polyQ repeat length of 23 glutamines), universally expressed protein that is present in varying levels depending on cell type.7 It has an extensive number of functions that are still being defined, but is thought to be involved in:8
- Brain development, with a crucial role in the formation of cortical and striatal excitatory synapses and signaling
- Regulation of the transcriptional process, providing neurotrophic support and neurotrophin receptor balance
- Balance of histone acetylation/deacetylation and glial activation
- Mitochondrial function surveillance and biogenesis
- Axonal transport of organelles by microtubules
- Regulation of signaling pathways
- Multimerisation of mHTT
In individuals with Huntington’s disease, the presence of an expanded polyglutamine tract in the HTT gene results in transcriptional dysregulation.4 This ultimately leads to impaired mitochondrial energy pathways, alterations in protein homeostasis, the increased presence of repressive aggregates, altered vesicular, organelle, and neurotransmitter axonal trafficking, synaptic plasticity failure, and glial activation.8
The signs and symptoms of Huntington’s disease
Individuals with Huntington’s disease gradually begin to develop motor, cognitive, and psychiatric disturbances, with signs and symptoms varying widely from person to person, and between stages of the disease.10,11
Involuntary, unwanted movements are the primary motor manifestations in Huntington’s disease, starting in the distal extremities such as fingers and toes, before spreading to all other muscles in the body.10 Motor symptoms include:11
Cognitive symptoms of Huntington’s disease may be evident more than 15 years before motor diagnosis and develop gradually, eventually being widespread across faculties at the later stages of the disease. These include:2,12–14
- Memory loss
- Poor attention
- Slow psychomotor functions
- Slow processing speed
- Poor executive functions
Psychiatric symptoms frequently present in the early stage of the disease, often before the onset of motor symptoms.10 The most prevalent include:2,10–12
Other less prevalent and often debilitating symptoms of Huntington’s disease include weight loss, sleep and circadian rhythm disturbances, and autonomic nervous system dysfunction.10
Some symptoms will fluctuate in severity during the progression of the disease, others will steadily worsen.15 It is important to recognize that each person with Huntington’s disease is different, and while the disease has an overall progression, the onset of symptoms and their severity is unique to each case.15
The estimated prevalence of Huntington’s disease
The prevalence of Huntington’s disease shows geographical variance and is highest in populations of European origin.2,16,17 In Europe, North America, and Australia, where Huntington’s disease is most common, the estimated prevalence is 6–14 in 100,000 live births.16,17
Following the introduction and wide implementation of genetic testing for Huntington’s disease, the accuracy of prevalence estimates has improved and resulted in several populations with substantially higher prevalence than previously thought.17
Determining a Huntington’s disease diagnosis
Huntington’s disease is currently diagnosed through a combination of clinical assessment and genetic testing.2,10,12
Patient history and clinical assessment
The preliminary diagnostic work-up of a suspected case of Huntington’s disease involves questionnaires, a general physical exam, a review of family medical history, and neurological and psychiatric examinations.18
Brain imaging (MRI, PET, or CT) may also be performed to assess the structure or function of the brain. These images may reveal structural, functional, and molecular changes in areas of the brain affected by Huntington’s disease; however, such changes may not be seen if imaging is performed early in the course of the disease.18,19
If symptoms and initial tests strongly suggest Huntington’s disease, it is recommended that genetic testing is performed to confirm a diagnosis.18
Performing a genetic test may also be valuable if there has been no known family history of Huntington’s disease.18 A predictive test indicates whether someone has or has not inherited the gene mutation, but it does not make a clinical diagnosis of Huntington’s disease if the gene expansion is present. International guidelines recommend patients undergo pre-test counseling provided by a genetic counseling unit to make an informed decision regarding the risks and benefits of testing.9,20
What is the prognosis of Huntington’s disease?
Huntington’s disease progresses slowly over 15–20 years,21 with the average age at death being 54 to 55 years.2 Pneumonia and injuries related to falls are the most common causes of death.10,22
Individuals diagnosed with juvenile and late-onset Huntington’s disease have a shorter duration of illness compared with those with disease onset between 20–49 years of age.23
CAG, cytosine, adenine, and guanine; CT, computed tomography; HD, Huntington’s disease; HTT, huntingtin; mHTT, mutant huntingtin; MRI, magnetic resonance imaging; PET, positron emission tomography; PRD, proline-rich domain; Ub, ubiquitin.
- World Health Organization, 2020. 8A01.10 Huntington disease.
Available at: https://icd.who.int/browse11/l-m/en#/http://id.who.int/icd/entity/2132180242. Accessed July 2022.
- Caron NS, Wright GEB, Hayden MR. Huntington’s Disease. 1998 Oct 23 [Updated 2020 Jun 11]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews®. US, 1993–2020.
- European Huntington’s Disease Network, 2016. About Huntington’s Disease. Available at: http://www.ehdn.org/about-hd/. Accessed July 2022.
- Tabrizi SJ, Flower MD, Ross CA, et al. Nat Rev Neurol 2020;16:529–546.
- Huntington Study Group. HD Basics. Available at: https://huntingtonstudygroup.org/living-with-hd/hd-basics/. Accessed July 2022.
- Huntington’s Disease Society of America. Overview of Huntington’s Disease. Available at: https://hdsa.org/what-is-hd/overview-of-huntingtons-disease/. Accessed July 2022.
- Bates GP, Dorsey R, Gusella JF, et al. Nat Rev Dis Primers 2015;1:15005.
- Gatto EM, González Rojas N, Persi G, et al. Clin Parkinsonism Rel Disord 2020;3:100056.
- McColgan SJ, Tabrizi P. Eur J Neurol 2018;25:24–34.
- Roos RAC. Orphanet J Rare Dis 2010;5:40.
- Kirkwood SC, Su JL, Conneally P, et al. Arch Neurol 2001;58:273–278.
- Paulsen JS. Curr Neurol Neurosci Rep 2011;11:474–483.
- Stout JC, Paulsen JS, Queller S, et al. Neuropsychology 2011;25:1–14.
- Papoutsi M, Labuschagne I, Tabrizi S, et al. Movement Disorders 2014;29:673–683.
- Rosenblatt A. Chapter 1: Overview and Principles of Treatment. eds. In: Nance M, et al. eds. A Physician’s Guide to the Management of Huntington’s Disease. US; 2011.
- Warby SC, Visscher H, Collins JA, et al. Eur J Hum Genet 2011;19:561–566.
- Baig SS, Strong M, Quarrell OW. Neurodegener Dis Manag 2016;6:331–343.
- Mayo Clinic. Huntington’s disease. Available at: https://www.mayoclinic.org/diseases-conditions/huntingtons-disease/diagnosis-treatment/drc-2035612 Accessed July 2022.
- Niccolini F, Politis M. World J Radiol 2014;6:301–312.
- MacLeod R, Tibben A, Frontali M, et al. Clin Genet 2013;83:221–223.
- Craufurd D, MacLeod R, Frontali M, et al. Pract Neurol 2015;15:80–84.
- National Institute of Neurological Disorders and Stroke, 2020. Huntington’s Disease: Hope Through Research. Available at: https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Huntingtons-Disease-Hope-Through. Accessed July 2022.
- Foroud T, Gray J, Ivashina J, et al. J Neurol Neurosurg Psychiatry 1999;66:52–56.