Huntington’s disease

What is Huntington’s disease?

Huntington’s disease is a rare, hereditary, neurodegenerative condition of the central nervous system.1 Progressive neuronal degeneration occurs throughout the whole brain. It is characterized by general shrinkage of the brain and degeneration of the striatum,2 resulting in unwanted choreatic movements, behavioral and psychiatric disturbances, and dementia.3  

The onset of motor symptoms can occur at any age, but the mean age at onset is typically between 35–44 years.2,4 The latest evidence suggests Huntington’s disease can be categorized into subcategories depending on the age of onset:2 

  • Early infantile onset (<10 years old) 
  • Juvenile onset (<20 years old) 
  • Adult (≥20 years old) 

Click here for the latest data on Huntington’s disease presented at international congresses

What causes Huntington’s disease?

Although the genetic origin of Huntington’s disease is well-defined, the molecular and cellular mechanisms underlying the pathophysiology are complex and not fully understood.2  

Genetic origin of Huntington’s disease 

Huntington’s disease is caused by an autosomal dominantly inherited cytosine, adenine, and guanine (CAG) repeat expansion in the huntingtin (HTT) gene that is located on chromosome 4 and encodes the protein huntingtin.5 This results in the production of mutant huntingtin (mHTT) protein with an abnormally long polyglutamine repeat.5  

The length of the CAG repeat in HTT determines whether an individual will develop Huntingtons disease and determines the rate of pathogenesis. Those with greater than 39 CAG repeats will most definitely develop Huntington’s disease, with longer repeats typically causing earlier onset.4,5 Repeats of between 36 and 39 CAG units are associated with reduced penetrance, leading to disease onset occurring at an older age with variable or absent clinical manifestation.2

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.6 It has an extensive number of functions that are still being defined, but is thought to be involved in:2 

  • 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 
  • Autophagy 

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.2 

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.7,8  

Motor symptoms 

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.7 Motor symptoms include:8 

Cognitive symptoms 

Cognitive symptoms of Huntington’s disease are reported to be evident at least 15 years before motor diagnosis and develop gradually, eventually being widespread across faculties at the later stages of the disease. These include:9–11 

  • Memory loss 
  • Dementia 
  • Poor attention 
  • Slow psychomotor functions 
  • Slow processing speed 
  • Poor executive functions 

Neuropsychiatric symptoms  

Psychiatric symptoms frequently present in the early stage of the disease, often before the onset of motor symptoms.7 The most prevalent include:7,8,12  

  • Dysphoria 
  • Agitation 
  • Irritability 
  • Disinhibition 
  • Euphoria 
  • Depression 
  • Apathy 
  • Anxiety 
  • Delusions 
  • Hallucinations

Other less prevalent and often debilitating symptoms of Huntington’s disease include weight loss, sleep and circadian rhythm disturbances, and autonomic nervous system dysfunction.7

The estimated prevalence of Huntington’s disease

The prevalence of Huntington’s disease varies substantially from country to country.13 The estimated prevalence in North America, North-Western Europe, and Australia ranges from 5.96 to 13.7 cases per 100,000 population.14 In contrast, estimated rates in Asia are considerably lower, ranging from 0.11 to 0.72 per 100,000 in Hong Kong, Japan, South Korea, and Taiwan.13   

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.14 

Men and women are equally likely to inherit the repeat expansion in the HTT gene and to develop the disease.15 

Determining a Huntington’s disease diagnosis

Huntington’s disease is currently diagnosed through a combination of clinical assessment and genetic testing.7,9  

Patient history and clinical assessment 

A full medical history, including any family history, is the primary step in determining a diagnosis.7 Neurological and physical exams to review reflexes, balance, movement, muscle tone, hearing, walking, and mental status should also be conducted.18 

Genetic tests  

Genetic testing for the HTT expansion is the current gold standard for diagnosis.7 It is recommended for individuals who are symptomatic and display unequivocal motor symptoms.16 Behavioral changes or cognitive impairment alongside a positive family history, without motor signs, are not sufficient to warrant a diagnostic genetic test.16  

A predictive genetic test is an option for people at risk of developing Huntington’s disease. The 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.5,17  

Diagnostic imaging 

If an individual’s family history and genetic testing are inconclusive, computed tomography (CT) or magnetic resonance imaging (MRI) may be used to reveal any neurological changes indicative of Huntington’s disease, such as brain shrinkage.18 

What is the prognosis of Huntington’s disease?

Huntington’s disease progresses slowly over 15–20 years,16 with pneumonia and injuries related to falls being common causes of death.7,18  

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.19 

CAG, cytosine, adenine, and guanine; CT, computed tomography; HD, Huntington’s disease; HTT, huntingtin; mHTT, mutant huntingtin; MRI, magnetic resonance imaging; PRD, proline-rich domain; Ub, ubiquitin. 

Congress activities

References

  1. 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 October 2021.  
  2. Gatto EM, González Rojas N, Persi G, et al. Clin Parkinsonism Rel Disord 2020;3:100056.
  3. Orphanet, 2011. The portal for rare diseases and orphan drugs. Available at: https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=399. Accessed October 2021.
  4. Tabrizi SJ, Flower MD, Ross CA, et al. Nat Rev Neurol 2020;16(10):529–546.
  5. McColgan SJ, Tabrizi P. Eur J Neurol 2018;25:24–34.
  6. Bates GP, Dorsey R, Gusella JF, et al. Nat Rev Dis Primers 2015;1:15005.
  7. Roos RAC. Orphanet J Rare Dis 2010;5:40.
  8. Kirkwood SC, Su JL, Conneally P, et al. Arch Neurol 2001;58(2):273–278.
  9. Paulsen JS. Curr Neurol Neurosci Rep 2011;11(5):474–483.
  10. Stout JC, Paulsen JS, Queller S, et al. Neuropsychology 2011;25(1):1–14.
  11. Papoutsi M, Labuschagne I, Tabrizi S, et al. Movement Disorders 2014;29(5):673–683.
  12. Paulsen JS , Ready RE, Hamilton JM, et al. J Neurol Neurosurg Psychiatry 2001;71:310–314.
  13. Rawlins MD, Wexler NS, Wexler AR, et al. Neuroepidemiology 2016;46:144–153.
  14. Baig SS, Strong M, Quarrell OW. Neurodegener Dis Manag 2016;6(4):331–343. 
  15. European Huntington’s Disease Network, 2016. About Huntington’s Disease. Available at: http://www.ehdn.org/about-hd/. Accessed October 2021. 
  16. Craufurd D, MacLeod R, Frontali M, et al. Pract Neurol 2015;15:80–84. 
  17. MacLeod R, Tibben A, Frontali M, et al. Clin Genet 2013;83:221–223. 
  18. 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 October 2021. 
  19. Foroud T, Gray J, Ivashina J, et al. J Neurol Neurosurg Psychiatry 1999;66:52–56.
MED-ALL-HD-2100002 | October 2021
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