Huntington’s disease

Huntington’s disease is a rare, hereditary, degenerative disorder of the brain characterized by a combination of motor, behavioral, and cognitive disturbances.^1–3 For most people, symptoms emerge during adulthood, the mean age of onset is 35–44 years.² It can also begin in childhood or early adulthood, and is then known as Juvenile Huntington’s Disease.⁴

Huntington’s disease is an autosomal dominant inherited disorder caused by a mutation in the HTT gene that encodes the huntingtin protein.^2,3 The single mutation in HTT is an expansion of trinucleotide cytosine, adenine, and guanine (CAG) repeats.^2,3 Unaffected individuals have around 20 CAG repeats in HTT, but those with Huntington’s disease can have 40 or more.⁵

This alteration in the HTT gene results in a variety of problems affecting:⁶ 

• Brain development 
• Regulation of the transcriptional process 
• Balance of histone acetylation/deacetylation and glial activation 
• Mitochondrial function 
• Axonal transport of organelles by microtubules 
• Regulation of signaling pathways 
• Multimerisation of mutant HTT
• Autophagy 

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.⁷

Global incidence has been estimated as 0.48 cases per 100,000 person‐years with geographical variance and significantly higher incidence of Huntington’s disease in Europe and North America compared with Asia.

The global prevalence of Huntington’s disease is estimated to be 4.88 per 100,000.⁸ Geographical variance has been demonstrated, with prevalence being significantly higher in North America and Europe compared with Africa and Asia.⁸

Signs and symptoms of Huntington’s disease vary widely from person to person, and between stages of the disease.^9,10  

Motor symptoms 

The onset of motor symptoms can occur at any age, but on average emerges between ages 35 and 45 years.^2,9 Motor symptoms are a mixture of chorea, bradykinesia, and dystonia, which affect posture, balance, and gait.^2,3 These symptoms start in the distal extremities such as fingers and toes, before spreading to all other muscles in the body.⁹ Motor symptoms include:¹⁰ 

Cognitive symptoms 

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:^2,11–14 

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

Neuropsychiatric symptoms  

Psychiatric symptoms often appear before motor symptoms and are typically present from the early stages of the disease.¹⁰ These can include:^2,10–12  

• Agitation 
• Irritability 
• Disinhibition
• 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.¹⁰ It is important to remember that while the disease has an overall progression, the course will vary between patients. Some symptoms may worsen, while others may fluctuate in their severity.¹³

Huntington’s disease is currently diagnosed through a combination of clinical assessments and genetic testing.^2,10,12  

Patient history and clinical assessments 

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.⁷

Diagnostic imaging 

Brain imaging (magnetic resonance imaging, positron emission tomography, or computed tomography) 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.^7,14

Genetic tests  

If symptoms and initial tests strongly suggest Huntington’s disease, it is recommended that genetic testing is performed to confirm a diagnosis.¹⁴

Performing a genetic test may also be valuable if there has been no known family history of Huntington’s disease.¹⁴ A predictive test highlights whether the genetic mutation has been inherited, but even if the gene expansion is present, that does not in itself confirm a clinical diagnosis of Huntington’s disease. 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.^5,13

Huntington’s disease progresses slowly over 15–30 years following the onset of symptoms.¹⁵ The prognosis and life expectancy of patients with Huntington’s disease can vary depending on age of onset, the severity of symptoms and rate of disease progression, as well as other factors. Pneumonia and injuries related to falls are the most common causes of death.^10,16 People who develop symptoms at a younger age, including those diagnosed with Juvenile Huntington’s Disease, may have a more rapid progression of the disease and shorter life expectancy compared with those with a late disease onset.¹⁷