Introduction 

Huntington’s disease (HD), previously known as Huntington’s chorea, is an inherited neurodegenerative disorder characterised by a trio of cognitive, behavioural and motor symptoms. HD follows an autosomal dominant inheritance pattern and is caused by excessive repeats of protein segments in the DNA, commonly known as polyglutamine-coding (CAG) repeat expansions. These can be found on the huntingtin (HTT) gene. These expansions produce an irregularly long version of the huntingtin protein that is coded for by the HTT gene. The elongated protein then breaks into small toxic fragments that collect in the neurons, leading to neurodegeneration and dysfunction of brain regions like the basal ganglia and cerebral cortex, which are responsible for our movements, sensing and complex thinking.

A key factor that influences the progression and clinical presentation of HD is the age of onset in patients, meaning when symptoms first appear, indicating the illness. Adult-onset HD (AHD) is the most common form of the disease, while juvenile-onset HD (JHD) is the rarer form. JHD generally progresses more rapidly compared to AHD and presents certain symptoms with greater severity.^1,2,3,4 

Clinical presentation of huntington’s disease

HD was first discovered and named after the physician George Huntington. He initially described this disorder as a unique form of chorea, which provides a relevant explanation for the motor symptoms associated with HD.¹

General symptoms of Huntington’s disease include:^2,3,4,5,6

• Motor impairment
  • Chorea (involuntary movement) - a hallmark of AHD
  • Rigidity
  • Bradykinesia (slowness of movement)
  • Dystonia (repetitive muscle contractions)
  • Difficulties with gait and balancing
  • Dysarthria (speech difficulty)
  • Dysphagia (swallowing difficulties)
• Cognitive decline
  • Slower mental processing
  • Trouble learning and decision-making
  • Weakened memory
  • Unawareness
• Psychiatric and behavioural changes
  • Irritability
  • Depression
  • Anxiety
  • Aggression
  • Psychosis

Significance of age of onset: juvenile vs. adult HD

HD is broadly classified into two main forms based on the age of symptom onset: AHD and JHD. AHD and JHD share most symptoms in general, although some clinical manifestations in JHD appear more drastic. The majority of individuals experience AHD with symptom onset between the ages of 21 and 65, which usually progresses for 10 to 20 years after clinical diagnosis.^2,5,7 

JHD represents the less common but more rapid and aggressive HD subtype. It typically begins in children and teens before the age of 21, accounting for 3-10% of all HD cases. JHD is further subdivided into childhood-onset (cJHD) and adolescent-onset (aJHD) with differing symptom patterns and severity. People with JHD generally have 10-15 years of survival after onset.^3,5,6 

The cJHD occurs in babies and children aged between 0 and 10 years old. While chorea is rare in cJHD, other motor phenotypes, including akinesia, bradykinesia and rigidity (Parkinsonism) are prominent. However, neurocognitive symptoms (learning difficulties and attention deficit) are the most prevalent in cJHD, but are still better retained compared to AHD patients. 

They may also experience global developmental delay and regression, as well as verbal and performance IQs that are lower than average for their age group; thus, poor performance in education is usually an early indicator of JHD. Other major symptoms of cJHD involve recurrent (epileptic) seizures, irritability and aggressive behaviours, which are significantly more common than in aJHD.

Alternatively, aJHD is obtained in teenagers between 11 and 20 years of age. Like in cJHD, psychiatric symptoms are more significant and precede motor manifestations, except for Parkinsonism symptoms, which are more severe in aJHD. 

Feelings of depression, apathy, psychosis and even behaviours like obsessive-compulsive disorder (OCD) affect approximately 75% of adolescent patients. Behavioural symptoms can increase in severity to the point where teens with aJHD insert themselves in dangerous situations like drugs, alcohol, physical or sexual abuse and suicide attempts.^1,2,5,6,8

Disease progression and prognosis 

The clinical course of HD varies depending on the different subtypes and is classified into stages to decide the disease stage: ²

• Stage 1 - Early HD: minor symptoms may be present, and individuals are functional, not affecting quality of life, and the patient can live independently
• Stage 2 - Early intermediate HD: individuals unable to commit to daily activities like normal, e.g work, driving and chores. Motor and cognitive symptoms become more prominent
• Stage 3 - Late intermediate HD: individuals begin to require supervision with daily activities as symptoms worsen
• Stage 4 - Late HD: symptoms become more severe, and the individual requires full-time assistance (24-hour care is endorsed)
• Stage 5 - Terminal HD: individuals become nonverbal, require assistance with all daily activities and are bedridden

Diagnosis and treatment

Diagnosis of HD largely involves detecting the presence of classic motor, cognitive and psychiatric symptoms. Diagnosis can be further confirmed by DNA analysis through genetic testing to confirm a positive family history. However, genetic testing for HD in individuals under the age of 18 is strictly prohibited unless they are presenting very intense symptoms, especially in younger children who are unable to give informed consent.

Before genetic testing, counselling is encouraged, as this provides individuals with the information they need to make informed choices about further testing, reproduction and life planning.

HD has no current definitive cure, but instead has a wide variety of treatments that can slow its progression in patients:

• Genetic modification: gene silencing and editing 
• Abnormal movement pharmaceutical therapies: e.g VMAT2 inhibitors, neuroleptics, benzodiazepines
• Psychiatric pharmaceutical therapies: SSRIs, antipsychotics, mood stabilisers
• Physical and occupational therapy 
• Speech and language therapy

There is a lack of evidence-based treatments for patients with JHD, which poses a challenge for developing new therapeutics targeted for them, as they are generally excluded from clinical trials. This is a complication since individuals with JHD require tailored treatment to compensate for their quickly progressing subtype.^2,6,8,9,3

Summary

Huntington’s disease (HD) is a neurodegenerative disorder that causes a progressive decline in motor and cognitive function, and psychiatric stability. This stems from a mutation that involves the expansion of CAG trinucleotide repeat sequences within the HTT gene, resulting in a faulty huntingtin protein that accumulates in neuronal cells of brain regions such as the basal ganglia and cerebral cortex, ultimately causing widespread neural damage. There are two main subtypes of HD: adult-onset (21 to 65 years) and juvenile-onset (below 21 years). JHD is further subdivided into childhood-onset (cJHD), occurring between the ages of 0 and 10 and adolescent-onset (aJHD), occurring between the ages of 11 and 20. The age of onset is critical in determining when the disease begins, how it develops and its clinical presentation, with both presenting their unique challenges. JHD is the rarer form of HD that lasts for a shorter duration than AHD but has a more rapid and aggressive prognosis, specifically with cJHD. Common symptoms of HD include motor issues like chorea (involuntary movements), rigidity, and slowness of movement; cognitive problems such as memory loss and slow processing; and psychiatric changes like irritability and depression. In cJHD, motor symptoms are different, with less chorea and more issues like akinesia and learning difficulties being evident. Behavioural issues like seizures and aggressiveness are more common. In aJHD, psychiatric symptoms often appear before motor ones, with severe depression and risky behaviours being common.

The progression of HD is categorised into five stages, ranging from early HD, where individuals still function independently, to terminal HD, where they require full-time assistance. Diagnosis involves identifying symptoms and confirming with genetic testing, although testing for those under 18 is often discouraged unless severe symptoms are present. Genetic counselling is recommended before testing to help with informed decision-making regarding the future. Currently, there is no cure for HD, but treatments such as gene editing, medications for movement and psychiatric symptoms, and various therapies aim to slow its progression. There is limited evidence-based treatment for JHD, which complicates finding effective therapies for this rapidly progressing form of the disease.