What is it?

Huntington’s disease (HD) or chorea is a progressive, neurodegenerative genetic disorder characterised by chorea (involuntary movements), in-coordination, cognitive decline and behavioural/personality changes. In general, symptoms develop in adults between the ages of 30-50 years, although a small proportion (≈5%) show signs before the age of 20 years. This is referred to as Juvenile-onset Huntington’s disease. The symptoms of HD are as a result of loss of neurons (brain cells) in certain regions of the brain.

Huntington’s disease is an autosomal dominant disorder. The mutation associated with HD is an expansion of the trinucleotide repeat sequence, CAG, in the IT-15 gene (HD gene) which encodes the huntingtin protein. Although genes often have repeats as part of their sequence, when the number of repeats becomes too large, it can lead to disease. The result of this expansion mutation is defects or deficiencies in the huntingtin protein leading to disease. This type of mutation (i.e. expansion of repeat sequences) can also be seen in a number of other genetic diseases such as Fragile X syndrome.

Four classes of HD alleles have been described:

• The normal allele containing ≤ 26 CAG repeats (less than or equal to 26 CAG repeats).*
• Alleles containing between 27-35 CAG repeats. Individuals with these alleles will not develop HD but there is the potential to expand into the disease range in the next generation.
• Intermediate alleles containing between 36-39 repeats.*
• Individuals with these alleles may or may not develop symptoms of HD.
  These alleles are described as having reduced or incomplete penetrance.
• The HD allele containing ≥ 40 CAG repeats (greater than or equal to 40 CAG repeats).*
  All individuals with these HD alleles will eventually develop symptoms of HD, i.e. having high or full penetrance.
  * Note that these numbers may vary slightly between different laboratories and regions.

In general, there is an inverse relationship between the number of repeats and the severity of disease, that is, the larger the repeat size, the more severe the symptoms and the earlier the onset of disease. However, the repeat size cannot be used to indicate the age of onset. In addition to this, mutated alleles are genetically unstable and have a tendency to undergo further expansion more commonly through paternal transmission to future generations, increasing the disease severity in subsequent generations. This phenomenon is known as anticipation.

Huntington’s disease tends to have a higher frequency in populations of European decent and in Australia affects between 6-7 people in every 100,000. HD remains prevalent in the population because of its relatively late onset, i.e. affected individuals are usually asymptomatic during their reproductive years, allowing the mutation to be silently passed onto subsequent generations.

Signs and symptoms

The signs and symptoms of HD are widespread and can vary from person to person. Generally, symptoms become more severe as the disease progresses. Some common symptoms include:

Physical symptoms:

• Chorea (rapid, involuntary movements of the fingers, limbs and facial muscles). This varies in severity from mild twitching to more severe thrashing as the disease progresses
• Reduced saccadic motion of the eyes (rapid movement of the eye used to focus from one object to another)
• Loss of motor coordination and fine motor movements e.g. difficulty writing.

Cognitive effects:

• Reduced short-term memory
• Concentration impairment
• Difficulty with communication e.g. slow, slurred speech; difficulty in finding words; disorganised speech and sentence construction.

Behavioural/personality changes:

• Change in personal hygiene and habits
• Unusually anxious behaviour
• Irritability and aggression
• Depression, particularly in later stages.

A number of complications can arise in late-stage HD including:

• Dysphagia (difficulty swallowing) resulting in weight loss and increased risk of choking
• Increased risk of respiratory disease such as pneumonia
• Incontinence and other urinary tract problems e.g. infections
• Falls and difficulty walking requiring the use of assist devices e.g. wheelchairs.

Tests

Non-laboratory evaluation

Non-laboratory evaluation includes a detailed family history and clinical assessments of the signs and symptoms of HD. The number and types of tests carried out will vary depending on the organisation and progression of disease. These tests are only useful in patients exhibiting symptoms of HD.

Tests to assess motor, cognitive and behavioural patterns.
   A collection of simple, clinical tests performed by doctors or nurses to determine
   the presence and severity of motor, cognitive and behavioural symptoms.

MRI or CT scans.
   Provides an image of the brain showing areas of degeneration. Imaging tests are not very useful
   in early stage HD because they are unable to show small regions of neural deterioration.

Laboratory testing

Molecular genetics testing

Molecular genetics testing is used to determine if the patient has an allele, or gene variant, that predisposes to Huntington’s disease. It can be used to confirm a clinical diagnosis of HD and for predictive testing in asymptomatic patients. The most common approach used is direct mutation analysis which involves analysis of the patients DNA to estimate the length of the CAG repeat mutation. There are a number of different methodologies adopted of which the most widely used are based on PCR (polymerase chain reaction) and for large CAG expansion either Southern blots analysis or Triplet-repeat primed PCR (TP PCR) is used

Predictive testing

Routine screening of the general population is not recommended, especially due to the lack of effective intervention to stop the onset of disease. However, it should be considered in individuals at an increased risk of HD, that is, in those with a family history of HD. This is done using molecular genetic testing as described above. Predictive (pre-symptomatic) testing, is offerd to individuals in affected families who are at a 50-25% risk of developing HD. Testing during pregnancy can be done to determine if a fetus is affected (prenatal testing) via an amniocentesis or chorionic villus sample. Preimplantation genetic diagnosis (PGD) may be a valuable option for couples who wish to avoid transmitting the disease without revealing their own status and to avoid termination of a pregnancy.

Treatment

Currently there is no treatment available for the cure or prevention of Huntington's disease. Most of the treatment and interventions available are supportive.

Counselling and care-giver support:

• Information regarding the expected signs and symptoms and how they can be recognised and effectively managed.
• Safety advice e.g. when to give up driving or working.
• Directing families to community support groups and relevant government agencies.
• Speech therapy, physiotherapy, swallowing therapy etc.
• Family planning services.

More information

RCPA Manual: Huntington disease genetic test

Healthdirect Australia: Huntington's disease

Huntington's NSW