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This article waslast modified on 17 January 2018.
What is it?

Huntington’s disease (HD) or Huntington’s chorea is a progressive, neurodegenerative genetic disorder characterised by chorea (involuntary movements), in-coordination, cognitive decline and behavioural/personality changes. The symptoms of HD are as a result of loss (degeneration) of neurons (brain cells) in certain regions of the brain which is why it is a neurodegenerative disorder. The symptoms get worse over time (usually over 10-20 years) which is why the disease is said to be progressive. It usually results in death.

In general, symptoms develop in adults between the ages of 30-50 years, although a small proportion (about 5% - 10% ) show signs before the age of 20 years. This is referred to as Juvenile-onset Huntington’s disease. The disease affects both men and women. Huntington’s disease tends to have a higher frequency in populations of European descent. It is thought that about 12 in 100,000 people in the UK are affected by Huntington’s disease.

What causes Huntington’s disease (HD)?

HD is caused by a gene mutation that leads to the production of an abnormal version of a protein called huntingtin protein. The huntingtin protein is found in various different tissues in the body with highest levels of activity in the brain. The exact function of the protein is unknown but it seems to play an important part in the function of nerve cells. The abnormal protein in the nerve cells seems to cause them to degenerate affecting the function of the brain and nerves.

The mutation associated with HD is caused by an expansion of the trinucleotide repeat sequence, CAG, in the huntingtin (HTT) gene, which encodes the huntingtin protein. A nucleotide is one of the basic building blocks for DNA. A trinucleotide is therefore a set of 3 nucleotides and it is used to code various sets information in our DNA and genes. A CAG sequence is made up of a series of three nucleotides (cytosine, adenine, and guanine) that appear multiple times in a row.

Healthy genes often have repeat trinucleotides as part of their sequence and normally the CAG segment is repeated 10 to 35 times within the gene. However, when the number of repeats becomes too large, it can lead to disease. The result of this expansion mutation is known as a trinucleotide repeat disorder. This type of mutation can also be seen in a number of other genetic diseases such as Fragile X syndrome. The expanded CAG repeat leads to an abnormally long version of the huntingtin protein. This abnormal protein then accumulates in the nerve cells disrupting their function. People with Huntington’s disease have 36 to more than 120 CAG repeats. People with 36 to 39 CAG repeats may or may not develop the signs and symptoms of Huntington disease, while people with 40 or more repeats almost always develop the disorder.

The gene for the huntingtin protein is located on chromosome 4. Chromosomes are packages of DNA inherited from our parents and are found in pairs. In humans each cell usually has 23 pairs of chromosomes. On each chromosome is something called an allele. An allele is one of a pair of genes that appear at a particular location on a particular chromosome and control the same characteristic, such as blood type or eye colour or in this case the production of huntingtin protein. As chromosomes are in pairs we inherit one allele for the huntingtin protein from one parent on one chromosome and another allele for the protein from our other parent on its pair chromosome. Anyone who has a parent affected by HD has a 50:50 chance of inheriting the HD allele causing the faulty huntingtin protein on one of their chromosomes. If their other parent does not have HD they will inherit a healthy allele from the other parent on the other paired chromosome.

Huntington’s disease is an autosomal dominant disorder however. In an autosomal dominant disorder inheriting just one allele from an affected parent can mean you will inherit the disease even if the other allele is normal. In Huntingdon’s disease anyone who does inherit the faulty gene will usually develop the disease at some point in their life. This means that if one parent has HD, even if the other parent is healthy, you have a 50:50 chance of inheriting the faulty allele and getting Huntingdon’s disease itself.

However there are different levels of mutation within each abnormal allele and the severity of the mutation in that allele controls the likelihood of whether a patient develops HD or not.

Four classes of HD alleles have been described:

  • The normal allele containing some 26 CAG repeats*
  • Intermediate alleles (also known as “mutable normal” alleles) containing between 27-35 repeats*
    Individuals with these alleles are not affected with symptoms of HD but may be at risk of passing the disease to their children.
  • Reduced penetrance 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 greater than or equal to 40 CAG repeats*
    All individuals with the HD allele will eventually develop symptoms of HD, i.e. having high or full penetrance. Individuals with very large repeats (greater than 65 CAG repeats) present with the juvenile form of HD.

* Note that these numbers may vary slightly between different laboratories and regions.

In general, there is a direct 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. In addition to this, mutated alleles are genetically unstable and have a tendency to undergo further expansion as they are transmitted to future generations, increasing the disease severity and the likelihood of developing HD in subsequent generations. This phenomenon is known as anticipation.

For further explanation on patterns of inheritance see Genetic testing: the basics

In around 3% -5% of cases however there is no family history of the condition. This is normally due to the death of a parent at a young age with the condition going unknown or adoption or mistaken paternity. Obviously due to anticipation it may be that a parent was unaware that they had the condition as they had little or no symptoms but the mutation got worse in future generations causing symptoms. Therefore most cases if not all are said to be hereditary. People with Juvenile-onset Huntington’s disease have usually inherited it from their father.

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About Huntington's Disease
  • Signs and symptoms

    The signs and symptoms of HD are widespread and can vary from person to person. Generally, symptoms become more severe and change as the disease progresses. Many people with early signs of the disease are unaware they have it. Early symptoms include fidgeting, slight incontrollable movements and clumsiness, lack of concentration, short-term memory loss as well as depression and changes of mood. It may also include aggressive behaviour. These symptoms may also be present in later stages but the symptoms tend to be more severe.

    The symptoms fall into 3 categories:

    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.  It usually starts in the hands and feet and spreads to the rest of the body.
    • 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, dropping things, difficulty walking, difficulty in swallowing and slower slurred speech.

     

    Cognitive effects:

    Cognitive effects affect the memory and the way a person thinks and understands things. They may develop before any physical symptoms. They include:

    • Reduced short-term memory
    • Concentration impairment and difficulty problem solving
    • A loss of motivation and drive
    • Difficulty with communication e.g. difficulty in finding words; disorganised speech and sentence construction.

     

    Behavioural/personality changes:

    These effects are quite distressing and can put a strain on personal relationships. They include:

    • Change in personal hygiene and habits
    • Unusually anxious behaviour
    • Irritability and aggression
    • Obsessive behaviour
    • Having fewer inhibitions
    • Depression, particularly in later stages

     

    Symptoms of early onset/juvenile HD:

    These can be different to the symptoms of adult HD and depend on the age of the child when the disease develops. For example muscle stiffness is more common in younger children than chorea. The first noticeable symptoms may be more cognitive and behavioural such as a decline in how well a child does at school or difficulty completing usual tasks such as riding a bike. Inappropriate behaviour such as sexual or aggressive behaviour may also be a sign.

    Late stage HD

    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/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 (nerve) 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. The most common approach used is direct mutation analysis which involves analysis of the patient’s 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 Southern blots. A new test called triplet repeat primed PCR (aka chimeric PCR) may also be used instead of a southern blot analysis.

    This test will only tell you if you carry the gene for HD and will not predict when you will have any symptoms. It can be very useful to detect people with HD before they develop symptoms. 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, even if they do not have any symptoms. It should be noted that genetic testing is a big decision to make especially as there is no cure for the disease. It should usually be done with the advice and guidance of a genetic counsellor. In the UK you cannot usually have a pre-symptomatic test (before you have symptoms) to check for a genetic condition before the age of 18.

    Molecular testing can also be used when you have symptoms of HD to aid with a clinical diagnosis. It is not always necessary in a patient with typical symptoms and a family history of HD but is the only way to know for sure that you have the disease. It can also help in patients with typical symptoms of HD but no known family history of HD. Again there are a lot of implications to consider. For example, if you test positive for the faulty gene but none of your parents have been diagnosed with the condition previously, this usually means that one of them is carrying the gene. Again the decision should be discussed with a genetic counsellor beforehand (i.e. before they develop any symptoms).

    Prenatal testing

    HD has survived evolution 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. We now use molecular testing pre-natally in known families with HD to avoid passing it on to future generations.

    This type of testing isused to determine the carrier status in females of child-bearing age and women already pregnant (antenatal testing) to assess the risk of transmission to any children they may have. The antenatal testing is usually only offered to women who would be willing to have an abortion if their unborn child is found to have HD. This is to prevent a child growing up with the knowledge they have a terminal illness without their consent.

    If you have a family history of HD but do not wish to be tested for the gene yourself (e.g. as you do not wish to know if you carry the disease) you may be offered a procedure known as pre-implantation genetic diagnosis (PGD) if you wish to have children. This is usually done as part as in-vitro fertilisation (IVF), even if you have no problems conceiving. This is because via IVF the embryos can be tested and only embryos without the HD gene can be selected for implantation. Therefore none of your children will be born with HD.

  • Treatment

    Currently there is no treatment available for the cure or prevention of Huntington's disease.

    Therefore most of the treatments and interventions available for HD are supportive. For example medication may be prescribed to help reduce the involuntary movements or antidepressants to help with depression symptoms. Mood stabilisers may also be used to help with behavioural symptoms. Usually a variety of professionals ( a multi-disciplinary team) are involved in the care of a HD patient and include doctors, counsellors, physiotherapists, clinical nurse specialists and other health care professionals.

    Examples of Mutli-disciplinary team 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
    • Helping families and patients with what financial benefits they may be eligible to
    • Speech and language therapists to help speech and communication and to assess for any swallowing difficulties
    • Physiotherapy to help strength and mobility
    • Dieticians to help stop weight loss
    • Occupational therapy to provide modifications to the home to help mobility and also aids to help eating
    • Family planning services
    • Counselling and local support groups
  • Research

    Research is underway to try and find treatment for the disease and try and switch off the faulty gene causing the disease. There is also some interest in stem cell treatment to see if one day these cells could be transplanted in a patient’s brain to help with the symptoms. Trials are currently being performed in patients with HD to see what treatments may work to help control symptoms and halt the progression of the disease. You can read more about the latest research at the European Huntington’s Disease Network. To aid research if you have Huntington's disease, your clinical team will pass information about you on to the National Congenital Anomaly and Rare Diseases Registration Service (NCARDRS).You can opt out of the register at any time.