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huntington's disease gene path

What is Huntington’s disease

 

Huntington’s disease (HD) is a rare, hereditary, degenerative disorder of the brain that was first described by George Huntington in 1872. Symptoms include motor (movement), behavioural (for example mood) and cognitive (for example understanding) disturbances, which in the majority of cases appear in mid-adult life. There are currently no therapies that effectively treat the underlying causes of HD, although there are treatments that can alleviate some of its symptoms and improve quality of life for those affected by it.

Symptoms & Disease Progression

HD is a rare disease that affects about 1:5,000 of the Scottish population. A similar prevalence is found in countries whose populations are primarily of European descent, such as the USA. HD is less common in Asian and African countries, where the prevalence has been estimated at 1 per 100,000 people. Men and women are equally likely to inherit the HD expansion and to develop the disease.

Movement (or motor skills): People with HD can suffer from repetitive involuntary movements resulting in mobility, balance and coordination problems as well as difficulties with speech and swallowing.


Thinking processes (or cognition): People with HD can develop a type of early onset dementia, which affects their ability to process information, make decisions, solve problems, plan and organise.


Mental health: People with HD can also experience a decline in mental health. Depression, anxiety, irritability, obsessive pre-occupations and apathy are amongst the most common mental health problems experienced. Psychosis may also occur.

Most individuals who carry the HD expansion develop symptoms between the ages of 30 and 50. Approximately 10% do so before the age of 20 (they have juvenile HD) and another 10% after the age of 55. In general, HD develops very gradually, so that it may go undiagnosed for many years. On average, disease duration is 15 to 20 years from diagnosis, but this varies between individuals and can also depend on the quality of care that the patient receives.

It is thought the number of repeated sections of DNA on the HD gene is about 60% responsible for determining age of onset. When looking at large groups of people with HD, scientists find a correlation between the CAG repeat number and the age at onset of symptoms. This means that, in general, the higher the number of CAG repeats, the earlier the onset of symptoms. However, for any given CAG repeat number, the variability in age at onset may be up to 30 years. This is probably because of genes other than the HD gene, and environmental factors such as lifestyle and diet. Taking this altogether, it’s very difficult to accurately predict the precise age at onset in any given person carrying the HD gene.

According to a classification developed by neurologist and HD specialist Ira Shoulson of Georgetown University in the USA, the progression of HD can be divided into five stages:


  • Early Stage:
    the person is diagnosed as having HD and can function fully both at home and at work. Early Intermediate Stage: the person remains employable but at a reduced capacity. S/he is still able to manage daily affairs despite some difficulties.

  • Late Intermediate Stage:
    the person can no longer work or manage household responsibilities. S/he needs considerable help or supervision to handle daily financial affairs. Other daily activities may pose slight difficulties but s/he usually only needs minor help.

  • Early Advanced Stage:
    the person is no longer independent in daily activities but is still able to live at home if supported by family or professional carers. Advanced Stage: the person requires complete support in daily activities and professional nursing care is usually needed.

When HD starts early in life (before the age of 20), involuntary movements (chorea) are less prominent as a symptom than slowness of movement (bradykinesia) and stiffness (dystonia). Early features of juvenile HD include marked behavioural changes, difficulties with learning and speech, and decline in performance at school. Epileptic seizures are occasionally reported, being more common in young patients. In general, the juvenile form of the disease progresses more rapidly than the adult form.

When HD starts late in life, chorea tend to be a more prominent sign than slowness or stiffness. In such cases, it is likely to be more difficult to establish a family history, because the individual’s parents may already have died, perhaps before they themselves showed signs of the disease.

Diagnosis & Treatment

HD is diagnosed by a combination of clinical assessments and a genetic test. Clinical diagnosis is based on a person’s medical and family history, as well as on standard examinations that make use of clinical rating scales to assess the frequency and severity of the symptoms of HD. The results of the clinical diagnosis are usually confirmed by genetic screening for the HD gene (known as diagnostic or confirmatory genetic testing).

The genetic change which causes HD can be detected through the analysis of a blood sample. Testing is usually only available to individuals over the age of 18 and is carried out at a genetics clinic. Children cannot have a predictive test as it is important that they are able to make their own decision when they are old enough.

Living with the knowledge that you may be at risk of developing HD can be very worrying and deciding whether or not to have a test is not easy. Finding out you have inherited the genetic change can have a significant impact on you and those around you. It can also affect other aspects of your life such as employment and insurance. Individuals are therefore encouraged to take time to consider their decision carefully and think about the implications of testing for them at that time.

While the test can determine if someone has inherited the genetic change it cannot predict the age when symptoms are likely to begin or the exact pattern the disease will follow for any individual.

People who wish to have a genetic test can be referred to their nearest genetic clinic by their GP. Some genetic centres will accept direct enquiries from individuals. There are four clinical genetics centres in Scotland: Aberdeen Royal Infirmary, Ninewells, Edinburgh Queen Elizabeth Hospital (you can find out details of the closes centre by going to our national care framework page and choosing the area in which you live http://care.hdscotland.org/) .

At the clinic appointment, you will usually be seen by a Doctor, Counsellor or Nurse who specialises in genetics. A family history will be taken and you will have the opportunity to talk over all the implications of testing, discuss your concerns and ask any questions you may have. The genetic centres in Scotland follow similar procedures where individuals are usually seen on at least three separate occasions before the test is carried out. This allows you to have enough time to fully consider all the implications of testing and have enough information about HD to make an informed decision. Attending the clinic does not mean that you have to go through with a test and you may only wish to receive information about the hereditary nature of the illness and what options are open to you, for example in relation to planning a family.

If you decide to go ahead with testing, you will be asked to return to the clinic for the result. You are encouraged to take a friend or relative with you to some or all the appointments.

After the result most genetic clinics will offer a follow-up service, which allows for ongoing support while you remain symptom free as well as monitoring of the disease as symptoms develop. The clinic can also refer on to any specialist services that may be of benefit to you. Even if your result is negative you may still wish to have a follow up appointment at the clinic. Finding out that you have not inherited the genetic change can raise a variety of emotions that you may need time to discuss.

The genetic test determines the number of CAG repeats in the HD gene. The test can reveal whether you carry the HD gene, but it cannot ascertain when the disease will begin, how rapidly it will progress, or which symptoms you might develop. The genetic test for HD is close to 100% accurate. The results from the DNA analysis are usually double-checked using two separate blood samples.

Our youth team (SHAYP) have produced an excellent guide to the options for planning a family which can be viewed by following his link https://hdscotland.org/wp-content/uploads/2018/09/Having-Children.pdf.

There are currently no therapies that can effectively treat the underlying causes of HD. However, basic and clinical research has dramatically increased our knowledge of HD in recent years, and many studies are now underway that are testing experimental treatments for the disease. If you would like to find out more visit our Research Headline pages (http://hdscotland.org/headline/) to get the latest information or visit https://en.hdbuzz.net/),

Treatments are already available that alleviate certain symptoms of the disease (symptomatic treatments), and so improve patients’ quality of life. These are divided into pharmacological (drug) and non-pharmacological (non-drug) treatments.

Yes, there are a wide range of treatments and support available to help with the symptoms of HD. Our National Care Framework sets out where you can get help. http://care.hdscotland.org/getting-help-with-the-symptoms-and-associated-difficulties-of-hd/

The benefits of a diet rich in vitamins, co-enzymes and other compounds have been the subject of much discussion, but remain to be proven clinically. However, as weight loss is a problem for some HD patients, especially in the later stages of the disease, it is important to ensure a healthy diet throughout the course of the disease. At later stages a high-calorie diet may become necessary. Referral to a dietician may be helpful.

Inheritance & What Causes HD

In 1993, scientists identified the genetic change that causes HD. The gene is located on chromosome 4 and makes a protein called huntingtin. The gene contains a sequence of three nucleotides (the basic units of DNA), cytosine-adenine-guanine (CAG), that are repeated several times. This repeat can vary in length. If a person has 40 CAG repeats or more in one copy of the gene, s/he will develop HD within a normal lifespan – that is, in mid-adult life. It is the faulty version of the huntingtin protein that causes brain cells to become ‘sick’ and later to stop working completely. Over time this leads to increasing difficulties with thinking processes, mood, and muscle function.

Genes are found on our chromosomes inside every cell in our body. A gene is a stretch of DNA that contains the code for a particular protein; the DNA is transcribed into messenger RNA (mRNA), which is then translated into the protein. Everyone inherits two copies of each gene – one from the mother, one from the father. In HD the important gene is the HTT (HD) gene, which makes the huntingtin protein. When a child inherits an expanded version of the HTT gene then that child will also develop HD.

Proteins are large molecules made up of building blocks called amino acids. The exact sequence of amino acids in a particular protein is determined by the DNA sequence of the corresponding gene. Genes therefore function as blueprints – sets of instructions to cells that tell them how to build specific proteins. The HTT gene contains instructions on how to build the huntingtin protein. Proteins are the molecules that do the work inside cells – they perform a large number of essential processes, such as enzyme reactions or structural support. If a protein functions abnormally or is missing due to an expansion in the gene that encodes it, then it can affect the cell and, ultimately, the whole organism, sometimes causing disease.

The huntingtin protein is a very large protein that is made or “expressed” to varying degrees in every cell of the human body; the highest levels are found in the brain. Little is known about all the functions of this protein, but is crucial in the development of the nervous system.

Genetic Risk is the phrase used to describe the possibility that someone may have the gene that causes Huntington’s disease (HD). HD is passed on from parents to their children. This means that anyone who has an affected parent is also at risk of inheriting HD.

Genetic Risk

Each person has two copies of chromosome 4 (the chromosome that the HD gene is found on). They inherit one from mum and the other from dad. If a person inherits a copy of chromosome 4 with the HD gene, this means they will inherit HD at some point.

Bill inherited the HD gene from one of his parents, and will develop HD. Bill’s wife, Maggie, does not carry the HD gene.

Bill and Maggie have a child called Polly. Polly has inherited either the HD gene or the normal gene from her dad. At the moment she doesn’t know which gene she has inherited. If Polly has inherited Bill’s normal gene she will not develop HD, however if she inherited the HD gene then she will develop HD later in life.

There are four possible gene combinations that Polly could have inherited. In two of the combinations Polly has inherited the HD gene and in two she has inherited the normal gene. This means that Polly has a ‘two in four’ chance of inheriting HD. This can be written as 50% Therefore there is a 50% chance that Polly has inherited the HD gene and a 50% chance that she has inherited the normal gene.

Like Polly, most people who are at risk of HD have a 50% chance of inheriting HD from one of their parents. This is sometimes called ‘50/50’ or ‘1 in 2’. If you are at 50% risk it is worth remembering that there is the same chance of NOT inheriting the HD gene as there is of inheriting it.

Certain functions of the brain such as the ability to move, think and talk gradually deteriorate in HD as crucial nerve cells become damaged and die. The part of the brain most affected by HD is the striatum, which is a component of the basal ganglia and located deep in the brain’s central region. The striatum is primarily involved in planning and controlling movements, but also in many other processes, including cognition and emotions. As HD progresses, it affects the cortex (the outermost wrinkled part of the brain), contributing to cognitive deterioration. In general, HD causes atrophy of the whole brain over time, impairing the individual’s general functional capacity.

For more information on what support is available you can check our National Care Framework, or contact your local SHA service. We also have various fact sheets and publications available.

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