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.