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 (about 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 huntingtin (HTT) 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 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 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 in subsequent generations. This phenomenon is known as anticipation.
Huntington’s disease tends to have a higher frequency in populations of European descent and in Western Europe affects between 3-10 people in every 100,000. 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.
For further explanation on patterns of inheritance see Genetic testing: the basics