Huntington's: Risk of developing disease 10 times higher than previously thought

More people than previously thought are at risk of developing Huntington's disease, scientists have said. They identified a greater occurrence of 'reduced penetrance' in the general population – the fact of having 36 to 39 repeats of a gene mutation known to cause the illness.

Huntington's disease is an inherited condition that damages certain nerve cells in the brain. It is a seriously debilitating condition which affects 12 per 100,000 people in the UK and is characterised by involuntary movements, as well as behavioural and cognitive problems.

The development of the disease can be blamed on a mutation of the 'Huntingtin gene'. This mutation is a long sequence of repeated CAG nucleotide in the gene, with the number of these repeat alleles determining whether or not someone will develop the disease.

Everyone has two copies of the Huntingtin gene – one from each parent. If people have 26 or fewer repeats on both copies of the gene, they will not develop the disease, nor pass it on to their offspring.

If they have one copy of the gene with 40 or more repeats, they will develop the disease and their children will have a 50/50 chance of inheriting the gene mutation.

The problem is for people who have between 27 and 39 repeats – a reduced penetrance of the gene. They may or may not develop the symptoms of the disease, and it is unclear what will determine which way it will go.

While previous studies had mostly looked at these CAG repeats in patients and their families, this research, published in the journal Neurology, has examined the Huntingtin gene for a large cohort in the general population. It indicates that the number of people with reduced penetrance is higher than expected.

10 times more reduced penetrance

The scientists evaluated CAG repeat length in 7,315 individuals from 3 population-based cohorts from British Columbia (Canada), the United States, and Scotland.

Three of the 7,315 people had 40 or more repeats of the gene, experiencing a full development of the symptoms, which is consistent with figures found in previous studies.

However, they discovered that 18 people had 36 or more repeats, a proportion which corresponds to about 1 in 400 people in the general population. This is ten times higher than previous estimates, which suggests that reduced penetrance may be much more common than scientists used to think.

Age and environment differences

Yet, some groups appear to fare better than scientists would have guessed. For people over the age of 65, the researchers estimate that only about 0.2% of those with 37 repeats go on to develop symptoms of the disease. Before, this proportion was estimated to be 10%.

Similarly, for those with 38 repeats, at least 2% percent of those over 65 are described as having symptoms, compared to the 19% previously estimated.

Environmental factors may explain the differences between people who have a similar reduced penetrance. "It's unclear why some people with reduced penetrance genes develop the symptoms of Huntington's as early as midlife, while others reach old age with no symptoms. Additional genetic and environmental factors may modify the likelihood that a person develops the disease," study author Michael R. Hayden concluded.