According to a recent study developed by researchers at the University of British Columbia in Canada, more people may have mutations linked to the development of Huntington’s disease (HD) than previously thought. However, the increase is only seen in people whose mutations are associated with a lower risk of developing the disease.
The study, “Huntington disease reduced penetrance alleles occur at high frequency in the general population,” has been published in Neurology, the medical journal of the American Academy of Neurology.
Huntington’s disease is genetic and caused by repetitions of CAG nucleotides in the huntingtin (Htt) gene. Everyone has two copies of this gene, one from each parent. But because Huntington’s is an autosomal dominant disorder, only one defective gene can trigger its development.
People who have 26 or fewer repeats will not develop the disease, while those with 40 or more repeats are expected to develop Huntington’s — and their children will have a 50 percent chance of inheriting the mutation.
People who have between 27 and 39 repeats are in what is called a gray area, in which they may or may not develop symptoms of the disease. Those with 36 to 39 repeats, particularly, have what scientists call a reduced penetrance, meaning they may or may not exhibit Huntington’s symptoms.
The researchers attempted to estimate the frequency of genetic variants that could lead to Huntington’s development, both the full penetrance and reduced penetrance. They examined the Htt gene in 7,315 people in the U.S., Canada, and Scotland, and identified 18 individuals who had 36 or more repeats. This suggested that 0.25 percent of the population had a variant of Htt that could induce Huntington’s disease symptoms, which was 10 times higher than previous estimates.
However, the increase was found mainly in patients with 36 to 39 repeats; those with 40 or more repeats in the Htt gene had an incidence that was consistent with previous studies.
But, the study suggests that the penetrance of Huntington’s disease in people carrying 36 to 38 copies was lower than expected, resulting in fewer people in this group developing symptoms of the disease.
In fact, previous studies had estimated that, in people ages 65 or older, 10 percent of those with 37 repeats and 19 percent of those with 38 repeats would develop Huntington’s disease. However, the researchers found that only 0.2 and 2 percent, respectively, would develop the disease.
“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,” concluded the study’s senior author, Michael R. Hayden, MB, ChB, Ph.D., a professor at the University of British Columbia in Vancouver, Canada, and president of Global Research and Development and chief scientific officer at Teva Pharmaceuticals, in a press release.