Huntington's Gene More Common Than Thought

June 24, 2016

A new study of the general population has found a far higher rate of the gene mutation responsible for Huntington's disease than expected.

Researchers led by Michael R. Hayden, MB ChB, professor at the University of British Columbia, Vancouver, Canada, who is also president of global research and development and chief scientific officer at Teva Pharmaceuticals, published their findings online in Neurology on June 22.

"The mutation for Huntington's disease is present at a higher frequency than we thought in the general population," Dr Hayden told Medscape Medical News. "In particular, there is a dramatically higher than expected occurrence of the reduced penetrance gene mutation ― when a patient may or may not develop the disease, which may manifest in a milder form and at an older age than the full penetrance form.

"Our results suggest that Huntington's disease is actually much more frequent than we had thought, and it may be occurring in many patients much later in life than we expect, so it is probably not being diagnosed," he added. "Doctors need to be aware of this and to think about the possibility of Huntington's in elderly patients with abnormal movements and dementia."

In an accompanying editorial, Martin B. Delatycki, MBBS, Bruce Lefroy Centre, Parkville, Victoria, Australia, and Oliver Bandmann, MD, Sheffield Institute for Translational Neuroscience, United Kingdom, say this new study is "impressive in its scale and intriguing in its results."

They add that these new data are important for a number of reasons. They agree that clinicians should consider genetic testing for HTT (the Huntington gene) in elderly individuals with subtle symptoms, and they point out that in the future, approximately 1 in 400 individuals who undergo whole-exome or whole-genome sequencing could be identified as being at risk of developing symptomatic Huntington's disease.

The "Most Disastrous Disease"

Prof Hayden explained that the frequency of Huntington's disease has been documented simply by recording how many people manifest symptoms of the illness, which is characterized by uncontrolled movements, loss of intellectual abilities, emotional problems, and eventually death.

"As patients become incontinent, paralyzed, and demented, it is often thought of as the most disastrous disease known to mankind," he said.

Because Huntington's is a genetic disease caused by one specific mutation in the HTT gene, genetic testing is a more reliable way of assessing how many people may be affected by the disease.

The mutation that causes Huntington's disease is a longer than normal sequence of repeated CAG nucleotides in the HTT gene. Normally, individuals have fewer than 27 CAG repeats on both alleles. Because it is a dominant genetic condition, people who have one allele with 40 or more repeats are very likely to develop the disease, usually between the ages of 40 and 60 years.

But people who have between 27 and 39 CAG repeats are in a "gray area." Those with 27 to 35 CAG repeats do not develop the disease, but offspring of these individuals are at risk of having an allele of more than 36 repeats. Those with 36 to 39 CAG repeats (known as reduced penetrance alleles) may or may not develop Huntington's disease.

Until now, researchers have studied how common this reduced penetrance is mainly by examining individuals who already have symptoms of the disease and their family members. In the current study, Prof Hayden and colleagues tested a random sample of 7315 people from Canada, the United States, and Scotland for the HTT gene mutation.

1 in 400 Risk

Of those, 18 people had 36 or more repeats, which extrapolates to about 1 in 400 people in the general population ― about 10 times higher than previous estimates, the researchers note.

Three of those people had 40 or more repeats of the gene, which is considered full penetrance. The remaining 15 individuals had 36 to 39 CAG repeats, which is considered reduced penetrance.

"We found that 1 in 2500 people had 40 or more repeats so were very likely to develop the disease," Prof Hayden commented. "This is higher than expected. Previously, we had estimated that 1 in 10,000 people get Huntington's.

"The number with 36 to 39 CAG repeats was dramatically higher than we were expecting," he added. "These people may or may not develop the disease, and if they do, it normally manifests at an older age ― in the 70s, 80s, or 90s ― than those with 40 or more repeats, and it can also be milder."

He said it is probable that many of those with this reduced penetrance gene would die of some other cause before they developed Huntington's, so they would never know they had the gene. Others may develop a milder form of the disease, which may be misdiagnosed as a different condition.

"They will still develop a significant dementia, but this is likely to be labeled as something else. Huntington's has not been thought of as a disease of the elderly before, but as the population ages, we need to be more aware that Huntington's can occur in the elderly."

The study also suggests that the penetrance of the disease among people with 36 to 38 repeats is lower than previously thought, meaning that fewer people in this group would develop symptoms of the disease.

For people older than 65 years, the researchers estimate that 0.2% of those with 37 repeats would have symptoms of the disease, compared with the prevous estimate of 10%. For those with 38 repeats, an estimated 2.0% of those older than 65 years would have symptoms vs the 19% previously estimated.

Prof Hayden noted that although people with reduced penetrance may be at relatively low risk of developing the disease themselves, they may play a larger role in transmitting the full penetrance gene to the next generation than was previously understood.

"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," he added. "Additional genetic and environmental factors may modify the likelihood that a person develops the disease."

The authors state: "In the absence of population-based penetrance estimates for incidentally ascertained Huntington's disease alleles, particularly in the 36–39 CAG repeat range, it will be challenging to counsel these individuals about their chance of developing the disease."

Funding for this study was provided by the Canadian Institutes of Health Research. Prof Hayden is president of Global R&D and is chief scientific officer of Teva Pharmaceuticals, in which he has financial interests. The editorialists have disclosed no relevant financial relationships.

Neurology. Published online June 22, 2016. Abstract, Editorial

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