For many people, the symptoms of Huntington’s disease will not begin to show for decades.
The genetic disorder is incurable but it is not uncommon for sufferers to reach middle-age before the physical symptoms — loss of motor skills and bodily functions, mental decline, emotional changes and depression — begin to manifest.
But buried deep in person’s genetic code, mutations are building and repeating, accumulating until they reach a breaking point, when the fatal disease begins to show itself.
Nerve cells in the brain then begin dying, leading to symptoms similar to motor neurone disease and Alzheimer’s, often requiring constant care despite years of no apparent illness.
But new research from MIT and Harvard has found why the deadly condition can lay dormant for decades, and offered a glimmer of hope on possible future treatment.
The new findings are now making waves internationally, with an Australian expert describing it as “one of the more important studies in the history of Huntington’s research”.
The genetic code that makes who we are
DNA serves as a blueprint for every person on the planet, an instruction manual for how our body is made up — from eye colour to blood type to whether you can roll your tongue or not.
DNA is made up of four bases — adenine (A), thymine (T), cytosine (C) and guanine (G) — and the sequence in which these four bases are placed determines who we are.
These bases usually form pairs (A pairs with T and C pairs with G), but occasionally a mutation will cause a triplet with three bases to form.
The Huntington’s mutation involved a stretch of DNA that has the same three-letter sequences repeated over and over. (Pixabay)
One of these triplets, CAG, was identified in 1993 as being associated with Huntington’s disease.
While everyone may have the CAG triplet, people with Huntington’s disease have the sequence “repeated” more than 36 times in their DNA.
These CAG triplets are constantly expanding in the genes of a person with the disease, slowly at first and then rapidly, repeating themselves.
Much like a snowball might gather size and speed as it rolls down a hill, a cell might slowly repeat CAG triplets at first, gaining a few extra copies over decades until it gains momentum, doubling in a few short years.
People with Huntington’s disease have many more repeat copies of the CAG protein, leading to eventual toxicity and cell death. (National Institute of Standards and Technology )
And new research from MIT and Harvard shows that once this snowball effect gets big enough, it begins to destroy the nerve cells in the brain.
Researchers took brain tissue from 53 people with Huntington’s, using it to pinpoint the moment when nerve cells began to die.
The breaking point for brain cells is 150
Danny Hatters, who runs a research program at the University of Melbourne with a focus on Huntington’s, called the new research a “milestone” for the scientific community.
“I think it’s one of the more important studies in the history of Huntington’s research,” Professor Hatters said.
The research found cells only started dying when they reached a threshold of 150 repeat CAG copies, giving each brain cell what researchers refer to as a “ticking DNA clock”.
As brain cells continually die, both physical and mental symptoms may begin to manifest, and then worsen. (Shutterstock: Atthapon Raksthaput)
Once a cell has repeated the sequence 150 times or more, it reaches its breaking point, becoming toxic and rapidly deteriorating until death.
“If you’re born with 40 [repeats], having 40 is not enough to be damaging to your cells, but over time, 40 will become 50, will become 60, and eventually will become above 150,” Professor Hatters said.
“By the time the disease has led you to die, then in those brain cells that are dying very quickly, those repeats can be hundreds of repeats,
“They can be anywhere upwards of 150, and that is a completely remarkable finding because it’s the first time anyone has ever shown that.”
Once enough brain cells die, physical and mental symptoms will begin to manifest, a process that may have taken decades to come to the surface.
Huntington’s disease affects neurons in an area of the brain known as the striatum, a region that controls movement, (Gladstone Institute of Neurological Disease: Steven Finkbeiner)
Professor Hatters said the exact mechanism of how cells were degenerating or dying was still unknown, it could be a defence mechanism from the body attempting to correct the vast amount of CAG copies it has made.
“The machinery that appears to be trying to fix the problem is inadvertently, for some unknown reason, making it a lot worse,” he said.
“We could potentially suppress the effects of the repair … and this could be a new way to tackle the disease.”
A new window of opportunity for therapy
Robert Handsaker is a staff scientist at the Broad Institute of MIT and Harvard and co-authored the new research.
He said the discovery that cells only began to die at 150 repeats of the CAG protein means new treatments might be able to save cells before they ever reached that point.
“You can think of the therapeutic approaches as trying to deal with the snowball once it’s gotten fairly big, or you can try to head off the snowball when it’s really small,” Mr Handsaker said.
“The protein isn’t toxic at the very beginning of life, but it only becomes toxic later in life. This … creates a really large therapeutic window at which we can treat.”
More than 2,000 Australians are believed to have Huntington’s disease — an inherited disorder.
When a parent has the disease, each child has a 50 per cent chance of inheriting the mutation.
An MRI of a brain, showing sections which have atrophied as Huntington’s disease progresses. (Radiopaedia: Frank Gaillard)
It means thousands more Australians could be at risk of developing the genetic condition.
But the ramifications of the research could go even further, applying to a range of similar diseases that affect thousands of Australians such as Fragile X syndrome and Friedreich’s ataxia.
Study co-author Sabina Berretta said the possibilities were exciting for researchers.
“There are several types of this particular disorder that are actually due to CAG repeats, it’s just in different genes,” Professor Berretta said.
“It is possible that the same mechanism that we discover for Huntington’s actually also plays a role in other brain disorders.”
