Surprise discovery sheds light on causes of Huntington’s disease, a deadly and devastating brain disease

Scientists are unraveling the mystery of what triggers Huntington’s disease, a devastating and deadly hereditary disease that strikes in the prime of life, causing nerve cells in parts of the brain to be destroyed and die.

The genetic mutation linked to Huntington’s disease has been known for a long time, but scientists have not understood how people can have the mutation from birth and not develop any problems until later in life.

New research shows that, surprisingly, the mutation is harmless for decades. But it gradually grows into a larger mutation, until it crosses a threshold, generates toxic proteins, and kills the cells in which it grew.

“The conundrum in our field is: why do you have a genetic disease that manifests itself later in life if the gene is present from conception? said Dr. Mark Mehler, who directs the Institute for Brain Disorders and Neural Regeneration at Albert Einstein College of Medicine and was not involved in the research. He called the research a “landmark” study and said “it addresses a lot of issues that have plagued the field for a long time.”

The death of brain cells ultimately leads to problems with movement, thinking, and behavior. Huntington’s symptoms, which include involuntary movements, unsteady gait, personality changes and impaired judgment, typically begin between ages 30 and 50 and gradually worsen over 10 to 25 years.

Scientists from the Broad Institute of MIT and Harvard, McLean Hospital in Massachusetts, and Harvard Medical School studied brain tissue donated by 53 people with Huntington’s disease and 50 others, analyzing half a million cells .

They focused on the Huntington’s mutation, which involves part of the DNA of a particular gene where a three-letter sequence – CAG – is repeated at least 40 times. In people without the disease, this sequence repeats only 15 to 35 times. They discovered that DNA sequences with at least 40 “repeats” expand over time to hundreds of CAGs. Once CAGs reach a threshold of around 150, certain types of neurons become sick and die.

The results “were really surprising, even to us,” said Steve McCarroll, a Broad fellow and co-senior author of the study, published Thursday in the journal Cell.

The research team estimated that repeat sequences develop slowly during the first two decades of life, then the rate accelerates dramatically when they reach around 80 CAG.

“The longer the repetitions, the earlier in life the onset will occur,” said neuroscience researcher Sabina Berretta, one of the study’s lead authors.

The researchers acknowledged that some scientists were initially skeptical when the results were shared at conferences because previous work had shown that repeated expansions on the order of 30 to 100 CAGs were necessary, but not sufficient, to cause CAG. Huntington. McCarroll agreed that 100 CAGs or fewer are not enough to trigger the disease, but said his study found that expansions with at least 150 CAGs are.

Researchers hope their findings can help scientists find ways to delay or prevent this incurable disease, which affects about 41,000 Americans and is now treated with medications to manage symptoms.

Recently, experimental drugs designed to reduce levels of the protein produced by the mutated Huntington gene have struggled in trials. The new findings suggest that this is because few cells have the toxic version of the protein at any given time.

Slowing or stopping the expansion of DNA repeats could be a better way to target the disease, researchers say.

While there’s no guarantee this will avoid Huntington’s, McCarroll said “many companies are launching or expanding programs to try to make this happen.”

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