New study may help diagnose this rare, fatal disease decades before symptoms appear

By Elizabeth Pratt | Fact-checked by Davi Sherman

Published February 21, 2025

Key Takeaways

Industry Buzz

“This is a really different way of thinking about how a mutation brings about a disease, and we think that it will apply in DNA-repeat disorders beyond [this] disease." — Steve McCarroll, PhD
'These results answer a really important question, which is why a gene mutation that’s present from birth only causes disease in [middle] or late adulthood. It also speaks to why we see a phenomenon in this disease called ‘anticipation,’ where generation by generation, the disease strikes earlier and earlier in life.” — Xenos Mason, MD

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In a groundbreaking study, researchers have uncovered a mechanism that could explain how the genetic mutation that causes Huntington’s disease leads to the death of brain cells.^[]

Researchers from the Broad Institute of MIT and Harvard Medical school have found that the inherited genetic mutation can remain harmless for decades but then slowly grows, generating toxic proteins and killing the cells in which it has expanded.

“These experiments have changed how we think about how Huntington's develops," Steven McCarroll, PhD, a geneticist and neuroscientist and co-senior author of the study, said in a press statement.^[]

"This is a really different way of thinking about how a mutation brings about a disease, and we think that it will apply in DNA-repeat disorders beyond Huntington's disease."

— Steven McCarroll, PhD, press release

A paradigm shift

Researchers have known for 30 years that Huntington’s disease is caused by an inherited genetic mutation in the Huntingtin (HTT) gene.^[] However, researchers have not known how the mutation, which is present from birth, causes brain cell death in middle or older age.

Experts say that the findings of the study are significant.

“These findings really have the potential to shift the paradigm for Huntington’s disease. It’s not necessarily a surprising finding; in fact, when you consider the mechanisms of disease and the findings of the paper, it all seems intuitive. But this is the beauty of meaningful results: they often seem elegant and simple,” Xenos Mason, MD, a neurologist at Keck Medicine of USC who specializes in movement disorders, tells MDLinx.

"These results answer a really important question, which is why a gene mutation that’s present from birth only causes disease in [middle] or late adulthood. It also speaks to why we see a phenomenon in this disease called ‘anticipation,’ where generation by generation, the disease strikes earlier and earlier in life,” Dr. Mason says.

“All of these [findings] probably come down to the way that DNA repair is involved in the generation of Huntington’s disease. At the same time, though, the results bring up some really important unanswered questions—most importantly, why specific types of brain cells are susceptible to the gene expansion that causes the cell to die. What’s going on with DNA repair in these cells that leads them to be so sensitive?” Dr. Mason adds.

About the research

The researchers examined over 500,000 single cells from brain tissue samples donated by 53 people with Huntington’s and 50 without the disease.^[]

The genetic mutation for Huntington’s disease involves a stretch of DNA in the HTT gene in which a three-letter sequence (CAG) is repeated at least 40 times. In those without the disease, CAG is repeated only 15 to 35 times.

The researchers found that DNA stretches with 40 or more CAG repeats expand until they are hundreds of repeats long. At the time the CAG repeats reach about 150, brain cells become sick and then die.

New treatment possibilities

Experts say this research could pave the way for new treatments.

“This finding attempts to explain the often decades-long delay in symptom onset in Huntington’s disease. Rather than a fixed, inherited mutation causing neurodegeneration, Huntington’s disease may actually represent a slow, progressive genetic expansion process that could potentially be modified or delayed. This has obvious implications for therapeutic development,” Hengameh Zahed, MD, PhD, a neurologist with the Stanford Medicine Movement Disorders Center, tells MDLinx.

“Most research into disease-modifying approaches so far has involved attempts at reducing the expression of the mutant huntingtin protein. However, this finding, in combination with other studies, suggests an important role for somatic repeat expansion in [the] onset of clinical manifestation, and [it] opens up the possibility of a new pathway for treatment where targeting somatic expansion could delay [the] onset of symptoms,” Dr. Zahed adds.