A genetic variant accelerates Huntington’s disease onset by over a decade, according to recent research, revealing how specific DNA changes drive the neurodegenerative disorder’s progression and offering new therapeutic targets.
Huntington’s disease, a progressive brain disorder causing uncontrolled movements, cognitive decline, and emotional problems, has long been linked to an inherited mutation in the HTT gene. However, a groundbreaking study published in Neuron and additional research from the Broad Institute and Harvard Medical School have uncovered new mechanisms explaining why some patients develop symptoms earlier than others. These findings, based on analysis of brain tissue, blood samples, and genetic data, highlight the role of somatic CAG repeat expansions in accelerating disease progression and point to potential strategies for intervention.
Mechanism of Somatic Expansion
For decades, scientists understood that Huntington’s disease arises from an expanded stretch of CAG repeats in the HTT gene. Normally, this sequence appears 15 to 35 times, but individuals with 40 or more repeats almost always develop the disorder. However, a study by researchers at the Broad Institute and Harvard Medical School revealed that the mutation itself is initially harmless. Instead, it undergoes a process called somatic expansion,
where the CAG repeats grow over time in specific brain cells, eventually reaching a toxic threshold. These experiments have changed how we think about how Huntington’s develops,
said Steve McCarroll, a co-senior author of the study.
The research found that somatic expansions occur selectively in striatal projection neurons, which are critical for movement and cognition. Once the CAG repeats surpass approximately 150, these cells begin to die, leading to the hallmark symptoms of Huntington’s. The mutational expansion seems to be selective for the brain,
noted Dr. Michael Hayden of the University of British Columbia, whose team studied how genetic variants influence this process. That may help explain why Huntington’s disease, even though the mutation is in every cell, is fundamentally a brain disease.
The Role of the CAG-CCG LOI Variant
While all Huntington’s patients carry the HTT mutation, a small subset with a specific genetic variant—CAG-CCG loss-of-interruption (LOI)—develop symptoms up to 12.5 years earlier. A study led by Hayden and published in Neuron found that this variant drives more frequent and severe CAG repeat expansions in brain neurons. People carrying the variant had dramatically larger expansions of the Huntington mutation inside their neurons, occurring about five times more frequently than in patients without the variant,
Hayden explained.
The study analyzed post-mortem brain tissue and blood samples from patients, revealing that the CAG-CCG LOI variant does not significantly affect CAG repeats in blood or bulk brain tissue. However, it profoundly increases the proportion of large expansions in medium spiny neurons, which are particularly vulnerable in Huntington’s. “Our interrogations of somatic expansion in blood, brain, and striatal MSNs of donors with and without the CAG-CCG LOI show this modifier does not increase small expansions in blood or bulk brain tissues, yet profoundly increases the proportion of genomic large (111–150) and very large (>150) CAG expansions in affected striatal MSNs,” the researchers wrote.
This discovery helps explain why blood tests may not reflect the disease’s progression in the brain. The findings suggest blood tests are not a reliable indicator of the disease unfolding inside the brain,
Hayden said. This is an important consideration for future Huntington disease research and clinical trials.
Implications for Treatment
The findings challenge existing approaches to Huntington’s treatment. Many candidate Huntington’s drugs aim to reduce expression of the HTT protein, but the study suggests these may not be having a therapeutic effect in most cells because very few cells have the toxic version of the protein at any given time. Instead, the research points to a different therapeutic strategy: stopping or slowing the CAG-repeat expansion in the HTT gene. If we can suppress that expansion, it may be possible to delay progression or delay the onset of disease,
Hayden said.
Several drugs in development target this mechanism, including those designed to inhibit the enzymes responsible for CAG expansion. This work answers that question and provides dramatic evidence that repeated expansion of the mutation is an important driver of Huntington disease and a potential treatment target,
Hayden said. This study and the work it informs could be impactful and make a major difference in relieving suffering in the short term.
However, challenges remain. The study also found that even in patients without the CAG-CCG LOI variant, CAG repeats continue to expand over time, resulting in a variety of lengths in different tissues. When we looked at the neurons that are dying in Huntington disease, we saw much greater expansion of the genetic mutation,
Hayden noted. This continues to strengthen the argument that DNA expansion is an important cause of disease.
Researchers are now focusing on developing therapies that target CAG expansion. The findings also underscore the need for brain-specific biomarkers to monitor disease progression, as blood tests may not be a reliable indicator of the disease unfolding inside the brain. The point of our work — what we all do — is relieving suffering caused by disease,
Berretta said.
For patients and families affected by Huntington’s, the research offers hope. These experiments have changed how we think about how Huntington’s develops,
McCarroll said. We think that it will apply in DNA-repeat disorders beyond Huntington’s disease.
As the field moves forward, the focus remains on translating these discoveries into effective treatments that can delay or prevent the onset of this devastating condition.