A new study has revealed why some people with Huntington disease develop symptoms 10 to 12 years earlier and experience a more aggressive form of the disease.
The research published today in the journal Neuron shows how a genetic variant can dramatically accelerate Huntington disease by driving runaway DNA changes inside the brain's most vulnerable neurons.
"People with this genetic variant have dramatically hastened onset of disease, but we didn't know why," said Dr. Michael Hayden, professor at the Centre for Molecular Medicine and Therapeutics at UBC and senior author of the study. "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."
Huntington disease is a rare, inherited neurological disorder that causes the progressive breakdown of nerve cells in the brain. The condition affects movement, thinking and emotional well-being, and there is currently no cure or treatment to slow progression.
A spelling mistake gone awry
One way to think about the process is like a typo in a document that keeps getting copied. With every copy, the mistake is replicated and interferes with the message.
In Huntington's, the mutation continues to repeat and expand within neurons over time. As those repeats become longer, they interfere with normal cell function and make brain cells increasingly vulnerable to damage and death.
"When we looked at the neurons that are dying in Huntington disease, we saw much greater expansion of the genetic mutation," said Dr. Hayden. "This continues to strengthen the argument that DNA expansion is an important cause of disease."
A small change makes a big difference
A small proportion of people with Huntington have this genetic variant, and researchers have known for years that they develop Huntington disease earlier in life.
But they didn't know why this seemingly small change in DNA had such a dramatic effect on disease onset and progression.
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. They also had fewer surviving neurons and earlier loss of particularly vulnerable nerve cells.
Why Huntington disease is primarily a brain disease
The researchers analyzed blood samples and post-mortem brain tissue, and found a clue that helps explain one of the mysteries of Huntington disease: why a mutation that is present in every cell of the body primarily damages the brain.
Although the mutation exists throughout the body, the researchers found that the expansion process appears to be highly concentrated in certain cells of the brain. Blood samples, by contrast, showed little evidence of the dramatic changes that take place within the brain's neurons.
"The mutational expansion seems to be selective for the brain," Hayden said. "That may help explain why Huntington disease, even though the mutation is in every cell, is fundamentally a brain disease."
The findings suggest blood tests are not a reliable indicator of the disease unfolding inside the brain, which is an important consideration for future Huntington disease research and clinical trials.
Implications for future treatments
While other factors besides expansion likely contribute to neuron loss, the findings provide some of the strongest human evidence to date that expansion of the Huntington mutation is a key factor in disease progression.
"It validates repeat expansion of the DNA as an important therapeutic target in Huntington disease," Hayden said. "If we can suppress that expansion, it may be possible to delay progression or delay the onset of disease."
Several experimental therapies in development aim to slow or prevent this mutation growth before the damage occurs. While more research is needed, this study's findings show research is moving in the right direction for a disease which has been so difficult to treat.
This research was funded by Huntington's Disease Foundation, the Huntington Disease Society of America, and the Huntington Society of Canada. The UBC HD Biobank and the NZ Neurological Foundation Human Brain Bank provided human tissue for this study. This work is only possible through the generous brain donations of Huntington disease patients and their families.
