Scientists Uncover Why Some Huntington's Disease Patients Decline Years Earlier

A study in the journal Neuron explains why some Huntington's disease patients develop symptoms 10 to 12 years earlier and have a more aggressive illness. Researchers led by Dr. Michael Hayden of the Center for Molecular Medicine and Therapeutics at the University of British Columbia (UBC) found that a genetic variant drives runaway DNA changes inside the brain's most vulnerable neurons, accelerating disease onset.

Huntington's disease is a rare, inherited neurological disorder that progressively breaks down nerve cells in the brain, affecting movement, thinking and emotional well-being; there is no cure. It is caused by a mutation in the HTT gene, where a DNA segment called a CAG repeat keeps copying itself inside neurons, like a spelling error duplicated with every copy. As the repeats lengthen, they interfere with normal cell function and make brain cells more vulnerable to damage and death.

A small proportion of patients carry a variant involving loss of an "interruption" within the CAG repeat, long known to cause earlier onset. Studying blood and postmortem brain tissue, the team found patients with the variant had far larger mutation expansions inside their neurons, about five times more often than in patients without it, plus fewer surviving neurons and earlier loss of medium spiny neurons, the nerve cells especially vulnerable in the disease.

Although the mutation exists in every cell of the body, the expansion was found to be concentrated in certain brain cells; blood samples showed little evidence of the changes seen in neurons. "The mutational expansion seems to be selective for the brain," Hayden said, adding this may explain why the disease is fundamentally a brain disease. The findings suggest blood tests are not a reliable indicator of what is happening in the brain, relevant to future research.

Hayden said the results validate DNA repeat expansion as a therapeutic target; several experimental therapies in development aim to slow or prevent this mutation growth before damage occurs.