As we learn more about genetic connections to Parkinson's disease (PD), researchers strive to understand the biological and functional impact of these variants. What does having a GBA mutation really mean for someone? Complicating matters further is that there are many different mutations on one gene. How does the type of mutation on that gene impact PD? (Learn more about genetics.)
Findings from two studies, one MJFF-funded, published recently in Annals of Neurology point to mutations in the GBA gene that may predispose some to cognitive problems with Parkinson's disease.
GBA Mutations Linked to Cognitive Decline
The MJFF-funded study, from researchers at Brigham and Women's Hospital (BWH) in Boston and the International Genetics of Parkinson Disease Progression Consortium, screened samples from more than 2,300 people with PD gathered from seven studies. The researchers found around 10 percent had a GBA mutation and classified some mutations as severe (so-called neuropathic mutations). About one to two percent of people in the studies had severe GBA mutations.
The paper reported having any kind of GBA mutation was linked to higher risk of cognitive decline, but those with a severe mutation saw their risk increase over time by 217 percent. Ten years after diagnosis, 50 percent of people with a severe GBA mutation had cognitive impairment compared to only 20 percent of people without a GBA mutation.
The other study, from a team at the Institute for Parkinson's Disease and Movement Disorders in Milan, Italy, looked at data from more than 2,800 people with PD seen there. They, too, found a GBA mutation was associated with higher risk of dementia and the risk was greater with mutations identified as severe.
Findings May Inform How We Develop Therapies
Mutations in the GBA gene lead to lower levels of the GCase protein, which are associated with more clumps of the protein alpha-synuclein. Scientists believe those clumps harm cells and cause PD progression. (Read more about GBA and GCase.) Researchers are working on therapies to address GCase dysfunction in people with GBA mutations, with some close to clinical trials.
The findings linking these mutations to cognitive dysfunction may offer a way to test the effects of those therapies.
In an accompanying commentary also published in Annals of Neurology, David Standaert, MD, PhD, a member of the MJFF Scientific Advisory Board, and David Geldmacher, MD, both of the University of Alabama at Birmingham (UAB) and not affiliated with the studies, wrote, "Use of cognitive endpoints may be a valuable strategy in these studies, as the rapid rate of decline observed provides a robust signal and may reduce the sample size and duration required in these studies."
To further enable drug development and testing, our Foundation is funding an initiative led by Clemens Scherzer, MD, who also led the BWH study, to investigate biological markers of Parkinson's in people with a GBA mutation and make more connections between genetics and the clinical presentation of the disease.
"This is the dawn of personalized medicine for Parkinson's disease," said Dr. Scherzer. "We see more precise clinical trials as the next logical step, and one that will help match the right therapies with the right patients faster."
Genetics Testing Can Inform Research but Not Yet Care
The UAB authors' commentary also acknowledges the impact of these findings on individuals' care. Should people be genetically tested for GBA to predict cognitive decline? Drs. Standaert and Geldmacher say some patients may want that information, although at this time there is no specific treatment for PD cognition. Also, there may be other factors that influence cognitive decline, so a negative GBA test may give a false sense of security.
Those who do have a GBA mutation can help us learn more about the disease and develop new treatments. Mutations in this gene are more common in people of Ashkenazi Jewish descent and are associated with Gaucher disease, a disorder where fatty substances build up and cause enlarged organs. The MJFF-led Parkinson's Progression Markers Initiative (PPMI) -- a study to identify biological markers of PD and learn more about its genetics -- is enrolling people of Ashkenazi Jewish descent with PD or Gaucher or a first-degree relative with one of the two diseases.
Take a survey to see if you're eligible for genetic screening and counseling through PPMI.