For Parkinson’s Patients, Genetic Testing May Open Possibilities

Physicians have had little incentive to order genetic tests for their Parkinson’s disease patients, although evidence suggests that up to 15% of these cases may be genetic.

“Mutations in several different genes increase the risk of Parkinson’s disease,” says Roy N. Alcalay, MD, MS, the Alfred and Minnie Bressler Associate Professor of Neurology at Columbia University Vagelos College of Physicians and Surgeons and a neurologist at NewYork-Presbyterian/Columbia University Irving Medical Center. “Until recently, we rarely offered genetic testing for people with Parkinson’s because the benefit had been unclear.”

But recent studies have shown that genotype can help better estimate the rate of disease progression in Parkinson’s. And as new drugs designed for people with specific Parkinson’s genes have entered clinical trials (including one at Columbia University Irving Medical Center), Alcalay realized the calculus has changed. 

“From our own genetic studies, I realized many people were eligible to enroll in such trials, but they didn’t know it because nobody told them about their genetic status,” Alcalay says. “I wanted to find a simple, ethical way to offer Parkinson’s patients information about their genotype if they are interested.”

Alcalay’s idea was championed by the Parkinson’s Foundation, which recently launched PDGENEration—a program that will offer free genetic testing and counseling to patients diagnosed with Parkinson’s. Columbia is the first center to participate in the program, which will open soon in several other centers across the nation. The program ultimately plans to test 15,000 patients. 

Alcalay, the principal investigator of PDGENEration, talked to the CUIMC Newsroom about how the program may help support the development of personalized therapies for Parkinson’s patients.

Why is now the right time to start genetic testing in Parkinson’s disease?

Parkinson’s disease drug development is at a transition point, with the focus on developing drugs that take a precision medicine approach. But in order for these drug trials to succeed, more patients will need to get tested to find out if they are eligible to participate. 

The PDGENEration program will test patients for the presence of mutations in seven genes linked to Parkinson’s disease, including the two more common ones, GBA and LRRK2.

Up to 10% of individuals with Parkinson’s have a defective copy of GBA, which increases the risk of disease by roughly five-fold. GBA makes an enzyme that’s critical for recycling debris inside the cell, so when one gene is defective, toxins may accumulate in the cell. Two of the drugs under investigation are designed to increase GBA activity; the other is designed to prevent the buildup of toxins in the brain. (Note: Current treatments for Gaucher disease, which occurs when two defective copies of GBA are present, do not enter the brain and are not suitable for Parkinson’s patients).  

An estimated 1% to 2% of people with Parkinson’s disease have a variant of the LRRK2 gene that makes the LRRK2 enzyme overactive. Researchers (including groups at Columbia) are still investigating how LRRK2 overactivity leads to Parkinson’s. The risk of Parkinson’s increases by around 30% in individuals with an LRRK2 mutation. 

It’s important to note that current testing would not find a genetic cause of Parkinson’s in most patients. However, learning more about the genetics of Parkinson’s may help us understand the underlying biology of the disease and ultimately lead to the identification of novel drug targets that could benefit all people with Parkinson’s. 

Why should patients interested in knowing their genetic status get tested through this program, not elsewhere?

First of all, genetic testing is not for everyone. Some people may be very curious about why they developed Parkinson’s, and others may not be interested in this information. This program offers genetic counseling to help people decide if they want to learn their genetic status before they get tested and will help them understand the results after they receive them. 

Some patients have already discovered they have a Parkinson’s-related gene mutation with home-based genetic testing kits. However, these kits are not comprehensive. They only look for one of several Parkinson’s-related changes in either LRRK2 or GBA. 

In the PDGENEration program, both genes will be sequenced to look for all known Parkinson’s-related changes. In addition, PDGENEration participants will receive information about changes in five additional genes, Parkin, PINK1, DJ-1, VPS-35, and alpha-synuclein. The analysis also may allow us to identify unknown variants of these genes that are related to Parkinson’s. 

Will the data collected through PDGENEration be used for other research studies?

Absolutely. In addition to testing and reporting result on these seven genes, we will conduct genetic analyses for research purposes, including whole exome sequencing, on all participants. These data may be used for future discovery of additional Parkinson’s-related genes.

We will invite all those who completed the genetic study to enroll in a longitudinal follow-up study, which could help us better understand how these mutations affect Parkinson’s progression. For instance, can patients with these genetic risk factors modify their risk with lifestyle changes? 

Who can enroll in the program?

Individuals who have received a clinical diagnosis of Parkinson’s disease—not family members—can enroll in PDGENEration.