Study of Mutation May Lead to New Treatments for Parkinson Disease

Parkinson disease (PD) patients with a mutation of the leucine-rich repeat kinase 2 (LRRK2) gene show a slower decline in motor functioning compared to patients without the mutation, according to a new study.

Major mutations in the LRRK2 gene are the greatest contributor to the development of PD and are present in 1% to 2% of the people with PD worldwide, study author Rachel Saunders-Pullman, MD, MPH, an associate professor of neurology at the Icahn School of Medicine at Mount Sinai, told MD Magazine. For certain ethnic groups, such as Ashkenazi Jews and North African Arab-Berbers, the gene is present in about 15% of those with PD.

“This study supports that with the G2019S mutation of LRRK2, the motor progression is slightly slower than other Parkinson’s as a whole,” Saunders-Pullman said. “This study is unique in that a large enough cohort was available to show this mild difference in progression. Our study is in contrast to risk variant LRRK2, a variant that occurs more frequently in the population and not considered a major mutation, that has been shown to be more rapidly progressive than in other Parkinson’s.”

From July 2009 to September 2016, researchers conducted a comprehensive assessment of patients with LRRK2 PD and non-mutation PD. Participants were pooled from 3 sites: Tel Aviv Sourasky Medical Center in Israel, Columbia University, and Mount Sinai Beth Israel in New York City.

A total of 545 patients of Ashkenazi Jewish descent with PD who had 1 to 4 study visits were evaluated. There were 144 patients that had the LRRK2 G2019S mutation (233 women, 312 men) and the mean (SD) age was 68.2 years for those with the LRRK2 mutation and 67.8 years for those without the mutation. Out of those who had the mutation, 72 were women; of those without the mutation, 161 were women.

Researchers examined the association between LRRK2 mutation status and the rate of change in Unified Parkinson’s Disease Rating Scale (UPDRS) III scores using disease duration as the time scale, adjusting for sex, site, age, disease duration, cognitive score, and levodopa (a drug for PD treatment) dose at baseline.

The estimate (SE) of the rate of change in UPDRS III score per year among those with the LRRK2 mutation (0.689 [0.192] points per year) was less than those without the mutation (1.056 [0.187] points per year; difference, -0.367 [0.149] points per year; P = .02).

“Our findings should help lay the groundwork for clinical trials of medications that address LRRK2 G2019S mutations,” Saunders-Pullman said. “Part of the problem with clinical trials for disease-modifying medications in Parkinson’s not showing benefit has been that participants have such a wide range of causes and the range of types of Parkinson’s may lead to a diversity of response. In this regard, it is of value to determine whether people with LRRK2 mutations, even in the absence of a study drug, have a different course of their Parkinson’s. If they do, as our study suggests, it might lead to more informative study results.”

Saunders-Pullman added that another major issue is that the mechanism through which LRRK2 mutations cause PD are likely present in a subgroup of non-mutation PD as well.

“It is hoped that studies of the G2019S mutation will improve therapeutics for people with Parkinson’s without the mutation as well,” said Saunders-Pullman.

The study, “Progression in the LRRK2-associated Parkinson disease population,” published in JAMANeurology.

This article was originally published by MD Magazine.