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Genetic Mutation Slows Motor Symptoms in PD

Genetic Mutation Slows Motor Symptoms in PD

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Action Points

  • Parkinson’s disease (PD) patients who carried the leucine-rich repeat kinase 2 (LRRK2) G2019S genetic mutation had slower motor function decline than patients with idiopathic PD, in a seven-year longitudinal follow-up study.
  • Not that while most cases of PD are idiopathic, mutations in the LRRK2 gene are the most common cause of PD in the small percent of cases that are linked to genetics.

Parkinson’s disease (PD) patients who carried the leucine-rich repeat kinase 2 (LRRK2) G2019S genetic mutation had slower motor function decline than patients with idiopathic PD, according to researchers for the LRRK2 Ashkenazi Jewish Consortium.

The annual estimated rate of change in the Unified Parkinson’s Disease Rating Scale (UPDRS) III motor score was less among LRRK2 G2019S carriers than non-carriers: 0.689 versus 1.056, or a difference of −0.367 points (P=0.02), reported Rachel Saunders-Pullman, MD, MPH, of Mount Sinai Beth Israel Medical Center in New York City, and colleagues.

In cognitive change, however, there was no statistically significant difference between PD patients who had the mutation and those who did not, they wrote in JAMA Neurology.

“Although a milder progression in motor symptoms in individuals with PD who carry the LRRK2 G2019S mutation has been posited in cross-sectional studies, the present study is the first, to our knowledge, to demonstrate this milder progression using prospective analysis,” the authors stated. “The slower progression estimates could inform clinical trial design for emerging LRRK2-targeted agents.”

While most cases of PD are idiopathic, a small percent are linked to genetics. Mutations in the LRRK2 gene are the most common cause of PD in this subset. The G2019S mutation of this gene has been linked to PD among people with Ashkenazi Jewish ancestry, among others.

For this longitudinal study, researchers conducted an assessment of PD patients of Ashkenazi Jewish descent from three sites — two in New York City and one in Tel Aviv — from July 21, 2009, to Sept. 30, 2016, excluding patients with glucocerebrosidase (GBA1) mutations and patients who had undergone deep brain stimulation.

Of 545 patients in the study, 26.4% carried the LRRK2 G2019S mutation.

Both groups had similar ages, UPDRS I-III subscale scores, Schwab and England Activity of Daily Living Scale scores, Hoehn and Yahr ratings, and total Montreal Cognitive Assessment (MoCA) scores.

Carriers were more likely to be women (50.0% versus 40.1, P=0.04) and to have postural instability gait disturbance (PIGD, 68.3% versus 55.1%, P=0.02). They also had longer mean duration of disease (8.2 versus 6.3 years, P<0.001) and a higher average daily equivalent dose of levodopa (407.4 versus 337.1 mg, P=0.06).

Using linear mixed-effects models — adjusted for baseline age, sex, site, duration of disease at baseline, MoCA score, and levodopa-equivalent dose — the researchers found that the rate of change in UPDRS III motor score per year was 0.367 points less for LRRK2 G2019S carriers (0.689 points) than non-carriers (1.056 points, P<0.001).

The rate of change in MoCA score per year among LRRK2 G2019S carriers (−0.096 points), however, did not reach statistical significance compared with non-carriers (−0.192 points, P=0.08).

“Our study did show a potentially provocative finding with regard to patients with PD who carry the LRRK2 mutation — namely, slower progression of disease in the setting of a higher frequency of classification as PIGD,” the authors noted. This included a slower decrease in total UPDRS, UPDRS I, UPDRS III, and posture, gait, and balance scores. Moreover, they noted, the difference in the change in UPDRS score remained significant after adjusting for PIGD.

“This population, and others like it, will likely be essential in the early days of finding the first medications to slow or stop the progression of motor and cognitive dysfunction associated with Parkinson’s disease,” said Andrew West, PhD, of the University of Alabama at Birmingham, who was not involved in study.

“We hope that genetically-defined disease will be similar to sporadic disease, and it appears to be true in this case,” he told MedPage Today. “Nominal differences were seen in how fast the disease moves forward, which suggests a slightly bigger group of volunteers than initially anticipated may be needed to find the best drugs.”

Because the researchers did not have extensive follow-up data, they designed this study with linear models. This might limit findings since PD may not have a linear course, especially in its late stage. To address this, the researchers performed a sensitivity analysis on individuals who had PD for 20 years or less; they found the overall association with UPDRS scores held.

Saunders-Pullman and co-authors disclosed no relevant relationships with industry.

2018-11-01T00:00:00-0400

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