In monogenic Parkinson's disease, mutation predicts DBS outcomes

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By Marilynn Larkin

NEW YORK (Reuters Health) - In patients with monogenic Parkinson's disease (PD), outcomes of subthalamic nucleus deep brain stimulation (STN-DBS) vary depending on the genetic mutation involved, researchers say.

"A pre-surgical screening of genes commonly associated with PD, such as LRRK2, GBA, PRKN, PINK1 and SNCA, might provide valuable information on the anticipated STN DBS clinical benefit," Dr. Aristide Merola of the University of Cincinnati in Ohio said in an email to Reuters Health.

Dr. Merola and colleagues conducted a systematic review and meta-analysis of 17 studies involving a total of 518 patients, including 135 patients with the most common forms of monogenic PD.

The research team analyzed post-treatment changes in scores on the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III), and in levodopa equivalent daily dose (LEDD). Outcomes also included activities of daily living (UPDRS-II), motor complications (UPDRS-IV), and cognitive function.

As reported online February 1 in JAMA Network Open, after STN-DB, the UPDRS-III score improved by 46% in LRRK2 patients, 49% in those with a GBA mutation, 43% in those with PRKN, and 53% in idiopathic PD.

The LEDD was reduced by 61% in those with LRRK2 mutations, 22% in GBA, 61%in

PRKN, and 55% in idiopathic PD.

Further, carriers of PRKN mutations showed sustained improvements in UPDRS-II and UPDRS-IV, whereas LRRK2 mutation carriers had sustained improvements only in UPDRS-IV.

Carriers of the GBA mutation showed worse post-surgical cognitive and functional performance. "It remains unclear whether this finding is associated with the surgical treatment or with a faster cognitive decline that is intrinsic to the more aggressive disease subtype," Dr. Merola said.

Until more robust evidence becomes available, he added, "we suggest paying particular attention to the neuropsychological evaluation of GBA patients, possibly excluding from the surgical option not only those with dementia but also with mild cognitive deficits."

The findings "highlight the need for additional studies in the field of PD genetics and raise awareness about the critical importance for a personalized approach to advanced PD therapeutic options," he concluded.

Dr. Rachel Dolhun, vice president of medical communications at The Michael J. Fox Foundation, told Reuters Health, "These results add to a growing body of evidence that genetics are at least partly responsible for differences in Parkinson's symptoms, courses and treatment responses."

"With DBS, for example, even the most carefully selected candidates can experience widely varied outcomes," she said by email. "Genetic status may be one piece of data to help predict how a person will fare with this treatment."

"While genetic testing is not a standard part of the clinical evaluation for Parkinson's, many people learn their status through clinical trials or online providers," she added. "Doctors can couple this patient information with research data to inform treatment decisions."

"Ongoing Phase I and II clinical trials are targeting Parkinson's genetic mutations - specifically, LRRK2 and GBA - with the goal of slowing disease progression, something no current therapy can do," she noted. "If a Parkinson's patient knows their genetic status, they might choose to join one of these trials."

The foundation is funding a registry of people who undergo DBS to identify best practices and improve patient outcomes, she added. (http://bit.ly/2I9248d)

Dr. Alessandro Di Rocco, Director, Northwell Health's Movement Disorders Program in Great Neck, New York, said by email, "The finding that individuals harboring specific mutations, such as GBA mutations, have a greater risk for long-term post-surgical complications is a potent argument to obtain detailed genetic information prior to DBS intervention."

"This is not routinely done," he added, "and clinical guidelines may be developed in the future to add genetic testing prior to surgery. In future clinical trials, defining Parkinson's patients by their genetic mutations may help understand medication response, and personalize and optimize treatment."

Dr. Brian Kopell, Director of the Center for Neuromodulation at Mount Sinai Health System in New York City, commented in an email to Reuters Health, "It is not surprising that linking the genotype of the PD patient with DBS response yields different outcomes. For many years, we have known that a certain type of genetic dystonia, DYT-1, results in far better DBS results than other forms of dystonia."

"While this particular study is impressive in scope, we should be cautious in making new treatment decisions based on a retrospective meta-analysis," he concluded.

SOURCE: http://bit.ly/2I8bKzU

JAMA Network Open 2019.

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