11:06am Saturday 30 May 2020

Intractable Seizures Halted with Experimental Treatment for Rare Pediatric "Pretzel Syndrome"

The disease – PSME or polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome, commonly called Pretzel syndrome – is caused by a double-deletion of a specific gene that encodes for STRADA. About 4 percent of Old Order Mennonite individuals in Ohio, Pennsylvania and New York have a single copy of the deleted gene. When a double-deletion occurs, the loss of STRADA causes an activation of mTORC1 and, subsequently, the kinase p70S6K. This causes intractable seizures and results in limited cognitive development and language function, leaving PSME patients wheelchair-bound, mute and completely dependent.

When five children, ranging from 8 months old to nearly 5 years old, were given doses of a drug that inhibits mTOR, the drug Sirolimus (rapamycin) significantly reduced seizures. Four of the five patients have been seizure free for the last year; previously no PSME patients had achieved freedom from seizures, even while on anti-epileptic medication. Starting the drug by three months of age seemed to stave off seizures; one patient who started treatment early had a single seizure and another has had no seizures.

The use of this drug in Pretzel syndrome patients stems from earlier research showing that sirolimus was an effective treatment for a related  and more common disorder, tuberous sclerosis complex (TSC), which is also associated with seizures, altered brain structure and enhanced mTOR activation.

The research was conducted by a team including the study’s senior author, Peter Crino, MD, PhD, now at Temple University School of Medicine and Shriners Pediatric Research Center; lead author and MD/PhD candidate Whitney Parker, and Ksenia Orlova, William Parker, Jacqueline Birnbaum, Marianna Baybis, Jetle Helfferich, and Kei Okochi from the Penn Epilepsy Center and Department of Neurology; Vera Krymskaya and Dmitry Goncharov from Penn’s Pulmonary, Allergy and Critical Care division, and collagues from the University of Groningen School of Medicine in the Netherlands, as well as partners from the Clinic for Special Children in Strasburg, Pa., the Department of Biology in Franklin and Marshall College and Lancaster General Hospital in Lancaster, Pa.

The study was funded by the National Institutes of Health (NS045022, HL110551, GM008216) and the Penn-Pfizer Collaborative Program, and a Ruth L. Kirschstein National Research Service Award.


Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 16 years, according to U.S. News & World Report‘s survey of research-oriented medical schools. The School is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $398 million awarded in the 2012 fiscal year.

The University of Pennsylvania Health System’s patient care facilities include: The Hospital of the University of Pennsylvania — recognized as one of the nation’s top “Honor Roll” hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; and Pennsylvania Hospital — the nation’s first hospital, founded in 1751. Penn Medicine also includes additional patient care facilities and services throughout the Philadelphia region.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2012, Penn Medicine provided $827 million to benefit our community.

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