Yale Researchers Identify Genetic Cause of Rare Infant Epileptic Disorder

MMPSI is a rare, severe brain disorder that appears in the first six months of life. It is characterized by treatment-resistant epileptic seizures and developmental delay. Further, the electrical activity appears to “migrate” through various regions of the brain, which gives the disorder its name. Although the recurrent seizures and electrical discharges in the brain abate with age, the patient’s intellectual and motor development is arrested in infancy.

In collaboration with a group at the Hopital Necker-Enfants Malades in Paris, France, the Yale team found that the disease-causing gene, which was identified by selective DNA exome sequencing in a dozen patients affected by MMPSI, results in the overactivity of a protein that normally controls the excitability of neurons. The Yale team also discovered that the affected protein interacts with another protein that, when defective, is known to produce Fragile X syndrome, the leading inherited cause of autism and intellectual disability.

“For the first time, we have a target for future therapeutic approaches to treating this devastating condition,” said co-first author Matthew Fleming, postdoctoral researcher at Yale School of Medicine.
All of the data to characterize the aberrant protein in this study were generated in lab of Leonard Kaczmarek, professor of pharmacology and of cellular and molecular physiology at Yale School of Medicine.

Kaczmarek explains, “We believe this to be the first epilepsy-associated gene to be identified by exome sequencing in a handful of affected patients,” says Kaczmarek. “Moreover, it provides a very important glimpse into why some epilepsies are so devastating for brain function while others seem to have no effect on intellectual development.”

Corresponding author Rima Nabbout, co-first author Giulia Barcia, and authors Aline Deligniere, Isabelle Desguerre and Olivier Dulac are with the Assistance Publique-Hopitaux de Paris. Other authors are Vali Gazula, Maile Brown, Jack Kronengold of Yale; Haijun Chen of the State University of New York, Albany; Avinash Abhyankar of The Rockefeller University; Roberta Cilio of Children’s Hospital, Rome; Patrick Nitschke, Anna Kaminska, Maeva Langouet, Arnold Munnich, Laurence Colleaux and Nathalie Boddaert of Hopital Necker-Enfants Malades, Paris.

The study was supported by grants from the Centre National de la Recherche Scientifique, the French National Research Agency, the U.S. National Institutes of Health, the FRAXA Foundation, the St. Giles Foundation, and the Rockefeller University.