Yale-led team’s syndromic approach identifies gene causing devastating epilepsy in babies

Epilepsy is perhaps one of many neurological conditions often misunderstood by the public at large. Generally, the disease is characterized by intermittent occurrences of convulsions, disturbances in attention and sensory processing and loss of consciousness, which is sometimes followed by memory loss. According to the medical community, epilepsy is caused by excessive bursts of neural or electrical activity in the brain. The result of these burst prevents the brain from exchanging its normal messages and interrupts the body’s ability to perform ordinary task. When someone experiences a seizure, the severity, length, and type of seizure is typically dependent on the type of electrical disturbance in the brain and how widespread it is. In most cases epileptic seizures occur between the ages of 5 and 20, since that’s the time the brain is still developing.  Different people experience different types of seizures, but for the most part, epilepsy is a treatable disorder. Nevertheless, the condition affects more than 50, million people worldwide, with approximately 85 to 90% of cases located in developing countries. While the disease can be controlled with medication, no cure has yet been found. More importantly, over 30% of those diagnosed with epilepsy are unable to prevent seizures even with the best medication available. Difficult cases sometimes necessitate surgery. Central to understanding epilepsy is that it is not a single disorder but rather syndromic. In other words, it’s a combination of symptoms or group that together characterizes or distinguishes it as it affects different people differently. A Yale-led team of researchers have taken this syndromic approach in their recent study of the disease, and have identified the gene that, when mutated, causes a devastating early-onset disorder in babies known as “malignant migrating partial seizures of infants,” or MMPSI. This disorder is a rare, severe brain disorder that appears in the first six month of life. It is characterized by treatment-resistant epileptic seizures and developmental delay. Furthermore, 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 over activity 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.

The Yale study is promising in that it gives hope to those that experience the devastation of rapidly progressive and continuous seizure discharges. The idea that severe global developmental delay caused by MMPSI, might ultimately have an effective treatment is a major development in the treatment of epilepsy on a whole.

In most cases epileptic seizures occur between the ages of 5 and 20, since that’s the time the is still developing.

With an estimated 2.2 million people living with epilepsy in the United States, and more than 50 million people living with epilepsy worldwide any group that finds relief is a victory for all as it will free up researchers to tackle other syndromic symptoms.


contributor D. Chandler

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