A new study by Yale researchers has shown that low levels of an enzyme in the brain are connected with temporal lobe epilepsy (TLE), which affects 40 percent of the 2.5 million Americans with epilepsy.

Dr. Tore Eid, associate research scientist in the laboratory of Nihal de Lanerolle at Yale School of Medicine, said patients with TLE had levels of glutamine synthetase that were 40 percent lower than normal. Glutamine synthetase is an enzyme that breaks down the amino acid glutamate, and it is important in glutamate’s removal from the brain. Excessive amounts of glutamate, which is only needed in small amounts in a normally functioning brain, have been shown to cause seizures and brain damage.

“These finding are important because for the first time, someone has shown an enzyme may be implicated in a serious disease like TLE,” Eid said.

TLE is a particularly serious form of epilepsy because it responds poorly to medication.

“The only [treatment] option, really, is neurosurgery — to remove the part of the brain where the epilepsy starts,” Eid said. “We study the part of the brain removed in surgery.”

This current research builds on a study conducted 11 years ago at Yale, by Dr. Matthew During and Dr. Dennis Spencer, the acting interim dean of the medical school. According to that study, patients with TLE showed higher-than-normal levels of glutamate.

Spencer was also involved in the current study. A neurosurgeon, Spencer performed the surgeries on patients with TLE and provided the tissue samples for study.

In addition to finding that glutamine synthetase levels in patients with TLE were low, researchers also discovered that the enzyme functioned less efficiently.

“We studied if the enzyme is active and capable of breaking down glutamate efficiently,” Eid said. “We found [glutamine synthetase enzymes in patients with TLE] were less efficient by 40 percent.”

In an effort to understand how glutamine synthetase contributes to seizures, researchers will try to reproduce TLE in animal subjects by decreasing enzyme levels in their brains.

“If we knock down the enzyme levels, we will look to see if [the animals] develop epilepsy and the same features as the human patients have,” Eid said. “For example, patients with TLE have brain damage — we’ll see if animals have it too.”

Further studies will also work to determine why the glutamine synthetase functions less efficiently and how to reactivate the ineffective enzyme.

This research may aid the development of new, more effective drugs to treat TLE.

“If we can understand why there is this difference in patients with TLE — the next step may be to manipulate the enzyme and make it more active,” Eid said. “It might be a drug target.”

Besides Eid, de Lanerolle and Spencer, the study was co-authored by Marion Thomas, Elise Runden-Pran, Niels-Christian Danbolt, and Ole Ottersen, all of the University of Oslo, and James Lai and Gauri Malthankar of Idaho State University.

The study was published in the January issue of Lancet, an international journal of medical science and practice.