New Clues Emerge in Rare Form of Childhood Epilepsy

Robert Macdonald, M.D., Ph.D., and colleagues, from left, Ciria Hernandez, M.D., Ph.D., Dingding Shen, Ningning Hu and Wangzhen Shen have uncovered new genetic clues to a severe form of childhood epilepsy. (photo by Susan Urmy)

Researchers at Vanderbilt University Medical Center (VUMC) are one step closer to understanding what causes early-onset epileptic encephalopathy, a rare form of childhood epilepsy that is difficult to treat and has poor developmental outcomes.

With the help of colleagues at Children’s Hospital of Philadelphia, the researchers identified six spontaneously arising mutations in the receptor for the neurotransmitter GABA in eight patients with the condition from around the world.

Their findings, published recently in the journal Brain, could lead to new targeted treatments for this devastating disorder, said Robert Macdonald, M.D., Ph.D., the Margaret and John Warner Professor of Neurological Education and chair of the Department of Neurology.

GABA receptors regulate the “excitability” of nerve signaling in the brain.
For several years, mutations in the receptor’s gamma-2 subunit have been known to produce relatively benign epilepsies, including seizures associated with fever.

This is the first time gamma-2 subunit mutations have been linked to epileptic encephalopathy, said Dingding Shen, a neuroscience graduate student and co-first author of the paper with Ciria Hernandez, M.D., Ph.D., research assistant professor of Neurology.

These were “missence” mutations, which change the amino-acid sequence of the encoded protein so that it does not fold or function correctly. Treatments that “fix” misfolded proteins should theoretically “cure” epileptic encephalopathy and other diseases, like cystic fibrosis, caused by misfolded proteins.

Technology has not yet caught up with the idea, Macdonald said, but “the more mutations we find, and the more mechanisms we find, the more therapeutic targets we find.”