Alfred L. George Jr., M.D.
Mild, severe epilepsy linked to same protein defect
Vanderbilt University Medical Center scientists have linked two very different forms of epilepsy — one mild, one severe — to similar functional defects in a sodium channel protein.
The unexpected findings, reported July 27 in the Proceedings of the National Academy of Sciences, suggest that other factors account for the clinical severity of the epilepsy disorders.
Defining the molecular defects that cause epilepsy will aid the development of improved anti-convulsant drugs, said Alfred L. George Jr., M.D., director of the division of Genetic Medicine.
Epilepsy — a group of disorders marked by disturbed electrical activity in the brain — affects 2.5 million Americans of all ages, according to the Epilepsy Foundation. Abnormal brain development, brain damage from illness or injury, and genetic mutations all can cause epilepsy.
Of the identified genetic mutations linked to epilepsy, more than 100 have been found in a sodium channel gene called SCN1A. This channel — a donut-like pore that lets sodium ions flow into the cell — is important for the general excitability of neurons, George said.
The first epilepsy syndrome that was linked to defects in SCN1A is called generalized epilepsy with febrile seizures plus (GEFS+). This inherited disorder causes relatively mild seizures that begin in association with fever in children between the ages of 6 months and 6 years.
Two years ago, George and colleagues reported that SCN1A mutations in families with GEFS+ cause the sodium channel to stay open when it should be closed. Thinking of the sodium channel as a gate, George explained, the GEFS+ mutations are like rusty hinges that keep the gate from swinging completely closed. The open channel “gate” lets sodium ions slip through, creating a state of hyperexcitability that makes repetitive electrical firing of the neuron — a hallmark of seizure activity — more likely.
Several other clinical epilepsy syndromes have now also been associated with mutations in SCN1A. One of these, severe myoclonic epilepsy of infancy (SMEI), is a disorder characterized by seizures associated with fever during the first year of life, followed by intractable epilepsy, slowed motor development, mental retardation, and death during the teenage years. SMEI seizures usually do not respond to anti-convulsant medications.
“We recognize a spectrum of clinical disease, from mild epilepsy to an incapacitating, devastating neurologic disorder that strikes children, caused by mutations in the same gene,” George said. “We wanted to correlate the effects of mutations at the molecular level with the clinical disease.”
The investigators thought that the SMEI mutations would have more severe consequences for the sodium channel than did the GEFS+ mutations. “Everyone working in this area had made rather simple assumptions,” George said, that GEFS+ was caused by the kinds of mutations that leave the channel open, whereas SMEI was caused by mutations that made the channel lose function completely.
Instead, George’s team showed that the same type of functional defects they observed for the GEFS+ mutations are mirrored by the SMEI mutations.
“This suggests that the functional defect in the channel is not the complete explanation for the clinical severity of these two syndromes,” George said. “That’s a new idea for the inherited epilepsies, and we now propose that other genetic or developmental factors or something from the environment drives the disorder into either a mild or severe phenotype. We’re now searching for these other factors.”
Certain individuals may be more prone to neurologic damage caused by excessive neuronal activity that occurs during seizures — so-called “excitotoxicity” — George said, making them more likely to develop a severe form of epilepsy like SMEI when they have the same type of mutation that causes mild epilepsy in another person.
“If we can identify the factors that make someone susceptible to excitotoxicity, that would have very broad implications,” George said.
In addition to pursuing this new idea, George and colleagues are developing high throughput screening methods using cell lines that express the various types of mutant sodium channels. They hope to identify drugs that block the abnormal properties of the channel while leaving the normal channel functions intact.
Authors of the PNAS paper include Thomas H. Rhodes, Christoph Lossin, and Carlos G. Vanoye in the division of Genetic Medicine and Dao W. Wang in the department of Pharmacology. The research was supported by the National Institutes of Health.
George is the Grant W. Liddle Professor of Medicine.
George to chair NIH Roadmap study section
Alfred L. George Jr., M.D., will chair a “Special Emphasis Panel” of the National Institute of Diabetes & Digestive & Kidney Diseases. The panel will review applications solicited by one of the new National Institutes of Health (NIH) Roadmap training initiatives.
The “NIH Roadmap” is a series of activities that aim to accelerate the pace of discovery in areas key to preventing, detecting, diagnosing and treating disease and disability, and to speed the translation of therapies from bench to bedside.
The NIH Roadmap points to the need for a new interdisciplinary research workforce. To build “Research Teams of the Future,” a series of initiatives will provide investigators with the training to effectively lead and engage in integrative approaches to complex biomedical problems. George will oversee the evaluation of applications to fund Programs for Interdisciplinary Research.
John P. Wikswo Jr., Ph.D., professor of Physics and Biomedical Engineering, will also participate in the review group.