Inherited Epilepsy Due to Defective Sodium Channels

The research was reported in the June 13, 2002, issue of Neuron.

Inherited epilepsy syndromes account for about 5% of all epilepsies. Many of the identified genetic mutations associated with inherited epilepsies are in genes that encode ion channels that regulate the flow of electric current, in the form of charged molecules, into or out of the cell.

The current study focused on three sodium channel mutations that are associated with a syndrome called generalized epilepsy with febrile seizures plus (GEFS+). Researchers from Vanderbilt University Medical Center (Nashville, TN, USA) isolated the human SCN1A sodium channel gene from individuals with this type of epilepsy and introduced the gene, with or without epilepsy-associated mutations, into normal human cells in the laboratory.

"We were able to reconstitute sodium channel function in the laboratory in a way that is very similar to the natural neuronal cell in a human being,” explained Dr. Alfred L. George.

With this system, the investigators examined sodium channels bearing one of three epilepsy-associated mutations. In each case, they found that the functional properties of the mutant channels were very similar to those of a normal channel, but that the mutant sodium channels failed to become completely inactivated. Complete inactivation protects the cell from repetitive electrical discharge by closing the ion channel.

"In the case of the mutant sodium channels, the inactivation process is defective.” Dr. George said. "What this does, is allow sodium to continue to enter the cell, leading to a state of hyperexcitability that makes repetitive firing--a hallmark of seizure activity--more likely. This minor defect is sufficient to render the cell susceptible to repeat firing. It is a plausible mechanism for epilepsy at the cellular and molecular level.”

Now that the physiologic event has been identified, drugs can be designed and tested to find those best at suppressing the abnormal non-inactivating current while leaving the normal current alone.



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Vanderbilt University Medical Center