Gene sequencing helps Northwestern team diagnose one cause of epilepsy

Three types of mutations found in the KCNB1 potassium channel are shown in green, teal and red.--Courtesy of Northwestern University

Researchers at Northwestern University's Feinberg School of Medicine used a form of gene sequencing to identify mutations that appear to be behind a type of epilepsy disorder.

The journal Annals of Neurology details the group's diagnostic advance, which involved the use of whole exome sequencing. This is where all genes in the human genome that encode proteins are sequenced.

Epilepsy can be caused by a variety of factors ranging from genetic to dietary and more. Some patients with epilepsy are treated for their conditions without having a root cause ever diagnosed. The Northwestern Medicine finding must be repeated in a larger patient sample, of course, considering the study involved only a handful of people. But further research may accomplish a number of things, including definitive verification of a genetic cause behind one form of epilepsy in children (epileptic encephalopathy). More than that, however, it could spur wider use of clinical exome sequencing as a diagnostic tool, the researchers said in an announcement of their discovery. As well, while gene sequencing is expensive, the cost continues to drop, so affordability will add to its wider use down the line.

"Our results illustrate the power of clinical exome sequencing to find novel gene mutations in patients with epileptic encephalopathy," principal author and associate pharmacology professor Jennifer Kearney said in a statement.

With so many possible genetic causes of epilepsy (which can present itself with seizures and problems with thinking and mobility), the researchers said they pursued whole exome sequencing on a child with epileptic encephalopathy, plus her sister and parents, who did not have the condition. The goal: to find mutations that could explain the disorder. With testing, mutations in the KCNB1 potassium channel gene came to the forefront for the epileptic child. Those results bore fruit in two other patients with a similar epileptic condition, where whole exome sequencing previously revealed KCNB1 mutations. Separately, in another study, scientists deleted that gene in mice, according to the medical school, which only caused a slight seizure risk. That helped support their ultimate conclusion that mutations caused the epileptic condition rather than gene deletion.

Further work will undoubtedly focus on different gene mutations that could be behind other epileptic conditions. For now, the KCNB1 connection to children with epileptic encephalopathy is giving scientists hope that they've at least solved one epileptic riddle, considering KCNB1's role in neurological function.

"KCNB1 potassium channels are critical for neurons to generate electrical signals and communicate with one another," Kearney said. "They normally dampen excitability of neurons. However, the mutations caused channel dysfunction that in turn causes excessive excitability, resulting in seizures and disrupted development."

She said that identifying KCNB1's contribution to at least one epileptic disorder is a crucial advance.

"Finally having a cause for the disorder is very valuable for alleviating stress and moving forward with knowledge that may improve medical management," she said.

- read the release
- here's the journal abstract

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