Precision Medicine in the Treatment of Epilepsy

VBCN - July 2014 Volume 1, No 2

Philadelphia, PA—Genomic sequenc­ing is starting to yield progress in unraveling the genetics of select forms of epilepsy, with some immediate clinical implications, said David B. Goldstein, PhD, Professor of Molecular Genetics, Microbiology, and Biology, and Director of the Center for Human Genome Variation, Duke University, Durham, NC, at the 2014 meeting of the American Academy of Neurology.

His laboratory is participating in Epilepsy 4000 (Epi4K), a series of worldwide research projects to explore whether de novo mutations affect the genes that are critical for neuronal function. Funded mostly by the National Institutes of Health, Epi4K is screening patient genomes for the relevant mutations that form the genetic basis for epileptic encephalopathies.

Genetic Mutations
Through the use of exome sequencing, the project has already enabled the discovery of genetic alterations that may cause infantile spasm and Lennox- Gastaut syndrome, said Dr Goldstein.

“We pursued a genetic design that would allow us to effectively and economically identify de novo mutations in the protein encoding part of the human genome, the so-called exome,” he said. “We performed whole-exome sequencing on probands and their parents.”

For the study, the exome sequences of 264 children, 149 with infantile spasms and 115 with Lennox-Gastaut syndrome, were analyzed. The investigators confirmed 329 de novo mutations, with the average number of 1 de novo mutation in the study, which is consistent with other studies.

A likelihood analysis showed a significant excess of de novo mutations in the 4264 genes that are the most intolerant to functional genetic variation in humans.

“In this small study of just 264 individuals, we have convincing statistical evidence that we can genetically explain about 10% of the cases, considering both already known genes and genes that we have newly implicated,” Dr Goldstein said.

Causal mutations were very rare, 6 of the 264 patients had GABA receptor mutations, and 7 of the 264 patients had mutations influencing vesicle trafficking.

“One slightly worrying note, however, is that the mutations that influence the condition are very rare, and, in fact, so rare that almost every patient has a different underlying mutation,” said Dr Goldstein. “This is something that has actually concerned a lot of people for a long time about the whole program of personalized medicine.”

The way forward appears to be organizing patients based on the biologic processes that are dysregulated by individual mutations, and then to tailor treatment to the dysregulated biologic processes, he said.

Clinical Implications
The progress being made into the genetics of epilepsies has immediate clinical implications. Duke University has a genome-sequencing clinic, where patients who are believed to have a genetic alteration but in whom traditional genetic testing has failed to classify the alteration, can be referred. These patients are then evaluated for possible whole-exome sequencing. This process has yielded 2 positive findings. In 1 case, mutations in KCNT1 have been identified as causal for patients presenting with an unrecognized condition. KCNT1 had recently been implicated in 2 different forms of epilepsy: autosomal dominant nocturnal frontal lobe epilepsy and epilepsy of infancy with migrating focal seizures, said Dr Goldstein.

“Most important, oocyte modeling of the mutations showed that the mutations have a pronounced gain of function effect on the potassium channel that KCNT1 encodes,” he said.

The gain of function could be suppressed strongly by the antimalarial drug quinidine. For example, 1 patient, who had 40 nocturnal seizures by age 4 years and had regressed to a nonambulatory, nonverbal state, had a mutation sensitive to quinidine: his seizures were reduced immediately with quinidine therapy.

Another patient was found to have a mutation in SLC52A2, a riboflavin transporter, and has started riboflavin therapy.

Related Items

Subscribe to
Value-Based Care in Neurology

Stay up to date with personalized medicine by subscribing to recieve the free VBCN e‑Newsletter.

I'd like to recieve: