WASHINGTON, DC — Genetic researchers are gathering important information on mutations linked to the development of epilepsy, including types of the disease that may be treatable.
For example, a new report that analyzed genes most commonly associated with epilepsy shows that in a third of patients with a disease-causing mutation, the results had immediate implications for treatment or management.
The emerging research reflects the exploding field of genetic testing in epilepsy. And it's a complicated field; a single gene may be associated with different forms of epilepsy, but 1 type of epilepsy may result from defects in any of a variety of genes.
Some of this new research was presented here at the American Epilepsy Society (AES) 67th Annual Meeting.
In a new study presented here, researchers performed molecular testing for 1600 individuals using next-generation sequencing and copy number analysis for genes that are most often associated with major forms of primary and syndrome epilepsy.
The comprehensive panel that was developed included 53 genes; this was broken out into 3 subpanels: infantile-onset epilepsy, including infantile epileptic encephalopathy (EE, 38 genes); childhood-onset epilepsy (40 genes); and progressive myoclonic epilepsy (PME, 12 genes).
The analysis was carried out by GeneDx, a gene testing company based in Gaithersburg, Maryland, showed that 16% of the patients had a "definitive positive mutation," according to Courtney Downtain, MS, CGC, a genetic counsellor at GeneDx, who presented the results at a media briefing.
Of the rest, 6.6% had a single mutation; that is, only 1 change was found. However, 2 are needed to cause the disease. Another 30% had a variant of unknown significance, where there was a change in a gene but not enough data to determine that it was a clear-cut pathogenic mutation and not a benign change, said Downtain. The remainder probably had benign or no reportable variants.
Although most of the known epilepsy-related genes are expressed in the brain and encode subunits of ion channels that help stabilize or propagate neuronal activity, many of the pathogenic findings in this study's participants were in non–ion channel genes. For example, 23% of individuals had mutations associated with disorders in the Rett/Angelman syndrome spectrum.
The analysis showed a pronounced incidence of autism and/or intellectual disability not only in patients with mutations in MECP2, STXBP1, SCN1A, and CDKL5 but also in those with variants in KCNQ2, SLC2A1, SCN2A, SPTAN1, and GABRG2.
Patients with infantile-onset epilepsy had the highest rate of disease-causing mutations (21%) while the percentages for the comprehensive panel of genes, childhood-onset epilepsy, and PME were 15.1%, 10.7%, and 9.1%, respectively.
Importantly, in about a third of the patients who had a positive disease-causing mutation, there were immediate treatment implications, said Downtain. For example, children with a mutation in the SLC2A1 gene have defects in the glucose transporter-1 protein, which moves glucose in and out of the brain, she said. These children can be treated with the high-fat ketogenic diet that can almost immediately stop seizures, she said.
Another example is a mutation in POLG. Patients carrying this mutation should avoid the anticonvulsant valproic acid.
There are up to 9 "actionable" genes: those that, if found, can direct therapy, according to Dianalee McKnight, PhD, assistant director, neurogenetics, GeneDx.
GeneDx has been offering genetic testing for about 2 years. Using information it gathers on genetic variants in patients, plus other relevant information (eg, results of parental genetic testing that could help interpret the results), the laboratory compiles a summary report that goes out to the clinician.
The more neurologic and other information the clinician provides, the more comprehensive the report. It is "crucial" that physicians provide as much information as possible for optimal genetic interpretations, commented Gabriele Richards, MD, chief medical officer, GeneDx.
With so many novel variants, the interpretation can take a significant amount of time and effort, said Dr. McKnight. "In our lab, we have genetic counsellors and geneticists who put a lot of work into writing a meaningful report, and really try to make an interpretation for the clinician on the variant."
Such testing is adding a new perspective on genes that appeared to be straightforward, where mutations were thought to cause "a very narrow subset of epilepsy," said Dr. McKnight. "We're finding in our cohort that these genes have a much broader phenotypic spectrum and are actually presenting in a different way in the clinic than was originally thought."
She and her colleagues recommend multigene testing. This approach is cost-effective and saves time; it tests several genes at once, instead of eliminating them one at a time. Also, there's significant clinical overlap between diseases caused by the different genes.
The company's comprehensive gene panel of 53 now includes 70 genes, but the company is developing a limited panel of about 18 of the most common genes that present in infancy, said Dr. McKnight. "These all present at exactly the same time, and about half of them have treatment implications."
According to Dr. Richards, her company is committed to speeding up the turnaround for test results, especially for subtypes such as infantile-onset epilepsy, prognosis for which may be based on the genetic findings.
Other gene-related emerging trends were released at the AES meeting. For example, a team of researchers, led by Gemma Carvill, PhD, senior fellow, University of Washington, Seattle, have identified important new genes for EEs.
These disorders are the most severe of the epilepsies, characterized by multiple refractory seizures, cognitive deficits, and poor developmental outcome.
Using molecular next-generation sequencing of 101 known and candidate genes in more than 600 patients with EE, the researchers identified pathogenic mutations in about 12% of the cohort.
They described 6 new EE genes, each of which accounts for about 1% of cases. Four of these genes are not involved in neurotransmission at the synapse but rather may regulate expression of other genes.
The studies were funded by GeneDx. Ms. Downtain, Dr. McKnight, and Dr. Richards are employees of GeneDx.
American Epilepsy Society (AES) 67th Annual Meeting. Platform A.08 (Downtain); A.07 (Carvill). Presented December 9, 2013.
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Cite this: Genetic Testing May Help Direct Treatment in Epilepsy - Medscape - Dec 17, 2013.