PHILADELPHIA—Genetic epilepsy testing can impact clinical care and practice by providing diagnostic certainty and suggesting an approach to medical management, said Annapurna Poduri, MD, MPH, in a lecture at the 69th Annual Meeting of the American Epilepsy Society.
With a precise genetic diagnosis, neurologists might be able to give more information about a patient’s prognosis. In addition, a genetic diagnosis can end a patient’s “diagnostic odyssey,” which can entail the burden of blood tests, lumbar punctures, and repeated imaging, said Dr. Poduri, Associate Professor of Neurology at Harvard Medical School in Boston.
“There are a small but growing number of genes associated with specific treatment recommendations,” she said. “We might be able to move toward precision medicine in epilepsy.”
Epilepsy genetics is “not a new topic, but it’s one where we have a lot of new evidence.” Twin studies and family studies helped establish the role of genetics in epilepsy, and in the 1990s, researchers identified several genes associated with epilepsy, including SCN1A, SCN1B, CHRNA4, and GABRB2.
When the human genome was sequenced, large association studies were not initially revealing about new causes of epilepsy. New sequencing technologies and the ability to assess copy number variation, however, have led to further advances. “In 2010, there were three papers showing us the role of copy number variation in epilepsy that had previously not had an identified etiology,” Dr. Poduri said.
Researchers found that as many as 3% of cases of genetic generalized epilepsy, formerly called idiopathic generalized epilepsy, might have deletions in the regions 15q11.2, 15q13.3, or 16p13.11. “You might say … that’s not a lot of our cases in epilepsy. But in fact, there hadn’t been this sort of robust evidence for the role of copy number variation in genetic generalized epilepsy and some of the focal epilepsies until this point,” said Dr. Poduri. “These were seminal discoveries that paved the way for further testing.”
The Epi4K Consortium and Epilepsy Phenome/Genome Project, which involved 26 institutions, undertook one effort that identified additional epilepsy-related mutations and genes. The project initially looked at individuals with infantile spasms and Lennox-Gastaut syndrome. Sequencing the exomes of 264 patients and their parents “allowed us to enlist the power of having a relatively large group of these otherwise rare disorders,” said Dr. Poduri. Among the known epilepsy genes identified by the study was SCN1A. “If we hadn’t already known … that SCN1A is an important gene for epilepsy, this is the sort of study that could tell us.” The study broadened the phenotype associated with mutations in STXBP1, which previously had been associated with Ohtahara syndrome. The investigators also identified a new epilepsy gene: DNM1. This gene did not achieve genome-wide significance in the initial study, but when researchers added about a hundred trios from a European cohort, EuroEPINOMICS, DNM1 rose to significance, said Dr. Poduri. “There were a total of five cases across these 356 trios, and a robust analysis of all of these data together through the Epi4K and EuroEPINOMICS Consortia was able to put this gene robustly on the map.”
The Effect on Practice
Such discoveries can affect clinical practice and patient management. “When you have enough data pointing to a new gene like [DNM1]—this is a synaptic gene, it makes sense, but previously was not on our radar—it means that gene testing panels are going to incorporate genes like this and be able to find more mutations like this,” said Dr. Poduri.
Certain genes are associated with specific phenotypes. The patients with de novo mutations in DNM1 had infantile spasms, and four of the five patients developed Lennox-Gastaut syndrome. “All of them had severe to profound intellectual disability and hypotonia,” said Dr. Poduri. “It gives you some sense of [the] prognosis.” Likewise, if a patient had a mutation that “uniformly was associated with a benign course, that might give us some reassurance that it’s not a progressive disorder,” she said. Findings like this might help to give physicians and patients’ families some diagnostic certainty.
Some genes suggest specific treatments to pursue or avoid. For example, in treating patients with Dravet syndrome and mutations in SCN1A, “we tend to avoid lamotrigine and phenytoin,” Dr. Poduri said. In general, neurologists avoid these sodium channel agents because they have seen patient worsening, although these recommendations are not universal, she said.
According to recent case reports, patients with SCN2A- and SCN8A- associated encephalopathies have responded to high-dose phenytoin. Mutations in SLC2A1 are associated with glucose transporter type 1 deficiency, which can be treated with the ketogenic diet. Mutations in ALDH7A1 are associated with pyridoxine deficiency, and mutations in PNPO are associated with a pyridoxal-5-phosphate deficiency. Rectifying the deficiencies may affect seizures in some cases, Dr. Poduri said.