The Genetics of Epilepsy in Clinical Practice
While precision therapy is not possible for most patients with epilepsy, genetic testing in specific scenarios helps to inform the patient’s prognosis. Further, there may be value in identifying a genetic cause for epilepsy, even when such findings do not currently alter treatment.
Q: How do you approach genetic testing, and what is the state of personalized therapy for patients with epilepsy?
Professor of Neurology
“In adult epilepsy, the little genetic testing that we can do has little or no practical consequence for treatment. Although it can allow for a precise diagnosis of some types of epilepsy, it does not generally change how we treat the patient.”
The genetics of epilepsy are fascinating, and there is tremendous research interest in this area. While there may be a huge impact in the next 20 years, right now, in my practice setting, we almost never perform genetic testing. It has very little practical value at this point, especially in adult epileptology. Exceptions include conditions such as Dravet syndrome, but most of these cases are encountered by child neurologists and child epileptologists. For Dravet syndrome, genetic testing makes sense, especially now that we have some drugs that are approved specifically for that condition. We also know that certain antiepileptic drugs, such as sodium channel–blocking agents (eg, carbamazepine, phenytoin), should be avoided. However, by the time we see an adult patient with Dravet syndrome, they should have already undergone that testing with a child neurologist. In adult epilepsy, the little genetic testing that we can do has little or no practical consequence for treatment. Although it can allow for a precise diagnosis of some types of epilepsy, it does not generally change how we treat the patient. One could argue that testing could lead to genetic counseling, but these epilepsies are not like hemophilia or muscular dystrophy; very few of them are monogenic. Juvenile myoclonic epilepsy might be, but we can make that diagnosis clinically, without such testing. Thus, testing might enable you to tell a family that their other children are at risk for some type of epilepsy, but we are unable to be precise about the risk. Pharmacogenomics is making strides with respect to providing some information on how different patients metabolize a given antiepileptic drug, but this is not yet a standard of care. Hopefully it will be at some point in the future, but we are not there yet.
Professor and Chief of Pediatric Neurology
“It is important not to underplay the role that genetic testing can still play in ending the patient’s diagnostic odyssey, particularly in pediatric epilepsy. Every family I see wants to know the cause of their child’s epilepsy, even if it is one for which we have no treatment, other than the drugs that I am currently using.”
I agree that we are not there yet in terms of using genetic testing to fix the patient’s epilepsy right there in the office. The exception, as Dr Benbadis mentioned, is Dravet syndrome, for which we now have approved medications and, more importantly, we know that there are certain drugs to avoid because they make the disorder worse. However, it is important not to underplay the role that genetic testing can still play in ending the patient’s diagnostic odyssey, particularly in pediatric epilepsy. Every family I see wants to know the cause of their child’s epilepsy, even if it is one for which we have no treatment, other than the drugs that I am currently using. State-of-the-art epilepsy genetic panels are available now at no charge to pediatric patients (aged ˂5 years) and their families. To be able to say that we finally know what is going on with their child, and not having to continue performing imaging or blood tests because we are still not sure what is driving the child’s epilepsy, is of huge benefit to families. It will be highly beneficial when we can “fix these genetic causes,” but just ending the family’s diagnostic odyssey is significant on its own.
The other aspect of this that is important in the era of social media is that these families can link up with each other and realize that they are not alone. I have seen this happen over and over in my practice, where 10, 15, or 20 kids in the country have the same genetic cause of their seizures, and they connect with each other across social media. Down the road, these social networks can serve as invaluable resources if and when treatments become available. That is part of what fueled the Dravet syndrome clinical trials; as soon as compounds were far enough along for clinical trials, the word was put out through the Dravet Syndrome Foundation.
“Unfortunately, we are not at the point where we can perform genetic testing to personalize the care of each patient who develops epilepsy.”
There is substantial interest in this area among the general public, and I suspect that this is spurred by commercial products such as those developed by 23andMe. There are also commercial kits available that will supposedly tell patients whether they will respond to drugs for a variety of different conditions, including depression, anxiety, and epilepsy. The truth is that, unfortunately, we are not at the point where we can perform genetic testing to personalize the care of each patient who develops epilepsy. There are certain genetic syndromes that are known to be associated with seizures (eg, Dravet syndrome caused by mutations in SCN1A). Thus, testing in the case of Dravet syndrome is important not only for diagnosis and treatment, but also for prognosis. Unfortunately, children who develop Dravet syndrome typically go on to develop a lifetime of intractable seizures, with multiple different types of seizures, including atonic (drop attack) seizures. They also have a high rate of premature death from complications such as sudden unexpected death in epilepsy (SUDEP). SUDEP is actually an area where I think that we are on the cusp of a better understanding of some of the relevant genetic underpinnings. If reliable genetic markers of SUDEP risk were discovered, we could potentially test for them in all patients with new-onset epilepsy to more accurately stratify risk. This would also potentially allow for the implementation of preventative strategies beyond just maximizing seizure control.
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