Plus, learn more about genetic forms of epilepsy in this episode of our Seizing Life podcast.

Audience Q&A with Dr. Katie Angione and Dr. Lacey Smith

At what point in the diagnostic work up of patient with epilepsy would it be appropriate to order genetic testing? For instance, do you need to wait until the patient has failed at least two different anti-epileptic medications?

I think in most cases, it’s completely reasonable to order genetic testing pretty early on in the work up. Unless there’s a very clear structural cause on a brain MRI, genetic testing is reasonably high yield, especially if it’s very early onset, so infantile onset epilepsy. Because there’s the potential for identifying a treatable condition, I think it should be an important part of the work up.

As we kind of went over, a lot of the conditions, earlier you start treatment, the better the response and the better the developmental outcome. Then there’s also the potential for helping with medication selection. I don’t think that there’s really a need to wait until they failed medication and put the patients unnecessarily through that trial and error, because genetic testing can potentially give us some evidence to support a particular medication.

I’ll expand on that too and we talked a lot about treatment, but there are certainly other benefits for genetic testing and diagnosis outside of treatment, right? You don’t necessarily need to fail two epilepsy medications in order to start pursuing genetic testing. If families are interested in recurrence risk or are thinking about having additional children and wanting to figure out what the likelihood of having another child with this condition is, it can be part of the work up. As I mentioned earlier, it could reduce the number of tests that are warranted.

If you have a SLC2A1 variant, you may not need to do an LP for that for a small child. It could certainly reduce the number of tests during the diagnostic workup.

How do you know which epilepsy panel is best for your patients?

I think it depends on the patient obviously, which is often our answer. Sometimes a very specific phenotype or maybe you’ve done some biochemical testing, that may be pointing you in the direction of a certain gene or a class of gene. I think in those cases, it might make sense to start with a smaller panel, maybe even a single gene and then reflex to something larger if that’s negative. But for a lot of our patients, maybe even the majority, we don’t really have enough evidence to point us in any particular direction. There is a lot of phenotypic overlap in genetic epilepsy disorders. I think doing a slightly more comprehensive panel is, in most cases, going to be the best bang for your buck.

That way, you’re not extending the time it takes to reach that diagnosis. I would also say as far as which panel is best, which panel to order, there is a lot of options out there and that’s always changing. Labs are always expanding their panels, adding new panels, different options for rapid options. So, there’s really a lot to navigate. I think some of the important things to keep in mind are how big is the panel, what genes are included. If you do a bigger panel, maybe you’re increasing the chances of getting variants of uncertain significance which can be hard to navigate. But you’re going to be better at catching more rare disorders and maybe newer disorders, especially if the lab is kind of continually updating their panels as new genes are discovered. Then I think you also want to think about what is the coverage of the panel? What’s the minimum depth of coverage and the average depth of coverage? Because that’s telling you what’s the quality of that test? Are you going to miss something? Is there any chance of detecting higher level mosaicism?

Then the parental testing policies I think are something to be aware of as well because that’s going to help to resolve any variance. It might help to see if there is a recurrence risk, if it’s a recessive disorder, and then just overall how comfortable you are with the lab. Is there good communication? Is there a report that you’re able interpret well and feel comfortable sharing with families? A lot of things to take into account and I think it definitely depends on your specific institution and the patient population you’re seeing, but I think it’s something to look into and make sure you’re evaluating the panels that you’re ordering and asking questions of the lab, working with the lab to make sure you’re getting the best testing for yourself and for your patients.

Is deletion, duplication, and copy number detection important for genetic epilepsies or should that be left as a secondary option after sequencing?

I think it’s important to include deletion duplication at the onset. We typically order panels that include both sequencing and deletion duplication. I think that if you’re really doing a sequencing only panel, you’re missing the potential for a diagnosis there and just by doing it sequentially, you’re just expanding the time to a diagnosis for these patients.

I think I’ve definitely heard people kind of maybe arguing against deletion duplication and saying, “We don’t see a lot of evidence of deletion or duplications in a lot of these genes,” but I think honestly, we don’t really have enough data at this point to say that it’s not an important thing to do, especially for some of the more recently discovered genes.

Maybe we’ve only seen sequencing changes so far, but that doesn’t mean that there’s not the potential for deletion or duplication. As Lacey said, it would kind of be a shame to miss that by just doing sequencing and then have to go back just to make sure that you’re not missing anything.

Was the exome resequenced in order to find the PROSC gene? What changed in the analysis?

Affirmative. Sammy’s DNA wasn’t resequenced, but rather the lab just re-analyzed the sequencing data that was already available. I think it was a combination of factors. I think that the lab, in the time between the initial exome and the time that we got our re-analysis done, they may have changed their policy on reporting out candidate genes. Some labs are more proficient at reporting out candidate genes, so genes that really may not have been associated with any particular disease or disorder, but maybe it’s expressed in the brain, for example, and it’s a neurological phenotype. They may report those out with the caveat that it is a candidate gene and we know nothing about this, but just to keep this on your radar. As you saw shortly thereafter, we had the publication that came out. That’s helpful.

Doing a re-analysis of exome either on a clinical or research basis, the data’s there. It’s just our understanding of the genes. We have so many genes that we just don’t know what they do and what their involvement is in the human body, so our understanding changes over time. It’s not a change in technology, per se, in most cases. It’s really just our ability to interpret it and draw conclusions from that.

What can we do to keep drugs like ezogabine on the market so they’re available for patients? Is it a regulatory issue or an insurance coverage issue?

I think it’s different for different drugs that are available. Sometimes, for ezogabine, I think it was more of a financial issue. Ezogabine does have some side effects. Physicians were pretty reluctant to prescribe it, unless there was a pretty difficult to control epilepsy. I think for ezogabine, it was a situation where just not enough patients were on it for it to be marketable by the company, which is unfortunate but a reality. I think that really it’s been the families I’ve seen who have put in a lot of effort and advocacy and putting the information out there on how important this is and some labs and others are starting to catch on.

Are there foundations or patient groups that can help pay for enzyme replacement therapy?

I think there’s definitely a lot of advocacy groups out there. As far as how powerful they can be, that’s kind of another story. There’s so many rare diseases out there and all of these families are advocating for their children, their families, and there’s a lot to be overcome. I think it’s definitely a great thing to do to get involved with those programs. Honestly, the more people that do get involved, especially those that I think are in healthcare and are connected in a different way than the families, it’s certainly really helpful. Honestly, I don’t know the specifics but it goes a long way, just getting involved and even reaching out to advocacy groups, writing letters to politicians. Those things, they sound like they don’t make a big difference for something so rare, but you put enough doctors, enough families together doing those things and that’s our hope is that we can get to the point that we don’t have to deny a life-saving treatment because of insurance coverage.

Would specific EEG patterns, apart from hypsarrhythmia, give you an idea of which genetic etiology could be causing a person’s seizures?

There have been some cases that neurologists have come forward with a specific EEG pattern that’s directed very targeted treatments, so hypsarrhythmia as Katie mentioned, there’s the burst suppression in Ohtahara that I mentioned. We recently had a case, I don’t remember the exact EEG pattern but it was really suggestive of a POLG  related epilepsy so they were looking for that and there was a hit on POLG. So I think that there are some patterns but even when you do have a specific EEG pattern, so if you have hypsarrhythmia and you have spasms, there are a variety of underlying genetic causes of infantile spasms.

That may help the clinical diagnosis and give a general direction for genetic testing. There’s still, as Katie mentioned, so much overlap with the genes and the phenotypes for epilepsy. Yeah, very true. CDKL5, ARX can cause infantile spasms. I think there’s a list of maybe 15 or 20 different genes, so genetic testing definitely still is an important part of that work up, even if the EEG maybe points you in a certain direction.

Do you have studies on isodicentric 15Q?

I’m not aware of any off the top of my head, but that doesn’t mean that there aren’t available. I would say clinicaltrials.gov is usually my go-to for specific disorder targeted studies. Beyond that, I would say maybe one of the patient advocacy or support groups would be a good place to go. Honestly, Facebook groups a lot of the time can get you in touch with new research studies. Families are definitely very good at staying up to date on what’s going on and what studies are available.