Plus, discover the latest in genetic testing advances in this episode of our Seizing Life podcast.
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Audience Q&A with Dr. Porter and Ms. Nye
We had one question that asked, ‘I am 66 and I’ve had epilepsy since I was 13. Is genetic testing important at my age? I have children age 31 and 28 who do not have epilepsy.’
Yeah. I think there’s a lot of detail that would have, to be fair, to have to determine if genetic testing would be helpful in this situation. I guess I don’t really feel confident in coming out strongly one way or the other, but I will say that genetic epilepsies are complicated. Mrs. Nye had the situation where her husband and her both have mutations in this particular gene and they’re completely healthy, and it was only when they came together that they had a child who had mutations in both copies of the gene. There’s other situations where a single mutation is new de novo in the child, and that won’t be passed on necessarily to the next child from the parents. I don’t feel very comfortable in saying that, but it’s something you can certainly talk to your epileptologist about.
What does Dr. Porter see as the major barriers to genetic testing in epilepsy?
Sometimes cost is as an issue. We have sometimes difficulty getting insurance to cover it or to cover all the testing costs, but many of the companies, including Invitae, but other ones as well are making the testing quite reasonable, meaning that there are programs for patients that are on Medicaid to help them fund the testing. Some of the companies have like a cutoff where you can’t be required to pay more than a certain amount for testing. That’s number one. I would say number two is sometimes interpreting the results. There, I’m very lucky cause I have a lot of genetics colleagues. I have a genetic counselor for just this situation, but we do come down to sometimes being not absolutely sure that the differences in the genetic testing are really causal.
I don’t think that that should deter you from testing because I think, as time goes on, it’ll become more clear whether differences are in fact causal, but costs and interpretation, I think, are still two issues that we face. The final thing though, is that there are patients that I know, I absolutely, in my heart, know have genetic epilepsy and we still cannot find a mutation. That’s why the EGI program is in existence, because if your exome sequencing, meaning the parts of the gene that make proteins don’t have a finding in them, the data can be uploaded to EGI, and it will continually be investigated.
I think in the future, some changes in certain genes that we don’t know right now cause epilepsy will be identified as causing epilepsy. So, it’s important to not think of this as a static question. Your gene testing is negative. Well, it’s negative at this moment. It doesn’t mean it’s going to be negative in a year or two.
Are there any consensus statements or practice guidelines that can be used to help support the need for early genetic testing in epilepsy when working with insurance or institutional send out labs?
Yes. I don’t know who sent that, but if you want to send me an email, I can send you a generic version of a letter that we use. I think the Lennox-Gastaut Syndrome also has some generic wording on some letters. I will not say that they’re always successful, but I think it’s a worthy cause, so it’s worth trying to do that. Feel free to just send me an email and I’ll give you our generic a letter. But again, some of the companies now have very low copays, or even an amount that you don’t have to pay over if the insurance refuses to pay for it. I think there’s ways to work around the insurance companies, to some extent, but I do have some generic letters I could send you.
If I don’t have many genetic colleagues at my institution, can I ask for guidance and testing and interpretation from the genetic testing lab?
Yes. They all have genetic counselors, at least when you say that. I’m almost positive they all have genetic counselors, at least in my experience they do. They can walk you through some of the interpretations. If that’s not fruitful, I think referring to some of the epilepsy genetics clinics that have been kind of springing up around the country, or to somebody that has more expertise in epilepsy genetics would be another reasonable option, even if it’s not at your institution. Sometimes families are willing to travel for something so important.
Do you recommend biochemical testing for metabolic disorders prior to genetic testing for epilepsy or should these be done simultaneously?
Yeah. We’ve spent a lot of time working up a protocol that we’re instituting here on how to work up a child, in this case, with suspected genetic epilepsy, including metabolic epilepsies. We have decided to kind of take a multi-pronged approach. So, we do metabolic testing, often simultaneous with the genetic testing. I would say there are certain circumstances where we might vary that slightly. It also depends a little bit on the patient’s situation. So, if it’s a very severe catastrophic epilepsy and they have features that make us highly suspect metabolic diseases, then we would definitely push for that more strongly. If the epilepsy seems to not be as severe or we think, it’s much more likely, it falls into a certain genetic syndrome, then we might skip the metabolic testing. But right now, our pathway is to do them simultaneously.
How do you broach the topic of genetic testing with a patient given that their diagnostic odyssey might already be expensive?
At our institution, MRIs are extremely expensive, especially if there’s a need for sedation. I think we just need to get our head around the fact that we don’t blink too much at the expense for that MRI, and our genetic testing is about a 10th of that. So, I agree medicine’s very expensive, but the yield from genetic testing is quite a bit higher frequently than an MRI, and I don’t really worry about the $10,000, $20,000 MRI. So, doing an exome sequencing seems like a bargain to me.
How early is too early for genetic testing in epilepsy?
If they were going to go forth and multiply again, I would guess maybe they would do testing in utero, now that they know what they’re looking for. If you don’t have a clear cut epilepsy gene that you’re looking for in a pregnancy, I don’t know that I would test the baby. That’s probably not reasonable in utero. We send genetic testing on neonates a couple of days old if we think they have a neonatal epilepsy.
Do you think it makes more sense to start with an epilepsy panel or whole exome sequencing?
So we still use epilepsy panels before we do exome. I don’t know when the tipping point is going to come when we stop doing epilepsy panels and we flip over to just doing exome, or then, now some of my patients get a whole genome if the exome has been negative. I guess for right now, anyway, I usually start with a panel because the yield is pretty high in many of my patients. But some of them that are negative, we do go on to do exome, or as I said, rarely now we’re doing whole genome.
How did you know which steps to take, to establish your foundation and work towards discovering treatment for your children’s condition?
I was really lucky to have friends that I had met along the way who also were dealing with rare diseases or had started foundations of their own. I was actually hesitant to do it. We tried triheptanoin first. We thought there was a treatment out there, and so we’ve tried the treatment before we started the foundation. It was only when it became clear that the gut instincts of treatments weren’t working that we decided to take a step back and formalize and organize everything. We continue to be close partners with other organizations. There’s a lot work to do. We certainly still work with CURE Epilepsy and other organizations that are also fighting the epilepsy battle. But I think it does just depend if you have enough patients and if there seems to be enough information to gather and enough work to do.
This is Brenda. I would just say that, of my families that I give them a diagnosis, I tell them to go out there and look. There’s almost always a Facebook page or some other group that they can meet with and start to talk about what their children have or how they’ve dealt with certain situations. So, getting together with other families that are sharing all the things that you’re going through is really important. Mrs. Nye is amazing, because she has taken it an extra step and raised money to really work on epilepsy that her children have, but even just getting together with other families is so helpful. It’s helpful to me sometimes in taking care of the kids, because the parents will say, “Oh, we talked to this family in Brazil and they tried this and it seemed to help their child. Can we talk about that?” That’s something I might not have known had they not been in contact with another family?
How do you know which epilepsy center is the best, and how do you find the best neurologist for your child near your home? How did you come to seek out epileptologists around the world?
I guess we tried to find the neurologist that had maybe seen something similar to what we thought we were dealing with. It might not be the same doctor or the same place for every family, but I tried to get an idea of what neurologists or epileptologists or geneticists might have seen something like this before.
I think seeing large numbers of patients with epilepsy and genetic epilepsies is very helpful. You start to see patterns. I can almost always pick up a kid now. Well, I shouldn’t say this, but usually I can pick up a kid with a glucose transporter, because I’ve seen enough of them over the years, fairly successfully. I think it’s a little bit just seen a lot of kids with genetic epilepsies that allows you to see patterns. People who specialize in epilepsy as opposed to some general neurologist who see some epilepsy, but maybe specialize in headache, they may not be the right person to take care of a child with really complicated epilepsy.
We would see a great doctor, that doctor would maybe have three or four ideas. We would try those three or four ideas, and then maybe it was time to seek out another opinion to see if anybody else had the next three or four ideas. As a parent, you don’t really have the option of giving up, so you just keep going and keep talking and trying to find a doctor who has an idea that hopefully moves the child’s health in the right direction.
I think also the idea that in some places there may not be a lot of specialists, but if your physician is willing to work with somebody else that’s more at a distance, that that’s always very reassuring. I certainly have people that I think of as colleagues around California, for example, or Hawaii I talk to about patients. They’ll send me some information and I’ll try to assist them as best I can. Even if your local physician may not be the world’s expert in X disease, they can certainly reach out to someone who is, and it is a collaborative environment for the most part.
How do you find support from other families if you don’t know your child’s genetic diagnosis?
I would say that there are both broad and specific diagnoses. While we went on a 10 year odyssey to find the genetic marker for the type of epilepsy that the two of my kids have, we had other diagnoses along the way. Epilepsy, in and of itself, is something of a diagnosis. So, there are certainly support groups for other families dealing with epilepsy. We seem to collect different labels. As the years went on, things like CP or ataxia or apraxia, or just developmental delay. There are support groups for all of those more clinical descriptions of what’s going on. I think families do find some comfort in those groups as well.
There are, that I know of, support groups for infantile spasms, Lennox-Gastaut Syndrome. These are all seizure types, or seizure syndromes, and all of those organizations have networks. The Lennox-Gastaut Syndrome foundation is having a meeting in Orlando next month that I’m going to. If you find the type of seizure your child has, often they’ll be a group. Then locally, the epilepsy foundation of America has local chapters all over. For instance, the one in Northern California has a very … well, I think most of them around the country have the very nice camp for kids that gives them a sense of inclusion. They have a parent support groups they help with as well.
If there’s a family history of a genetic epilepsy and another child is born with the same genetic condition, would you start antiepileptic medication before seizures begin, or do you need to wait for symptoms to become apparent?
We do not have epilepsy prevention therapies. I work on a trial right now trying to look at that in tuberous sclerosis, whether we can actually prevent the development of epilepsy and autism in children with tuberous sclerosis, treating them before they develop seizures. But for the most part, right now, we don’t have therapies focused on the prevention of epilepsy. I personally, if I know that a child is at high risk for epilepsy, I often use EEG to try to make sure I’m not missing any seizures that are subtle, or just present on the EEG, but that is a conversation you would need to have with your physician to determine whether your child would benefit from frequent EEGs.
This is also important to note that some genetic predisposition to epilepsy does not absolutely say that child will have epilepsy. There are certain mutations that it’s highly likely they will have epilepsy, and there are certain mutations where some small percentage of patients have epilepsy and others don’t. So, it really depends on the specific situation.
Do you think that technologies such as antisense oligonucleotide therapies and gene therapy using the new vectors provide hope for various types of genetic epilepsies, or will these type of advances take many more years?
They definitely provide hope. I think that the timing of when these kind of therapies will be available is much more challenging. The neuromuscular field is obviously ahead of us as far as getting across the finish line with antisense or vector-based approaches for gene therapy. I don’t think epilepsy is that far behind, but it is a little bit more complicated in some situations about how to get the protein and all the cells in the brain, how to get it early enough. There are a lot of challenges, I think it’s coming and it probably isn’t fast enough for anybody that’s on the phone with a child with epilepsy, but I don’t know when, but just take heart that it’s coming. I just don’t know when.
What would you say to a mom who’s just beginning the diagnostic odyssey for their child with epilepsy?
I would say that there’s going to be some good days and an awful lot of bad days where you want to just give up, but I just take a step back, take a deep breath, and then when I’m ready to go at it again, you just keep trying. I think that you can’t just make the diagnostic odyssey the whole goal. A diagnosis helps certain parts, but it doesn’t actually change your child. Your child is the same child the day before you receive a diagnosis, as he or she is the day after. Even though continuing this research and finding a diagnosis are really important to me, and I think they are to a lot of parents and families, the majority of my time is still spent doing physical therapies and occupational therapies and figuring out IEPs at schools, and just trying to make sure my kids have hobbies that give them something to look forward to.
I think the diagnostic odyssey or a diagnosis in general is like a piece of the puzzle, but it’s not the whole puzzle. So, try not to just completely go down that rabbit hole, and try to have fun with your kid because you don’t get these days back.
What is the yield for a multi-gene panel and for exome sequencing for a patient with epilepsy? What would the yields be if the patient has additional features?
I’ve seen papers trying to address this question, and I think it’s extremely challenging because it all comes down to the denominator like what kind of patients you include in that group. I’ve seen 30% for a panel. Again, though, it really depends on the denominator. When did the patient develop epilepsy? What kind of epilepsy do they have? Do they have some other syndrome features? Syndromic features, meaning their ears are set differently, their eyes are set differently, their MRI has an abnormality on it that’s frequently associated with a certain genetic disease. I don’t know the specific answer, but I think it’s not 1%, and it’s probably not 100% percent. It’s probably somewhere less than 50%, but in the 10s to 20s to 30%, so good we’re doing, I think.
I just wanted to say that I liked Mrs. Nye’s description of ending on this that, understanding your child’s epilepsy is so important, but having fun with your child and doing things that you and your child both can enjoy is so important. The families that I see in clinic that really take that to heart and do things with their kids that their kids can enjoy, and that they can enjoy watching their kids enjoy is so important. Maybe your child’s not going to be able to play regular soccer. I had a patient last week that is playing in the special Olympics soccer team, and he absolutely loves it. He’s so happy with it, and his parents were really enjoying it too. That is so important, to taking care of a child with special needs, is finding out what they like to do and helping them do that. It just is a nice way to end, I think.