[00:00:00] Dr. Allan Bayat: My name is Allan Bayat. I'm a child neurologist living and working in Denmark. I'm also a consultant at the pediatric department in the Danish Epilepsy Center. And I'm primarily working with patients or children that have neurodevelopmental disorders and epilepsy, meaning that they have problems with learning, communicating and interacting with other people.
And one of the major topics of my research is how genetics can cause you to have learning problems, but also epilepsy and how we can treat this better.
[00:00:36] Rachel Lea: Thank you so much. So. Let's dive into this. What is the definition of an epilepsy gene? And, if you know, how many are there?
[00:00:45] Dr. Allan Bayat: You can always debate how many genes there are, but let's say there are a few hundred. And these numbers grow every day because of research. And you know, due to research progress, new genes are discovered all the time. And this is really important for us to understand what is the genetic basis of epilepsy.
And to answer your question about what is an epilepsy gene. Well, that's a gene where if you have a mutation or alteration, then that change contributes to development of epilepsy.
[00:01:22] Rachel Lea: So how do we understand that any given gene is associated with epilepsy?
[00:01:29] Dr. Allan Bayat: You try to understand if epilepsy is more often reported in patients with a certain gene than in patients without that given gene. You can also try to see how the gene affects the brain function and how it may lead to seizures. And essentially what you do as a researcher is that you combine genetic data with experimental data and clinical observations to sort of determine whether a gene is a cause of epilepsy. Let me give you an example.
Let's say you find in a patient a gene where you think, “This is interesting. We have a mutation, the mutation’s in the patient. It's not in any of the healthy parents.” And you think this might be the cause of the disease. Then of course an important thing is to do some experiments in the lab where you can, for example, use animals where you knock out that specific gene. And then if the animals start seizuring, that is strong evidence that supports that this gene is actually linked to epilepsy.
[00:02:40] Rachel Lea: So let's say a child with epilepsy undergoes genetic testing, and it reveals a variant in the gene that's not previously known. When do you start suspecting that this gene is associated with epilepsy?
[00:02:52] Dr. Allan Bayat: I think that very much depends on what kind of gene, where you find the mutation. Let's say you find a genetic change in a gene that is linked to the ears and hearing loss, for example. And if that's the only symptom that has been reported before, then that's not linking you to epilepsy. So then it becomes a bit tricky to prove that that specific mutation also causes epilepsy.
Of course, what you have to do is you have to try to find other people that have mutations in the same gene and also have epilepsy. Then you start seeing patterns and associations that can help you to think, “Okay, maybe that gene is actually linked to epilepsy.” And of course, as I said before, you also need to do different lab tests and one of them would be animal models where you knock out a certain that that specific gene and see how does the mouse behave.
[00:03:56] Rachel Lea: How long would you say this process takes?
[00:03:59] Dr. Allan Bayat: It could take anything from six to 12 months to several years, because of finding other patients with similar phenotypes. Let's say you have one patient with epilepsy and a mutation in a gene. Within a few weeks or months, because there is an international collaboration between physicians and researchers online, you can start within a few months to find other patients like yours. But if you want to sort of take it to the next level where you do functional testing in a lab to prove that this gene is really an epilepsy gene, that will take months and even years to solve.
We as doctors, we try to carefully note all the specific health issues that patients have. And since we're talking about epilepsy, of course, some of the things we're looking at when we're describing new genes is, for example, the age when the seizure started, what kind of seizures you have, how often they come, what the EEG looks like, and also the treatment outcomes, like are there any specific anti-seizure medication that work better than others? But we also go beyond the epilepsy, like we look at other health issues, for example, your developmental milestones, IQ levels, how your behavior is, do you have any psychiatric problems, autistic traits, for example. Do you have any problems with sleep, hearing, vision, heart issues and so on.
And we start trying to sort of find patterns between the patients with a mutation in a gene. So trying to see how are they, how do they look the same, and are there any specific ways where they're different? Are there any specific patterns where we can say, “Ah, these patients with these mutations, they all start to seizure within the first three years, or three months of life,” for example. So we look at patterns. So at the end of the day, it's about carefully looking at the medical charts to try to ensure as much as you can that you're not missing any important features.
[00:07:28] Rachel Lea: So another major component of genetics, aside from the genes themselves is epigenetics.
[00:07:52] Dr. Allan Bayat: Epigenetics is the study of how different factors can change the way a gene works without altering the DNA sequence itself. Think of a gene like music coming out of the radio. So the music is a gene. Now epigenetics controls how loud the music is. So the epigenetics can turn up the volume, but it can also turn down the volume, meaning epigenetics controls how a gene is expressed. And this is, of course, influenced by our age, what we eat, the environment we live in, our lifestyles, and so on.
Can epilepsy be caused by both epigenetics and a mutation in a gene? Well, the answer would be yes. A good example is a syndrome called Angelman syndrome, where you have epilepsy and neurodevelopmental disorders.
Commonly, Angelman syndrome is caused by mutations in a gene called UBE3A. And if you have mutations on this specific gene, then of course that causes neurological impairment and epilepsy. But the thing is the UBE gene is located on a chromosome that you get from the father. That gene is often silenced, leaving you with a copy from your mother. That's epigenetics, like silencing one copy from one of the parents. So if you have a mutation in the copy that you got from the mother, you also get Angelman syndrome. So that's an example of how either mutations or epigenetic changes can cause epilepsy.
[00:09:28] Rachel Lea: Okay. So it's usually both. It's usually not just epigenetics or you're not really sure.
[00:09:34] Dr. Allan Bayat: I would say it's more often genetic mutations that cause this. Like, if we look at early onset severe epilepsies that start very early in life, these are mostly caused by genetic changes, like mutations that child has. But we know that when we do genetic testing, we only solve around 50% of all the cases with severe epilepsy. The question is how much of the remaining 50% is due to epigenetics and I really don't know. I don't think a lot, but basically what I'm saying is that we could expect that epigenetics to be the cause of some of the 50% that we're missing.
I mean, certainly, epigenetics is very important for a lot of the processes that are happening in us as human beings, but I think in terms of explaining these very severe early onset epilepsies that children have like within the first few years of life, I think the majority of them are mutations in a single gene, and then some of it will eventually show to be epigenetic factors that we might not know anything about at this time.
[00:11:03] Rachel Lea: So can you share a specific sample of a gene discovery related to epilepsy from your own research?
[00:11:11] Dr. Allan Bayat: Yeah, sure. One of the things that we're currently working on right now are some genes called GRIA. And these genes are very important for normal function of the brain because they sort of, they create a receptor that is located on the all brain surfaces, or the majority of the brain. And what happens is if you have a mutation in any of these genes, then the receptor will either be overactive, too active, or it's going to be silenced. And we're trying to see if we can find patterns between patients that have mutations that are causing the receptor to be silenced and compare this to those that are overactive. And we can actually see differences in the symptoms that patients have, both in terms of what kind of seizures they have, when the seizures start, what their body tone looks like, whether or not they have movement disorders and so on.
So that's one of the areas that we're working on currently. We've come a long way so far because when we started around three years ago, we knew very, very little. We had a lot of patients we knew of with different mutations in these genes, but we weren't really sure whether these mutations were actually the cause of the disease. And we also didn't know if it was the cause, then if the receptor was overactive or silenced. And why is that important? Well, if you have an overactive receptor, then there are drugs that can block the receptor. And you don't want to sort of give these receptor blockers to patients that have mutations where the receptor is already damaged and not working because that would make them even more sick. So we've come a long way, but there's still a long way ahead, so to speak.
[00:13:21] Rachel Lea: How do new gene discoveries translate into both understanding the mechanism of epilepsy and potential therapies?
[00:13:32] Dr. Allan Bayat: That's really a good question. You know, when, when we, as researchers or clinicians link a gene to a disease, and discover that, that helps us to understand how a disease works and also how to treat it. For example, let's say if we understand what a mutation in a patient does in the brain cells of the patient, then scientists can create medications or therapies that can fix that specific problem caused by that specific mutation. So finding new genes helps us to just create better and more personalized ways of treating our patients with epilepsy.
[00:14:24] Rachel Lea: Okay. Is there anything you would like to add to our conversation before we end for today?
[00:14:32] Dr. Allan Bayat: Yeah, I was thinking just to briefly mention that the future looks very exciting, especially because of gene therapies, you know, gene therapies are a promising way where we as scientists can fix a gene that causes disease, like we find a gene, we describe the gene, we go to the lab and understand what that mutation in the gene causes. And then in the end we want to find a treatment that sort of cures the disease. And I think gene therapy has the potential to treat or even cure patients in the future.
So it's really an exciting area of research with a lot of potential for the future.
