Epilepsy Genetics: Testing Can Make a Difference

I’m Kelly Cervantes and this is Seizing Life,
a weekly podcast produced by Citizens United for Research and Epilepsy Cure. My daughter Adelaide has been through more
tests than I care to remember, from MRIs, to biopsies and countless blood draws. Some of the most informative tests though
can be related to genetics. That is why I’m excited to have Dr. John Millichap
on the show today talking about the connection between epilepsy and genetics. This evolving field of study is a key element
to identifying and curing many forms of epilepsy in the future. Dr. Millichap is an attending physician for
neurology and epilepsy at Ann and Robert H Larry Children Hospital here in Chicago. He is also an associate professor of pediatrics
and neurology at Northwestern University Feinberg School of medicine. Thank you so much for being with us today,
Dr. Millichap. I’m glad to be here. So, we know that our DNA controls our eye
color, our body type, but what is the connection between genetics and epilepsy? Sure. So, we know a lot about the causes of epilepsy
and in the same breath, I’ll say we know very little. So, we know of hundreds of genes that are
related to epilepsy, and having a variation in the genetic code for those specific genes
alters the function of the machinery in the body that, that gene codes for. So, for example, a very common cause of of
epilepsy is related to ion channels. So, a channel is like a hole. So, if you can imagine a cell and a brain
has a wall to it and there’s a small hole in that wall where salts like sodium and potassium
might go in and out and that balance of those salts going in and out is what keeps the electrical
activity of the brain cells stable. So if there’s a variation in that piece of
machinery in that channel, then the balance can be off. So, where are you have more electricity in
that brain cell and more electricity then leads to seizures. So, that’s just one example. There can be other genes that are related
to the actual structure of the brain so they can lead to actual malformations of the brain
that we can see on a picture like in an MRI. So, talking about variants in the genetic
code, not all epilepsies are necessarily inherited. You get your test results back and they’re
talking about this variant and that variant, what causes those variants if it’s not hereditary? Sure. This is one of the first things that I talked
to parents about when I’m leading in to talking about doing genetic testing or were recommended
genetic, is that most of the early onset childhood epilepsies are actually new and the child
and not from the parents. So, back to basic biology, after the egg and
the sperm come together, then it forms the child, and the DNA has to be copied every
time the cell splits, and in everybody, you, me, every time that, that’s copied, there’s
going to be a little mistakes, little changes to the DNA. And sometimes those changes don’t make any
difference whatsoever and we just go on being ourselves. And then sometimes early on, one little change
will be then important, it will change the function of that one gene, of that one piece
of machinery that it can cause epilepsy and be in all subsequent cells in the body. So, you get your epilepsy diagnosis or, in
our case, we just saw developmental delay in our child and that was when our neurologist
started to order the genetic testing. But for a lot of people it may be after that
initial epilepsy diagnosis. What are the tests that are available? What are the tests that you order as a clinician? And what are you looking for in those tests? Sure. I got into neurology about 11 years ago and,
at that point, genetic testing was not used as a first line test whatsoever. Things have changed to the point where almost
every patient that I see today, once I’ve established the diagnosis of epilepsy, taking
a history, and looked at the EEG, the MRI, my examination, and I haven’t determined a
cause of the epilepsy, I’ll talk to parents about the availability of genetic tests. And in many cases, the first test would be
a focus test that would look at genes we know to be associated with epilepsy. And this test is called, epilepsy gene panel,
and it has a high sensitivity for those specific genes that we know to be related to epilepsy. So, maybe a 100 or 200 genes that have a strong
association with epilepsy are included on the panel and once we’ve done this test, we
know that there’s not a change in those genes because it looks at it with such depth and
accuracy. And if that’s unrevealing, we can go to the
next step, which often involves the parents even more. Where we’ll take the child’s blood and then
also the blood of the parents and look at all of the portions of the DNA that make a
machinery, make the body. That’s called whole exome sequencing. And the reason we take the parents’ blood
is because, as I said, we all have little variations that don’t change anything in our
bodies or have any significance, and so we subtract any of those inherited variations
from the child. So-
Right. So if you see the variant in the parent, and
then you’re also seeing the variant in the child, but the parent is symptom free, then
that’s probably not your culprit. Yeah. So the GI testing company has a huge computer
that does a lot of this initial sifting. And another thing that I’ll constantly be
reminding other doctors, and trainees, and parents, is that the genetic testing that
we do is not a static test. So, if you had an MRI last week and the radiologist
read it and the neurologist looked at it, that happened. That is what the MRI shows. But if you had a genetic test last month,
or six months ago, or a year ago, that test is not static. We’re always learning new things. The variations that were meaningless or the
genes that were meaningless to epilepsy a year ago, may today be the cause for your
child’s epilepsy. So, let’s say you get through whole exome
sequencing, and this was the case with our daughter, there were some variance of unknown
significance, but there was no smoking gun, if you will, what does that mean? These variants of unknown significance and
what do you do next when you still don’t have an answer after you’ve done the whole exome
sequencing? The terms that we use have changed over the
last five years or so. Where instead of using the word mutation,
which a lot of people think of, a change in the DNA that leads to disease, the genetics
professional association got together and it made a pretty clear criteria for us doctors
to discuss these findings with families and with individuals. So, now we have this confusing or unknown,
a VUS, we call it, a variant of unknown significance. It’s right in the middle. And then above that we have likely pathogenic,
or likely causing the disease, or, in this case, likely causing the epilepsy, or straight
pathogenic, or causing the disease. And then on the other end, likely benign,
or likely not significant, or just plain benign, or not the cause of the disease. So, as you can imagine, VUS means we’re not
sure. So, it neither has the criteria to make it
definitely the cause or definitely not the cause. So, I’ll always warn parents when I send genetic
testing that if we send this test may lead to more tests or I may lead to this uncertainty. Sure. So, now then in very recent, I mean, talking
like within the last year really, there is now whole genome sequencing that has become
available. Mostly, it seems to me, and you correct me
if I’m wrong, but really just on a research level, it’s not fully available commercially. What is the difference between the whole exome
sequencing and whole genome sequencing? How can someone get their hands on … get
submitted for testing for whole genome sequencing and when should they? So, whole exome sequencing has some differences
from the panel that I referred to first, having 200 genes that we look at it very deeply and
we can be sure that we didn’t see any changes in those genes. The whole exome is still very good, but it
doesn’t have as many, we call it reads. So, if you have a gene say, Case C and Q2
is one cause of epilepsy that I’m very familiar with. On that panel, it would read over it 200 times. So, it’s like you read a book 200 times, you
really know that book, right? And so then whole exome sequencing may only
read over it 30 times or less. So, it covers it, but not quite as deeply. Okay. And this is also the problem with whole genome
sequencing. So, it’s an enormous amount of data. As you can imagine, whole exome is the parts
of the book that we can read, or we think makes the story. And then whole genome sequencing is everything. It’s the binding, it’s the cover, it’s the
spaces around the letters, it’s everything, the entire book. So it’s even parts of the DNA that we don’t
know how they may be related to how the body works. And so that’s an enormous amount of data. So, we’re learning more and more about how
a variance outside of the traditional readable portions of the DNA can lead to disease. So, the whole genome sequencing is available
clinically now, and there’s different companies that are making it available for insurance
payment and it’s still at a higher cost but that will surely drop down. So, I would say, that in the next few years
that, that technology will probably takeover the other technologies we have, and at that
point, if somebody had testing several years ago, it would probably be a good time to get
retested if no cause was found. And, again, the number of reads will continue
to increase as the technology improves and the cost drops. So we’ve got the tests, we know what we’re
looking for, the variance, the number of different tests progressively going up, why should someone
get tested? What can they get out of knowing what’s causing
the epilepsy, aside from peace of mind to know that there is somewhere to direct their
frustrations. Sure. And I think this is a really an important
point. And I was trained in neurology and we knew
something about genetics back in 2007, 2008, we would be looking for various genetic causes
of epilepsy, but it was 2012 when I really saw the power of genetic testing. A patient of mine was having the gene test,
after gene test. They were almost two years old at that point. And we tested for Case C and Q2. They had, had seizures when they were born,
and it came back with a variation. And the way that was the cause of the epilepsy. And the way that affected the family really
struck me more than anything else that I could see with the value of genetic testing. It just changed the way that they looked at
their child and the way that they approached me and the rest of the community, it allowed
them to then combine or meet other families of children who have a genetic cause of epilepsy
with the same genetic cause. And gave them a lot of support which otherwise
they didn’t have. They said, “We don’t know why our child can’t
talk and-” Under prognosis. It gives us a better idea-
Or at least a better idea of what that looks like. If you can look at other families and other
children who have a similar unit can be like, okay, this is what we can look out for. This is what we can expect. There’s so much peace of mind in that. And then that’s one of about 20 genes where
it may change our approach. So we may choose different available seizure
medications based on the genetic testing result. So, tuberous sclerosis is a common cause of
infantile spasms and other types of seizures. In the case of infantile spasms, we may prefer
or recommend one treatment over another if we know that that’s their cause. So, a genetic diagnosis there can really help
us. And in Case C and Q2, SCN 2A, SCN 8A, several
of these, these are all names of ion channels or the holes in the wall of the cell. We may choose a specific type of medicine,
very common medicines, that we use to treat epilepsy, but we may not think to use in such
a young baby unless we have this specific genetic diagnosis. So, it’s changed my practice. I look for the clinical signs of these genetic
causes of epilepsy, confirmed them, and then I’ll choose specific medicines for that specific
cause of epilepsy. Genetic testing can clearly be very helpful
in terms of treatment. I also imagine that it can be incredibly useful
on the research side of things. If you start to understand the cause behind
some of these epilepsies, then we can focus our research and get closer to curing some
of these epilepsies, I would hope. Do you have a sense of how genetics is changing
epilepsy research? Yeah, absolutely. This goes along with some of my research interests
as well. So, back to that Case C and Q2, it’s actually
one of the precision medicine genes, so to speak. So, even before we knew that Case C and Q2
was a cause of serious epilepsy, a seizure medication that was approved for the use in
adults and was going to be approved for children, but it was only released for adults, focuses
on that gene or the channel that, that gene makes. Just because increasing the amount of this
potassium salt, that goes out of the cell, stabilizes things for everybody. So, a veteran who has a concussion, a, uh,
person who had a stroke, a adult who had a stroke and has epilepsy, either of those people
would also benefit from this medicine that targets that specific gene. So, once we learned it causes newborn onset
epilepsy, it really opened our eyes to how important this system is for epilepsy and
is a potential target for treatment. And the work we’ve been doing for the last
five years has been to try and see how we can use that drug or ones that are similar
to it to hopefully reverse, not only the seizures, but then all the developmental consequences
as well. These genetic tests can be so beneficial for
prognosis, for treatment, but they can sometimes be difficult to obtain from the insurance
companies because they are very expensive. What advice can you give to parents in trying
to fight the insurance companies to approve this genetic testing, which can be so helpful? What conversations can they have with their
doctors to try and make sure that they can get this testing for themselves or for their
child? Sure. I think when things are new, the insurance
companies, and the hospital systems have to take some time to catch up. I’m sure in the 1980s, when MRI was new, there
were doctors who said, well, we’ve been doing just fine with our CT scans, why do I need
this new fangled test? But we’ve seen how helpful it’s been with
diagnosing our children and our adults more accurately with Epilepsy and led to improved
outcomes and a probably lower costs overall. So, I think genetic testing is there too. I think if I have a positive genetic testing
result, I may do a fewer EEGs, I may do fewer MRIs, I may do fewer invasive tests like lumbar
punctures, that’s putting a small needle in the back to get the fluid from around the
brain or muscle biopsies where I would take a portion of the muscle to look at under the
microscope. So, those tests were much more common just
10 years ago and less frequently done now because of the genetic testing results. So, once we have that a result, there could
be enormous cost savings which the insurance companies will probably soon realize that
an earlier accurate diagnosis will lead to better outcomes and better use of our resources
in the longterm. But really the price has dropped so much,
an EEG, especially one that’s done overnight, compared to a genetic test, the EEG is much
more expensive. Really? Yes. And also, an MRI that requires sedation with
all the anesthesia, and all those other costs much more expensive. So, I think these things really dropped down
to where they’re less expensive but it’s just a matter of being covered or not covered and
we have to change the understanding. I have to constantly remind myself how new
all of this testing is. That insurances, these companies, and doctors
they’re really just learning how useful this can be and how it can cut down on the prices. I know I have found, in speaking with parents
who have children who are 10 years old, they’ve never had the genetic testing done because
it wasn’t available to them when their child was first diagnosed. Where it was one of the very first test that
was done on Adelaide. And that it’s just so shocking to me how quickly
genetics has taken off. Where do you see it going? What new studies are being done out there? What’s on the horizon for genetics and epilepsy? Well, I think the testing will become a part
of our common practice. So, once we determined the patient has had
a seizure or epilepsy, we’ll do our usual history taking exam, a picture of the brain
of some sort, MRI likely, and then EEG. And in in most cases we’ll have a good idea
of what the cause is maybe from those tests. But even beyond that, I think we may want
to know what the underlying cause is or what the background of that patient is going forward. So, I’m going to go out and say now that I
think we’ll be doing genetic testing on almost everybody very shortly because even if we
have a malformation of the brain, that malformation must’ve come from somewhere, it must be some
genetic genetic change, or if your child had a stroke, or I had an infection, and had a
particularly bad response to the brain infection, even though it might not be at an epilepsy
gene, there’s going to be some genetic predisposition to that child’s over-exaggerated immune response
to the bacteria and there may be treatments that infectious disease specialists are looking
at to ameliorate that. So, everything is genetic I think will be
the mantra going forward. But genetic-
Tell your kids to go into genetics. Well, I do a lot of this myself, obviously. I’m able to talk to you about it, but genetic
counselors are really helping us sub sub specialists with this explosion in genetic testing. So, they’re very important for talking about
all of the inheritance and other questions that come up that are beyond my epilepsy wheelhouse,
so to speak. I think one of the things that’s so exciting
to me is that we have these staggering statistics in epilepsy where over half the people who
are diagnosed don’t know what is causing their seizures, and just how helpless that can make
a person feel when you just don’t know why, and how do you treat something if you don’t
know why. But I have to imagine that with the availability
of genetic testing that we’ll start to see those numbers come down, that we’ll start
to see more and more people having an answer, and less people being undiagnosed. Absolutely. I think that, that, as we talked about in
the beginning of our conversation, just having a cause is so reassuring for families. Even if it’s not a cure or we don’t have an
answer today, just meeting other families that are going through a similar experience,
avoiding further testing that can be invasive or expensive, is really important. And our goal of precision medicine is still
there, it’s very complicated and we’re inching towards it in different ways. Wow. Crossing fingers that we get there sooner
rather than later. Thank you so much for joining us today and
for helping keep this very sciencey conversation accessible to the lay person like myself. So I really do appreciate your time and letting
me pick your brain. iT was great talking with you. Thank you. I’d like to thank Dr Millichap for his insights
and experience on the genetics of epilepsy. While we have made steps towards understanding
how genetics causes epilepsy, we have so much more to do. More than 50% of people with epilepsy still
do not know the cause. Without this information, it can be extremely
challenging to find the best treatment. But further funding of genetic epilepsy research
could close this gap. Cure has been instrumental in leading us towards
personalized medicine based on epilepsy and genetics. Help us do more by donating to citizens United
for Research in Epilepsy at ceasinglife.com The opinions expressed in this podcast do
not necessarily reflect the views of Cure. The information contained herein is provided
for general information only and does not offer medical advice or recommendations. Individuals should not rely on this information
as a substitute for consultations with qualified healthcare professionals who are familiar
with individual medical conditions and needs. Cure strongly recommends that care and treatment
decisions related to epilepsy and any other medical condition be made in consultation
with a patient’s physician or other qualified healthcare professionals who are familiar
with the individual’s specific health situation.

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