Decoding Genetic Epilepsy - Sam Berkovic, University of Melbourne, Australia
Genetic epilepsies are way more complex than we thought!! Clinical neurologist and scientist Prof. Sam Berkovic shares the differences between inherited, de novo, and somatic forms, challenges in diagnoses, impacts on families, and societal stigma. However, Sam also shares the exciting, positive advancements in genetic research, how understandings have far, far improved over the past few years, and how cool, effective international collaboration in research has led to and shall lead to further advancements in precision medicine! Transcription and links to Sam are below! 👇🏻
Reported by Torie Robinson | Edited and produced by Carrot Cruncher Media.
Podcast
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00:00 Sam Berkovic
“The stigmatisation through genetics is really important. My own sense, at least in Australia, is it's less than it used to be but it's still there in our so-called advanced “First World” society. It is still a shameful thing to talk about…”
0:16 Torie Robinson
People often think that genetics (and therefore epilepsy genetics) is black and white - like, it’s a yes or no; you either have it or you don’t have it - the data is easy to read and understand, right? Well. If only! It’s often frustratingly, but also fascinatingly - more complex than this - we are on an exciting, accelerating journey to deepen our understandings and figure out how to help individuals and families affected by genetic epilepsies! Today, we chat with the renowned neurologist and scientist, professor Sam Berkovic who gives us a fab overview of just some of the new understandings!
If you’re new and you haven’t done so already, please do like and comment on this episode and subscribe to our channel, so as to get way more people learning about and understanding the epilepsies!
01:03 Sam Berkovic
I'm a clinical neurologist and physician-scientist. I work at the University of Melbourne here in Australia and our work is predominantly concerned with the genetics of epilepsy.
01:18 Torie Robinson
With the genetic epilepsies, I mean, how “common” are they? If we could even use that word.
01:22 Sam Berkovic
It's, difficult way to talk about it because every human disease is a combination of both genetic and non-genetic factors and the same is true of epilepsy. There are some epilepsies where there are very influential genes; if you've got a change in them you will almost certainly get an epilepsy, but for most people with epilepsy there is a genetic component but it's not down to a single gene that we can measure - it’s so-called “polygenic” and that's very likely influenced by environmental factors, most of which we currently don't understand particularly well. So, we can't say of 100 people with epilepsy “so many” are genetic and “so many” are not genetic. That's just too simple.
02:08 Torie Robinson
Could you tell us, then, what are the differences between inherited genetic epilepsies and de novo epilepsies? And just tell us the difference; what do those things mean?
02:18 Sam Berkovic
So, this is an important new concept that, well, it's not that new anymore(!), but it's an important concept to understand that not every genetic epilepsy is familial (that it runs through a family). So, before the revolution in molecular genetics, we recognised genetic epilepsies by the fact that they ran in families; that they might go through, for example, 3 generations; a grandparent or parent to a child. And those disorders definitely are genetic and for most of them now, we've nailed down what the particular gene is. But one of the new understandings has been that particularly in severe childhood epilepsies - but also, in other epilepsies - you can have a genetic epilepsy without having a family history. And that's because the change in the gene or the mutation - what we call a pathogenic variant - occurs after fertilisation (that is after the sperm and the egg unite in the mother to create the child). So, there's no evidence in the mother or father that there is a genetic change, but it appears in the child for the first time “de novo” or “new” and we now know that that's a very common mechanism of severe epilepsies.
03:46 Torie Robinson
Interestingly enough, actually know somebody from Finland who this has happened to. She has a rare genetic epilepsy and her mum, her whole family, mum, dad, etc., were tested. They had nothing. So, yeah, it really happens, right? And people seem to be quite surprised by that today.
04:00 Sam Berkovic
Yeah, it's a very important new mechanism. And more than that, to go further, the sort of further development of that is what we call somatic mutations. The de novo mutation that we just talked about affects all the cells in the body of the child. A somatic mutation occurs well after fertilisation and, for example, may just affect the brain, and therefore you get a brain disease like epilepsy whereas there is little or no trace of the change in the rest of the body! And that’s even harder to detect. In epilepsy we've detected it largely through people that have had brain surgery, sSo, by the very nature of the detection it's going to be in people with severe epilepsy. But this so-called somatic mosaicism is also extremely important but harder to detect in the clinic as you may not be able to detect it from a blood test.
05:05 Torie Robinson
I think I know a family affected by Ring20 who were talking about this. They said that they had this similar experience where it was difficult. They had the normal genetic testing and nothing showed and then it turned out to be somatic.
05:17 Sam Berkovic
Ring20 has its own challenges because it's not necessarily detectable on routine sequencing; you need old-style cytogenetics.
Torie Robinson (05:03.824)
God, it just gets more and more complex, right? It's not what makes people think on the outside, it can go into a lot more. So, talking about detail I guess, how would you say genetic epilepsies - looking into them, the research into them and the understandings of them - has changed or hopefully improved over the past 10 years or so?
05:46 Sam Berkovic
In terms of the technology has been amazing - In terms of our ability to interrogate people's DNA for these changes! And we get new surprises basically every year! We've gone from classical cytogenetics to the ability to sequence individual genes, then the ability to sequence the whole genome - or whole so-called exome in an individual (which means the genes) - and now the whole genome. And we now know that there are, sort of, secret tricky bits of the genome that aren't always revealed and we've got new tricks to find them and will continue to unravel newer things as literally each year! It's quite amazing how the technology has rolled out.
06:37 Torie Robinson
Have you found that international collaborations have been really valuable in this - so that we can all, like, share work, and et cetera, et cetera.
06:46 Sam Berkovic
They've been essential! Individual labs can make important contributions but by and large the really significant discoveries have largely been made by large collaborations and there are a number of these at the moment. There's so-called “EPI25” which is winding up which aimed to sequence 25,000 people with epilepsy - we've actually exceeded that and it's got a rich yield of data and then there's the International League Against Epilepsy consortium on complex epilepsies which looks at the so-called “common variants”. The exomes look at things that are relatively rare and the common variants which make up our so-called “genetic background” are also very important, and that's been cracked open by very large numbers that we've gathered from around the world. The only big problem with those consortia is that they're largely confined to people of European ancestry, simply because that's where the samples have been and where the sort of academic strength has been, and we really want to expand it to peoples all around the world and understand the ethnic diversity in the genetic causes of epilepsy.
08:06 Torie Robinson
I agree. I think it's just so, so, important. I mean, I live in London, you know, a very genetically diverse city, and it's something that always quite frustrates me quite a lot (to put it politely) how, at least as you were saying today, it's quite a, sort of a, basically it's a white sample, largely speaking. So, to get more people involved would be fantastic. What have you found have been the impacts on families affected by genetic epilepsies?
08:33 Sam Berkovic
In many, many cases, it's sort of the end of what's called the “diagnostic odyssey”; everybody wants to know what's caused the epilepsy in their beautiful child who was really well and then started to develop seizures and then it started to impact their life. And that's an incredibly frustrating thing when you don't know and the doctors tell you don't know. And that's all we could say 20 years ago “We don't know.”. And that knowledge, even if you can't do anything directly about it immediately, is extremely powerful information that the vast majority of families find really helpful. It enables them to then focus on the particular genetic defect in their child, it allows them to then associate on the internet with other families and share experiences, which gives them the feeling that they're not alone and they may indeed get some sort of useful tips, and there now are therapies beginning to emerge for these epilepsies so, we hope the game will change even more in the next few decades.
09:41 Torie Robinson
So, when we talk about, well, this can apply to epilepsy as a whole, but I think particularly with identified genetic epilepsies; in some cultures, people can feel almost like “Okay, I can't tell anyone, I have to be ashamed of this, nobody's gonna marry my child or anybody else in my family, et cetera, et cetera.”. What are your experiences when it comes to that?
10:01 Sam Berkovic
The stigmatisation through genetics is really important. My own sense, at least in Australia, is it's less than it used to be but it's still there in our so-called advanced “First World” society. It is still a shameful thing to talk about, it's even worse in some other societies, where, as you say; are prohibitions or social prohibitions in marrying into a family with somebody with epilepsy or marrying a person with epilepsy., so these things are terrible. They are slowly being worked back I think, but it remains a problem. And historically, I think it was definitely even worse. Very little in genetics was done after the Second World War, until the 70s and 80s. And I think this was still a hangover from the eugenics period where you just couldn't talk about this. That is certainly... I sense that that is certainly better through my career, but it's still a problem and still a big problem.
11:14 Torie Robinson
Yeah, I mean, I've spoken with many people in countries such as, like, India or parts of, like, the African continent and particularly, but even with people actually in the UK, who have been so unknowledgeable about the epilepsies: a lady the other day, I couldn't believe it, she asked me if epilepsy was catching! And [I said]...
11:36 Sam Berkovic
Yep.
11:36 Torie Robinson
“No, it's not. It's really not!. So, I think we've got a lot to do, but, like you say, we've come so, far. Like, in my lifespan, it's just beautifully shocking how far we have come. And I see that speeding up now, would you agree? Like…
11:52 Sam Berkovic
Yeah.
11:52 Torie Robinson
…things are really, kind of taking off.
11:53 Sam Berkovic
No, it is. I agree.
11:56 Torie Robinson
Could you tell us what you think the future holds for the next, I don't know, like, 5, 10, 15 years for epilepsy research and then being able to implement new things that we've learnt into… I was going to say “treatment”, but also, potentially prevention as well - of development of the epilepsies?
12:15 Sam Berkovic
So, I'd be hopeful in that time frame we get a really good understanding of what we call a genetic architecture of epilepsy; that is in an individual patient or more broadly in a group of patients with the same type of epilepsy, exactly what are the genetic contributions to the epilepsy. It’s what we call “rare variants” that have a large effect, and the so-called “common variants” that contribute to the background. And we're getting close to that aim; that aim would have seemed unachievable, you know, 15 or 20 years ago - I think we're close to that. There is, then, of course, the very important aim of applying that to therapy in what we call precision medicine; that if you know what the actual genetic basis is you should be able to get treatment that targets that. I think that most people agree that that's gone a little slower than many of us would have hoped. We began talking about this 8 - 10 years ago in a very serious way and thought it would be a much quicker course. It is proving more difficult, but I am hopeful that the game will change for that and that we will be able to see a person in the clinic figure out what the genetic causes of their epilepsy is and then give them a therapy that directly targets the fundamental abnormality. And I think there are quite a few steps that have to happen before that becomes a common experience. It's happening occasionally, but it's still not a common experience. It hasn't happened as fast as we initially had hoped.
13:53 Torie Robinson
So, I'm just thinking like, for instance, there are some genetic epilepsies more commonly known as like, say, Dravet or like, I don't know, SCN2A/8A, for instance. What about for people who cite they have what is commonly, more commonly known as a temporal lobe epilepsy, they don't know the cause, but it could be, well, could it potentially be, do you think, identified in the future, the genetic components that may have contributed to a more common epilepsy such as temporal lobe epilepsy (but it could be anything) rather than the more commonly, like “Okay, this epilepsy is solely down to this one gene.”.
14:32 Sam Berkovic
Yeah, So, you've highlighted the divide between so-called “monogenic” or single-gene epilepsies and “complex epilepsies” by which we mean they're due to a combination of genes and temporal lobe epilepsy is a good example. We've been working for many years on so-called familial temporal lobe epilepsy where it runs in families but it's not (for the most part) due to a single gene, it's due to multiple genes and in what we call a “polygenic architecture”, and we're now well on the way to tracking that down, but there's still a way to go. So, I'm hopeful we will do that. And the other big group is of course, what is variously called the “idiopathic generalised epilepsies” or the “genetic generalised epilepsies”, where again, for the most part, you don't see a single gene, but it's due to multiple genes, and we're hopeful - well, we already do have a somewhat better understanding of that, but that's also got a way to go.
15:33 Torie Robinson
Thank you to Sam for giving us a brill overview of where we are regarding our knowledge of, our understanding of, and our hope for the future for for those affected by the genetic epilepsies - which, is heaps more that previously thought!
Check out more about Sam and his work on the website t-or-i-e robinson.com (where you can access this podcast, the video, and the transcription of this entire episode) all in one place. And if you’re new and you haven’t done so already, please do like and comment on this episode, subscribe to our channel so as to get more people learning about the epilepsies! See you next week!
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Sam F. Berkovic AM, MD, FAA, FRACP, FRS is Laureate Professor in the Department of Medicine, University of Melbourne, and Director of the Epilepsy Research Centre at Austin Health. He is a clinical neurologist and clinical researcher with a special interest in establishing close research links with basic scientists. His group, together with molecular genetic collaborators in Adelaide and Germany, discovered the first gene for epilepsy in 1995 and subsequently have been involved the discovery of many of the known epilepsy genes. This has changed the conceptualisation of the causes of epilepsy and is having a major impact on epilepsy research, and on strategies for diagnosis and development of new treatments. He is currently a principal investigator of Epi4K, the NINDS Epilepsy Genetics ‘Center without Walls’. He also has active research interests in surgical evaluation and outcome, new onset seizures, treatment of epilepsy and imaging in epilepsy and in Australia heads a large Program Grant integrating genetic, imaging and physiological studies in epilepsy. He was elected a Fellow of the Royal Society in 2007.
Sam has been awarded:
Companion of the Order of Australia
Member of the Order of Australia
Australian of the Year Award
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University of Melbourne sam-berkovic
Austin Health three-research-giants-honoured-by-austin-health
Australian Honours Search Facility (Companion of the Order of Australia & Member of the Order of Australia) berkovic
Australian of the Year Awards: professor-sam-berkovic-ac
The Royal Society samuel-berkovic-11075
Australian Academy of Science sam-berkovic
ResearchGate Samuel-F-Berkovic