Episode 1: SCN2A Overview
Since the first publications linking SCN2A with severe genetic epilepsy, developmental encephalopathy and autism, research has progressed significantly. To help understand the progress made and where research is heading we talk with Prof Ingrid Scheffer who has published many key papers in SCN2A and genetic epilepsies.
Hosted by Kris Pierce and David Cunnington, parents of Will, who has SCN2A.
Laureate Professor Ingrid Scheffer has pioneered and led the fields of epilepsy genetics and epilepsy classification over 25 years in her work as a paediatric neurologist and epileptologist at the University of Melbourne, Austin Health and the Royal Children’s Hospital. With Professor Samuel Berkovic and molecular geneticists, she identified the first gene for epilepsy and subsequently discovered many more. Now she is building on her work defining the genetic basis of epilepsy to develop precision treatments for these serious diseases.
Professor Scheffer’s website has more information on her research and achievements.
Ms Kris Pierce RN MHSc MWellness, is a rare disease advocate and mother to Will who has SCN2A. Kris has held a range of board, project management, advocate and consumer representative roles and has been instrumental in working with local, state and federal governments to secure funding for multi-million dollar projects. Kris is highly skilled in building teams to work together collaboratively and is a co-founder of Genetic Epilepsy Team Australia (GETA) and SCN2A Australia, and a RARE Global Advocacy Leadership Council member.
Dr David Cunnington: Welcome to SCN2A Insights. By starting this podcast, we hope to provide good quality information about SCN2A to better inform the SCN2A community around the world.
For our first episode, who else but to interview Professor Ingrid Scheffer. Ingrid has been associated with genetic epilepsy over many years and has really followed the evolution from first finding a single gene associated with an epilepsy syndrome to now having a really in-depth understanding of a whole range of different genetic epilepsies.
In SCN2A, Ingrid has been one of the key people involved in developing the knowledge base of SCN2A from where it first started, recognising the association of that gene with this epilepsy syndrome and now really getting into the science in looking at gain-of-function and loss-of-function and starting to understand how that might impact on treatments.
Kris Pierce: Laureate Professor Ingrid Scheffer is a pediatric neurologist and a professor at the University of Melbourne, Austin Health and the Royal Children’s Hospital Melbourne.
Good afternoon, Ingrid. Thank you for your time today and for having such a big impact on the field of SCN2A and genetic epilepsies in general.
Ingrid Scheffer: Thanks, Kris. It’s great to be with you.
Kris Pierce: You’ve had a long association with genetic epilepsies and SCN2A. When did you first start that?
Ingrid Scheffer: Well, my association with finding genes for epilepsy actually go way back before SCN2A was found as an epilepsy gene. It started with my PhD when I started working on large families with epilepsy back in about 1991 when I started as a PhD student of Professor Samuel Berkovic. And at that stage, we started studying large families. It took me a year to study a large family. This led to us working with molecular geneticist our gene-finding scientists really who found the first gene for epilepsy ever in the world in 1995. And that really was a start of a fantastic chapter in understanding the genetic basis of epilepsy and going from one gene back in ’95 to now probably about 400 genes implicated in the epilepsies.
David Cunnington: Ingrid, how did you then go from recognizing that genes were associated with epilepsy to looking at SCN2A?
Ingrid Scheffer: Well, that was really an exciting discovery. We had a couple of families who had a familial epilepsy which is really mild. It began in either the newborn period or anywhere up to the age of 6 months. This had been described in one large family as benign familial neonatal-infantile seizures, neonatal meaning newborn.
What happened is we then started studying two of these families. And with our gene-finding scientists, we were drawn to discover SCN2A as the cause of this very mild epilepsy. And these people grew out of the epilepsy and they were completely normal. It was quite frightening when it first started in the newborn baby or the infant but then the grandmas knew the story then you don’t worry that the baby is having the seizures but they will be just fine and they will be normal. So the families understood these were mild disorders.
And it was really through old fashion genetic techniques such as genetic linkage analysis and then mapping the locus of where the gene lie in the truly affected members of the family that we then discovered SCN2A and showed that it caused these mild epilepsies with a very good prognosis.
David Cunnington: We know now that SCN2A is associated with autism and developmental epilepsies and intellectual disability. When did that start to come on the radar that maybe there’s a broader clinical phenotype?
Ingrid Scheffer: Well, I think with most of the epilepsy genes, the more that we discovered gene mutations, the more we understand that there’s a much broader spectrum than we ever recognized to start with. It’s an interesting journey actually because you identify a group of children perhaps with the same presentation of seizures and intellectual problems and maybe cerebral palsy and then you suddenly realize there’s a pattern and then you say, “Well, this is – I’m describing is new epilepsy syndrome.”
Then when you got all – a number of patients with the same disease, nowadays with the new gene finding techniques, you can actually discover they may have the same genes. So the poster child for that is Dravet syndrome which is due to another subunit sodium channel gene SCN1A, and that has a very distinctive pattern of presentation. I find that 90% of the patients that are diagnosed with Dravet syndrome I will find a mutation of one gene SCN1A.
Now, SCN2A is much, much different to that really even though it’s related. It’s also a sodium channel subunit. It presents with a whole spectrum of presentations which makes it in some ways much harder to pick who might be SCN2A. Now, there are some groups that we know are more likely to have an SCN2A mutation but because the spectrum is so broad, you can’t pick that nearly as well.
David Cunnington: And you wrote a case series that got published in 2015 teasing out some of the clinical features of SCN2A. How has that then evolved now you understand sort of different gene variants better?
Ingrid Scheffer: So what happens is we started to find more patients with SCN2A pathogenic variants. That’s a new term for mutation. And we realized that there was really a spectrum of severe developmental and epileptic encephalopathies associated with SCN2A. So we’d done that original work back in 2002 and understood the very mild epilepsies associated with SCN2A but suddenly, here we had 10 patients with severe presentations associated with SCN2A.
And before our paper, there had been a smattering of single cases or just two or three, a few cases in the literature, but not really a good handle on what SCN2A could look like. So together with my PhD student at the time, Katherine Howell, we put together a series of 10 patients that we had found, most were Australian. I don’t think they all were from memory. We started to delineate the spectrum of SCN2A encephalopathies. Encephalopathy; meaning a disorder of the brain and really being used for some more severe disorders, so those associated with intellectual disability and severe epilepsy.
And it was fascinating with those 10 children we started to map out the spectrum. But we really were only just at the beginning of that story that has evolved hugely from there. And there’s a very important German paper, really Pan-European, it’s not just German but with a German lead author, Dr. Wolff, that illustrates the spectrum of SCN2A is even broader again. So we realized it’s a disease or SCN2A mutations produce very different epilepsy syndromes and that’s important to understand because it affects how we manage patients with SCN2A encephalopathy.
Kris Pierce: Can you tell us a bit about the different spectrums of SCN2A presentations?
Ingrid Scheffer: So SCN2A encephalopathy presents with many different epilepsy syndromes which has panned out to be really interesting. So there are a group that begin under 3 months of age and in particular, Ohtahara syndrome. And SCN2A accounts for a fair number of patients with Ohtahara syndrome.
The other place that we found that SCN2A was important in our paper was that it accounts for a quite a few patients presenting with epilepsy of infancy with migrating focal seizures. Both of these are rare syndromes but I guess the early onset is what makes you think SCN2A. So if a child or a baby begins in the first week of life, we think SCN2A if they begin in the first 3 months of life, we think SCN2A. And we have a large paper currently under review looking at the genetic landscape of epilepsy of infancy with migrating focal seizures, 7% of patients with that syndrome have SCN2A. So it gives us a bit of a handle of if you have a baby presenting with that very severe syndrome then they have a 7% chance of being SCN2A.
The spectrum of SCN2A encephalopathy seems to break into an early onset group which again under 3 months of age and late onset group of encephalopathies that begin after 3 months of age and in fact can even begin into middle childhood with syndromes such as Lennox-Gastaut syndrome, fairly rare but it can be caused by SCN2A and myoclonic-atonic epilepsy.
The important point though is that those beginning under 3 months of age seem to be caused by pathogenic variants that cause a gain of sodium channel function and those beginning after 3 months of age are caused by a loss of sodium channel function.
The biggest group really is West syndrome which typically begins around 6 months of age. So it seems that 3-month mark is a real point of differentiation between gain of channel function disorders and loss of channel function disorders.
David Cunnington: You see, some of the terminology, can I just tease you out about that, so you’re using terms like Lennox-Gastaut, Ohtahara, West, and then you are using genes. Can you just talk through that? Because that’s a bit confusing for some people that might be given a diagnosis of Lennox-Gastaut and then told they’ve got a particular gene. How did those two parallel nomenclature systems work?
Ingrid Scheffer: That’s such an important question. Thank you for asking that. I think one is about how we classify a child’s disorder based on their epilepsy, their EEG, and a host of other features including MRI, developmental course whether they were normal and became abnormal with loss of skills or whether they’re never normal and they have very slow development, did they have autism, a whole of other features. So that makes up an epilepsy syndrome diagnosis.
It’s really important to understand that as well as the cause. So SCN2A encephalopathy is talking about the cause and that is about an abnormality of the gene encoding SCN2A which makes the alpha-2 subunit of a sodium channel. So for my patients, they need to know both. I need to know which epilepsy syndrome they fit into and what is their cause? And if you know just half of that, you can’t target or tailor your management nearly as well. So you need to know both aspects; cause and also epilepsy syndrome.
Kris Pierce: So how do we take this to the next step?
Ingrid Scheffer: Well, the next step is really complex and needs a hugely differently skillset to those – to the clinician scientist like me. What it needs is basic scientists, physiologists, who can really understand what’s going wrong at the cellular level and then they can explore that both in animal models and also in cells.
So Dr. Géza Berecki working with Professor Steven Petrou from the Florey took this to the next step recently in a PNAS paper and they looked at two different mutations and tried to understand what the different of gain-of-function mutation versus the loss-of-function mutation did. So they looked at the mutation called R1882Q, and I say, R1882Q, which we discovered first in one of my little patients who had an Ohtahara syndrome picture and sadly, very sadly, she died at 21 months of age.
And they looked at that mutation and compared that early onset mutation so we thought that was gain-of-function, with a mutation that is associated with West’s syndrome or epileptic spasms beginning in infancy and is also found in several children called R853Q. And they compared that again with the mild form that we found back in 2002 which is the benign familial neonatal-infantile seizures and the mutation for that. And they compared all three of them with wild type which refers to the normal variant that most of us have. And they showed beautifully the loss-of-function and gain-of-function according to the different mutation. And this is actually the paradigm we need to then find a new treatment and to see if the treatment works because one of the greatest fears as a clinician is that you might give a treatment that could make a child worse. So you can imagine if you gave a sodium channel blocker to a child whose sodium channel had a loss-of-function mutation, you could actually make it – it could be very dangerous. You could even put the child at risk of dying.
So you really need to understand the syndrome, what that mutation does, is it gain or is it loss-of-function, and then the treatment. And these basic science or laboratory science experiments are critical to teasing this out.
Kris Pierce: So Ingrid, you talked about the differences between gain and loss-of-function of the sodium channel in SCN2A. How will families find out whether their child is a gain-of-function or loss-of-function?
Ingrid Scheffer: Well, I think it’s just incredibly important but also difficult. And it’s difficult because to do these studies, might take a physiologist in the laboratory six months or a year. So it’s not a quick thing.
One of the issues is there is a recurrent variance which means that the same variant occurs by chance in many children around the world. Is it really by chance? We don’t know that. There may be some previous position in the genes of that mutation. But if it’s a recurrent variant and that variant has already had physiology studies performed, the answer may already be well-known and published and accessible so that you know whether it would be safe.
The second thing though is, has that variant been tested for a different type of the drugs? And if that variant has been tested against Dilantin, phenytoin, or carbamazepine, Tegretol, you may already know if it looks like the response is good and maybe something you would trial on your child.
Taking into the next level though which I think is where we are already headed is about gene therapy and will this be the right one for gene therapy or not. And I think that’s going to take a lot more work for us to know. Clearly, the mouse model that Steven Petrou has developed and the testing in that mouse model will answer for that specific variant but it doesn’t mean that you can then apply it across all to gain-of-function or loss-of-function. I suspect we might be able to but I think we need a lot more information to be sure.
David Cunnington: Moving forward, as potential treatments are developed, what’s the role of a natural history study?
Ingrid Scheffer: I think the natural history study is absolutely essential if we are going to get new gene therapy trials to the patient. And the best example of that really comes from Batten’s disease or a CLN2 disease it’s called where they developed a gene therapy. It was actually a gene therapy, it was a replacement of the missing enzyme that gets placed by a cannula into the child’s brain every two weeks. It’s a big deal, this treatment. And the reason it got across the FDA and in Australia as well is because they had natural history data showing that children with that disease died in a matter of years and this new therapy completely changed the trajectory of the disease.
Now, we have to be ready for that, poised for these trials so that we can show in the shortest possible time that they make a huge difference to changing our children’s lives so that hopefully they are normal and the epilepsy goes away. That’s what we are aiming for.
And the idea of a natural history study is to have very good robust data over many years. Watching the natural history of this disease and mapping it out in terms of seizures, when are they bad, when do they get better, when do they change types of seizures? In terms of development, was it normal? If it was abnormal, how slow was it? Did it get slower when the epilepsy took off? Where did they end up? In terms of autism, when did the features show in terms of cerebral palsy? When did that become apparent?
And when you have all that data, then when you have a new therapy and ideally a gene therapy, you can say, “well, this child isn’t following the natural history of their disease.” And this very expensive, usually, new treatment is transformative. And that’s what gets you across the line in terms of getting the government to fund the treatment and to save a child’s life.
David Cunnington: So given the importance of a natural history study in moving treatments forward and being able to justify the cost and risks and understanding better, how would you map out a natural history study?
Ingrid Scheffer: Well, I think it’s really important to be all-inclusive and try and work with everybody to get a full picture of the spectrum of a genetic epilepsy, be that SCN2A encephalopathy or any of these severe epilepsies. And I think to do this really well given that often the numbers of any of these patients with the disorder are relatively small in one country, one should work together with a global perspective.
And just to reflect on my career, I’ve got so many collaborations with clinicians in more than 30 countries and it has been a real joy because you then work together to help people all around the world and you make friendships around the world and you also get to think together and find new ideas or new treatments or new approaches. So, global collaboration is really important. We are very fortunate in Australia to have such a supportive patient family community and a network of clinicians that really want to work together because their aim is to improve outcomes for the children and adults we look after. But I also think there are people in other parts of the world that maybe isolated and it means that they can then connect with us at a research at a clinical level. And to be honest, I get emails often like, “I’ve just got a new patient with an SCN2A encephalopathy. What advice would you give?” And I think it’s fantastic that we should all work together and create a global network.
David Cunnington: Thank you very much, Ingrid. What a great interview. That has given us such a great background of where the research in SCN2A started from and where it’s going to in the future.
Kris Pierce: Keep up to date with the latest updates by subscribing to this podcast.
David Cunnington: Or get regular updates on SCN2A through SCN2A Australia’s Facebook or Twitter @SCN2AAustralia.
Outro: This podcast is not intended as a substitute for your own independent health professional’s advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider within your country or place of residency with any questions you may have regarding a medical condition.