Clinical Features of SCN2A-Related Disorders

Webinar 2: Clinical features of SCN2A-Related Disorders

Mutations of the SCN2A gene can result in a range of different clinical syndromes. Whilst most presentations have epilepsy, autism and a degree of developmental impairment there is a lot of variation, and these variations reflect different expressions of gene function.

Understanding these different clinical presentations can help to guide treatment, and will be critical as SCN2A treatment moves towards disease modifying treatments. It can also give insights in to prognosis and help families better understand what the future holds.


Dr Katherine Howell is a paediatric neurologist and epileptologist at The Royal Children’s Hospital, Melbourne, and a Clinician-Scientist Fellow at the Murdoch Children’s Research Institute. an honorary senior fellow at the University of Melbourne and an honorary senior research fellow at the Florey Institute of Neuroscience and Mental Health. Dr Howell’s work on SCN2A-related disorders has been important in describing their clinical features, determining a number of different subgroups (phenotypes) of SCN2A-associated epilepsies, and understanding the relationship between the SCN2A phenotype and the impact of the mutation on brain cell function.


Dr. David Cunnington: So, welcome to this webinar, hosted by SCN2A Australia. We’re delighted to be able to bring you regular webinars and podcasts to the SCN2A community and the rare disease community that also incorporates developmental and epileptic encephalopathies. And we really want to ensure everyone’s well informed about the latest research, clinical practise and issues facing families and those affected by these conditions.

So in today’s webinar, we’re going to talk about the Clinical Features of SCN2A-Related Disorders and that’s going to be presented by Dr. Katherine Howell. Katherine is a paediatric neurologist and epileptologist at The Royal Children’s Hospital, Melbourne and a clinician scientist fellow at Murdoch Children’s Research Institute. And Katherine’s work on SCN2A-related disorders has been very important in describing the clinical features from an original paper in 2015 and then a number of subsequent papers that link together some of those clinical phenotypes together with brain cell function or how those gene mutations changed the function of neurons in the dish.

Katherine is also the principal investigator of the SCN2A Natural History Study that’s ongoing. Thanks for your time today, Katherine.

Dr. Katherine Howell: You’re welcome, Dave. Thank you for having me.

Dr. David Cunnington: So you’re a researcher, you’re a clinician in those roles, what’s your day to day work look like?

Dr. Katherine Howell: Oh I guess it depends if it’s a clinical day or a research day. My clinical work is almost solely in epilepsy, paediatric epilepsy and with a real focus on severe early-life epilepsy. So a lot of my time is seeing children with severe epilepsies in a clinic or in the hospital if they’re in-patient. And then I also report EEGs and video EEG studies as well. Research days are a real mixed bag and I do the SCN2A work as you mentioned. I also have a study on infantile spasms and a number of other things relating to epilepsy.

Dr. David Cunnington: And what about outside of work, you’re a mother as well?

Dr. Katherine Howell: I am. I have two children, preschool-age, so life is busy. I love to read, I love to travel and there’s not a heck of a lot of time for those things but if you think what I get. So today, I’m going to speak about the Clinical Features of SCN2A-Related Disorders. Just upfront we received some research and salary support from a number of sources so just to declare them upfront.

So today, my talk is going to encompass a number of things, just a very brief mention of sodium channel function to start with. I’m going to go through a little bit of history and discovery of the SCN2A-related disorders, some of the correlations between the genotype, the type of gene change and the clinical symptoms or phenotype. I’m going to talk about the different clinical phenotypes that we see with SCN2A mutations. And then at the end, I’m going to talk briefly about the… I guess forgotten SCN2A-related disorders which are the chromosomal deletions that encompass all of SCN2A and some of the adjacent genes.

So let’s launch into it. So there are four neuronally-expressed sodium channel genes and SCN2A is a major one. These all encode the subunits of the voltage-gated sodium channels and they differ in where they are in the cells which neurons therein and at what ages they’re expressed. So the SCN2A gene codes for the NaV1.2 subunit. Now, that’s the major sodium channel in excitatory neurons in early life and it’s replaced with NaV1.6 at a later age.

So the initial description of an SCN2A-related disorder was that of benign familial neonatal-infantile seizures back in 2002 and this was a condition with seizure onset in infancy with treatment responsive seizures that remitted at the end of infancy or before with normal developmental outcomes and described as a condition that ran in families.

A number of years later, there were descriptions of more severe epilepsies which shared some of the features of the BFNI… sorry, BFNI, yes, excuse me… phenotype in the – that had seizure onset in the neonatal period and they had a focal seizure but they were much more severe and much less treatment responsive.

Subsequent to that, there was another description of what seemed to be a completely distinct phenotype with seizure onset in mid-infancy and where the presenting seizure type was usually epileptic spasms, infantile spasms. And in contrast to the neonatal phenotypes which often responded well to Phenytoin and other sodium channel blockers. The mid-infancy seizure onset phenotype didn’t seem to be distinct disorders.

There have been other phenotypes reported too including intellectual disability and/or autism without epilepsy and a condition called episodic ataxia where people are intermittently unsteady and have problems with balance.

So SCN2A-related disorders as the descriptions sort of part of in the literature seemed to be quite complicated and it was becoming increasingly clear that this was not one gene-one disorder. So what do we make up all of this mess? So there were a number of laboratory studies done that really have been quite very important in trying to tease out these conditions. Is this all a spectrum of severity? Are there distinct disorders and in fact, it’s shown that they are clearly distinct disorders?

So what you’re seeing here is what we call DC curves where you’re basically looking at neuronal firing in the dish with different cellular models or excuse me… Sorry. Up in the top row, the black curve, you’ve got the wild-type, so normal sodium channel. And then in the bottom three, you’ve got different mutant sodium channels. So the green and the pink ones are neonatal mutations seen in people with neonatal onset SCN2As and you can see that compared to the wild-type trace up the top, there are a lot more spikes.

So each spike is an action potential from the neuronally-electrical signal. So these seemed to be over-functioning channels and in fact, the severe phenotype seemed to be over-functioning more than the benign functioning one. But this study suggested that the neonatal onset forms are gain of function disorder. 

In contrast, the mid-infancy onset seemed to do the opposite. These cells were firing a lot less than the wild-type did and it suggested that this form was a loss of function disorder. Subsequently, there have – there’s been more work which is born with us and also shown some of the other phenotypes I mentioned to be either gain or loss of function as well and I’m going to go through these now in detail.

So making a little bit more sense of the table that I had before, we’ve got in the pink and red, gain of function phenotypes and in the blue, loss of function phenotypes. So the darker colours are relatively more severe types and the lighter colours, are relatively less severe. So the pink ones are typically onset early in life, in the first few months of age with a gain of function mutation you can occasionally be unaffected. In some families where the phenotype is relatively mild, we do occasionally see unaffected family members.

Those who have better developmental outcomes often had inherited SCN2A variants and de novo or a new change in the affected person variant is more often seen in those with more severe conditions. And in contrast, the late onset phenotypes tend to present after age 3 months. Now as far as the epilepsies go, there is a benign form in the pink line up the top. And then the more severe forms which spanned both the gain and loss of function phenotypes and they are otherwise known as developmental and epileptic encephalopathies and for quite a while, we lumped these together.

And as I’m going to go through these now, I think it’s becoming increasingly clear that these need to be split and considered different things. There is not just one SCN2A-related DEE, there is a number.

And the other thing to mention is that missense variant. So a single spelling mistake can cause gain or loss of function phenotypes but truncating variants where you get a shortened protein cause a loss of function phenotype. So sometimes knowing the gene change can help us predict that.

So coming to the gain of function phenotypes now, I’m going to talk through each of these in a little bit of detail. So the benign phenotype reported is the BFNIS, the original report of an SCN2A-related disorder is not always familial but it can be. So there may be a family history of similar conditions in the family and sometimes you may not know that until you ask the grandparents of the presenting child because sometimes the parents will never know that they are infected seizures because they’ve done so well and haven’t had ongoing epilepsy.

Most have a seizure onset between 1 and 4 months of age but can be in a newborn period, it can be as late as 23 months. Typically, as with focal seizures, very varying frequencies from very frequent –any one or two. Usually, the EEG in between seizures is relatively normal and the child when you look at them is behaving fairly normally for age unless they’re excessively sedated from medications.

Most children with this phenotype have treatment responsive epilepsy occasionally need no treatment at all. And in contrast to the more severe neonatal form, sometimes they are responsive to non-sodium channel blocking anti-epileptic drugs although some are resistant to those but will respond to the same channel blockers. Seizures remit by 12 months in most, the developmental outcome is usually normal and it’s rare to have any symptoms beyond the newborn period except for the occasional person who has later episodic ataxia.

The other end of the neonatal spectrum is a really severe phenotype. These are usually due to de novo mutation so there’s usually no family history. Seizure onset is before age 3 months but the majority in the first week of life. Typically, again, a presenting seizure type is a focal seizure and children often have many different types of focal seizures and these are incredibly frequent, sometimes multiple hourly in the early weeks or months of life.

Typically, the EEG in between seizures is very abnormal and when seizures are recorded, they show focal ictal rhythms. The epileptic syndrome that is the sort of clinical features, the type of seizures at what age and what the EEG looks like all put together is frequently described as one of the well-recognised severe neonatal onset epilepsies including early infantile epileptic encephalopathy or Ohtahara syndrome or epilepsy of infancy with migrating focal seizures which is EIMFS.

Most of the time, children with a severe phenotype appear to be neurologic… behaving neurologic – sorry, in a neurologically abnormal way from early on in – they’re quite sleepy and visual attention and interaction is less good than expected for age often is excessive startle, maybe poor feeding and sometimes there are other unusual movements which are not seizures. Initial brain imaging is usually normal as most of the… or in fact, all of the metabolic tests and things like that. So these were children, who, in the past, would – before the age of genetic testing would never have received a diagnosis because there is no single characteristic clinical feature or a feature on the investigations we had available to us.

What we know is that these epilepsies are highly treatment-resistant to non-sodium channel-blocking antiepileptic drugs and this includes most of the seizure medications used in neonates at least the first, second even sometimes third-fourth line are not sodium channel blocking drugs. And the recognition that this and some of the other bad neonatal epilepsies are preferentially sodium channel blocker responsive is actually changing how we manage newborns with any epilepsy.

So these children with this condition won’t respond to non-sodium channel blocking drugs but they often will respond to sodium channel blocking drugs and particularly Phenytoin seems to be the drug that is most effective. It is often very high therapeutic or even super therapeutic above the usual therapeutic range in the blood are required to maintain seizure control.

There are reports of benefits in – with other sodium channel blocking drugs but in fewer children and it’s not clear whether it’s the drugs are less good or whether you’re less likely to reach a super therapeutic level because some of the other ones are drugs that you give orally as opposed to giving an IV loading dose in hospital.

So how much benefit do they give? Well, about half of children get a mark seizure reduction, about a third will have periods of seizure freedom and they’re often more alert and feed better and sometimes this allows children to be discharged from hospital whereas historically, they may have been in hospital for weeks or months, we’re now seeing much shorter initial hospitalizations. However, a few children remain seizure-free, one of the biggest problems is that Phenytoin is an incredibly difficult drug to use in young infants. The drug levels fluctuate wildly and that’s very difficult. So during the periods of time when the drug level is low, there’s a seizure occurrence.

In addition, despite seizure control, we often don’t see a significant developmental acceleration. It’s a little bit difficult to know where the children are doing any better than they might have had we not had seizure control. And even if we can have seizure control and get a child out of the hospital, it doesn’t always mean the quality of life is better. There is sometimes a trade-off between seizure control and a movement disorder or abnormalities of tone for reasons I don’t really understand yet and I don’t think anybody does. Sometimes they fluctuate. The seizures can be better but the movement disorders and dystonia can be worse.

So in most of these children that are ongoing focal seizures or at least a tendency to this, there sometimes exacerbations to status epilepticus with undercurrent illness or low drug levels, some children develop other seizure types and some don’t and the other seizure types can include infantile spasms. Some, in fact, many children have some improvement in seizure frequency after about age 2 years although most tend to have some ongoing seizures throughout childhood at least. We don’t really know beyond that stage just yet as there are not too many descriptions of what happens in adulthood.

Development is often quite severely impaired. There are multiple factors impairing development including the underlying channel, abnormality, epilepsy, seizure medications, poor sleep irritability relating to movement disorders, there are a lot of factors at play. Interestingly, we’ve seen a number of times that children often have relatively better receptive language cognition and nonverbal expressive language than they do expressive language. Yeah, children may not speak words but it’s quite clear that they – that some who have almost no speech understand a lot and can communicate nonverbally.

Non-seizure, non-developmental things are quite prominent and often cause significant quality of life issues, irritability and poor sleep are major factors. Movement disorders, particularly, dystonia can be really problematic. Gastrointestinal symptoms can be particularly severe and often not taken seriously until the diagnosis of SCN2A is known and people recognise that this is a feature. Some children require enteral feeding, so a tube into the stomach or into the – even into the intestine to feed them. And the other one I haven’t mentioned here is autonomic symptoms. So abnormalities of temperature control, blood pressure, those kinds of things.

This is an incredibly severe condition and we have had some children who have died from their condition for a number of different reasons including complications of severe neurologic impairment such as chest infections. At this point, we don’t really understand how frequent – what the mortality rate of this condition is.

Having painted such a dire picture, not everyone with a SCN2A-related neonatal epilepsies whose phenotype isn’t completely benign has such severe impairments. In fact, it’s becoming increasingly clear that there is a more intermediate severity phenotype as well. Oftentimes, these children present quite similar to those with a severe phenotype but end up doing better. And there may be some clues early on to suggest who will fare relatively better in the long term. So these children can have very severe epileptic syndromes including EIMFS. They’re often resistant to non-sodium channel blocking antiepileptic drugs but they sometimes do have complete seizure control with sodium channel blocking drugs other than Phenytoin.

Oftentimes, their seizures remit or become less resistant either during infancy or early childhood and many of them have seizures stopped before age 2. The EEG in between seizures is often abnormal although less abnormal in the severe phenotype and these children don’t develop infantile spasms. Development can be normal but can be mild to moderately impaired and in some children, their impairment is solely in motor domains and in some, it’s a global impairment.

The other clinical features are present as well in some children and include those listed here. One of note is episodic ataxia which is relatively common in this intermediate phenotype and very occasionally occurs without having seizures beforehand which you might remember I mentioned that that other phenotype was described there. In fact, there are more people who are described with this – with episodic ataxia now would now recognise that almost all of them have seizures in infancy before that although not 100%.

So we and others had previously considered these three neonatal phenotypes to be distinct but I think it’s becoming increasingly clear that it’s actually a spectrum of severity. There are overlapping clinical features between the three and knowing the particular SCN2A variant is not always predictive. In some – with some of the recurrent mutations, there’s a consistently severe or consistently benign phenotype but in others, it’s quite variable including within families.

And the family tree listed here actually shows a father and his two offspring who are half-siblings. The father has an intermediate phenotype, one of the children has a benign phenotype with normal development and one child had an Ohtahara syndrome, a very severe phenotype, so the same variant, same family, very different symptoms. So it can be difficult to predict. So we would now consider these to be a real spectrum of severity or gain of function, SCN2A-related spectrum.

So being able to predict the outcome when a child presents with neonatal seizures due to SCN2A is really important both in clinical practise for the family of the child and also when it comes time to – when we do have clinical trials of novel agents available, you know who is going to need these treatments and who will actually do OK without them.

So the mutation and the inheritance doesn’t always predict severity. So we’ve previously thought that inherited variants really always have a benign outcome. It’s not 100% true and vice versa doesn’t always hold true. At this point, we don’t know whether testing in the lab clearly distinguishes milder from more severe phenotypes, more work needs to be done there and we are currently looking at whether the clinical features of epilepsy onset do predict outcome and we think that there are some predictors early on but it would be nice to have a bit of a scoring system I guess to be able to determine this in a more scientific way.

Some of the things we think might differentiate as severity or how good is the child’s visual attention early, will they fix on you, will they follow, what is the EEG look like in between seizures, how normal is that for age and what is the treatment response and do you require sodium channel blockers or not to get seizure control, do you need Phenytoin versus another sodium channel blocker or were you not able to get seizure control.

So, moving on now to the loss of function phenotype. So we’ve got a phenotype with seizure onset in the mid-infancy period, one with seizure onset in childhood, so the second year of life or beyond and one in which there are no seizures but there is intellectual disability and autism or and/or autism.

So taking this one by one, the mid-infancy onset, the epilepsy begins mostly in the first year of life between 3 and 15 months. But in most children, seizures aren’t the first manifestation and many have developmental delays beforehand. Sometimes it’s irritability, vomiting, failure to thrive and there is a movement disorder, and sometimes these symptoms have been significant enough that a child had a long period of hospitalisation even before seizures start. In others, the symptoms before seizures are milder and they’ve been relatively well.

So the initial seizures most commonly are epileptic spasms, infantile spasms. The EEG is usually really abnormal, often showing a chaotic pattern called hypsarrhythmia and the combination of spasms and hypsarrhythmia gives these children syndrome, epileptic syndrome diagnosis of West syndrome. Most seizures in this phenotype are very difficult to treat in children who often have an ongoing and poorly controlled seizure.

Some have an initial treatment response to the drugs that were used to treat infantile spasms so namely, corticosteroids. But most seizures do recur and continue to childhood mainly with different types of generalised seizures. Again, similar to the more severe early onset seizures, we do see a change in seizure frequency around the 2 or 3 age mark in that they become a little less problematic although they do tend to continue.

The response to sodium channel blockers in this cohort is not surprisingly –  it’s not positive and not surprisingly given it’s a loss of channel function and if you block that further, you’re not going to be doing a good thing by most children, so the clear exacerbations with these drugs in some children. But interestingly, others report no change or even occasionally even benefit. And so we really don’t quite have our heads around exactly how that works and why that happens.

There isn’t any single anti-epileptic drug consistently reported to be of benefit. Many children are on multiple drugs. Development which was often delayed before seizure onset continues to be a problem with moderate to severe intellectual disabilities reported in the longer term. Many have additional features, some of which overlap with the neonatal phenotypes and some of which are a little distinct. Some children have a prominent movement disorder called, choreoathetosis and that’s well described with a couple of the SCN2A variants and not seen in others. Gastrointestinal symptoms and other episodic symptoms including episodic agitation can be problematic for some children.

As far as the childhood onset phenotype goes, again, there’s usually no family history. Seizures begin in or after the second year of life and the types of epilepsy really are very variable. The number of children has generalised epilepsy and then epilepsy usually starts around the age of 1 or 2 and many children have focal epilepsy often beginning later than that although they can begin in the second year of life.

Again, treatment response is quite variable with no real – no one drug being reported to be significantly better than others, a proportion does become seizure-free. The benefits most frequently reported with non-sodium channel blocking drugs, again, unsurprisingly given it’s a loss of function phenotype and some have a frank exacerbation with sodium channel blockers. But again, there are occasional reports of benefit and we don’t really understand how that comes about whether it’s some kind of compensation mechanism going on where other sodium channels might be overactive to compensate for the loss is one theory as to why that might happen.

In the long-term development and other symptoms really mirror that of the other phenotypes that I have already spoken about and one thing I haven’t actually really mentioned with the loss of function phenotype and the – some of the gain of function phenotypes behaviour and sleep can be very problematic at times.

The other thing I haven’t really mentioned is that other than – so the symptoms that I’ve mentioned other than seizures and development, you know things like movement disorders and sleep and things like that, there really aren’t – we don’t really have great treatments for those and in fact, many children have tried many treatments without significant benefit. And so unfortunately, there’s – we don’t have a lot to recommend for specific treatments for those conditions over and above what you would do for these symptoms in another condition, unfortunately. And hopefully, that will come with time.

There are children who have no seizures at all and these children have a… I guess wide variability in the severity of their developmental impairments. Again, they often have other symptoms like abnormalities of tone and gastrointestinal symptoms. And one of the things that are often a really important question for parents when their child who has an intellectual disability is diagnosed with an SCN2A-related disorder is will my child develop seizures given that is a major feature of many of the other SCN2A-related phenotypes?

A figure we have at this point is about a third of those whose initial presentation is with intellectual disability or autism spectrum disorder will develop epilepsy in childhood. So that means two-thirds will not. But at this point, we don’t have a great way of predicting who will and who won’t.

So we have these sound three loss of function phenotypes that I’ve mentioned and at this point in contrast to the gain of function phenotypes, we don’t really have a great handle on whether these represent a spectrum of severity or truly distinct disorders. Where we have recurrent mutations, we, for example, the R953Q mutation that causes West syndrome and choreoathetosis, one of the I guess prototypic mid-infancy onset phenotypes. Children with that variant, all have the mid-infancy phenotype. So for some mutations, we can see they really– or cluster within one of these three things I’ve described. But really at this point, we don’t know enough about whether these are separate or overlapping things.

So this is where we’re left with. We see that the majority of children with seizure onset… seizure onset under 3 months is almost always gain of function. The majority with seizure onset over 3 months have loss function with the exception of the tail end. I guess it’s the gain of function phenotypes which tend to be those at the milder end.

And so if you have a child with seizure onset after 3 months who has otherwise normal development and has focal seizures that are relatively treatment responsive, then they may well have a gain of function phenotype. If you don’t have those features, then you’re much more likely to be a loss of function phenotype. But that’s sort of 3, 4 or 5-month period is not 100% separation between gain and loss of function.

To briefly come onto chromosomal deletion, the SCN2A gene is on chromosome 2, the long arm at position 24.3. It’s actually next to a number of other sodium channel genes, five of them I think, including SCN1A and 3A that are also expressed in the brain. So you can delete different combinations of these, you can delete all three of them or just 1A and 2A or just 2A and 3A plus or minus other adjacent genes.

There are a number of reports of children with each of these in the literature although overall the clinical features in phenotypes and not particularly well understood but there are some differences depending on which genes you have deleted. So if you delete 2A and 3A, there seemed to be a couple of different things that can happen. The first is that you can have developmental delays, intellectual disability, autism spectrum disorder with no seizures or you can have severe epilepsy.

Typically, with a mid-infancy seizure onset or later with otherwise quite similar features to the loss of function phenotypes that I’ve previously described, I don’t know and I don’t think anyone knows why some children have no seizures and others have quite severe seizures. This may be telling us that the loss of function phenotypes I’ve previously described is a spectrum and these are just children who are variably affected or there may be another reason.

If you delete 1A, 2A, and 3A or just 1A and 2A, you often have quite similar features. The seizures begin usually at a couple of months of age. There are multiple seizure types, often, focal seizures are early – occur early on and the epilepsy phenotype can often be consistent with epilepsy, the infancy with migrating focal seizures. Early on seizures often happen in clusters of short seizures and frequently require emergency medications to stop clusters. And then this is often interspersed with seizure-free days. Later on, seizures can evolve to occurring everyday but at a much lower frequency and not needing emergency medicines.

Sodium channel blockers seem to worsen seizures in this case but improvement with a number of other drugs is reported and those are listed on the screen there. One interesting thing is that seizure improvement with sodium valproate or Epilim is reported although a number of people have also reported worsening of development and overall interactions with this drug and the reasons for that are not well understood.

Interestingly given SCN1A is also deleted and that’s the gene for Dravet syndrome. Some of these children do have some Dravet-like features to their epilepsy but also different features. So the similarities include that seizures are sensitive to fever or heat and will be worse during those times and that some of the seizures what we call, hemiclonic, it’s jerking of one side of the body.

In contrast to Dravet syndrome, they are much less likely to have prolonged seizures and myoclonic seizures. And there are a number of other features, again, many of which are overlapped with the other things I’ve spoken about earlier. One of the things that’s a little bit distinctive is described in a number of children and I haven’t mentioned it previously is early puberty has been seen in some.

So just about to finish up there and I think we might have some – hopefully, time for some questions. But I just want to leave you with a couple of references for – that I think… well, hopefully, useful papers summarising the SCN2A-related phenotypes. And I wanted to say a big thank you to Dave and Kris, SCN2A Australia for having me today.

And also, a big thank you to all of the families who have been involved in our Natural History Study. I think I’m very grateful for over the time people have given us to try and understand these conditions better. Our studies received support from RogCon Sciences. We have support from the Simons Foundation in recruitment and sharing of data and we’ve had support from a number of patient groups around the world. So, thank you all very much for that.

Dr. David Cunnington: Great! Thanks very much, Katherine. Things have certainly moved on since you published that paper in 2015 with the three sort of phenotypes?

Dr. Katherine Howell: Yup.

Dr. David Cunnington: If you are to sort of summarise how you’re thinking about things has changed with five years more clinical experience, now you can test things in a dish and look at the activity at a gene level, you’ve seen a number of people in the Natural History Study and really tease that out.

Dr. Katherine Howell: Mm-hmm.

Dr. David Cunnington: Yeah, how would you summarise how you’re thinking so far over that time?

Dr. Katherine Howell: Oh, probably the most pertinent one has we entirely missed the mid-infancy onset phenotype in a paper. And obviously, being an epileptologist and it being in epilepsy paper, we hadn’t even thought about the phenotype of children without epilepsy. But we didn’t have any children with a mid-infancy onset phenotype and we went across that and now that’s become very clear that’s quite a distinct phenotype and part of the spectrum.

We now… at that point, we didn’t have any understanding of the gain versus the loss of function spectrum and I think that’s been hugely important in directing treatment for these children. And particularly as I briefly mentioned before, getting children out of hospital early on because we can get better seizure control early on than we otherwise would – wouldn’t have – has made a big difference.

Dr. David Cunnington: OK. You talked a bit about some of the autonomic features.

Dr. Katherine Howell: Mm-hmm.

Dr. David Cunnington: Can you just sort of in some respect try to explain to families how they’re important? So things like inability, the amount of blood pressure response of a temperature response and why does that translate to that sort of serious illness in young children?

Dr. Katherine Howell: Mm-hmm. Mm-hmm. So usually, when someone becomes unwell, any child, any person for any reason, there are a number of compensatory mechanisms that the body has which sometimes the heart rate will go up, sometimes there are changes in your blood vessels that will mean your blood pressure changes to deal with how you’re feeling unwell and things like that. And in SCN2A-related disorders, your – this is recorded on autonomic responses.

In SCN2A-related disorders, they sometimes don’t work well. One of the things that can happen is that children can become more unwell with an illness or sometimes not be that much more unwell but look really unwell. You know they’re sort of I guess profusion like how much and how well the blood is getting to their extremities can be different. They can look really – you know be really cold, have cold extremities. So things that people consider when that someone is very unwell.

And so sometimes they can actually be more unwell than you think, sometimes they look more unwell and that’s obviously a problem trying to work that out. Oftentimes, children with SCN2A-related disorders have seizure exacerbations during illness too. So often, we just get the sort of I guess, perfect storm of things going on and the autonomic dysfunction doesn’t help trying to assist children there.

Dr. David Cunnington: And you said the treatment approaches in some respects trying to mitigate the downstream effect, what about some of the disease modifying approaches for SCN2A that are in development, do you think they will have a better impact on autonomic problems?

Dr. Katherine Howell: Well, we hope so. And that’s I guess one of the major drivers for new… well, the drivers for new treatments are really that our current treatments aren’t effective, but our current treatments really are directed at treating the symptoms and not the underlying cause and we can do that partially for some symptoms and not at all for others and trying to get at the underlying reason theoretically has a much better chance of helping those other things.

And this point, some of our drugs do act on the sodium channels such as Phenytoin, but they do so in what we would call a very dirty way. So not specific to that channel but also impacting on other channels as well in ways that might actually be harmful. So hopefully, the neater and more specific approaches of the precision medicines that are being developed will be better, not just for seizures but also for development and things like autonomic symptoms that you mentioned.

Dr. David Cunnington: Yeah, that’s really important because often, the autonomic features are what impact on families and may actually mediate some of the mortality risks early on with SCN2A.

Dr. Katherine Howell: Yeah, absolutely.

Dr. David Cunnington: Yeah. And that paper from 2018 really nicely showed how in the dish you can look at the electrical activity in cells and map it to those three phenotypes. You know you’ve now shown it’s a spectrum and there are many, many different other phenotypes. How’s that going in terms of been matching that to cellular function? Are you starting to see the abilities to tease that apart in the lab?

Dr. Katherine Howell: Yeah. So I think we’re now pretty happy that we can pick a gain versus a loss of function phenotype and what we think clinically is gain of function or loss of function is what it turns out to be in the lab and with these kinds of tests. And we – but we don’t yet have a great handle on whether – so for example, in the gain of function finishes up the amount of by which the channel is malfunctioning predicts the severity, it may not. We don’t know yet. That would be important to tease out.

And it’s really important I think to understand that those things I showed are just looking at some cells in a dish, cells that have a mutant sodium channel in it, you know. And then – and cells in the dish is not a whole brain or not a whole animal or not a whole person and so translating from a dish upscaling it to something to a person is tricky and we obviously don’t see things at a network level in a dish.

Dr. David Cunnington: Yeah. And for you who works in this area and others that work clinically in SCN2A, you have a sense of it now if you see a child presenting, you’ll think, yeah, OK. It’s this particular phenotype.

Dr. Katherine Howell: Mm-hmm.

Dr. David Cunnington: How are you – how are we going to translate that skill to other areas within the hospital so an SCN2A family comes to the emergency department and they’re concerned and there’s a particular presentation, how do you go disseminating that?

Dr. Katherine Howell: So I think now is a very important issue and yeah, there’s a number of things here. Firstly, this condition is not just seizures and development and many of the manifestations of SCN2A and things I don’t primarily deal with but a paediatrician or someone else might.

Dr. Katherine Howell: Or, these children are found well and coming to the emergency department and seeing someone who’s not me or another neurologist primarily. And for example, in some children with status epilepticus with SCN2A-related disorders, we might treat them differently to what our usual status epilepticus protocols are for all comers.

And so I think the really important thing here is education and information and so information specific to that child and specific to that disorder, the kind of combination of that. So when I have children with these conditions and I guess similarly other severe epilepsies, I will often provide the family with some information about the condition that can be also given to other medical professionals, ambulance officers, even lay professionals are usually right at an emergency seizure guideline for ambulances and emergency department which often includes whether or no modifications to the approach are required and whether – and for example, things like seizures may become more subtle but it doesn’t necessarily mean they’ve stopped. Those kinds of things where they’re relevant to make sure that those specific things to their child are within their records.

And obviously, we sort of need information to be able to be disseminated more broadly. So there are things that we’ve written such as the SCN2A page on the human disease, the Human Disease Gene website. The link is in my presentation. That has a section for professionals and a section for families as well. And hopefully, those kinds of things are helpful.

Dr. David Cunnington: Yeah. OK. That’s really helpful. And you know we’ve looked at this or the way you presented it is from sort of the start of life through childhood with gene testing starting to get into the adult realm. We’re going to start diagnosing SCN2A in adults with developmental issues and seizures.

Dr. Katherine Howell: Yup. Mm-hmm.

Dr. David Cunnington: Do you have any sense of what the phenotypes look like in adults?

Dr. Katherine Howell: Not a great sense. We know of some adults with SCN2A-related disorders, there will I’m sure be many out there who are undiagnosed.

Dr. Katherine Howell: In our Natural History Study, we’ve had a number of people in their 20s. And it’s a little difficult because we don’t have I guess enough experience with enough people of each of the different phenotypes to be able to give a good answer about that. But the developmental and intellectual issues, often and surprisingly persist. Whether seizure is persistent to adults who seems to be a bit variable and how prominent other features are is also a little bit variable and we don’t really have a good sense at this point as to whether people continue to function at the same level or make gains or the contrary. I think we really just understand very little actually at this point.

Dr. David Cunnington: And hopefully, that some of the answers that the SCN2A Natural History Study that you’re the principal investigator for are going to give for us.

Dr. Katherine Howell: I hope so. Yeah. We would love to have people of all ages in the study. We certainly haven’t restricted it to paediatrics even though I’m a paediatric neurologist. And I think it’s really important to understand the other end of the spectrum. So if anybody would like to participate in this out there as a child or adult with this condition, we’d love to hear from you.

Dr. David Cunnington: Yeah. And what’s the best way for people to get in touch if they do want to participate?

Dr. Katherine Howell: Yup. So we have a study email. It’s scn2a@mcri M for Mary MCRI is the Murdoch Children’s Research Institute. That will get you to our study team and you can let us know that you’re interested and we’ll send you some information on the study to have a read.

Dr. David Cunnington: Yeah. And I think it’s really important that people participate because it is going to help us answer some of those questions about what does SCN2A look like at the age of 18, 20, 30, later on in life or what does a 5-year-old turn into as a 10-year-old which we really– which really is cross-sectional data points but we don’t have that longitudinal data at the moment.

Dr. Katherine Howell: Absolutely. And so that’s the real driver for the Natural History Study both to be able to tell people what to expect in the future but also then to be able to have a comparison or whether the treatments we give are making a difference over and above what you would have expected without that treatment.

Dr. David Cunnington: OK, great. So, thank you very much for your time today, Katherine. We really appreciate the explanation that you’ve given and the insight you’ve given into the clinical presentations.

Dr. Katherine Howell: You’re welcome. Thanks for having me.

Dr. David Cunnington: So, thank you everyone else for your participation in the webinar. The webinar will be available on SCN2A Australia’s website for download. And there are also previous copies of or copies of previous webinars that are there. SCN2A Australia also features a podcast, Katherine has been a guest on one of our podcast episodes talking about the Natural History Study. And you can subscribe to that or find that or need the podcast streaming app, it’s called, SCN2A Insights and follow SCN2A Australia on social media or SCN2A Australia. Thank you very much.