Multidisciplinary Management and Treatment in CLN2 (Batten Disease)

This transcript was produced by automatic speech recognition and edited for readability; it has not been fully verified word-for-word. It may contain errors — particularly with names, technical terms, and where English is a speaker's second language. It is provided as a convenience only. For anything clinical, please refer to the video recording to hear exactly what the expert said.

Introduction and How CLN2 Is Treated

Dr. Dipak Ram: Hello everyone and welcome to the CLN2 Batten disease webinar. I am Dipak Ram, pediatric neurologist in Royal Manchester Children's Hospital and over the next half an hour to forty minutes or so I will be giving you an overview of CLN2 disease as well as the importance of multidisciplinary management of these complex patients. Just to mention, because we are going to talk about patients, please, avoid taking any screenshots, we will have some time about questions and answers at the end which you can put into the box which I will answer right at the end.

Of course, the webinar will be available online, so you don't need to take screenshots because you can re-watch it online. And just to mention that of course this is sponsored by Biomarin but they had no influence at the content or the topic which is all my own material. So a little bit about CLN2 disease, I mean, many of you may have heard about Batten disease, and some of you will be familiar with CLN2 disease, which is a very specific form of Batten disease.It's an umbrella term really, Batten disease, and a lysosomal storage disorder. And essentially there's an issue with the recycling centre of the cells, and lysosomes which are not working.

Enzyme Replacement Therapy and the Infusion Device

Usually they need TPP1 enzymes to break down materials and in this condition the deficiency in that enzyme leads to lipofuscin building up and that becomes toxic to the nervous system as well as the retina where it classically builds up. CLN2 disease is very unique compared to other Batten diseases because it has a very characteristic trajectory in its classical form.

Bear in mind that there are attenuated forms of CLN2 disease which present a little bit later but this is exceedingly rare. The classic form which is almost universal presents with speech delay in almost everyone and then they start having seizures which could be febrile initially but then very clearly become epileptic seizures. They could be different types of seizures.

They could be focal, could be myoclonic or could be tonic-clonic. So any of those are known to be there in the early presentation of the CLN2 disease.And then if the diagnosis is not picked up as yet, they then start developing ataxia within the next year of their life, and usually between three to five years of age, they start going off legs.

So they become very unsteady and then stop walking independently, and then subsequent to that there is visual decline because of the involvement of the lipofuscin building up in the retina, and they then unfortunately become blind. And most of these children without treatment tend to die within the first decade of life. And you can see here the awful natural progression of this condition where there's a very narrow window of opportunity up here in terms of trying to get the diagnosis early because once the seizures start shortly after that developmental regression starts appearing, and you can see here that majority of the children are not walking, you know, independently by the age of five, and language, you know, becomes intelligible um by that age.

So very quick progression really within that couple of years, but you can See here when we go through the the presentation that there might be a potential window of opportunity if we can try and understand why it's important to pick up the diagnosis really early on. So in terms of treatment, of course this is a neurodegenerative condition progressive and there is no curative therapies available right now in neurodegenerative and neurometabolic conditions.

Normally when cells have been damaged you can't repair them and therefore the only thing you can do is to see if you can slow down the progression. And cerliponase alfa which has been licensed in many places in the world which is recombinant TPP1 enzyme replacement has been given as intraventricular fortnightly treatment to slow down the progression of the disease.

And children who receive this, you'll see some examples of cases are children who have a much more attenuated form of progression, and it tends to improve the quality of life of these children from a family's perspective as well. So, in terms of when you should be thinking about CLN2 specifically, is that there are some caveats here and it's really important to think about them in combination.

So we know that speech delay is very common, and you wouldn't be testing any child with speech delay on its own for CLN2 because that's a very common problem in pediatrics. But if you see someone presenting with speech delay and they then have seizures which are not febrile in nature, that could be an early indication that that combination tells you that this could be CLN2.

And the ones in our cohort who have been picked up the earliest have been with this exact combination where they have had speech delay present with seizures and they've had testing and a diagnosis done right at the top of that curve before they start declining. Another important thing is to see if you see myoclonic jerks in young childhood; that is always an indicator of possible neuro metabolic or neuro genetic Conditions and we would always think about testing for CLN2 amongst other conditions.

Of course, if there's a family history in an older sibling or previous sibling who has passed away, you'd always want to test that because we could pick up a pre-symptomatic sibling. And of course, this would be the last cohort which ideally wouldn't be the ones that you want to be thinking of because it might be too late.

Really many of them, but if they start losing skills, so this is when they're starting to fall off their trajectory. test to important really It's them very quickly. But anyone who stagnates with their development or starts regressing should be tested for CLN2. And a little bit about our patients who first started on treatment. So this is going back to almost five and a half years ago, and you can see that the first sibling here is almost a characteristic picture of someone with an average age of diagnosis between four to five years of age when they start losing skills.

So a child who already had refractory seizures, very difficult to control. Tried even the ketogenic diet; still having ongoing different types of seizures. He did have pre-existing speech delay and started to lose skills. And initially had an epilepsy gene panel, but this is back before there was whole genome and whole exome sequencing, which came a year and a half later.

So the TPP1 gene was not on the panel, and the diagnosis was not picked up. And the second sibling, who was younger, then started at the age of three um to have um apart from speech delay also focal epilepsy. So she underwent a whole genome sequencing, which confirmed the TPP1 mutation, and then that was diagnosed on the older sibling.

So you can see here already: this first sibling was diagnosed at four and a half years of age. Second sibling was diagnosed just after her third birthday. So we can imagine that their trajectories be would different. And when we started the service, where they were both seen with us, they were both actually independently walking. The boy had a bit more ataxia than the girl, but we knew that she was much earlier on in her disease trajectory compared to her brother.

So we had a multidisciplinary team review with myself, the metabolic team, neurosurgeons because this needs to be an intraventricular device as I mentioned, and obviously the psychology team to obviously counsel the family who have received the diagnosis suddenly of both their children at the same time. And we had to insert the device quite quickly and start infusion really within a few weeks.

And what we have seen is what you would expect really that the older sibling has slowly declined over time, and the younger sibling is doing much better. So still ambulant, able to walk independently, able to climb and do things now five half a and years down the line at the age of It while the boy who is turning ten has sort of lost some mobility now, is less ambulant.

But at a much later stage than you would expect compared to natural history. And we then realized that you know it was really important for us to have a whole team of people looking after these children because it can't be done by one person. So apart from the neuro metabolic team, which is myself and the metabolic consultants, it was really important to engage our neurosurgeons, especially if there are any issues with the device where you're accessing every two weeks to provide infusion.

The Surgical and Nursing Team

So the neurosurgeons are there to insert the device and troubleshoot really but the infusions are done by our specialists nurses who access the device using a needle and then the infusion runs over four hours every two weeks. And then they just monitor so the specialist nurses are needing a lot of this, our psychology team to help  support the family.

This is still a progressive disease you cannot alter the outcome or you may be able to slow down progression so it is very important to have our team of psychologists supporting the families. And because there is slow progression, but the progression is still there, it is important to have our team of physio-occupational therapists help to manage the tone, dietitian, and language-speech therapists.And we realize very quickly that these patients were traveling to Manchester and all over the region on our peak we had 19 patients on enzyme replacement therapy coming from all over the England we were seeing them every two weeks.

So we felt that we ended up knowing the patients and their families much better and the local teams would not be able to see and build that relationship with the family as easily as us. So at that point we thought that we needed to make things better for families who were traveling to us every two weeks, coming for enzyme replacement.

So we realized that we needed to be a little bit more involved, you cannot just be providing the enzyme and then sending them home and leaving all the other issues to be dealt locally because we had a lot of expertise with this condition, we see all of them together in our clinics and we realized that we needed to try and see them more regularly.

So all patients now are seen in a one stop clinic where they have the pediatric neurologist, metabolic consultant, specialist nurses, psychologist, and the therapists to try and answer all the questions in a one stop clinic. And the families found that really helpful because they get all their questions answered as much as we can and we still involve the local team.

So we have sometimes multidisciplinary team meetings including the local team to try to engage them especially when things become very challenging, because the patient is declining in the local area and we are seeing them a lot and we notice it and ask the local teams to escalate support. And it is very important because a lot of them come with complex neurological problems, epilespy, dystonia, spasticity, can be quite challenging to manage sometimes and it is important to have specialists involved for that reason.

And one of the most important things is when the first shock at giving the diagnosis is done because it is very important that the correct people are there and being able to possibly access treatment depending on where you are, where you work and access to cerliponase alfa, you want to make sure that you engage with a specialist first so the diagnosis can be given together with information about access to treatment that is available.

So the team should be there. It should be a specialist team who will give the diagnosis to the family, help answer all the questions that are not possible everywhere in the world, so sometimes a pediatrician or a neurologist will need to provide the basic diagnosis and information to the family and then assign them to a specialist center.

But it is always helpful before you speak to a family to find out is there access to treatment and maybe contact a specialist center and see if there is a possibility for your patient to access treatment, are they eligible, are they not? And what is the means of going through this? Because it helps the family journey when you have already got that information when you speak to them for the first time.

And you know, I think this is for all diseases. Really, it's really important to make sure that you know families remember that first diagnosis. And some people tell us exactly what they remember from that first experience, good and bad, and they tell us if they remembered someone having to look at their phone just because a text message came through; it could be something important work related.

But when they looked at their phone, family sort of felt that it was disengaged, um, and the consultation didn't go as well as they wanted. And really important for the family to be able to debrief afterwards after a difficult diagnosis. How we do it here? I um, we always make sure there's a list of questions from the family.

Sometimes families coming to us even before they get a diagnosis may have questions, and sometimes they notice their child declining or having lots of seizures, and many of them are worried, you know, about death, and they might be actually thinking about that but scared to ask that. So if you have a list of questions from the family, you

roughly know what kind of things they are thinking about when you are going to your consultation. We try to give them very basic information about the condition and then really about access to treatment that is suitable for their child or that is available for their child and what it means. Because it is very important to set expectations so that families understand that this is not going to the condition but if they are eligible for treatment it may help prolong the time before this.

The supportive therapies are probably more important because if you are just looking up ERT and you are not looking up the disease they can become very challenging to manage. The long- term outlook is very important to outline from the start so families do not get false expectations about what to expect down the line. And I always find it really helpful after having that intense consultation with the family it sometimes could help to have some is becoming slower, it is very important that the speech and language therapist assesses the swallow.

Because this is probably one of the hardest things to pick up, and sometimes families may not notice it as much, and they start choking, but they are thinking that it is because they are eating too quickly, and may dismiss it. And it is important because there are patients that their swallowing becomes weak and there may be check infection and it could become quite serious pneumonia.

So being very vigilant and watching their speech and if the speech is slowing down, making sure that the speech and language therapist are assessing the swallow and doing it regularly. The visual decline can happen. In terms of the patient cohorts, they are actually quite different. So the ones on the bottom here are the patients not on ERT whicih we don't see as much here because they are not here every two weeks.

So they tend to decline like that between 3- 5 and then slowly continue to get worse. The patients on ERT however, are quite different because they have a modified disease course even if they come off treatment. They have been on ERT for two years and they come off treatment they progress more slowly. And they tend to a more complex movement disorder than the patients not on ERT.

So other than having seizures and dystonia they also develop a movement disorder which can be managed with medications and the progression may be very different from the expected. So other than having what is known as a linear decline, we see on patients not on ERT, you may sort of see them fluctuate up and down when they may sometimes lose some skills, and they gain them back.

I mean some of them overall if you watch the years when they gain the skills and overtime they go down and come back up and overall decline at a slower rate. And that is quite unique with the patients on ERT to see this flunctuating cohort. And it is really important when looking at the patient to look for something really reversible.

So I am going to give you some examples about some of our cases, what we learned from the patients that have been quite complex. So this was a patient with known CLN2 who was not on enzyme replacement. So we know already from what I've told you that they are going to have a very classical trajectory. The patient is now bed- bound, having increasing seizures, a lot of stiffness, and needing a lot of medications, and is quite drowsy.

So at this stage, you can be quite confident that this child is actually entering their terminal phase of illness because you know that. They've lost their mobility. They're now not just bed bound, but having a lot of move comorbidities, and they're quite sleepy. And you know they will be starting to suffer. And it's really important to think about best interests.

So we started to approach this with the family and offered a second appointment after two weeks. And the family rightly agreed to reorientate care so rather than having active hospital admissions, we tried to keep them at home. Got our palliative care team involved to look after end of life with the community teams in the UK. They can have access to the hospices as well.

And together with that, they started on subcutaneous infusions of midazolam and morphine to keep them comfortable. And the child passed away comfortably in the hospice. I think that's really important to recognise end of life in a patient not on treatment and keep them comfortable because that is the key. Because there is no treatment for some patients who are already too far advanced.

And the main thing would be to have that. Markers of progression, like I talked about, but also knowing how to support them towards the end of life. But sometimes things go wrong because you have to remember that these are complex patients, and although they have specialist care, if they're unwell, they may end up going to their local hospital.

And this is a very rare condition, and many people may not have seen CLN2 disease, and may have said something to the family which may not make sense to the family, or they may not recognise, for example, that the patient may deteriorate and then come back up when they are on treatment. They may think that this patient is CLN2, and from their recollection of CLN2 patients, the natural history is that when they decline, they continue declining.

So if they see a patient with ERT who's declined, they think that it's end of life, and then the family have a conflict, and we need to think about what we can do to make that better.

Multidisciplinary Team Meetings

And usually, the best thing to do is to involve them in a multidisciplinarity meeting first of all with the local team, all the important people looking after the child in the tertiary specialist hospital as well as the hospital that the patient is. Form if that's a different state or different country, depending on where they're accessing treatment. And then you invite the family into the meeting as well, explain what has gone on and try and resolve that conflict.

I think that's really important so that families understand that you know for rare diseases we need to work together to try and work with the family to try and provide a solution. The service we offer now is much more robust. You know we see the patients much more regularly. We try and manage the complications and comorbidities, and we then try and make sure we communicate with the patient clinicians, which could be in another part of the UK because these patients are travelling to Manchester for treatment.

And then I'm just going to talk about three cases where it's really important to think about the comorbidities, especially when they are on treatment. So this first patient on ERT was quite complex. They will have ERT for a while and They were having quite difficult dystonia. They were on six different medications to try and manage the dystonia, quite sleepy, um, and the team were even thinking at one point of considering deep brain stimulation.

You know which, of course, is quite a big thing to think about for someone with Batten disease. But because they were on treatment, everyone was quite perplexed why the dystonia was so challenging. Um, and this child was about uh seven years old to eight years old at that point time. in The child unfortunately had a little fall and had a fracture of the femur and came into hospital.

And at that point, the dystonia became much worse as the child was on infusions, and we realized at that point that the child was posturing especially after feeds were given, and we wondered whether that could be reflux. And you know that such a simple thing which a lot of children who are not mobilizing suffer from. So some anti-reflux was introduced, and suddenly the child improved dramatically, and Four of the anti dystonics managed to be weaned off, and the child got very good control of dystonia with good quality of life.

And I think the learning point was there that the child had declined with dystonia a lot of movement disorder, but actually the cause of it of the dystonia was actually the reflux, and treating the reflux was the most important thing because the child then improved and had good quality of life for many more years and continues you know to manage uh to with the dystonia quite well at the moment.

The second patient is someone else again. So this patient was on ERT and started to be tube fed with mobility every time they started to get an illness, and we realized that they were not gaining weight; they were quite small. They were not eating as much, and every time they got unwell, they were not eating, and then they became a little bit stiffer, lost a little bit of skills, and then over two to three months.

Started to slowly recover a little bit, so they're declining and then slowly recovering after hospital admission. And we see this with a lot of neurometabolic conditions where intercurrent illnesses may make them decline a little bit, but the patients on treatment may start slowly improving again. So we had discussions with the family and said although they were overly eating and the patient was able to eat when they got illnesses, they just had no appetite.

So we felt that the gastrostomy would help to boost the nutrition, and as soon as we did that, we realized that with the intercurrent illnesses, we could give a lot more calories, and the patient was not deteriorating. So it had very small deterioration, and within a few weeks started improving again. So a small little step, not related to the condition, it was mainly about nutrition that we did, which managed to alter the outcome.

And then this is a third patient again with comorbidity. So, patient on ERT, six years old, starting to have increasing myoclonic jerks and then became very sleepy. He was not really every time he went to school; they noticed he was just drooling and lying there. And we did an EEG and realized that he was having plenty of seizures going in and out of non-convulsive status.

Um, so we introduced more antiseizure medications to help with the jerks, and suddenly he woke up and started a to be lot better. In the past, if these patients were not on ERT, many people would not be so aggressive with seizure management and would think that this is heading towards end of life. But I think with the patients in ERT, we are a lot more aggressive because we realize that there is a lot of reversibility in these patients because they're getting ERT and not dropping down as quickly as the patients who are untreated.

So it's really important to always look for reversible things. And also be vigilant that overall, if the child is deteriorating, there may come a time where you may need to have to talk to the family about end of life. But it's not as straightforward as that with the patients on treatment because they do have a lot of reversibility in many of them.

So in terms of the approach I have when I think about a patient with CLN2 and you're thinking about managing comorbidities, the first question is: Is the patient on ERT? Because if they are, you should always think about a reversible cause for decline, and that could be simple things like hip dislocations, chest infections, urinary tract infections, um, and other things like reflux management of the epilepsy and dystonia.

Can you optimize things? And are they sleepy because of many seizures or the or sleepy because of side effects of medications? And trying to tweak that balance to try and look after the child and see if you can get improvement. Because in the majority of them, you will see some improvement when they're on treatment. And then it's that important thing to think about when they are declining, and you've done everything to look at reversible causes.

You need to think: could this be real decline that I need to actually take quite seriously and discuss with the family? And this is when we really make sure the palliative care teams are involved, start planning with the families about end of life, although they're not going to die imminently, but even years in advance to make sure that if the child is declining, going off legs, and starting to become bedbound, that's really important to think about that.

And of course, you need to think about what the patient's current quality of life is because they are all very different. And the honest thing is that where they started treatment, it really impacts their final outcome, which I'll summarise later on. And you want to know: are the family aware that you know that the child is changing, and are they up to date with everything we are doing?

Because importance of keeping family up to date cannot be stressed enough. Because if they are unaware about what is happening and they think that the child is just going to bounce back every single time, that may not be true. And if you think the child is slowly declining, you have to be open and honest with the family.

I think what we've learned really is that you know the early diagnosis does make a difference. The patients who have started treatment either pre-symptomatically because of an older sibling or very early on because of seizures are doing really well. And of course, we know that the earlier we diagnose them, the better the outcomes are. So really thinking about the the things where I mentioned earlier about when to think of testing is really important because you can do chemical testing and get the diagnosis really early.

You have only one shot at explaining the diagnosis, and I think that is really important before you explore before you explain the diagnosis to explore where the treatment is available and if that is appropriate for that family before you speak to the family. And the multidisciplinary team is only a text away. So when you're finding things complicated, always ask others, the specialists, nurses, the therapists, other people who know the family, what are the main challenges and how you can overcome them?

And always listen to the families because sometimes there is no quick fix, and you need to spend a lot of time waiting to see if the child is going on ERT, is going to slowly recover again over some time. And I think this is what we're trying to change: getting the diagnosis a little bit early, because the patients we have in our cohort who have been diagnosed here are doing much better than the patients who've been diagnosed just here.

So although it looks like this is not that far off, if you can diagnose a patient here with their first seizure and speech delay, with enzyme testing that you do testing the TPP one enzyme or rapid genetics that you can do in your country to get the diagnosis and think of CLN two. Then you may alter the trajectory because these children take a lot longer to decline compared to the children here who start ERT.

Because ERT does take time to work and gets takes time to get into the neurons and the cells to start working, so we're trying to push the average age of diagnosis to move more from between four and a half years of age to three years of age, so that we can try and think about the future. Of course, newborn screening, which is done in some countries, may help to change the future as well.

So a lot of these things are going in parallel: education events like this today, as well as newborn screening, may help change the trajectory of these patients in future.

Questions and Answers

And of course you know all this you can see it is a big team, for one condition there is a lot of people who need to be involved to try to think about how we can improve the quality of life for these patients and their families who are affected as well. And here is the team who work in Manchester, very thankful for all the help the families.

And I am very happy now to take some questions. So if you have a child you are worried about what is the single fastest test to request? So, depending on availability, you just need to check between these two things. So, in the UK the fastest test that you can do is the enzyme test which is available so the TPP1 enzyme can be done as an enzyme test.

However, the enzyme test might not be available in all countries. And the other thing you may have access to is rapid genetics. So if you have access to rapid genetics and epilepsy panel, in almost all countries they will be able to turn around things in a few weeks. So if you have a rapid and an epilepsy panel and you have someone presenting with speech delays and seizures and you are thinking about CLN2.

So the next question is when siblings are diagnosed together how do you manage the family? And I think that is very good question because that is extremely challenging and is a big shock to the family because they were hunting for diagnosis in the older child which was not found and then the younger child uncovered the diagnosis of the older child who was much more symptomatic.

And I think it is very important to be open and honest with the family. But you are completely right to ask because actually coming from the first question, if the enzyme testing was done on the first child, we would have picked up the diagnosis. But it was not thought of. So genetics was done. Enzyme testing was not thought of, and the diagnosis was not picked up until a year and a half later, and that was challenging.

But we were open and honest with the family about how rare the condition was, and also it was really important to get our psychologists involved right at the start. And I think when you have families where children are different trajectories, having clinical psychology input is really helpful because sometimes the families just need to speak to someone else about their journey and how stressful it is.

But also when they come, if for example you may have a family where one child is eligible for treatment and one is not, in this case I gave you both on treatment. But we've had some children where one is much more advanced and has come off treatment, and the younger child is still on treatment and doing well.

And managing that with the family is very challenging, but it's really important. I guess every single time you see them, to talk about the markers of protracted progression both in children.

And explain again that you know the disease trajectory might be very different in both children, even if they are on treatment because one has been picked up later along the curve. I sometimes find it very helpful to show the family that that exact curve I showed you. I sometimes print that out and show family when I first explain the diagnosis to say this is where we are on the curve and that I'm a bit more worried that even you know with treatment that sometimes we see this kind of decline.

Um, but at a slower trajectory, and I try and draw a slower line beyond you on, earlier up picked they're when And try that. and draw an imaginary line. And this is just your experience of saying that you know the earlier their diagnose, the slower you expect them to decline. But every single child is different, and it's very variable with how they decline.

But I think clinical psychology, the specialists, nurses, everyone are really important for this uh kind of uh support for that family which struggle with these uh important things of having two children. And we have a number of families like that. So the first thing, the the next question is about the case I showed move from referral to first infusion in about a month.

And the main things: what can I do at the referral stage to help things very quickly? So I think that was one of the real important points I mentioned earlier on.

Is sometimes it's really important to make sure you have all information before you even speak to the family. And I know it sounds like you the get diagnosis, let's say um you know on in your email from the genetics laboratory and you feel that you need to share that with the family immediately. But in this rare diagnosis, I don't think that is probably the best thing.

The best thing to do would be to gather information quite swiftly, not over weeks and months, but you want to try and immediately know which is your nearest center, which is offering treatment, is that suitable for this child, and where can I access this? So depending on where you are, you might this might be crossing borders. You may be speaking to another centre, another country. You may be speaking to the company to try and see whether you can access the treatment and where is the nearest area.

So you want to first of all gather that information quickly, and ideally you want to do that before you speak to the family because it is really tricky if you speak to the family and say right the next step is for us to find out whether your child is eligible for treatment and we can access that because the family have already heard something very stressful a diagnosis where it's life changing and that without treatment they are going to die in the id normally in the first decade of life so that is a lot to process and when you say that there might be possible treatment but I don't know whether we can access it or not that become it becomes added stress so sometimes already trying to discuss the case with a treatment centre and seeing how far advanced the child is or if the child is early stages is that something possible?

And yes, they may not be eligible Until they go for an assessment, but at least you can tell the family that we've already explored it with a treatment center and they can go and get an opinion. And that would mean that the treatment center is already aware of a child. So in this case, for example, we were made aware of this child.

So before we saw the siblings, we told the pediatrician saying, "Before you speak to them, just give us some time to see whether this is possible for us to facilitate." So we spoke to our neurosurgeons, try and spoke spoke to the company, try and got everything in line within a week or two, and said right, we can do this.

Then the pediatrician spoke to the family and said that you know we've got the results back. This is what it is. You need to go to the treatment center to make sure they can assess eligibility. They came to us within 48 hours. We assessed everything and moved things quickly, but the reason is because we did some background work in one or two weeks.

So I think that one or two weeks before speaking the to the family is important so that you can ascertain are they eligible? Where can they go to for treatment? How quickly can we get treatment? And I think that helps to move things quickly rather than the delay. So not really, I'm not trying to promote a delay in speaking to the family, but I'm trying to say that in rare diseases, it's really important that the correct people give correct information to the family, and sometimes that means that you hold on to that genetic report and speak to people first about it before speaking to the family, because when you share it with the family before the treatment center, you may end up spiraling the family downwards, and they may be expecting something going not they're to get. So hopefully that makes sense.

Okay, and then the final question: After diagnosis, you mentioned that the families come back to us, and what's the most useful thing a general pediatrician can keep an eye on between their specialist review? And I think you know this is really important because I talked about how they come and see specialists, you know, teams very regularly. Although they may not see me as a neurologist every two weeks, but they see the specialist nurses every two weeks who keep an eye.

And I think an open communication between the pediatricians and our team is really important. Sometimes families share things with pediatricians locally which they don't share with us because they may feel that they're coming to see us very regularly. And sometimes I have to say we may not recognize some kind of subtle kind of decline because we see them so often.

So we may see them going up and down or so. But when the pediatrician sees them after six months, they notice that actually they're not actually how they were six months ago. So I think the best thing is really that markers of progression I talked about, making sure that school, you know, are reporting back if there's anything.

So many community pediatricians may hear back or even do reviews in school and may notice with school that things are changing. That families may find that they are okay at home, but a lot of these children spend most of their time in school. So they're going into school from nine o'clock to three o'clock or four o'clock. By the time they come home, it's five o'clock.

Families feed them and then put them into bed and don't notice a lot of how sleepy or engaged they are. But school may feedback to the pediatrician, or the pediatrician may do a clinic in school and realize that. So I think the most important thing is keeping an open communication. If medications are being changed, it has to be two ways.

I realized, but when I initially started making changes in medications, that I may see them on a Monday, and the general pediatrician may see them on a Thursday. And we may not know that we've made made changes. So we realize that that email communication with these patients being seen so often is really important because our letters may not go out to each other until a week or two later.

So normally, if I make changes to a patient where I know a pediatrician is going to see them, or the family tell me they're going to see a pediatrician in a few days, we would normally email the pediatrician and just keep them up to date. And likewise, the pediatricians normally tend email to us and keep us up to date.

Um, and I think working together is really important. We're actually supporting the pediatric team locally in end-of-life stages. So I think it's really important to know that leadership in these patients may change over time for that same patient, based on where they are and when they are coming so often to us. We tend to take leadership, and I think pediatricians find that very helpful.

But again, when they start becoming more community-based, we try and empower the pediatricians to take their leadership with us, supporting you know heavily as much as we can with our expertise, but making sure that what can be done locally is offered, especially towards end of life.

So just to mention, you know, there's lots of information here from uh the company about uh the product as well, and as I mentioned, that you know it's really important to check if this is available and accessible sometimes before the diagnosis is provided to the family to make it easier um for the family journey. And I'm going to wrap up this webinar and thank you all for your time in terms of attending this. And hopefully, you have found this helpful. And as I mentioned, the recording will be available on the website as well.

Thank you all for your time.

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