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[00:00:07] Prof Erik Eklund: Welcome, everybody, to this IEP webinar on Newborn Screening and Sibling Testing in Metachromatic Leukodystrophy, or MLD. My name is Erik Eklund, and I'm a pediatric neurologist in Lund in southern Sweden, and I'm lead of the Qualified Treatment Center using gene therapy in MLD, and I will be moderating this exciting seminar today. There are some housekeeping rules that we should mention before we start. First of all, please do not take any screenshots, and there will be plenty of time for questions after the three talks that will follow. So we will come back to that later on in this webinar. So, I would first like my co- presenters to introduce themselves, so I hand over to Ally.
[00:01:09] Mrs Ally Wallace: Hello, everyone. I'm Ally Wallace. I'm the mom of Nala and Teddy Shaw, so I'm going to have a little pre- recorded video just with our journey of the disease so far, and, yeah, I will answer any questions that you might have at the end.
[00:01:25] Prof Erik Eklund: Great. Thank you. And Andreas?
[00:01:27] Dr Andreas Oberg: Yeah. Hi. My name is Andreas Oberg. I work at Oslo Eriks Hospital at Oslo University Hospital. I work both clinically with the metabolic inborn areas of metabolism, and I also work at the centralized newborn screening unit in Oslo.
[00:01:52] Prof Erik Eklund: Great. So we will start out. This webinar will be in three parts. First, we will hear Ally talk about her experience being a mom of two beautiful children with MLD, and then I will introduce shortly why screening is good and how it's done, and then Andreas will talk about the Norwegian experience, since Norway is the first country in the world actually screening for this condition. So, please, if we can have Ally's video start first.
[00:03:40] Mrs Ally Wallace: and to wait until she was walking. Nala took her first steps at 16 months old, which was a little later than usual, but all told no different was what I thought. Her foot still bothered me when she started toddling about as she would hold it on its side and almost drag it slightly, so back to the doctors I went. This time I was reassured she grew out of it, but as the weeks went by I still didn't feel it was normal and kept going back and forth to the doctors until eventually they referred her to a physiotherapist. Nala was seen a couple of times by the physios, who again felt she would grow out of her problems and discharged her. A couple of months after the first discharge from the physio, we moved back to my hometown, so I registered Nala with our local doctors and made an appointment straight away. She was again referred to a physio, a different one this time, so I had some hope. This physio agreed there were some issues with Nala's foot and how she walked, and she saw her monthly for a while to keep an eye on her. eye on things. However, not long after, she also discharged her. Around a month after Nala's second birthday, she began to fall over a lot. It seemed she was starting to lose her balance and her legs also seemed to be getting stiff. She was struggling more with her walking. And by December that year, Nala had started to develop a tremor in her arms and hands and would stare into space, unable to come out of it. After googling symptoms, I was convinced Nala had a brain tumour. We were sent back to physio, who were shocked at how much Nala had progressed with her walking, and she admitted she should never have been discharged. She also arranged for some x- rays, which showed Nala may have a slight hip dysplasia, and from there she was referred to an orthopaedic. A few weeks later, in January 2022, Nala attended this appointment, where within minutes the doctor said there was nothing wrong with Nala's bones, and he was more concerned this was a neurological issue. He suggested Nala see a paediatrician as quick as possible. It took me weeks of relentless phone calls to the local paediatrician secretary to try and get an appointment, and I was met with such rude and belittling responses. Finally, near the end of February, Nala was seen. As we sat down, the doctor asked me to tell them what I thought was wrong with Nala. I was dumbfounded at this question, as surely it was their job and they could see from Nala's records just how long these issues had been going on. I expressed I was very concerned she had a brain tumour, but that was pushed aside, as the doctor said she was too bright to have a tumour, and thought it was more likely cerebral palsy. I totally disagreed with this, as I believed that would have been picked up much earlier. We were sent away and told an MRI would be arranged. By this point, Nala could no longer walk more than 7 to 8 steps without falling over, and her limbs were extremely stiff. We tried everything to encourage Nala to keep walking in the following weeks, seeing the fear in her eyes as she knew she'd fall over was heartbreaking. Her arms and legs became more and more stiff, and the tremors happened daily. She was given a walking aid by physio in March 2022, but it was far too late for this. Nala was clearly in too much pain trying to walk, and just cried when we tried to help her use it. By April, we still had no news of an MRI, despite my constant phone calls chasing this up. One night, I watched Nala get herself off the sofa with completely straight legs. She couldn't bend them at all, and I had to help her walk along the corridor to bed by holding both hands behind her. That night, she screamed and screamed in her bed. Her whole body was tremoring, and her temperature went sky high. I decided it was time to call an ambulance, as I felt this might make me be taken more seriously. Once we were at hospital, I demanded an MRI. Neurodoctors rushed to see Nala straight away and agreed with me. They also believed she had a brain tumour. She was rushed for an emergency MRI, and just 45 minutes later was when everything changed. They told me Nala didn't have a brain tumour. However, a brain disorder, algodystrophy, was found, and more tests would need to be done to determine which type. The next few days were a blur, as we found out Nala had MLD, and due to it being found too late, she was now terminally ill and would go on to lose all of her functions and die in childhood. She was just two and a half years old. The whole process was staggering. This had gone on for two years, and I never once felt supported or listened to. I felt I was constantly shrugged off and treated like a neurotic first- time mother. I felt so angry, and I felt like I had lost all trust in medical professionals. My daughter could have had a chance of life if a simple test had just been done before it was too late. I can't stress how much a different attitude from most of the doctors would have had. To be spoken to and listened to with empathy and care, and made to feel like some urgency for my child's health would have gone a long way. I was a terrified mum who had a feeling time was running out, and the manner in which most of my phone calls and worries were dealt with was upsetting, causing more agitation on top of an already scary time. A few days after Nala's initial diagnosis, while she was still in hospital, the news broke that MLD was genetic, and therefore our younger daughter would also need to be brought in for testing. Teddy was 10 months old at this time. The day after that conversation, she was brought in for blood testing, which me and the girl's dad also had. Then we waited the news. A week later, I received a phone call asking me to go back to hospital for a meeting with the team, and I was told to bring someone with me, so I knew immediately that it was some bad news. I drove to the hospital in silence, feeling like I couldn't breathe. Total fear had taken over. We were sat down, and it was broken to us that Teddy also had MLD. However, because it had been caught quick before the symptoms started, there was chance of treatment, and a video call to the team at Manchester's Children's Hospital was arranged there and then. In that appointment, the effects of MLD were explained to us more in depth, and the reality of Nala's future hit me like a ton of bricks, and I could no longer hold back the tears. After speaking to the team at Manchester, we were relieved to find that Teddy's treatment would begin within weeks and give her a chance at life. It was bittersweet. One daughter could be saved while the other would die, and this could have been prevented if I had been taken more seriously in those many initial appointments. Simon Jones, Dipak and their team were amazing. They spoke to us with such empathy and care and we could genuinely tell that saving children's lives meant so much to them. We felt heard. I think a lot of medical professionals could do with taking a leaf out of their book when dealing with parents going through times like this. From the very beginning, they were so supportive. They kept us informed about everything going on and also extended their care to Nala. We have relied on them for both the girls since that first phone call in 2022 and we still have a brilliant relationship with them all now. And I know they're always a phone call or email away between appointments. I cannot stress enough how much newborn screening is needed for MLD. It is simply one of the most devastating, heartbreaking and cruel diseases that strips away everything from children and adults and leaves them with no future other than death. Leaving families in utter grief for the rest of their lives, no parent should ever have to bury their children. There is now treatment available for MLD. It makes absolutely no sense to keep it from the blood spot test. No price can be put on a child's life. Here in the UK, we only test for nine conditions on newborn screening test, which is simply not good enough and quite frankly, disgusting. I have been on this journey for over three years now. And while it's extremely difficult physically, mentally and emotionally, I have learned to be the best advocate for my children. I have studied the disease to give myself the best chance at knowing how to deal with Nala's needs and care and to try and balance that with keeping Teddy engaged and thriving. She's had to go through and overcome so much for such a small person. And luckily she is so full of life. The treatment she received really has saved her. While Nala is now blind, fed through a peg in her stomach, has epilepsy, can't move her own body and is on several medications multiple times a day just to keep her comfortable, we still try to give her the best life. We take her on holidays abroad, which is not easy, but totally worth it. We give her as many experiences as we can and we shower her in love every day. We try to remain as positive, fun and as happy as possible to get us through. And without this attitude, we'd struggle. Seeing Nala still smile means everything to us and we will do everything in our power to make that happen for as long as possible. To all other families going through this, I encourage you to try and stay strong and keep fighting and find the joy in the small things. Thank you all for listening to our story and I'll be joining back later if anybody has any questions. Thank you and goodbye for now.
[00:12:26] Prof Erik Eklund: Thank you so much, Ally, for this very emotionally strong presentation. This is what makes us all wanna work for this so hard. So thank you so much. We will now move on to my presentation, the why and how of MLD screening. The why, I think Ally already at least partially touched on that no child or no family should ever go through this journey again and that there are good ways of preventing it. So I will move here. So as you know, of course, metachromatic leukodystrophy is, as Ally said, a leukodystrophy, a disorder that affects mainly the white substance of the brain causing degeneration. It's a progressive neurological disorder where at least children with the earlier forms always die from this disorder and it has different speed but it ultimately takes their lives in a horrible way. So this is a great disorder to study if you can make a change because the costs of having this disease is so immense. In short, there is, at least in a European context, about one to three MLD patients born per 100, 000 births. So in a country the size of Sweden with about 10 million people and 100, 000 births per year, we expect to find somewhere between two and three children every year with this disorder. It results from pathogenic biallelic variants in the ARSA gene, which encodes an enzyme called aryl sulfatase A. And this enzyme is involved in the breakdown of a molecule called sulfatide or a group of molecules called sulfatides, which are very prevalent in myelin- producing cells. So the main symptom is obviously having dysfunction in these cell types, which causes neurodegeneration. But you also get problems in the liver, the bile ways, the kidneys, and so forth. So it's not only a brain disorder. The demyelinization occurs because you get this accumulation in the myelin. As I said, this is a progressive and fatal disorder in most forms, if not treated. The four types are arbitrarily divided and it's based on the age when the child gets their first symptoms. So the earliest form is called late infantile or LI and that occurs before the age of two and a half years. The second earliest form is early juvenile which is between two and a half and up till seven years of age. Then we have late juvenile which is between seven and 16 years of age and the adult form which occurs symptomatically after 16 years of age. The disorder presents a bit differently depending on which age you get symptoms. In the earlier forms in LI and EJ we see mainly motor symptoms or a combination of motor and cognitive symptoms whereas the later forms often have their debut symptoms in form of cognitive or neurocognitive problems. So the initial symptoms are often different depending on which age they debut. You can also see it in this. This is from a very nice review spearheaded by Dr. Arang in Philadelphia which shows that as you can see motor symptoms are more common early and cognitive symptoms are more common later on in the disease. As a neurodegenerative disorder we have a phase you can see here with normal development. This is in Norwegian. I stole it from Andreas. So you have a phase of normal development. The disease of course is ongoing the whole time but you see no symptoms. And after some time you reach a plateau phase where you stop developing so you're stable. And then at some point you reach a rapidly progressive phase where you start losing a lot of functions. And then in the end you have a longer not so active phase with severe neurological damage. And of course every treatment we want to do we want to do during the normal development so that that can continue. So it's important to come in early with any treatment in this disorder. Before gene therapy the early forms were mainly treated by supportive treatment. Pain relief, spasticity relief, all these type of non-interventional therapies including psychologists for the family and so forth. But we could not treat the disease in the earlier forms. For a quite long time allogeneic human stem cell therapies have been used with sometimes good results, sometimes worse results. So it's not clear how good HSCT is in these forms but it seems quite clear going through most cases that the earlier you treat the better result. But they also come with more side effects than gene therapy. So why would you want to screen for MLD? If you're not being convinced yet I will try and convince you. So first of all eligibility for treatment. So what is the indication for gene therapy in MLD? The indication for gene therapy is pre-symptomatic, late infantile, and early juvenile. And early symptomatic, early juvenile. Which means that once you have symptoms in late infantile you are too late to be eligible for treatment. The reason for this is that there are no studies showing convincing results when you are symptomatic in the early forms. There are data showing that if you have early symptoms in the early juvenile form then you still have an effect of the treatment. So that's why you still have that indication. And, what we mean by early symptomatic in early juvenile is that you must have an IQ over 85, so your cognition cannot be more affected than that, and you must be walking without support, but the quality of walking can be reduced and the length of walking can be reduced. So, early symptomatic is still quite not very symptomatic. Timing is crucial in this disorder. That's why, up until we can start screening, few, if any, LI-MLD patients can be diagnosed clinically and still be eligible for treatment. So, as in the case Ally talks about, it's siblings to index cases with LI-MLD that can be treated, which causes these horrible situations with one treated child and one untreated child and how to manage that psychologically. Another reason to screen for MLD is effectiveness. A lot of people say, well, if you can treat early juvenile when they're symptomatic, why do you need to screen for it? So, in the studies that's been done, I'm coming back to this screen. As I said, if we can diagnose early, we can treat early and we have a chance of keeping the normal development. So, that's why we want to also find the later forms early. And if we look at the study results of gene therapy, these are patients in blue that have pre-symptomatic early juvenile MLD, and you see that after treatment in both language scales and performance scales, cognitively and in brain severity scores, you can see that they are doing great over a long time, whereas the natural history cohort is not doing good at all. But if we look at the cohort of early symptomatic early juveniles, they also do much better. As you can see, the blue lines compared to the natural history cohort that's untreated, but they do not do as well as the ones treated pre-symptomatically. So, there is also a reason to find these patients before symptoms. Timing is always crucial. Thus, the reason to screen for MLD is to find patients to make them eligible for treatment and also to allow for the best timing of treatment in the group that is eligible. What about later onset forms? Because when we screen, we might also find patients that are not eligible for the gene therapy that are only eligible for stem cell therapy in the normal way, but we have good data now coming out that the earlier you treat with stem cells, even if they're not genetically modified, the better results. So, we think that there is a good benefit of finding these forms as well early on. So, what is the context of MLD screening in Europe at the moment? As we said before, Norway has already implemented screening early 2025, and Andreas will tell his story shortly. Also, for a long time, Germany has had a very big screening pilot that, after some years, also included Austria. They have now screened over 200,000 children, and they have found, if I am correctly informed, at least seven patients, out of which I think six have been treated already. So, that is showing that screening works very well. And there are other pilots ongoing in France and Italy and in Sweden, in Denmark, and I think the Netherlands, there have been applications submitted to include MLD in the national screening programs. So, hopefully, for instance, Sweden will start screening next year if everything goes as planned. The screening pathway, how do we do this? Is it an easy screening? Andreas will tell you in depth, but it all comes, of course, from the PKU blood spots, and this is a three-tier screening process that will be used probably in most places. The first tier is looking for the sulfatide, the molecule that cannot be degraded when you miss ARSA, and if you have a high or increased amount of sulfatide, that means you're positive for the first-tier screen, and you move on to the second-tier screen, which will be measuring the enzyme, the ARSA enzyme. And if that is low or below the cutoff, that will move you on to the third-tier screen. In some places, this means that you will have to be recalled and get the patient in after the second step, but in the Norwegian one, for instance, Andreas will talk about that, the third-tier screening, the genetic screening, is also done in the blood spot. And if you find pathogenic or suspected pathogenic variants in the third-tier screen, then the patient is recalled for confirmatory diagnostics. This is a method that has been tested now for many years and it seems very good and superior to many other screening methods. And from a recent review by Dr logowitz in Tubingen, she has summarized evidence that supports newborn screening for MLD and it shows that there is good testing available. There is a standardized method for confirming the diagnosis. There is a population-based prospective study that shows that it works, especially the German pilot- and we know that if we identify the patient via MBS, this will result in better health outcomes compared to the standard clinical investigation. So there is a lot of evidence supporting that MBS for MLD is the right way to go. So now I will leave over to my colleague, Andreas Erberg in norway, who will tell the story about the nationwide newborn screening for MLD in norway. So welcome, Andreas.
[00:26:46] Dr Andreas Oberg: Thank you so much, Erik. I will pursue further on what you have said and thank you for inviting me to to tell a little bit about the implementation and performance of our nationwide screening for metachromatic leukodystrophy. A couple of the few slides here would be similar to Erik, but that's okay, I'm sorry. So this is the natural course of MLD and to understand why it's important to screen for MLD you need to know the natural history of the disease and the importance of newborn screening, and erik has gone through most of that and these are two important situations and the next slide. This slide is not only relevant to MLD but for many lysosomal diseases where new therapies are emerging or already available. For the vast majority of children with the lysosomal disease, the only chance of pre- symptomatic diagnosis if if they have an older sibling, as in Ally's case, but with new newborn screening, diagnosis can be made before symptoms, giving an opportunity to reduce or at best arrest further disease progression. And you can see this. We want to treat these children pre- symptomatically. Norway is a small country. We are six or seven millions, I don't remember the last numbers. We are not an aggressive screening, pushing the limits, but we are a bit astonished that we are at this place now, given the quite vast amount of knowledge about the newborn screening and the poor performance of the MLD in newborn screening. The next slide: let me see how Norway implemented nationwide MLD screening. The important thing with this parallel slide is to show that, in contradistinction to most screening systems where you have the long process of treatment approval and then start screening development, which is costly and you don't want to start that if the new therapy doesn't arrive through- actually through spinal muscle atrophy screening, which also were the first in the world, we learned that you have to have some kind of dialogue with the decision makers, the health authorities. So in 2022 we established a consensus that we should try in parallel to start the therapy approval process and start method development and try to see if, is this feasible? Can we find these children? Because it's difficult. It's pre- symptomatic children that you have to give the expense of the therapy- not a major problem, but to give the right children the right therapy. Right after 2022, we started method development based on 10 stored newborn brides plots. We have a national buy bank. From 2012 we have stored every newborn sample. A few exceptional parents have opted out, but there is a high confidence rate in the Norwegian newborn screening. We relocated 10 of the patient and started method development on that basis. I will show you the results afterwards. In 2023, the Norwegian government approved our cell or gene therapy Libmeldy and actually a month after the application was submitted. Then we have done every method we have used one year quite intensively to, and our message back to the government was that we can do this, based on the previous work of other people, and in 2025, in January, Norway become the became the first country to implement nationwide MLD newborn screening. There's there's a bit of a time lag and I'm impatient, so I'm sorry about that. Yeah, these are our 10 MLD. These are known newborns with with MLD. Why these are important is that we know that sulfatides in the newborn body after 2, 3, 4 days it increases, so it's important to know the reference ranges of MLD newborns, where they are, when they are two days old, where we take the samples in in Norway. So we were fortunate actually, through people like Ally in Norway, to go through their networks and recruit parents to consent to test their children, which were not, of course, to seek to be eligible for this treatment. The most important thing was with this slide is that we found out that we would be. We would detect 10 out of 10 patients eligible for pre- symptomatic treatement so that gave us the assurance that this is the way forward. We have to do this and this is. We then conducted a retrospective validation study to test the method, test RSI enzyme, to test sulfatides, and in the left side you see that we recruited about 2, 405 controls and maybe you can see my markers, the value in the y- axis in the multiple of the median, and there you can see complete separation between our 10 historical patients. And these controls were recruited from the HMAT cohort. So, there was no overlap. On the right side, you see on the Y- axis, R is the percentage of the mean. Here you see the distribution of the controls. And actually, this area should be zoomed in. I haven't got that slide, but there is the MLD patients at between 0 and 2. 7%, and the lowest control in this cohort was 13. So, no overlap in that case either. And I must stress to people that are not familiar with newborn screening to have two of these kind of tests that show no overlap between sick and control is very rare. I can think of one or two other screening conditions, and we screen for almost 40 conditions in Norway. So experience so far, we started in January, now it's December, we have screened, I think actually now it's 53, 000. Things have run, I must say, as expectedly because we invested a lot of energy into method development to predict how this would be going. Two important facts is no false positives. We have no false positives, and evenly, importantly, not evenly, but quite importantly is that we have no gray zone cases. There were no cases where we were wondering, is this an MLD or not? So so far, gray zone cases will probably come, but based on one- year experience, they probably will be rare. We had identified one through positive, which is marked in red dot, quite in the range of the MLD profile, completely different from the healthy controls. He was identified at six days of age. He was homozygous for a well- known MLD variant, so we were sure that he has had not only MLD, but the late infantile with a clear indication for treatment. And diagnostic workup confirmed our results, and the patient actually has received pre- symptomatic gene therapy, I believe this week. So not that important and probably too much detail, but to go over the basic facts, and this method is based on, on the bottom of the page, it's developed by other people, so we have emulated, and so it's not, it's other people that stands by this. We start with the sulfatides in the dried blood spots, and then our enzymatic activity, and then we do a whole genome sequencing in the filter cards. So before the parents know anything, we have assured that we find the genetic variants that fits. It gives us a bit more assurance when we call the parents out, that maybe hinder risk of false positives. That would be extremely low without, with places without access to genetics in the filter card, but it's an assuring thing to have. So for the facts, extremely high specificity in terms of what we are used to in newborn screening, and with this algorithm that we, we started out with a more research- based algorithm to recruit data, but we landed on this, and it's in line with the Baker et al. publication from 2024. So only 0. 01% proceed to second tier. In Norway, there are born 60, 000 children per year. Approximately 60 controls, or possible MLD, go from first- tier sulfatides to second- tier sulfatides in our context, in our context of our experience, extremely low number. We don't, of course, we can't say about the sensitivity because the disease, the children are developing symptoms when they are one, two, three, and so forth, but our algorithm would detect 50 out of 50 reported MLD in newborn cases that have been stored at different places around the world. They're all published. Importantly, the screening method is integrated in newborn screening, easily integrated. We have no running issues, easily integrated. We have hired one more person in our staff to do this. In our view, it's cost effective. We have estimated that about $ 1 extra per newborn to screen for this. In other labs, it may be more expensive. And I must say, it can be $ 2. We have just, for interest, looked into it. But low cost and very cost effective. I've talked about performance exceed most other conditions. And in our view, it's over ready for a global implementation. I have one last slide. Just post- screening pathway. I will quickly through this because Eric has outlined the major steps. But in Norway, we have a fast setup with sulfatides, ice activity, and genotyping. You don't have to have that. But the genetics is very integrated in our screening system. So we get all answers around one week of life or before. And in Norway, every MLD children is, the parents are called out by one of us very familiar with MLD. And actually, we are calling them Mondays or Tuesdays and admitting them to our hospital the day after. Norway is a very long country. If you turn it upside, you will get to Rome. So if they live far away, we will fly them in. It's so important that you get fast access to experienced people. And for many cases, for most cases, we already have the genetics. So then the eligibility would then be clear. So we can tell the parents quite fast that this is the plan. But in uncertain cases, and in all cases, because we want to follow them up, we re- admit them at two to three weeks of age. And then I see that my time is running up. So the rest of this pathway is probably well- known. So I am cut. I think you can go through it. I think you can go through it. OK, there we are. So there are, at this point, when the child is two to three weeks old, or at the admission point, if you have a genotype that we know are strongly associated with the late infantile or early juvenile MLD that we know are treatment- eligible for ARSA cell, we would immediately contact the nearest qualified treatment center, which in our case is Eriks Hospital, Skåne University Hospital in Lund, and start the process towards treatment. Approximately, I can talk a lot about this, but between five and eight kilos of weight, the newborn or infant, in this case, would be sent to Lund to do apheresis, and then actually go home. And after that, these cells are sent to Milano for gene editing, ex vivo modification of autologous stem cells. And approximately one to two months after the child has been in Lund, they will be readmitted there to get final treatment with the infusions of the gene-modified autologous stem cells. And after engraftment and stabilization, you are actually finished with the treatment, and then the families are coming to our hospital, at Eriks Hospital, and also University Hospital, for one day to plan further. And then we do, initially, half-year follow-up, and after then, yearly follow-up protocol-based, based on the existing European guidelines. So. Okay, I had some acknowledgements, but that's okay. This has been a team effort with many important people, including people at Skåne, and not to say the least, the MLD Initiative, which has been extremely important to getting this together for Norway's part. So thank you.
[00:45:58] Prof Erik Eklund: Thank you so much, Andreas, for this very nice presentation. And also, again, thank you, Ally, for your beautiful presentation. So now we have moved over to the panel discussion, and if you do have questions, please send them in via the chat function. But I think we can start out from the parents' and patients' perspective. So after hearing Andreas's talk, Ally, what do you think of the future, and how do you react to what has been said so far?
[00:46:34] Mrs Ally Wallace: Yeah, no, obviously, it's extremely positive. You know, if it's going ahead in certain countries, then it just hopefully means that eventually it will get accepted on the UK newborn screen, and I know that we tried not long ago, and it was rejected. But I think it just means that there's definitely more hope if other countries are going to go, that we'll follow suit eventually, hopefully sooner rather than later.
[00:47:07] Prof Erik Eklund: Yes, I agree. And I know that UK, for instance, will be looking at the newborn screenings that are actually both piloting, but also included in the normal screening procedures, and they will follow that, I guess, closely. So hopefully other countries can follow. We know that many countries are now setting up for this. So hopefully in a maybe five-year period, a big chunk of countries with access to treatment will also screen for this condition. I think it would be strange if you have access to a treatment and then don't find the patients. That is a very, very odd situation. So, also, Andreas, do you have any, how do you think this will affect how we, the risk when you start screening for something is that you forget the population that actually has symptomatic MLD. I know a lot of parents have been almost scared that, will scientists now start, stop looking for how to, in the best way, facilitate care for MLD patients with our symptomatic. So what's your thought on that? How can we continue helping that population of the MLD family? Because I think it's super important that even if we are very excited about a treatment that works, how can we continue and develop our help with afflicted MLD cases?
[00:48:48] Dr Andreas Oberg: I very much agree. And I, as a doctor, you have been involved in, you are accustomed to difficult situation. And I've talked to 10 of Ally's counterparts in Norway, which I didn't know I knew one of them before. And it was quite emotional for me too, because these were parents that were actively engaged in doing research and method development on their children. Most of them deceased to offer the opportunity for future parents with children of MLD to not experience what they have done. So it was like grief on the one side and hope for the other side. I really much agree with your question that it's really important to have a double focus, which maybe is a danger that you only focus on the future of MLD children, which will hopefully be a whole different story than what existed before.
[00:50:09] Prof Erik Eklund: Yes, I agree. So there is a question now, what is the critical age cutoff for effective LI- MLD treatment? And there is no... There is no set critical age. It is all based on on symptoms. So for LI-MLD, whatever age you have, you you can get treatment as long as there are no symptoms from from the brain. But of course we know that there were a few cases where you didn't have symptoms going into the process of making this product and that unfortunately developed symptoms under those months it took to prepare, to prepare the product, and then a patient actually risks of going from eligibility to non eligibility in the process. We will get away from that using screening, because now we we gained so many months then having siblings that had already. I don't remember, but Teddy was 10 months when she was diagnosed. Yeah, yeah, she was exactly one one year old when the treatment started, so, yeah, so of course it would have been preferable had she had the diagnosis from the beginning and then she could have been treated even earlier, even though this was lucky that she was found on time. So I think I think it is despite the fact that you can treat later on- we really want to treat as early as possible and that's why we have the five kilo lowest range. That's when it's technically possible to to get cells from a child at this time. Perhaps that can be moved even even quicker. And then there is a question, probably for Andreas mainly: what is the main source of false positives in the, this three-tier pathway, or will there be any false positives in this three-tier pathway, the know?
[00:52:25] Dr Andreas Oberg: The answer to that is quite detailed, but the main source of? I would not. I, I would, you should be careful with going bold with propositions. But I have a real difficulty seeing false positives with this three- tier algorithm, especially when you have genetics in the filter cards in as the in the dried blood spots. The main, the possible scenario where you can have a false positive with the out genetics. You can make that argument. If you have a lot of, you have some ARSA polymorphisms that we, many of us, carry around.
[00:53:13] Dr Andreas Oberg: But if you get those on one allele and you have are a healthy carrier on the other allele, then you can get quite low RSA enzyme values. But in theory you should not get high sulfatides. But we have encountered one of these at 5% ARSA enzyme, not MLD range sulfatides but a bit above the normal, like at the 99% value, but easily detectable through through genetics. So I would say the biggest would be a manual error, that there is some kind of handling the fact. I feel that the method is extremely solid.
[00:54:01] Prof Erik Eklund: Yeah, now there is a question: why is an IQ of above 85 a mandatory treatment inclusion criterion for early juvenile, which is a? It's a good question. It came out of the clinical or the the study done in Milan where they saw that patients with IQs lower than that they did worse in the treatment. It is problematic because, of course, there can be people with a static IQ that's lower than 85. The normal level, the normal range, is from 70, so you can have a normal range cognitive function less than 85, but but the reason they had this was that the patients they had probably had declined. So what we are looking for is cognitive decline and the hard line of 85 is difficult and this is something we usually discuss in the MLDI that Andreas mentioned, where we discuss cases. If we think that you have an IQ of 80, which is due to other causes- it could be another disease, it could be that you have parents that actually have some cognitive issues not related to MLD- then this This value might might be overlooked, but it is. It is difficult that we have this quite high level of IQ as a as a mandatory inclusion criterion, but the reason is we could see in the studies that patients below that were doing worse, but probably all those patients had lost IQ points, so they were in a degenerative phase. I think that's the reason. What do we think is the biggest policy challenge to national implementation in Europe? The biggest policy challenge- Andreas, Ally, you've been working against the UK authorities a bit- what do you think is the biggest challenge towards national implementation of newborn screening in Europe? You could speak okay.
[00:56:26] Mrs Ally Wallace: I would say I'm not an expert in this kind of thing, I am just a parent. I'm not massively, you know, intelligent, but I personally I find that it's mainly down to money and that's my thoughts on things and you know we have the NHS over here and- and I'm not sure if that is a lot to do with why the UK and keep going against it. I could be completely wrong, but after speaking to a lot of parents in the UK and with children, with MLD and other people within the MLD community that I know and I think we're all kind of on the same page that we feel it mainly comes down to the cost and the money and not wanting to pay for it to be put on newborn screening and therefore have to pay for treatment when it's found.
[00:57:16] Prof Erik Eklund: We we hope you're wrong, but but I cannot say you you're not. What is interesting is, yes, it's a very costly treatment, but it's a one-time treatment and it also lasts, at least hopefully, for many, many years. We now know, yeah, 15 years from treatment and still preserving functions.
[00:57:40] Mrs Ally Wallace: Yeah, this has been my argument a lot with if I, you know, if I did ever get to speak to someone from the government about it- is that yes, the treatment is expensive and things like that, but the cost that Nala is is taken from the NHS due to all of the medication she's on, which some of them are extreme, like diazepam, is extremely expensive. All of her and equipment to keep her comfortable and a disability vehicle- all of this stuff over a long period of time would probably end up costing more than the treatment and I think sometimes that kind of overlooked and but yeah, I agree with with what you're saying there.
[00:58:18] Prof Erik Eklund: And another thing I think is that we have to make policy people understand how good this screening method is because there is always- and that is as that, that should be part of it- there's always a skepticism towards both false positives and false negatives, but mainly false positives because that can be psychological problems, to call recall patients talking about this horrible disease and not being sure if they have it or not.
[00:58:51] Prof Erik Eklund: And also there is reluctance because some of the patients that will be screened will get their their symptoms much later on, and we are not sure about how effective the human stem cell therapy is, even though we think it's also very, very effective. So I think I think having policymakers understand how good this method is, I think is crucial to get it implemented. So I see that our time is running up. We have we have only 25 seconds left. So I would like to thank Ally and Andreas so much for joining us on this webinar, thanking the EIP staff for for giving us the opportunity to talk on this very important, important issue, and also for everyone listening, in that you show an interest in this severe and very, very important disorder. So thank you all so much.
[00:59:55] Mrs Ally Wallace: Thank you everyone.
[01:00:00] Dr Andreas Oberg: Yeah, thanks, thanks so much.