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[00:00:05] Dr Florian Lagler: Hello, and a very warm welcome to our today's webinar on Lessons from Germany and Austria's Successful MPS and alpha-mannosidosis Screening Initiative. My name is Florian Lagler, and I am a pediatrician specialized on the management of lysosomal storage diseases. I'm located here in Salzburg, Austria, and I'm heading the Lysosomal Specialized Center at the Children's Hospital and the Center for Rare Diseases. And it is a great pleasure for me to do this mutual webinar together with my good friend and internationally recognized expert in MPS, Dr. Christina Lampe. Dr. Christina Lampe is Director of the Center for Rare Diseases in the Department of Pediatric Neurology, Epileptology, and Social Medicine at the University Hospital of Gießen. And we have a long history of cooperation, and in one of these cooperations, Christina leaded us into an interesting research project for the identification of alpha-mannosidosis, and we are going to share the first results of this project and the future plans within this project in today's webinar. But before we do start with the presentations in which Christina is going to give an overview on alpha-mannosidosis and mucopolysaccharidosis, I have to share some housekeeping notes with you. So, we kindly ask you to please do not take any screenshots, do not reproduce any of the slides, content, or images without the expressed written permission of the speaker. We are going to have a 45-minute presentation followed by a question and answer session. So, please text your questions so that we can try and answer it right after the presentation. Christina is going to make the start and give the overview in the first 20 minutes, and if you have questions meanwhile, we are happy to address them. And I will continue with the second 20 minutes, and then we are going to have the question and answer session. Questions can only be submitted via the text and not verbally, so please use the text function of the broadcasting platform. The presenters, so Christina and me, will answer as many questions as possible at the end of the session. And this webinar from today is going to be recorded and available on Excellence in Pediatrics online library. And you can see the online link right at the slide, www.ineip.org. So, have a lot of fun, and let's have an interesting discussion on alpha Mannosidosis and mucopolysaccharidosis. And with that, I hand over to my good friend, Dr. Christina Lampe, for your presentation. Christina.
[00:03:25] Dr Christina Lampe: As you can see here in the gallery of pictures, you see that there's quite a lot of similarity between alpha- mann and MPS. And this is why actually this screening initiative is performed for alpha- mann and MPS. And since we wanted to find alpha-mann patients that are much more rare than MPSs, we focus a little bit more in this talk on the alpha-mannosidosis patients. But to give you an overview about these two different diseases, they are both rare, genetic, extremely heterogeneous and variable in the clinical signs and symptoms, multisystemic, but they are both life- threatening. So MPSs is a group or are a group of diseases. We know about seven types of Mucopolysaccharidosis caused by 11 enzyme deficiencies, which is actually not really true because we know already eight types of MPSs and 12 enzyme deficiencies. So one was recently described, newly described. We know that it is the cause of the diseases are genetic defects leading to enzyme deficiencies. And these are leading to a defect of degradation of glycosaminoglycans in MPSs and oligosaccharides in alpha-mannosidosis . So we have actually storage of undegraded material in both diseases. To show you the first description of alpha-mannosidosis, I would like to show you here the original publication from Ockerman, who described in 1967, the first patient with alpha-mannosidosis. And he said, it's a generalized storage disorder resembling Hurler syndrome. And this is actually the reason why alpha-mannosidosis is also called Hurler-like syndrome. And if you see here the description with the signs and symptoms of the patient that he described, he said he had recurrent infections, psychomotor retardation, gargoyle- like face, tallness of stature, hepatomegaly, muscular hypotonia, gibbous, widespread teeth, storage cells in the bone marrow. And actually this patient died at four years and four months. Histologically, he found in the CNS ballooned storage cells and in the liver, greatly increased amounts of a mannose-containing component not yet identified. I mean, we are talking about a publication from 1967. And the activity of the alpha-mannosidase enzyme was low in liver, spleen, and brain.
So it seems it was looking or it seemed to be MPS, but actually not really an MPS because the alpha-mannosidase enzyme was deficient. And here you can also see some pictures and you can probably see the similarity to MPS. So his conclusion was this may represent a disease not previously described. And he was correct. Actually, it was the alpha-mannosidosis that he described for the first time. If you here see some pictures from alpha- mannosidosis and MPS patients, I think it is quite difficult to say or to decide which is an alpha-mann and which is an MPS patient. And look at the pictures and give a guess for yourself what you think, which is alpha-mann and what is MPS. But to give you the solution, you see here the first picture is an MPSI patient and the other two patients are alpha- mann. And I think it is clear how really similar they are in particular at a very early age. I hope. If we look for the delay of diagnosis across the MPS types, we see that MPS IVA or Morquio disease has the highest delay with six and a half years, while MPS-III with six years and MPS-II and MPS-VI with almost four and a half years have a quite big delay between early signs and symptoms and diagnosis. So in median, the delay in all MPSs from first signs and symptoms to diagnosis is almost three years. 20% of cases have a delay of more than 10 years. And actually some physicians are not really combining the symptoms or the earliest signs and symptoms of MPS or alpha-mannosidosis and think to these very rare diseases. If we see the diagnostic delay in alpha-mannosidosis, we see that the earliest signs and symptoms start at the age of 1. 9 years and we have a diagnostic delay of 6. 1 years. So very similar to Morquio's disease. We see that the diagnosis is mainly performed at the age of eight years. And since we are talking about chronic progressive diseases, storage diseases, it means that the earlier we find diagnosis, we diagnose the patient, and the earlier we can start treatment, the better is the outcome.
And this is why it is so important to find screening programs that help in detecting these patients much earlier. And we'll talk about that later. So alpha-mannosidosis, you see here, there is a very heterogeneous prevalence across countries, but in general, we can say that alpha-mannosidosis is for sure underdiagnosed, because maybe MPS is more of, physicians are more aware of MPS, they exclude MPS, but they may not think to alpha-mannosidosis since the prevalence is one to 500, 000, so even more rare than MPS is, but we should always think to MPS and alpha-mann in one. So we have quite unspecific early signs and symptoms, and that obviously could explain the common, could explain why these patients are not detected early. And if we see here, the alpha-mannosidosis signs and symptoms or the earliest symptoms that can be seen in patients, we see that as a speech delay, it is hearing loss and developmental delay. Also, we have other signs and symptoms that could lead to a diagnosis of alpha-mannosidosis, like motor disturbances, facial features, infections, hepatomegaly and hernia, so very similar to MPS. But all these signs and symptoms are resembling common diseases of childhood, and probably this is one of the most important reason why these patients are detected late, and this is actually the gap that we want to close with the screening programs.
So the earliest signs and symptoms in an overall population of 111 patients with alpha-mannosidosis, we can see here that cognitive impairment is present in 97% of patients, coarse facial features in 70% of patients. Bone abnormality is very common also in MPS, but 81% in alpha-mannosidosis patients, but also respiratory tract infections and hernias, organomegaly, short stature, dysmorphism are very present. Interestingly, or this is the difference between alpha-mann and MPS, beside the storage material that is different, is that we have in older alpha-mannosidosis patients an ataxia that we don't see in MPS. alpha-mann is also, as we know from MPS, it is not a single disease, but it is a continuum of different severity, so we have a very severe form that is immediately recognized with skeletal abnormalities and obvious disease progression, and the patients die early due to CNS involvement or myopathy and infections. The more frequent type is actually the moderate and mild forms. Type II or moderate form is the signs and symptoms that appear prior to the age of 10 years, they have skeletal abnormalities and a slower disease progression than type III, and the development of ataxia is at the age of 20 to 30 years of age. The more mild form of alpha-mannosidosis, so signs and symptoms appear older than 10 years of age with no or only a few skeletal abnormalities and very slow progression. But we have to take in our mind that this is not a clear distinction between the different types, but it is a continuum of the disease, and it's sometimes very difficult to decide the clear severity of the patients. Just to show you that not only from one patient to the other but also in one family, there may be different signs or times of onset on signs and symptoms. We see here two siblings that were diagnosed at the age of 24 years, and the other patient or the sibling 21 years of age, and you see they had quite a lot of similarities in their signs and symptoms, like hearing loss, recurrent airway infections, delayed speech, transelectomy, developmental milestones in time, attention deficit, and mild learning difficulties. But if we go a little bit more in detail, we see that sibling two, for example, in pink, had a hearing loss at the age of six years while the other sibling had a hearing loss already at 32 months of age. The one sibling had recurrent otitis media while the other one had only once in his life an otitis. One of the siblings needed adenoidectomy, the other didn't. The IQ was quite similar, but the social interaction was normal in one, but not normal in the other. So you see that even intrafamiliar, you have acquired disease heterogeneity. So there are also some other differential diagnoses from the lysosomal field from alpha-mannosidosis. It's mucopolysaccharidosis, but there are also the multiple enzyme deficits like mucolipidosis that can be very similar to alpha-mann and MPSs.
So what is the rationale for an early diagnosis? I mentioned already, but I would like to focus here a little bit on the patient's point of view, because patients have often non-specific or unspecific signs and symptoms, and they are misinterpreted and often not taken serious. This means the patient is sent home, but they are, it's a common disease of childhood, but nobody's thinking to these diseases that are chronic, progressive and need early treatment. Sometimes patients visiting several physicians without having any diagnosis, they search for experts, they have an uncertainty. Also, they have sometimes problems with authorities or insurances if they need any support, rehab or whatever, because there's no diagnosis made at this point. Diagnosis means in rare diseases often misdiagnosis and then wrong treatment, for example, unnecessary surgeries or surgeries that are not helpful for the patient. So delayed diagnosis also means delayed treatment, and in this case, we have an irreversible organ damage. The diagnosis could help to understand which treatment options are available to connect to expert centres for these patients. They can also discuss and understand family planning even better, and patients can connect to patient associations to exchange experience and ask questions, which is extremely important.
So concerning therapy, it is important to understand, is there any treatment option? Yes and no. Patients can be seen by a multidisciplinary team and receive multidisciplinary treatment, and we can detect life-limiting disease complications as well as quality of life-limiting disease complications. And actually, what is our goal? It's living with a rare disease in the best way possible, and this is what we try to get. To show you that the early versus late treatment with enzyme replacement therapy that is available for some MPSs, but also for alpha Mannosidosis, we see here a comparison of two siblings. One sibling that started enzyme replacement therapy at the age of nine years and the sister at the age of one year and seven months, and the follow-up was 85 months. And what you can see is that one that is much more or more severely affected, probably because of the disease progression, and the small sibling that started at the age of one year and seven months had not that clear signs and symptoms of the disease. But when you see them, the one that started later in life with enzyme replacement therapy, and she had already irreversible organ damage, and you see this smaller child that started earlier with enzyme replacement therapy, and you see the picture where they are standing together here on the right part of the slide, you see that the smaller one seems to be less severely affected, but clear is it is due to the fact that she was treated much, much earlier than the older sibling.
So this means the earlier you start treatment, the better is the outcome. Another reason to detect patients early and why these screening programs are important is that we have an improvement in survival of treatment versus untreated patients. And we see here, for example, from the Hunter Outcomes Survey, the international registry for MPS II or Hunter's disease, we see here that patients that are treated early have longer. longer life. The mean onset is very similar but you see the survival is 10 years higher than in untreated patients. So this is actually extremely important to detect these patients as soon as possible. So before Florian will talk about this training initiative that we started, just some key lessons from this talk. It's the ultra-rare lysosomal diseases that I presented, alpha-mann and MPSs. They have a wide spectrum of symptoms and individual presentation. In particular, the earliest signs and symptoms are very, very unspecific and very common in childhood. We have different types of the disease from mild moderate to severe, which is a continuum at the end. We have a broad range of clinical manifestations that places a high burden on patients and caregivers. We have an overlapping nonspecific symptoms with other lysosomal diseases and in some countries is an enzyme replacement therapy available and this is actually even more a reason to detect early. With this, I would like to hand over to Florian. If there are any questions, we can start with that but otherwise I would like to hand over to Florian who will explain and show the screening ideas that we had and how we can develop them to a more international level. Florian, it's your part. Thank you very much.
[00:21:43] Dr Florian Lagler: Thank you very much, Christina. Before I continue with our project, I would like to forward some questions to you. You made it entirely clear that it's a complex situation of unspecific multitude of different symptoms and that as well in mucopolysaccharidosis as well as in alpha-mannosidosis, ENT problems and respiratory infections can be one of the early signs as well as hearing and speech problems. But on the other hand, in the private practice pediatric situation, hearing problems and speech problems are very common signs. So in your personal opinion, what can help finding the red flags or finding an indication that further diagnostics are needed and that the chronically rare disease could underlie the observed problems? What is your experience with that? What could help the pediatrician out there? I totally agree that the first signs and symptoms like recurrent infections, ear problems, otitis and speech problems is one of the most or the earliest signs and symptoms in these diseases and it is very common in childhood. So this also explains the gap between early signs and symptoms and diagnosis because you cannot test all these children on a rare disease because it makes also, it irritates parents and it's probably not the right way.
But what I think is that if we combine signs and symptoms, so if we have only one symptom it is not actually needed to test, but if I have recurrent infections, I have the speech delay, I have a mild developmental delay, I have a strange skeletal situation or I have hernias or anything, so if two or three unspecific signs and symptoms in combination that could lead actually to the suspicion that there might be a rare disease behind and then I would test. So it is not the one symptom that leads to a diagnosis or a suspicion but it is the combination that would lead. Very well. So you're saying it's kind of a pattern, a combination of different symptoms that should be indicative of further help and if I may add from my personal experience in most of the European countries there are centers for rare diseases and reference networks of course as well. So when indicative pattern is observed in a combination of respiratory infect, common or very frequent respiratory infections together with developmental delay and or skeletal findings, it is always a good reason to contact your local reference center or center for rare diseases whether or not you should send the patient for further diagnostics as you clearly showed that the early diagnose offers on the one hand more very more comprehensive and high quality management of the families as well as disease modifying and causal therapies for these patients. So thank you very much, Christina, once more. And it's my pleasure now to highlight a project that has been initiated by Dr Christina Lampe, and it is based on the examination that is done prospectively in German- speaking countries, so this refers to Germany here, but it's similar programs attend in Switzerland as well as in Austria, and in some countries these programs are referred to as well- child programs, well- child visits programs because the children are seeing the pediatrician not only if they are ill but also as a prospective measure of health activity.
And of course this aims for early detection of developmental abnormalities and treatable diseases and it's done at specifically or specified time points of infanthood nd the age group of 24 to 26 months of age is seen in a well- child visit called U7A and it looks for possible problems in physical, linguistic and social development at an early stage. And this goes the wrong direction. Now it's fine here. As I said, the U7A well- child visit takes a look at exercises, examinations to test gross motor skills, to test fine motor skills and language development. I will not go into detail with that regard, but German language is called das gelbe Heft, the yellow book, because every family has got such a book, and in the book there is specified assessments and questions directed to the parents in order to identify motor development gross as well as fine motor development delay and language developmental delay. So this is how the pages of this book looks like and that's the original one. So it is in German language and you can see here is a part that is called erfragte Befunde, that would mean medical history. So the pediatrician is asking for signs of seizures, of problems with urinary micturition and so on. So there's a lot of questions that are asked here about the abdomen, which is examined, as well as the sexual organs, skeletal system and so on. The oral symptoms are assessed and motor and neural function is assessed and so on. So a lot of specific subjects to be tested and if there is any finding, then this is noted here and in the end of the assessment that is done by the family pediatrician there is a recommendation for further examination or not. And here in red you can see highlighted findings that may be common in patients with mucopolysaccharidosis and alpha-mannosidosis that could be indicative of such a problem, and obviously not in all patients. We would find all of the findings here, but that's what Christina referred to with regard to patterns. If there is some of these findings seen in a patient. This should be indicative for further diagnostics, and that is practically the The basis of the project that Christina started some years ago, here again in English, recurrent infection, enlarged head circumference, dwarfism, language delay and delay in verbal understanding, fine and gross motor developmental problem, behavior problems, hearing loss, hepatosplenomegaly, hernias, skeletal deformities, visual acuity problems, strabismus, heart murmur, obstructive nasal breathing, dyspnea, pathological auscultation, dental abnormalities and seizures.
That is all findings that may be indicative, not only if all of them are present, but also some of them are present that could be indicative for an MPS or alpha-mannosidosis disease. So that was the starting point for Christina to create an initiative with the support of a pharmaceutical company that allowed her to prepare this very nice information leaflet on the different diseases that could be found by these well- child examinations at the U7A level, which gives some information of alpha-mannosidosis and mucopolysaccharidosis and information on centers for rare diseases that could be approached. And again, this was done with a kind of a survey that was filled in by the parents regarding these findings that you find here. I will not go again through all the details here, but if anything was indicating an alpha- mannosidosis or MPS, the pediatrician was encouraged to order a diagnostic test using a dry blood spot on a filter card that can test for MPS- I, MPS- II, MPS- IVA, MPS- VI, MPS- VII, and alpha-mannosidosis. And that's not just incidentally these specific diseases, that's the treatable MPS forms and alpha-mannosidosis. And this was very successful. So that is the first results of Christina's project.
[00:32:23] Dr Florian Lagler: Within two and a half years, 400 test kits were ordered by the participating pediatricians, 19 dried blood spots tests were sent in. So about 5% of the tests were used and an incredible number of eight positive cases, MPS cases, were found. And everybody who is familiar with other patient identification or patient screening programs, that's really, really convincing, that's good data or that's an excellent success of such a diagnostic initiative. Because usually you need to test hundreds and hundreds, or even thousands, of patients in order to find patients with mucopolysaccharidosis, as these are very rare diseases. So we thought this success should encourage further initiatives in order to use the Well-Child Visit program as a platform, as an opportunity to identify patients with these rare diseases. And I had a closer look on what is known about the findings in this Well-Child Visit programs. And as a matter of fact, it was a good time point to have a closer look because in 2024, the final report of an evaluation study on the National Well-Child Visit program in Germany was done in a total of 656 participating family pediatricians have sent in information from 44, 000 Well-Child Visits, not only U7A obviously, but a lot of data anyways. And I will share now the results they have found in order to discuss the results of Christina's project as a starting point for further ideas and further discussion of possible future programs. So in this 44,000 cases. observed and documented in these German pediatric, family pediatrician practices, speech and language developmental findings were by far the most common findings. So 50% of all abnormal findings referred to speech and language development. Motor developmental disorders ranged right after that with 23% and orthopedic problems with 21%.
So you can see that speech and language development as well as motor development and orthopedic problems are key red flag symptoms for MPSs. So this says that the target group of MPS and alpha-mann patients are in focus of the well- child visit assessments done in the German program and the Austrian and the Swiss program is not so different from that. So as I've shown previously, the well- child visits not only include physical examinations of the patients but also family or parental interviews. And as a matter of fact, also in these parental interviews, in 39 up to 60% of the abnormal parental or abnormal findings referred to language development and about 28 to 47% of parents of this subpopulation reported that the child is not well understood by other children or other people in general. So again, the language development, speech and language development is a very predominant finding and in addition to that, a clear indication that the parental reports are very important. Now this is a little busy here, the table, and I will quickly guide you through what is given here. So we have on the one hand the history, in other words, the parental interviews and then the pediatrics examination results and it refers to indications of speech and language disorders and to the time point of assessment. So as I said, U7A is done between the 34th and 36th months of age and in 20% on the one hand in the parental interviews and on the other hand based on the pediatrician's examination, abnormalities with regard to speech and languages are found. In the later assessments of U8 and U9, there is even a higher percentage. But on the other hand, why do we discuss this data? Because it's interesting whether or not U7A is the right time point or if we could even go earlier to find patients that are suspicious for having an MPS or alpha-mannosidosis. And as a matter of fact, also in an age of 21 to 24%, indications of speech and language disorders are quite prevalent in this German cohort.
But on the other hand, as Christina highlighted in her presentation and also in the questions and answers part, it's not only about one single finding of speech and language problems, but it's about a pattern of a combination of motor problems, orthopedic problems and so on and so forth, ENT problems and so on. So I think that the U7A with a 34 to 36 months of age is a very well suitable time point of assessing the probability of an MPS or an alpha-mannosidosis disease. And due to time reasons, I will close the presentation here now with a summary and a short outlook on how we're going to proceed on that project. So I want to summarize that rare diseases like MPSs and alpha Mannosidosis often present initially with unspecific signs and symptoms, recurrent infections, hernias, developmental delays, speech and hearing problems and so on, which are very common, isolated, but it is about the pattern that leads us into the patients that should undergo further investigation. The early diagnosis and initiation of treatment is very, very important because, on the one hand, early treatment in the treatable MPS forms and in alpha-mannosidosis is associated with a better outcome. And of course, it's also about family management, so that consulting of the families and the holistic approach of support for these families is only possible in an optimal way once the diagnosis is done. Screening initiatives that are included in pediatricians routine in terms of the well child visit may be helpful beyond that pilot study that Christina did, and therefore we are considering to further use this approach and enlarge our sample not only to Germany but also to Austria and Switzerland, and if there is pediatricians from these countries in the group of our participants from today or see the video later on on demand, please feel free to contact us in order to see if you could be part of the initiative. And with that I want to close my part of the presentation and I am happy to address the questions raised in the text and by Christina. Thank you very much, Christina. I think you need to activate your microphone.
[00:41:37] Dr Christina Lampe: Yes, you're right. Thank you very much. After so many times, so long time on virtual meetings, I should know. Thank you very much for presenting this just to give a short history of that project. It was that I always thought that at a certain point we should find different symptoms in a child at one time point, so that we have a suspicion. And I found this U7A at the age of 3, 3 and a half years and I think it's a good time because you have also in this, rare diseases. You have the signs and symptoms present. You said we have to discuss whether we have to go a little bit earlier or later, but when we started we decided for that time and actually we had quite a good success. So I think the time was correct. But I also have to admit we started asking questions to parents which were not that easy maybe, and maybe too extended or not clear enough. So the project was successful, but it is not optimal at the moment and this is why I'm very happy, Florian, that you presented also the data of this publication showing what are the real signs and symptoms that children in general present, and I think the next step would be to combine symptoms and to find a better way to ask also parents about signs and symptoms, and I know that you have already an idea and I would like you to present that.
[00:43:29] Dr Florian Lagler: Thank you, Christina, and I think you are completely right. So this project has been really, really successful. But it was only a first step and in order to unravel the whole potential of that approach, it will be necessary to roll out to further pediatric practices in different countries. And I had a lot of discussions with colleagues that work not in the hospital, like myself, but in the private practice or in the pediatrics practice, and they said: well, you know, it's not so easy to do even further questions and further examinations with the families because we are working on a very tight schedule in that context and it would be it's questionable whether or not there is enough time to do this selective screening with the patients. So this made me think about it and we are currently preparing an artificial intelligence based approach that will end up in a possibility for parents to be interviewed first by a chat bot to give the information that will then further assist the assessment by the pediatrician. So the chat bot would ask the parents ot only about developmental delay or whether the child has been very well understandable for her peers and so on, but also the other questions that could be indicative for orthopedic ENT and other problems. And another thing that was highlighted by a very experienced pediatrician from the practice setting, he said, you know, it's so different from family to family and it's also a language challenge to do that because we have a lot of families with a migration background and sometimes language is really a barrier. And of course the artificial intelligence platform again comes in because it should be pretty nicely feasible to have this in other languages so that all families can or all parents can give their answers in their own language.
Of course when it comes to online artificial intelligence solutions, data protection is always an issue. So the third challenge that we have to address within the continuation of the project will be how to build a data protected approach so that families are not pushed to share information that they should rather protect. And this is a matter of how the questions are raised and what informations are given. And I think lastly it's a very important aspect that it's not the artificial intelligence that decides whether further diagnostics with regards to dried blood spots on a filter card should be done or not. It always needs to be the pediatrician, the physician in charge that does this decision. And the role of artificial intelligence can only be a supportive one in terms of raising the questions to the families that indicate whether or not there is a relevant risk for having such a disease.
[00:47:46] Dr Christina Lampe: Yeah, absolutely. And we are working on that and I am very curious to see whether we can find out patients with that. Here's one question in the chat, Florian, and they say U7A well child visit assessment. Is it subjectively a problem with missed alpha-mann and MPS patients who should have been tested?
[00:48:14] Dr Florian Lagler: I'm not sure if I understand the question right. What I understand is, is it a problem that patients have been missed in earlier well child visits? Is that the question? Do you see it like that, Christina?
[00:48:34] Dr Christina Lampe: Yeah, this or also maybe I think that how many, maybe also the question could be how many signs and symptoms should be present in order to test a patient. So is it subject, is it a personal opinion or is it in general? So I think we decided that three questions on these 10 questions should be answered with yes in order to send the DBS card. But Florian, please go on. I interrupted you now.
[00:49:12] Dr Florian Lagler: No, no, that's fine. So, well, I think the aim should not be to come up with a scoring system that says from a cutting point of, let's say, 10 points or three positive findings, diagnostics should be done. And I believe that cannot be the approach because some of the signs may be well explainable with common diseases. Like, for example, if you have a patient with currently recur, with chronically recurring ENT infections, it's very possible that the same patient has hearing problems. And if the hearing problems are severe, it's very probable that there will also be language and speech developmental delay in that patient. So these three findings refer to one common cause and therefore they should be addressed differently from other three findings, like having a skeletal involvement, having a hearing problem and in addition, for example, having facial findings, facial abnormalities, for example, because the three of that findings presumably are not explainable by one common reason. But I still want to try and give a very concrete answer to the question. I think from our project guidance perspective we can only give a slight recommendation and, as you said, if there is three signs that obviously are unlikely to have one mutual common explanation, then it's very reasonable to go for a diagnostic testing and that's what I always also recommend to colleagues in the field that ask: when should we send the patient? It's not about the number of signs, it's more about the questions: are there signs, relevant signs, that cannot be explained by one mutual common explanatory or explanation as a common disease as the underlying cause for that? I think we got a new question here.
[00:51:47] Dr Christina Lampe: Before we go to this question I have, I would like to just to ask: you said we don't want to have a scoring system, which is for our screening initiatives, and this is absolutely correct. But nevertheless we found from this recent publication, from all this examination- well, child visit assessments- that the speech delay you mentioned already is one of the common or most frequent symptoms and probably this would be the next step of our initiatives: to have this sign and symptoms and combining this with other signs and symptoms, if I understood correctly. No, yes, exactly.
[00:52:39] Dr Christina Lampe: So we don't score, but we see in the most important one that speech developmental or language developmental delay, and from this point we search for other symptoms and then to test. But sorry, just to clarify this point because I think it is extremely important. And now to the next questions: have there ever been any cases of false positive or referrals from the screening kits and how is diagnostic confirmation managed to avoid and do parental anxiety? You want me to answer first, Florian, yes, please. Yeah, actually it is.
[00:53:24] Dr Christina Lampe: We had no false positive cases and the confirmation was done with the genetic testing directly from this dry blood test. So meaning, whenever the enzyme activity test and the dry blood spot test was positive, there was immediately and parents signed for that before testing- that a genetic testing is immediately done.
[00:53:54] Dr Florian Lagler: Yeah, and maybe the question also refers to: is there patients that are referred to further testing that will not end up with a diagnose or anything like that and for sure there will be patients where no treatable cause of the observed symptoms can be found, but that is the case for any selective screening approach. The number or the extent of patients that are referred to diagnostics for not, and where there is not a positive result, that will be it has not been assessed systematically so far, because when Christina started the project it was predominantly a diagnostic initiative and the results of the diagnostic initiative have been so encouraging that we said we not only want to expand the project, we also want to understand what is the statistics behind that approach in order to learn from that and maybe even further improve the approach. And that's why, when we continue this project, we are going to have a statistical and hypothesis driven approach so that we can learn how many patients have to be tested in order to find a number of patients with alpha-mannosidosis or MPSs.
[00:55:35] Dr Christina Lampe: Yeah, and actually since the enzyme activity testing that was positive and then the immediately genetic testing means that parents really got this diagnosis when it was clear. There's another question, Florian, before we discuss. In countries without a structured well child visit program like Germany's U7a, what alternative strategies would be recommended for integrating MPS- alpha-mann screening into routine care?
[00:56:12] Dr Florian Lagler: Yeah, so that's a really good question and that would be interesting from a research perspective as well because obviously the key aim of the well child visits as established in the German-speaking countries and also in other countries is to build a platform, to build an approach that makes sure that treatable diseases or chronically diseases are diagnosed early and systematically.
[00:56:47] Dr Florian Lagler: But our approach would also work without such a well child visit program because patients with, in our experience, patients with mucopolysaccharidosis and alpha-mannosidosis, they would see the pediatrician very often and if you recall what Christina showed about the two alpha-mannosidosis patients that have been diagnosed as adults, they have been quite symptomatic even in childhood. So how could this be used without a well child visit program? There could be information material in the waiting room of the pediatrician, so if the child is referred to the pediatrician with just the next of 20 yearly ENT infections to the pediatrician, it would be good to see for the family, okay, if there is not only ENT infections but also developmental delay plus motor function problems plus facial patterns and so on, that they may address this to their pediatrician. So I think this approach of making the parents aware and helping them via artificial intelligence to be aware of the relevant questions and supporting them by giving this information to their private pediatrician or family doctor, that could also work without a well child visit program. And then, as I said, from a research point of view, it would be very interesting to find, to see and if there is any difference in the efficiency of such a project within the frame of a well child visit program or outside such a program.
[00:59:04] Dr Christina Lampe: Absolutely, and it shows also the importance of listening to parents when they have a suspicion. I had yesterday a family with an MPS II boy and the mother said to the pediatrician several times, the head is enlarged and he looks strange and the pediatrician said, no, there's everything fine but we will send you to the hospital to make a check-up because just to make sure that nothing is there but they don't expect and it is an MPS II. And this shows actually how important it is also to listen to parents and I think, Florian, you have nine seconds to say goodbye.
[00:59:51] Dr Florian Lagler: After what you just said, this is very easy because it couldn't be more true. It's always important to listen to the parents, have fun with it, find a lot of patience and please don't hesitate to reach out to us for assistance or a collegial discussion. Thank you very much and hope to see you soon.