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[00:00:00] Dr. Nathalie Guffon: Hello everyone, it's my pleasure to welcome you to this first webinar of the second series dedicated to a shine a light on alpha-mannosidosis. The topic is providing personalized care. This is an educational webinar sponsored by Chiesi in collaboration with and hosted by Excellence in Pediatrics. As the content is disease focused, presentation will not include information on specific treatments or medication. This webinar is for healthcare professionals only. Before starting, I will give you some housekeeping information. Please do not take any screenshots or reproduce any slides, content or images without the express written permission of the speaker. We will have a question and answer session at the end of this webinar and we will answer as many questions as possible. You can submit your questions at any time via the questions panel. Your questions can be submitted only via text and not verbally. This webinar will be recorded and available on demand. The main learning objectives of this webinar are listed on this slide.
[00:01:48] Dr. Nathalie Guffon: The first one is to understand the cause and heterogeneous symptoms of alpha- mannosidosis. Then we will describe the aims and key outputs of the Delphi consensus study and practical recommendation for care in alpha- mannosidosis. We will discuss the steps in establishing a diagnosis and early assessment. We will also explore approaches to personalize care through the lens of a real- life case study example. After this welcome and a short introduction, I will present the objectives of the alpha- mannosidosis Delphi consensus. Then Dr. Magner will speak about spotting the signs and timely diagnosis of alpha- mannosidosis and present case study images. Then Dr. Lopez- Rodriguez will talk about personalized care in alpha- mannosidosis and present a presentation with a real- life case report. Then, as I already said we will have time for the Q& A session at the end. Don't forget to ask your questions throughout the webinar via the question box. Now I would like to introduce my colleagues: Dr. Monica Lopez- Rodriguez from Madrid in Spain looks after adults with alpha-mannosidosis. Dr. Martin Magner from Prague in the Czech Republic, is a pediatrician and looks after patients with alpha-mannosidosis. My name is Nathalie Guffon. I am from Lyon in France and look after both pediatric and adult patients with alpha-mannosidosis. Here are our disclosures. In 2023, the first part of the Shine a Light on alpha-mannosidosis program was presented with two webinars focusing on the various signs and symptoms of alpha-mannosidosis, challenges, solutions for timely diagnosis, and best practices in multidisciplinary care.These webinars are available on demand. You can scan the QR code to access them. Alpha-mannosidosis is an ultra-rare lysosomal storage disease with an estimated incidence of 0.1 per 100,000 live births.
[00:04:45] Dr. Nathalie Guffon: However, alpha-mannosidosis is underdiagnosed and current evidence suggests an incidence of 1 per 500,000. So quality of life of individuals and their families is severy affected. However, the rarity of alpha-mannosidosis and the variation in symptoms and severity between patients means that diagnosis is challenging and often delayed, contributing further to patient and caregiver burden. Alpha-mannosidosis is caused by lysosomal enzyme alpha-mannosidase deficiency, which leads to defective degradation of glycoproteins and accumulation of mannose-rich oligosaccharides in all tissues, resulting Alpha-mannosidosis is a genetic disease and pathogenic variants in MAN2B1 gene lead to enzyme alpha-mannosidase deficiency. Alpha-mannosidosis is a progressive multisystemic disease with heterogeneous symptoms. Speech delay and early onset childhood hearing loss are very common. Patients present immunodeficiency and recurrent infections. Immunoglobulin G deficiency is present in more than 30% of patients. Various degrees of intellectual disability occur in all patients, but early psychomotor development may appear normal or near-normal. Unlike other lysosomal storage diseases, like neuronopathic form of mucopolysaccharidosis, these patients have potential for continuous cognitive development during childhood and early teenage years. About 25% of patients develop acute psychiatric manifestations, generally after 10 years of age. Patients with the severe form of the disease may present hydrocephaly. Skeletal abnormalities are also very common and include asymptomatic multiplex dysostosis and various degrees of bone impairment with progressive destructive polyarthropathy in adults. Genu valgum is frequent and contributes to gait disturbance. Children present motor function impairment with muscular weakness, mild hypotonia, balance and coordination disorders. Progressively worsening ataxia is common in adults. Patients show some degree of dysmorphia with macrocephaly and coarse facial features like in mucopolysaccharidosis.
But, as you see in Dr. Magner's presentation, it may be very subtle and overlooked. Craniosynostosis with microcephaly has also been reported. Ocular manifestations with hypermetropia and strabismus are common. Mild corneal clouding are possible and adult patients may develop retinopathy. Patients may also develop cardiorespiratory complications with sleep apnea, restrictive pulmonary insufficiency, mild to moderate valvulopathy and cardiomyopathy. The inheritance of this disease is autosomal recessive, which means that both parents are healthy carriers of a genetic variant in MAN2B1 gene and around 25% of the children could be affected with alpha-mannosidosis. To date, 183 pathogenic variants in MAN2B1 gene have been identified. So, it is very difficult to find genotype-phenotype correlation. So, now, what are the rational and objectives of the global alpha-mannosidosis Delphi consensus? Despite a growing awareness of alpha-mannosidosis and improved diagnostic methods, gaps remain, such as limited knowledge of natural history, limited information on the monitoring of disease evolution, lack of consensus on initial assessment and routine follow-up care, limited information on treatment response and associated complications outside the clinical trials. So, it is a need for improving the implementation of an integrated care approach in alpha-mannosidosis. The Delphi consensus aims to lead healthcare providers on three key areas of disease management. First, initial assessment of newly diagnosed patients and any factors that may influence this recommendation. Second, guidance for short and long term monitoring of patients. Third, treatment-related follow-up, including coordination of multidisciplinary care teams. Regarding the Delphi consensus study methods, two experts in alpha-mannosidosis, Dr. Nicole Muschol and myself, served as non-voting co-chairs for the Delphi process. A multidisciplinary panel of 20 physicians participated in the study. In round 1 panelists provided assessment to 57 questions, and the rest were screening to identify. Then, the responses from round one were used to develop consensus statements for voting in round two. Finally, these statements were refined based on feedback, and 60 final recommendations were developed. A consensus was reached on 60 statements agross three key areas in voting round three. Five are recommendations on key area one, relating to initial assessment in newly diagnosed patients, including recommendations on genetic testing. Forty-three provide guidance on key area two, about routine follow-up of affected body system and other mannosidosis-related manifestations. And 12 recommendations encompass key area three, on treatment-related assessment and implementation of a multidisciplinary care approach. Now, I would like to hand over to my colleague, Dr. Martin Magner, who will talk about spotting the sign and timely diagnosis of alpha-mannosidosis, and present case studies images for discussion.
[00:12:35] Dr. Martin Magner: Hello. Ladies and gentlemen, it's a great honor to be here and to share my knowledge about alpha-mannosidosis in children and adults with you. Nathalie, thank you for your introduction. As Nathalie said, alpha-mannosidosis is a multisystemic disorder. We got our lysosomes in all of our tissues, and lysosomal disorders, their clinical manifestation really depends on what is stored and in which tissues. So, in case of alpha-mannosidosis, alpha-mannosidosis is a disease that belongs to the greater family of oligosaccharides, and so oligosaccharides are stored. And they are stored in all of the organs and tissues we can see in front of us. The thing is, this storage is very slow and progressive. So, all of these clinical manifestations we can see in front of us at this slide, they develop only gradually, and it takes a really long time until the full manifestation of alpha-mannosidosis is present. Let's proceed to the next slide, and we will talk about particular symptoms in deeper detail. And maybe the first, the best example about what I said is the cognitive impairment or developmental delay. When I said it's only slow and progressive, the majority of children are in a broader norm in their infant or toddler age with their development. Some of them may be several months delayed with their speech or with the gross motor development, but otherwise it's nothing really so apparent. But still, some kind of early developmental delay is really like a constant symptom, and it's present in nearly all children. This might be really mild, especially in the... I'm sorry.
This might be mild, especially even in the younger school age, when these children still may manage the normal education, but it progresses and usually it gets to the area of moderate mental retardation within the second decade of life and then it progresses further and goes to the severe mental retardation usually with the second or the third decade of life. So we see there is a developmental delay, but it's really slowly progressing. Next slide please. What is also very common is hearing impairment and if there is anything to take from this lecture, we should always suspect the diagnosis of alpha-mannosidosis when two of the symptoms hearing impairment and developmental delay are present. It's early childhood onset and the pathophysiology is not fully clear. It might be caused by recurrent ear infections, there might be chronic otitis media, but still there is probably also some conductive and perceptive hearing loss. And this may participate and take part also on the developmental delay, so these children do not understand well and so their vocabulary is also limited because of this. Next slide please. Alpha-mannosidosis as a disease is very similar to mild forms of some mucopolysaccharidosis where coarse facial features are present. That's why it's also called this symptom that it is like Hurler-like facies or coarse facial features. But in comparison to most of the mucopolysaccharidosis, alpha-mannosidosis is less severe in majority of cases and therefore also the appearance in these children might be very mildly pronounced or subtle. What does it comprise? It's a macrocephaly with prominent forehead, arched eyebrows, depressed nasal bridge, macroglossia, widely spaced teeth and prognathism. We will see some of the pictures later. Next slide please. For this, quite typical for alpha- mannosidosis, even if not present in all patients, and it's not so typical for mucopolysaccharidosis, is the immunodeficiency. Some of the children with alpha- mannosidosis suffer from recurrent, even severe infections like pneumonias, of course, what is typical for lysosomal storage disorders like ear infections and so on. But also some kind of atypical infections sometimes occur like endocarditis, arthritis and so on. The pathophysiology of this is explained by the higher level of oligosaccharides which block IL- 2, interleukin- 2. Next slide please. When we talk about skeletal abnormalities, I could say that when there is a skilled and experienced radiologist in the field of lysosomal steroid disorders, that he or she can recognize this disease or the changes in 100%. But again, these changes might be very subtle and mild, also in comparison to mucopolysaccharidosis.
So let's not wait until the full progression of the disease. If we could focus on some of those signs, they cover all of what is mentioned in the list, so thickened calvaria, ovoid configuration, flattening and hook-shaped deformity of the vertebral bodies, hypoplasia of the inferior portions of the ilia, mild expansion of tubular bones in the hands, asymptomatic osteopenia, and even some kind of focal lytic or sclerotic lesions might be present. Some children suffer from osteonecrosis, and what is also typical for all lysosomal storage disorders is a poor pneumatization of the sphenoid body. Next slide, please. I said already that the gross-motor development might be slightly delayed in the beginning. For example, the independent gait is not achieved in the still normal limit of 18 months of healthy children, but for example 21 or 24 months. So this might be slightly delayed, but what is really affecting the quality of life of these patients and hampers them from an independent gait is the ataxia. And ataxia is coming in the second decade of life and severely progresses, and as I said, it hampers these patients from independent gait, and many of them are wheelchair-bound afterwards. Next slide, please. Traditionally, alpha-mannosidosis was classified in three types, but now we should talk about two types of the severity. The severe neonatal form, which leads to prenatal loss or early death, or manifesting also with hydrocephalus, is very, very rare, but it might be the cause of some spontaneous abortions, and it should be examined especially when there are hydrops fetalis. The great majority of patients suffer from attenuated form. It was previously classified as mild or moderate, and the majority of them have some symptom already in the first year of life when we are very careful and focus on these symptoms. So it progresses slowly with intellectual disability, hearing impairment, speech delay, skeletal abnormalities, motor function impairment, ataxia, and psychiatric symptoms, which also come into the manifestation usually in the second or third decade of life. Next slide, please. So individuals with alpha-mannosidosis may present with different symptoms and at different ages, but if we are very careful in the medical history, as I said, we usually find some symptoms already in infancy or toddler age. Next slide, please. This slide's information is from the publication of Zielonka, who published 111 patients with alpha-mannosidosis. It was a literature review, and I just have to say that in this review, the first symptom was noticed already at the age of one year, but the great majority of these children, the median of diagnosis, was at the age of five years. And it illustrates quite a long diagnostic delay. And when we see all of these symptoms and frequencies with all of these symptoms, we see they are not fully expressed. So again, what is to take from this slide is let's not wait for the full expression of all of the symptoms to make a diagnosis. We should always suspect this disease when there is a combination of at least two or three of them. And cognitive impairment, hearing loss, and eventually organomegaly, bone anomalies are the most common ones. Again, organomegaly is not so large, the liver is usually 2- 4 cm at the diagnosis. When we want to diagnose alpha-mannosidosis, there are several approaches. The most common is to send the urine to the special metabolic lab, which can measure the urinary excretion of the oligosaccharides. The problem is that in older patients this excretion may physiologically decrease and the diagnosis may be missed. What is really an exact analysis is a measurement of enzymatic activity in blood leukocytes, before in fibroblasts, but now also in dried blood spot in some of the laboratories. Histopathology with vacuoles in the lymphocytes is already an older method and genetic testing is maybe the most common one, but please always check that if you send the NGS panel that the gene MAN2B1 is also involved in this panel. What is also to mention, when we suspect other lysosomal disorders, like other types of mucopolysaccharidoses, and the analysis is negative, we should always exclude alpha-mannosidosis as well.
A recommendation for initial assessment in newly diagnosed patients is genetic testing. Genetic testing should be always incorporated for a confirmatory diagnosis of alpha-mannosidosis, also for the sake of genetic counseling in the family. The diagnosis may be done also without it, but the genetic testing is strongly recommended. The next slide, please. And these are already the list of analyses and examinations we should do in the newly diagnosed patient. I just want to say that, as we know, the manifestation is multisystemic, so we should focus on all of the symptoms that may occur in this patient. Next slide, please. And this manifestation may be different in a pediatric and an adult page, so decision-making for specific assessment may vary according to the clinical presentation and patient age, and it may also depend on the availability within a geographic region. Next slide, please. And now I will already show some pictures of the children and adults with the lysosomal storage disorders and just try to make your diagnosis. All of them have lysosomal storage disorders. So, please, the next slide. So the first child, it's a girl, and it's kind of tricky, because it's a mucopolysaccharidosis type 2, which is X-linked inherited disorder, and the manifestation in girls is very, very rare, but it also can occur. In the second picture, B, we see a child with knock knees and pectus carinatum without coarse facial features, and this is a typical manifestation for a young child, for a young boy with mucopolysaccharidosis type 4A, Morquio syndrome. Then at picture C, we see the mild coarse facial features in adult patient with moderate psychomotor retardation with alpha-mannosidosis. And in D, we see also subtle craniofacial dysmorphia in a child with MPS II with attenuated form. So we see that it's kind of hard to discriminate between them in these mild forms. Next slide, please. So one more time, the test. Okay, and the answers. So first child is the one with alpha-mannosidosis. The second child, very subtle dysmorphia in a child with MPS II. And then there are two boys with MPS IV. What I want to remind as a conclusion from my part is always suspect alpha-mannosidosis when there is a mental retardation and hearing disorder. And don't wait until the full progression of the disease, which might be very mild and slow reprogressing. So you would postpone the diagnosis. The next slide, please. There is a discussion.
[00:31:15] Dr. Nathalie Guffon: So thank you so much Martin, for this presentation on alpha-mannosidosis and Delphi recommendation for newly diagnosed patient. Your case study images illustrate the subtle natural range and overlap of dysmorphic feature and challenge in making a differential diagnosis between alpha-mannosidosis and mucopolysaccharidosis. So which signs should be red flags for alpha-mannosidosis? Do we want to start, you or Monica?
[00:31:51] Dr. Monica Lopez Rodriguez: Well, I don't know if we should separate children and adults from, maybe. But I think, for example, in people older than 10, we should pay attention to the psychiatric symptoms, for example. Not only the fasciitis, the dysostosis, but also the psychiatric symptoms like psychosis or something similar. We can pay attention with these kind of children or adolescents to make a good diagnosis.
[00:32:51] Dr. Nathalie Guffon: Thank you. So I think for children, the most important is hearing impairment. And we have to check for very mild signs of dysmorphia and sometimes only macrocephaly. So thank you. So now I would like to invite Monica to speak about personalized care in alpha-mannosidosis, which will be illustrated by a case presentation.
[00:33:21] Dr. Monica Lopez Rodriguez: Thank you very much, Nathalie. And thank you also to Kiersey to this opportunity to be here with you and with everybody over there, the screen. And first of all, I will say that it's very difficult for us to give recommendation for a follow-up for an ultra-rare disease. Okay, but I'll try. Then the first part is about the muscular and motor function. It is important to monitor not only gait, ataxia, or walking, but also activities of daily living, fine motor coordination, gross motor function, and tolerance for the exercise, the tone for the muscle, and the contractors also is very important for these kind of people. This is the schedule of my speech, and we will divide in what, how, who, and when. For example, for the motor function, we should be a neurological examination, balance, and coordination test, and what the patient or the caregivers can report in the symptom assessment. At least, I think, every year. In the ataxia or fine motor function, we should perform the six minutes walking test or the three minutes stairs climb test, and we should make any kind of assessment about the rating of ataxia. I think every six or twelve months, and at least every year, and of course, the assessment and follow- up with a physical therapist or occupational therapist as needed. Maybe in some places, in some centers, we don't have a therapist occupational only for us, but we can find it. In the skeletal abnormalities, it's important to monitor, I think, the whole body of our patients with special attention in joint pain, in symptoms or signs of arthritis or arthrosis. Scoliosis is very important in patients with alpha- mannosidosis, pain in anywhere. Genu valgum, I think the majority of our patients have genu valgum. Osteopenia is very important in our patients. Most of them have osteopenia or osteoporosis. We should be very careful with this. And height, pain, and abnormalities in any X- rays. Short stature is very common in these patients, and the abnormalities could be in anywhere. Pectus, long bones, cranium. We should analyze these skeletal abnormalities at least every year and refer to an orthopedic or in another when needed. For example, with a gait, a finger, or something similar, they should be referred to an orthopedic specialist. It's very important. As needed, it's right, but we're careful with the x- ray in exit and only when needed. About the cognitive function, it is important to monitor cognitive delay or decline. Learning difficulties, speech, social problems is very important.
Here is the point I have said before about the psychiatric symptoms in adult patients or in adolescent period. And problems with attention or memory is very important to train this kind of assess. Then cognitive function, intelligent test, formal assessment at school is very important. First of all, in the periods of transition from the childhood to the adulthood, adulthood is very important. And refer to any specialist when needed. I have here, and I want to share with my colleagues this case study discussion because it's very illustrative for the personalized care in alpha- mannosidosis. Then I invite you to be with me. This is a male, now he is 15 years old, living with parents, obviously. He started the hearing loss at 2 1⁄ 2 years, mild cognitive impairment, which is speed and development delay, and cognitive involvement were observed, and also recurrent infection during the childhood. And then the patient did not receive a diagnosis of alpha- mannosidosis until 9 years of age. He started the treatment with these clinical characteristics suggest patient could be a good candidate for ERT. The treatment now is at home and for more than 5 years since the diagnosis. And, of course, it's very important the family support. It's an important factor where we consider these treatment options. Okay, what challenge do we have with managing and monitoring this patient? It's the real life that they have no baseline assessment due to the lack of alpha-mannosidosis experience at the university hospital where the patient started the treatment and is very close to their home, but there were no baseline assessment. Four hour distance from home to the treatment center, which may influence test results, and also the poverty may be a challenge for regular treatment appointments to go to the hospital, but the patient has been compliant so far. It's the real life. And what kind of consideration we can do? There are several steps. For example, baseline assessment were established, but only two years after treatment initiation. In Spain, we say, best late than never. This is when we had the baseline assessment two years after the treatment initiation. And regular assessment seems to have enabled this comparison to assess treatment outcomes.
Treatment initiated without premedication is very important for our patient, no allergy in medical history, and transferred to at-home treatment after the first six months of treatment. Some follow- up assessment were performed by parents and the patient, the parents by parent and the patient, and results were brought to checkup visits. It's to make easier the life of our patients and the caregivers. If anything was pathological, assessment were repeated then. And it's very important during the transition period, adolescent care initiated with private conversations without parent to empower the patient, and not only in alpha-mannosidosis, but also in all rare diseases when we are doing the transition period. And the patient now is 15 years old and has been receiving treatment for more than five years. Patients and caregivers report fewer infections, less fatigue, more agility and endurance, a stable hearing loss, a stable neurological status, improvement in well-being, and no problem with the tolerability. Then this is a case provided by Christina Lampe. And I think it's very similar than other cases, but this is during the period of the transition and it is very important to talk over this case here. I don't know if you want to say something about this case or this information.
[00:43:55] Dr. Martin Magner: Well, I think this is the typical effect of enzyme replacement therapy. Sometimes it's very hard to measure that patients really do have more energy, less fatigue and less infections. It's really something that we may observe, however, sometimes it's really hard to objectivise all of these endpoints. Of course, in all of our countries we got some criteria for the treatment and we should always do the most effort to have as many examinations in the baseline before the treatment and then the follow-ups. Also, for the authorities or health insurance companies, the disease is stabilized, and there is no progression in heart function; there is an improvement or stabilization in the 6-minute walking test. Patients who are able to comply with the respiratory test, they should undergo this as well regularly on a regular basis. So, we can objectivize and document the course of the disease and its stabilization on therapy.
[00:45:34] Dr. Monica Lopez Rodriguez: I think we need, as doctors, as scientists, I think we need some biological biomarker or something to measure, but it's very important that the quality of life of our patients, the sensation they have, we have to notice and we have to take care with this because in this kind of diseases, very rare, with no evidence in the clinical trials. Then the biomarkers is not a good form to measure the response of the disease in the treatment. Then we should look at the quality of life, the pros for the patients and these clinical symptoms. So, I totally agree with both of you.
[00:46:48] Dr. Nathalie Guffon: We have to stop the discussion because we are a little bit late. So, but it is very important to personalise a follow-up regarding the treatment, the possibility of the country and the complication of each patient. So, now I would like to open a question and answer session. So, I invite all the attendees to inform you that each webinar is associated with an infographic that will be available to view alongside the on-demand video. Sorry, I forgot. Next, please. So, now it's time for the question. So, for the moment, I can't see any questions. So, maybe if you want, you can continue to discuss about the recommendation if you want to add something.
[00:48:04] Dr. Martin Magner: I think what is really the most important, and you have said it, Monica, even more that some like endurance tests and respiratory tests, what I see after my experience in my life, what is the most important thing is the quality of life. And we should really focus on the measurement of quality of life on the therapy and without therapy and its progression. Yeah.
[00:48:32] Dr. Nathalie Guffon: So, we have one question asking, can disease severity be estimated from genetic testing? So, I say in my slide with the gene, there is too many pathogenetic variants, and it's not possible to predict the severity of the disease in such a rare disease with genetic testing.
[00:49:00] Dr. Monica Lopez Rodriguez: Indeed, I have two siblings with the same mutation and it's not really the same disease in the two siblings, the genotype, phenotype, like in many other diseases.
[00:49:19] Dr. Nathalie Guffon: So another question is, are there in speech a sign to look for along with hearing or is speech not always such a clear sign? Do you want to answer, Martin, as a pediatrician?
[00:49:35] Dr. Martin Magner: Well, I think these are two separate things and we should be always careful about these children when we say that we shouldn't just overlook the thing that the child still doesn't talk at the age of one year, one and a half year and say that the speech will develop a bit later because the common excuse is that it's a boy, it's not a girl and it will come then later.
[00:50:03] Dr. Martin Magner: I think we should really follow up these children and if we see any other signs of like a hearing disorder or some repeated infections or inguinal hernia or whatever, we should always suspect the lysosomal storage disorders including alpha- mannosidosis. So when we see in this age several of unspecific and in this time at this age already only mild symptoms, we should always ask a question, is there anything that could connect all of these symptoms together? Yeah. It's like if there is a child with a delayed speech, we should really go into the detail and go through the medical history and the physical examination. Isn't there anything else that is like an additional symptom to this?
[00:51:00] Dr. Nathalie Guffon: Yeah, and speech delay, for example, after 20 or 24 months of age, generally linked to a hearing evaluation and sometimes to a hearing impairment diagnosis and at that time it's very important to check something like only macrocephaly or a recurrent infection or low IgG level to go to the diagnosis with less delay. Okay, so another question is, not cost-effective, I think, for the government, not for clinical or not for patients, but for government it's not cost-effective, then I don't think so.
[00:52:12] Dr. Martin Magner: I think the newborn screening for alpha-mannosidosis is surely not widely spread and it will take several years to have this disease in newborn screening. But I'm pretty sure that many of this disease, alpha-mannosidosis and such similar disorders are much more or better treatable than they were just several years ago. These new treatments really change the outcome of these children. So, for example, children who died before can attend the school now and so on. And I strongly believe that in five or ten years we will have really very spread screening for many metabolic disorders, but not yet.
[00:53:01] Speaker 4: Are there specific genetic factors that impact the speed of disease progression? I don't know.
[00:53:19] Dr. Nathalie Guffon: I don't know.
[00:53:21] Dr. Monica Lopez Rodriguez: I'm not sure.
[00:53:22] Dr. Nathalie Guffon: I don't know. Like yours, your people, maybe. Like for children I don't think there are specific things to alpha- mannosidosis. Cognitive impairment is slow in all cases or quicker in some, slower than mucopolysaccharidosis.
[00:53:48] Dr. Martin Magner: Well, definitely, if I can answer this question, there is, of course, some range. I mean, some children even at the school are still in a normal area, let's say low normal. Some children have already in the school age mild to moderate development delay, but the majority of them really progresses with development delay in the second decade of life, and that's already too late for the diagnosis. Even in alpha-mannosidosis, there are rare exceptions of patients, adult patients with a normal development leading an independent life with the age of 40 to 50 years. So this is not a constant sign and there are really rare cases without development delay, but as we said, it's really present in the majority of cases. And to answer the question of comparison with mucopolysaccharidosis, well, even in mucopolysaccharidosis, there are types or forms with the CNS impairment and forms when even the patients have above normal IQ, as I had in my follow-up. But in comparison to the majority of MPSs, of neuropathic forms, alpha-mannosidosis is much less progressive disease.
[00:55:26] Dr. Nathalie Guffon: Yes, clearly, definitively, it's lower in alpha-mannosidosis than in neuropathic form of MPS, and the cognitive impairment may be more severe, more important in the very severe form of alpha-mannosidosis, but it's very, very rare. So in most patients, it's mild to moderate cognitive impairment, and it doesn't progress very rapidly in adults, I think. So how do you tell if repeated infections is part of normal early development, especially if the infant is in daycare setting or too many infections?
[00:56:28] Dr. Martin Magner: I'm happy for these challenging questions we have today. It's really a nice discussion, and we got not much time, so very briefly. It's very hard to differentiate whether the child has already some immunodeficiency or not. Of course, as we said, as we normally see, the preschool children may have even 8 to 10 upper array infections within one year, and it is still okay. But the thing that should raise our suspicion for any kind of immunodeficiency even associated or not with alpha-mannosidosis is the repeating severe infections like bacterial pneumonias or repeated ear infections in connection to other symptoms that might be present in alpha-mannosidosis, and then the atypical infections, which normally with atypical etiology, viruses, or bacterias that are not commonly present in otherwise healthy children.
[00:57:38] Dr. Monica Lopez Rodriguez: Indeed, Martin, one of the proposed biomarkers in the response of the treatment is the measure of IgG for patients who are under treatment because the levels of IgG are higher when they are under treatment.
[00:57:59] Dr. Martin Magner: Yeah.
[00:58:00] Dr. Nathalie Guffon: And for the children, another point for recurrent infection is that patients with alpha-mannosidosis or mucopolysaccharidosis very often start early with ear infection and chronic renal areas of normal child, and they don't answer well to surgery. So there are no further questions, and now it's time to close this webinar. I would like to remind you to complete the feedback survey. It is very important for us to have your opinion. I will also remind you that the webinar will be available to view on demand. I would like to... thank the speakers for their presentation and discussion. So don't forget, we will have a second webinar next week, and goodbye. Goodbye, Martin. Goodbye, Monica.
[00:58:57] Dr. Martin Magner: Thank you very much.
[00:58:58] Dr. Nathalie Guffon: Thank you, Nathalie. Thank you.
[00:59:00] Dr. Nathalie Guffon: Thank you.