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[00:00:06] Prof. Susanne Gerit-Kircher: Hello, ladies and gentlemen, dear colleagues, I'm very grateful to the Institute of Excellence in Pediatrics to give me the opportunity to speak about Mucopolysaccharidosis type I, about the Hurler and Scheie and all the different types between. I was asked to put questions to me and you can put these questions only via text and not verbally, but I will be there to answer all your questions you have after that talk. First my disclosures and what I wanted to say, all the pictures you will see with the sign of MPS are from our Austrian MPS society. First I have to start with an overview and I have to explain what are mucopolysaccharides and therefore what are mucopolysaccharidoses and which types of MPS do we know today and what can be observed in all types of MPS. But then we go into detail about the MPS type I and what we know about that and how can we predict the disease cause and why is it necessary to diagnose MPS so early, how to confirm the diagnosis. So if I start now with the mucopolysaccharides, which give the name to the disease and what they are, the acid glycosaminoglycans, I have to explain that these are sugars. These are sugars in long chains and these are bound to proteins and called then glycoproteins or proteoglycans. They are on each cell surface and are responsible for the interaction with the extracellular matrix, but they are also in the extracellular matrix of connective tissue and this tissue you find in the skeleton, in the joints, in the ligaments, in the intravertabrae disk, in the heart valves, cornea so they are responsible for the organ specific consistency and the water content and other characteristics and therefore you find them everywhere in the body. The physiology of these chains is that these chains are modified glucose and galactose molecules and they have different rests put on it. So we have N- acetyl groups and sulfate groups and due to these compositions they are called chondroitin sulfate or heparan sulfate or dermatan sulfate or keratan sulfate and hyaluronic acid. But you also find some other rare sugars at the end of these chains such as mannose or fucose. And this composition of these chains is made in the endoplasmic reticulum and golgi apparatus of each cell and then they are excreted and have big compositions outside the cells. These sugar chains are correct in the MPS diseases, but these sugar chains need a stepwise degradation process and this degradation process is due to the aging or for renewing the tissues in the body and this degradation starts outside the cell and by endocytosis we have bigger part of these chains brought into the cells and then they are brought to the lysosomes and the lysosomes are small cell organelles containing many lysosomal enzymes and the MPS chains are degraded by 11 different enzymes. So the smallest substance you see here, this end of the chains are small substances, they are recycled and incorporated into new macromolecules or they are excreted. In MPS you have this process disturbed and it is only because one of these enzymes is deficient. You have a blockage in these steps and there is a lot of non- degraded material and all the next steps cannot be performed. So you have increasing storage of non- degraded material and if it is involving chondroitin sulfate, heparan sulfate or dermatan sulfate or keratan sulfate, you have for each of these disturbed chains different clinical symptoms and therefore different clinical diseases, MPS diseases. We will speak about the deficiency of the alpha- iduronidase today because this is responsible for MPS I and the storage is because of dermatan sulfate and heparan sulfate. The mucopolysaccharidoses are therefore diseases, they are inborn metabolic diseases and due to disturbances in the degradation process of GAG- chains and due to defective enzymes in the lysosomes. And you can see this stored material in the blood cells where they make vacuoles or in the electron microscope, but you also can find this elevated excretion of urinal GAGs dependent which chain is disturbed in the urine and you have a normal urine or urine with increased substances you can there find in this Predispot test for instance. The cause of MPS is that these lysosomal enzymes are not working correctly. They are gene products and these gene products are responsible for production of protein chains in the gallbladder apparatus and then a little bit modified in the endoplasmatic reticulum and then they get a marker, the mannose-6- phosphate and due to this marker they are transported into the lysosomes and there they can perform these degradation steps. And each of these enzymes we need, each of these enzymes has a different gene and each of these genes can be mutated. Which types of MPS do we know today? We have a lot of different enzymes necessary for our degradation processes, but we only will speak about MPS I and this MPS I is called Hurler or Scheie. And Scheie was the earlier type V, so therefore you cannot find the type V between IV and VI in this list. What can be observed in all types of MPS and of course in MPS I? At the beginning you have a very, very healthy and really nice baby, but with increasing age you have increasing symptoms and these symptoms start over months or years and they have different organs, the effect, and it can vary from very severely affected patients even with a hydrops fetalis to attenuated or mild forms in adults. And very early you start with very unspecific signs and this makes the diagnosis so difficult. Sometimes you have babies which are taller and heavier than the average and they have a relatively large head, perhaps they have a congenital dysplasia of the hip joints. Often they have infections in the upper airways and a snoring breathing and they breathe with an open mouth and they have repeated ear infections with fluid in the middle ears and often they need ventilation tubes, but such signs you have in many other children too. Soon they have an overgrowth of adenoids and tonsils and sometimes you find a hernia a urinal hernia or umbilical hernia and if you look at the growth tendency you will find perhaps soon a tendency of impaired growth. Early unspecific signs are too the enlarged head, frontal bossing you can see here, dolichocephaly, mid- face hypoplasia with a saddle nose, you will see it in later pictures. You have thick lips, enlarged tongue and often you know from the history of the patient that there were early operations of adenoids and tonsils and perhaps you see a distinct dysmorphic feature. Sometimes you see chest deformities or bushy eyebrows and stiff hair. Specific because not in all the children you find hepatomegaly and very often skeletal deformities and when the children are sitting you have a lumbar kyphosis. Sometimes you have a language delay or hyperplasia of the gingiva with small teeth, disproportionate small size you can have. Sometimes corneal clouding or cardiomyopathy or sometimes a development delay. In some of the cases of MPS types you have really a stop in the development and even regression. What do we know about MPS I? MPS I was described 100 years ago by two doctors, medical doctors, Meinrad von Pflaundler and Gertrud Hurler. This is why we often say Hurler instead of Hurler and they were from Austria and Germany and they described two boys you see on the left side of the pictures. These boys were very specific with a very big abdomen due to hepatosplenomegaly and umbilical hernia, a big head, a short neck and here you have it too. And if you compare it to a patient we have now it is very similar. Gertrud Hurler also described skeletal deformities and these skeletal deformities they are still valid. It is a special head form, special malformed vertebral bodies. It is a special form of the fingers and the end points of the fingers and the broad ribs and all these is called dystostosis multiplex and this is something the radiologists still know today what it means. And if we look at pictures from nowadays they have the same signs, the hip dysplasia, the malformed vertebral bodies and the very shortened and thick wounds in the legs and perhaps arms or fingers. For decades, these patients got the name gargoylist. So these gargoyle faces or gargoylism, these funny figures outside of churches with water or without water, this gave the name to the patients because they had a similar face. And so for a long time, this disease was called gargoylism. But nowadays, we speak about Hurler or Hurler when we think on MPS . And the storage in this disease predominates. It is very, very specific. At the beginning, the infections I have already mentioned. But on the other side, you have hernias, lumbar kyphosis, joint stiffness of the fingers, and very early carpal tunnel syndrome, which you do not usually find in children. But the joints all can be stiff, especially in the shoulders. You have a hepatosplenomegaly, skeletal changes, a short stature, MPS- specific face, and sometimes development delay and cardiomyopathy or heart insufficiency. And in MPS, in the classic MPS, the Hurler, you have very early the start of corneal clouding. If you look at the pictures here, you see that children have a really different head. And they have a very small nose, a saddle nose, a low set ears, a small neck. They look really different compared to healthy children. And you see here the bushy eyebrows and the stiff hair. But we also have to speak about Scheie. And Scheie was, at the beginning, thought to be a different MPS type. It was called the form fruste of Hurler. It was in 1962 when Scheie and co- workers described a form fruste of Hurler's disease. And this was due to the investigations he made on skin and cornea and conjunctiva of patients with Hurler. And he compared that with Scheie patients. And therefore, this disease was called MPS type V. Several years later, it was found that the defect in Hurler and Scheie was the same. It is a deficiency of the alpha- L- iduronidase enzyme. And therefore, from that time on, we speak about MPS I H for Hurler and MPS I S for Scheie disease. Scheie patients are different to the Hurler patients. They have a normal intelligence. They have, very often, heart valve problems when they get older. They can have coronary artery stenosis and myocardial infarctions. They have carpal tunnel syndrome and myelopathy due to storage in the cervical spine. And therefore, they are really necessary to be diagnosed rather early. They can have lens opacity, corneal clouding, and even glaucoma. And often, they have joint contractures and pains and are treated or they are diagnosed for rheumatoid arthritis, but it is seronegative. Many of them have orthopedic treatments and surgeries since childhood. And often, they get, when they are older, endoprosthesis in hip and knees. This variability of clinical severity and science made that we speak about Hurler and Scheie, and Hurler- Scheie and compound, and many, many different forms between which do not really fit to Hurler or Scheie. And if we see the natural variability of these patients, you'll see you have patients which are looking like Hurler, but have much, much more intelligence as you would expect. But you have children looking very similar to Hurler and even going to school. So they are intermediate forms. But you also have patients which are adult and have a very late onset, the Scheie - like patients. This patient, for instance, was diagnosed when he was older than 30 years ago. And what we have now is intermediate forms due to the treatments. Here, you'll see patients which were Hurler patients, but had a hematopoietic stem cell transplantation when they were very young, or which have enzyme replacement therapy when they were diagnosed. So you have intermediate forms also today due to the treatments the patients get. Can we predict the severity of disease cause? What we have to know is that it is an autosomal recessive disease, and if you have in your two gene alleles of the IDUA gene one mutation, you are just a carrier, you are healthy, but you need one gene mutation in each of the two alleles and then you have the disease. And here we have some differences. You can have a very severe mutation, stop mutations, deletions, duplications, insurgents, and all these results in no enzyme production, it is a zero activity. But if you have missense mutations, you just have the exchange of one base in the DNA, and therefore one amino acid is changed in the enzyme protein. And these enzymes can have a reduced enzyme activity, some residual activity. And therefore, if you mix all these, then you have different forms if it is very severe, if you have very severe two mutations, or if it is very mild, attenuated, if you have two gene mutations with some residual activity. Why is it necessary to diagnose MPS so early? We have three things we can offer. If a child is very young, a classical MPS child, very young, we can offer the hematopoietic steam cell transplantation. And you have seen patients which have a very good development. The other is that you can start now with enzyme replacement therapies. These therapies are available for several types of MPS, but also for MPS I. But the third is that you have to look to the cervical spine, and you have to do everything to prevent myelopathy there in the cranial- cervical junction. What we should not forget is that we have a lot of clinical trials running at the moment with ERT enzyme replacement therapy, intrathecally or intraventricularly, gene therapy, substrate reduction therapy, chaperone therapy, and even read- through gene therapy for MPS I patients. But they are not on the market now, but in clinical trials. How can we confirm the diagnosis? The diagnosis first is confirmed by biomarkers, the urinary glycosaminoglycans, which are stored and then excreted by the enzyme activity. It can be very low or even missing, I told you already. And you make the genetic confirmation. And this genetic confirmation can be in the single gene if you are very sure, because due to other patients in the family, that it is on the IDUA gene. But if you are not sure, I would prefer to tell you make a panel with genes from MPS, different MPS types, or make a clinical exome sequencing. All of these cannot be offered in a usual laboratory office. It is really something they offer in the Centers of Inborn Metabolic Diseases or in a genetic counseling unit. So with this, I hope I could tell you something about MPS I and the different forms. You can have very severe forms or very mild forms and many, many forms between where we have the problem to say, is it Hurler- like, is it Scheie- like, or is it Hurler-Scheie compound, or what is it? It can be a really broad phenotype you can observe. With this, I will stop and I am ready to answer your questions you perhaps have sent in the meantime to the Institute of Excellence in Pediatrics, and I will start now with the questions I have already. At the moment, I just ask you, please submit your questions you have after my talk. Oh yes, I have already questions. So I do not want to get over. The first question is, what is the best age for a Hurler patient to be treated by hematopoietic steam cell transplantation? It must be very early, one has to say that. It must be very early, and as earlier as better. The real limit is 18 months, and if you think on finding a donor, it is really necessary to diagnose these patients very early, that you have time enough for a few months to find a special donor. The limit for the transplantation is 18 months. Another question.
[00:21:33] Prof. Susanne Gerit-Kircher: There is a question. I have seen a young child suffering from many symptoms fitting to MPS I. But the reports came back and were tested to be negative for Hurler. What else could it be? When it is a young child, I have to tell you that it can be also MPS II if it is a boy, the same signs you find also in MPS VI in Maroteaux–Lamy . So if you have a negative report for MPS I, I would recommend to look for MPS II for Hunter disease if it is a boy or better for look MPS II and MPS VI both have very, very similar signs when they are young.
[00:22:26] Prof. Susanne Gerit-Kircher: Next question. We have to look. Oh yes, there is a next question.
[00:22:34] Prof. Susanne Gerit-Kircher: I have a patient with a mild form of MPS, the Scheie type, and she is getting the enzyme replacement therapy. The young woman is working and has a nice partner. She asked me what I think about the pregnancy. Is it possible for her to have children or a child with that disease? Because if the patient has Scheie, it is very unusual that her child will have MPS II. It is only in the case if the partner is a carrier too. So if the partner is no carrier for MPS I, all the children of such a patient are carriers but healthy. On the other side, we have several patients, older patients with MPS who have children who had a successful pregnancy. Of course, you have to think that it is a risky pregnancy, but if you really have good survey from all the involved doctors, the cardiologists and anesthetists or whatever you need for a pregnancy and a section, it means you should not have the normal delivery but you should have a section. If you all have these doctors found and then if they are prepared that you will have a child, in many, many cases you have a healthy child. Enzyme replacement therapy is under observation in a clinical trial, but we know from patients that they continue with the enzyme replacement therapy because the risk to have an impaired disease after stopping with the enzyme replacement therapy, it makes it really more worse if they stop. They often continue with the enzyme replacement therapy as they are used to have during their normal life. And if we have another, are there algorithms that can be used to diagnose MPS patients? This is always difficult because not each patient shows everything.
[00:25:00] Prof. Susanne Gerit-Kircher: But if you have a young child and you find infections, ear problems, ear tubes, tonsils which are really enlarged, a big abdomen, then you have involved different systems. You have involved perhaps the liver, the spleen, the skeleton, the mucoses. So in that case, I would prefer to look if it is MPS. And then the first look is, have they an increased GAG excretion in their urines? I would not think on a special enzyme at the beginning, but if they have an increased GAG excretion, you know it is from that group. If they do not have, it can be MPS III, they do not often have increased GAGs, or it can be MPS IV. But if you have a 24- hour urine collection, in most of the cases you find if there is an MPS. Another thing is that we have other lysosomal diseases which are very similar and that one has to think on. Fucosidosis , or mannosidosis, or sialidosis, or GM1 gangliosidosis can look very similar. And in that case, I would make a genetic investigation with a panel or with a clinical exam. And then look if the results show, is it really fitting? And combine the gene variants and clinical science and the urines. The last question is, I think there is no more questions and I have to thank you really very much for hearing this lecture and I hope you learned a little bit about MPS. And I say goodbye to everybody in the world, goodbye. And thank you all for hearing the lecture and thank you to the Institute of Excellence of Pediatrics for making it possible to speak to you. Thank you. Thank you.