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[00:00:05] Professor Susanne Gerit-Kircher : Hello to everybody. I am proud to make this webinar about MPS and early signs and to speak about the many, many different phases of this disease. I am in Vienna in Austria and I say hello to all of you looking at this webinar. This webinar is offered by Excellence in Pediatrics Institute and these are the notes for the attendees you can see later on and these are my disclosures. I want to point out that the pictures of the patients were kindly provided by the Austrian Society of Mucopolysaccharidoses and Similar Disorders and some of the pictures are out of the book, Mucopolysaccharidoses , a guide for physicians and parents. I will speak about the mucopolysaccharidoses,what they are. The mucopolysaccharides or the glycosaminoglycans, what are the early signs and when should we think on MPS and which tests should be performed and why is it necessary to diagnose MPS so early. What are mucopolysaccharidoses? The first description of these diseases was in 1917, exactly 100 years ago. It was made by a Canadian medical doctor, Charles Hunter, and he described two brothers with the age of 8 and 10 years and he just told it as a rare disease in two brothers. He did not know in any case what it is. If you look at these pictures of Charles Hunter, you can see that on the right side, two brothers living now have very, very similar gestalt and these brothers suffer from MPS too and they are 6 and 9 years old. Soon after the description of Dr. Hunter, in 1919, there was this description of two boys by Professor Meinrad von Pfaundler and Gertrud Hurler. Professor Pfaundler was working and living in Vienna and later on in Germany and Gertrud Hurler was a pediatrician from Germany and they described a paper about the type of multiple changes, especially in the skeletal system and you see two boys and the younger one, George, is about 3 years old and you can see on the right side a boy with 3 years suffering from MPS I. He looks very similar to this boy described by Pfaundler and Hurler. The x- ray is from Gertrud Hurler. The images she made were taken in a student's book in the 1940s, you can see here, and Professor Pfaundler used them to describe what is summarized as dysostosis multiplex. What is it? It is a sclerosis of the skull, especially of the bases of the skull, a J-shaped sella turcica , malformed vertebral bodies, especially in the thoracal and lumbar region, there are broad ribs and malformed metacarpalia and all this together is called dysostosis multiplex. For decades, this disease was described as gargoylism. Gargoylism is the word for gargoyle faces and the gargoyles are figures on the outside of churches, Gothic churches, spraying water or not, and these figures had some similarity with the patients, but one did not know what the patients have. So these faces made them for a long time to be called gargoylistic patients or gargoylism. What are the mucopolysaccharides or glycosaminoglycans, sometimes called acid glycosaminoglycans? The mucopolysaccharides are these substances giving the disease the name. These are sugars and these sugars are made in chains. You see such chains here, long chains, and they are bound to proteins and we call them in combination glycoproteins or proteoglycans, depending on the predominating part. The proteoglycans and glycoproteins are on each cell surface, as you can see here, they are called glycosaminoglycans, and have an interaction with the extracellular matrix or other cells, especially in the nervous system.
[00:04:49] Professor Susanne Gerit-Kircher : In the extracellular matrix of connective tissue, you can find them in the skeleton, in joints and ligaments, intervertebral discs, heart valves and cornea, and they are responsible for the organ- specific consistency, the water content and other characteristics. So you can imagine that these substances and molecules are everywhere in the body, they are ubiquitous. The cause of MPS, one has to explain. We have a correct composition of the chains, first in the endoplasmic reticulum and Golgi apparatus, and these chains, or shorter chains, are excreted and the composition is made to macromolecules outside the cells. But due to the aging and for renewing processes, you have a stepwise degradation and this degradation starts outside the cells and by endocytosis, these shorter chains are brought into the cells, incorporated and brought to the lysosomes. And in the lysosomes, these lysosomes are small cell organelles. In these organelles, you have a lot of enzymes, and these enzymes are important. These enzymes are chain products, and these chain products are made of proteins, and these proteins are formed in the ribosomes and some sort of modified in the Golgi apparatus. They get sugar chains and such things, and they get also a special marker, the mannose 6- phosphate marker. And this mannose 6- phosphate makes them ready to be brought to the lysosome, and in the lysosome, they are incorporated, and there, they are responsible for one degradation step. And if you have many enzymes, you have a lot of possible degradation steps you can perform. In the mucopolysaccharidosis, you need 11 enzymes, which are involved in this degradation process of this sugar chains. And the cause of MPS is that you have chain mutations causing defective enzymes in these diseases. Here you see the sugar chains, and these sugar chains are modified glucose and galactose, and they have sulfate groups or N- acetyl groups, and these different compositions make them, that we call them, chondroitin sulfate or heparan sulfate or dermatan sulfate or hyaluronic acid. And sometimes at the end or side chains, you have other rare sugars such as mannose or phucose. And you have a stepwise degradation by 11 different enzymes, and all of these enzymes remove, for instance, one sulfate group or N- acetyl group or one of these sugars. And so you have a stepwise degradation. And if you have only one enzyme deficient, all the others increase and are stored, and the next steps cannot be performed. So you have a blockage in this degradation process, and the non- degraded material is stored. Mucopolysaccharidoses are storage diseases of that non- degraded material. This material increases continuously in the lysosomes and in the cells and organs, and you can see it. In the light microscopy, you see, for instance, in the leukocyte, the small white vacuoles. These are filled up with glycosaminoglycans. Or in the electron microscopy, you can see that the cells are full of such lysosomes, filled with stored material. And if this cell dies these glycosaminoglycans, this material, comes into the blood, into the urine, and you have an elevated excretion of the urinary GAGs. And this is specific for all MPS types. So if you say, what is the cause of MPS? MPS is caused by inborn metabolic disturbances in the degradation process of these GAG chains due to defective enzymes. Now we have a big group of MPS. We have 11 types, we have 11 defective enzymes, and we have 11 genes we know so far, and these are all the gene loci you can see on this table. What are the early signs? That is difficult to describe, because MPS diseases are diseases with increasing symptoms and signs of storage, and therefore, at birth, all the children look healthy. If you look at these children when they develop the next months and years, they have increasing symptoms, but these symptoms are very heterogeneous, and they can involve many organs in different combinations. And so they can vary from very severely affected patients to attenuated forms in the adult patients. And therefore, at the beginning, you have early signs, but they are very unspecific. At birth, the children often look taller and heavier than the average. They have a relatively large head, they have dysplasia of the hip joints, they have often catarrhal infections of the upper airways, they have snoring, breathing an open mouth, they have repeated ear infections, they have fluid in the middle ears, so they need often ventilation tubes, and they have an overgrowth of the adenoids, and they have hernias inguinal and umbilical hernias. But if you look at all these symptoms, you would say, I have a lot of children I have care of, and many of them have these signs, so they are very unspecific. Other signs can be unspecific, but it really can show you that there is something wrong. It is a slowing down of the growth, so it results in a disproportionate short stature. Still, they have an enlarged head and perhaps frontal bossing and dolichocephaly.
[00:11:31] Professor Susanne Gerit-Kircher : They can develop a mid- fisthead hyperplasia with a settled nose, they have thick and bulging lips and an enlarged tongue, and they need operations of the adenoids and the tonsils and they develop distinct dysmorphic features , especially they develop contractures, and especially in the shoulders and in the fingers and hips and feet and they can show chest deformities and bushy eyebrows with stiff hair. But early signs which are really specific are if they develop hepatomegaly, sphenomegaly, lumbar kyphosis as you can see here, changes of the facial features, skeletal deformities, a language delay, a gingival hyperplasia or small malposed teeth, disproportionate small size and optional corneal clouding, cardiomyopathy, developmental delays and epileptic seizures. So you can observe a stop in the development and some sort of regression. And if you make an X- ray of these patients, here you see the radiological pictures, very similar to those I have shown before from Dr. Wöhler. These patients have MPS and these signs of dysostosis multiplex can be seen on the sclerosis of the skull bases with the J-shaped sella, on the malformed vertebral bodies, malformed lung bones, malformed metacarpalias or flattening of the femoral head. If we try to group MPS disorders, all these 11 MPS disorders, I would say one can make three groups.
[00:13:26] Professor Susanne Gerit-Kircher : The group 1 is the classic type of MPS and this means it is predominant storage. And under this group I summarize MPS I, Hurler's disease, MPS II, Hunter's disease, MPS VI, Maroteaux- Lamy disease and MPS VII, Sly disease. But very different from this classic type, we have the skeletal types of MPS. These are the Morquio diseases A and B and here you see predominant skeletal changes. And the group 3 is again different. And this I call the neuronopathic types of MPS. They have predominantly psychomotoric problems. And here we have the central lipid diseases type A, B, C and D. If we start with the classic types of MPS, it is the disease where the storage dominates. You have the recurrent infections, upper airways and ears, inguinal and umbilical hernias, lumbar kyphosis, joint stiffness of the fingers. These are responsible for the special MPS fingers you have in the logo of these patients. And very early carpal tunnel syndrome. This is a very remarkable sign. Stiffness of all joints. You can see the shoulder is the maximum this boy can move.
[00:14:46] Professor Susanne Gerit-Kircher : And the elbow is also the maximum he can move. And you have reduced movement. You have hepatomegaly sometimes hepatosplenomegaly, you have the skeletal changes I have already told you, short stature, MPS specific facial features, heart valve insufficiency, optimal corneal clouding and cardiomyopathy or psychomotoric retardation. And if you see this picture you will see a lot of these signs. Perhaps you see from outside, the large head is the frontal bossing and the very deep nose here, the saddle nose. You see the different facial features. You see the enlarged tongue. You see the teeth which are not okay. The lumbar kyphosis, the stiffness of the joints and the special hands. Patients are not able to hold anything really correctly. But you have a variability of the phenotypes and on the left side you see severe forms of this disease. But you can notice that other patients do not really look so different. They can even have a normal size, but some of the faces are perhaps not as you expect and they also have a milder form, an attenuated form of these diseases. The skeletal type, the second type, is very different. You have severe skeletal changes with short stature, very short ribcage here and chest deformity, hip dysplasia and flattening of the femoral head. Often these patients are called to have Perthes disease on both sides. They have a laxity of ligaments, exactly the opposite of before, a laxity of ligaments and this is responsible for a waggling gait, this genu valgum, hypoplasia and aplasia of the dense axis, the second vertebral body. And they have progressing corneal clouding, hearing deficits, but they are very intelligent and have high, especially, social competences. And here you see a lot of these symptoms. They do not look like storage disease. They have very severe skeletal problems, its the knees, its the hips, its the size and they have a lot of operations and you can see when they are standing it is really flat foot and the hypermobility and this special hypoplasia of the second vertebral body is responsible that you have instability and severe compression of the myelopathy . And here you can see severe forms. They start very early with operations, neck stabilization operation, leg operation. A lot of problems they have from the orthopedic side. But on the right side you see a man who was diagnosed when he was 52 years old. He had a hip joint replacement operation and some of the medical doctors thought on an MPS. It was an MPS IVA. So we have a third group and this group starts really differently. This is the group where behavior problems, hyperactivity and attention deficit dominates. And they have a progressive developmental delay. They have no language or if they speak already some words, they regress and show regression and lose any language. They have loss of skills. They haven't learned or are not toilet trained and lose it or they are not toilet trained at all. They have sleeping problems which is also the problem for the parents because they do not sleep at night. They have epileptic seizures. And in the progression of the disease they lose everything, even their ability to walk. So they are wheelchair bound and then even they are unable to swallow, to cough up.
[00:18:54] Professor Susanne Gerit-Kircher : They have apneas and increasing paralysis. If you look at these pictures, you never would think on a gargoyle face. It is a very beautiful face all these children have but they are very hard to care on because they are really bad children. One says if they come to a medical office, one never forgets it because everything was changed and nothing was in the place as it was before. They take everything in the hand, in the mouth and so on. And they have very beautiful hair but you see the thick hair, they have bushy eyebrows, you can see here . But they look very beautiful and with the time they have the regression and are not able to walk any longer. And they are really very severely sick patients. Here you can also see a variability. Sometimes it starts very early and you have all these symptoms even in childhood. But sometimes it is late. You see here a man looking really normal at the age of 28 years but due to his mental behaviour he was diagnosed to have Sanfilippo. When should we think on MPS? As soon as possible because we have theurapeutic options. We have to accept that rare diseases are rare but diseases of the whole group of MPS is not so rare. So you should think on if you have disproportionate macrocephaly, if you early carpal- tunnel syndrome, if you have unexplained cardiomyopathy or dysostosis multiplex, especially in the hips and if you have an unexplained psychomotoric retardation, think on MPS. And if you have language problems in your patients. And I discussed it with my colleagues and they said if you have an unspecific sign and another unspecific sign and a third unspecific sign, this makes it suspicious to have MPS at the beginning and you should think on. That is really difficult, I can imagine. Which tests should be performed? The first is that you think on MPS due to the clinical symptoms. Then you make perhaps radiological pictures and you see the features of dysostosis multiplex. You can look at the urinary GAGs, but I have to say they can be false negative in MPS III and MPS IV, but they also can be false positive, for instance, during infections or after operations. So you can look at the defective enzymes and I have to remember that there are 11 enzymes which can be defective. And you have gene mutations in 11 possible genes. So one should think to perform perhaps a whole exome sequencing investigation. I am encouraging for broad clarification because it is not possible that you can see this is MPS type I or this is MPS IIA. It is impossible even for me after so many years. But if you have some results, you always have to look. Is it right? Are the clinical and laboratory results fitting together with the clinic of the patients? The genetic counseling for MPS is that all of them except one type, MPS II, all types are inherited in autosomal recessive state. So you have carriers, they are healthy, they can be males and females and they have one gene allele mutated. We call it heterozygous. And you have the patients, they can be males or females and they have both gene alleles mutations. And if you have homozygous mutations, the disease is confirmed. If you have compound heterozygous mutations in the sequencing, then you have to prove that it is not in the cis, but in the trans position. It has to be confirmed, the trans position of the two different mutations on the two different gene alleles. The MPS II type is X- linked and we call it X- linked recessive, although I'm not so sure it is recessive all the time. The carriers are always females, they have two X chromosomes and they are healthy and they have one mutation on one of the two X chromosomes and they call it heterozygous. The patients are always males and they call it hemizygous if they have one mutation on the X chromosome. But I have written down that very rare you find females with this type of MPS, the MPS type II, due for instance, due to X inactivation of the non- mutated X chromosome. Why is it necessary to diagnose MPS so early? I think one of the main causes is to prevent myelopathy and tetraplegia due to the instability of the craniosacral junction. It is especially in MPS IV, but you can have it in a milder form in all the other cases. So first look if the dense axes have a hypoplasia or aplasia and correct them by operation as soon as early to prevent this tetraplegia. The other cause is that if you find early enough patients with MPS I, you can offer a hematopoietic stem cell transplantation and this disease or this treatment of the disease is now the gold standard for MPS I. But it must be before the 18th month and this is very early. For many other patients, you have enzyme replacement therapy. This means a weekly intravenous infusion of the deficient enzyme. So the enzyme is produced and given to the patients every week. This is available for the patients with MPS I, II, IVA and VI and it is planned in the next year for MPS VII. But there are a lot of multiple clinical trials with intrathecal and intraventricular enzyme replacement therapy for instance in a neuroneuropathic form of MPS II and III, gene therapy for the MPS III patients. All these difficult trials are because intravenously given enzyme cannot come through the blood- brain barrier and this is the reason why one has to take other ways to break the enzyme into the body. We have trials with substrate reduction therapy, chaperone therapy and read- through gene therapy in MPS I patients. For many patients, the enzyme replacement therapy is part of their daily life and they can get it in the hospitals but they can also get it in the doctor offices of the pediatrician or other medical specialists. And here you see this patient get this in their home therapy and this is a very good way to have a lot of quality of life. Now I have shown you my presentation and I live in Vienna, perhaps Vienna is known, some of you, due to Mozart and Kaiserin Maria Theresia or Empress Sissi and this is my place where I'm working on. Here you see a list of the webinars in other LSDs and I want to mention that there are webinars about Gaucher disease, Fabry disease and now also MPS disease, you can see at any time you want. And now I'm ready to answer your questions, you probably have. I still wait for the first questions, thank you that you have been going with me through that presentation. I see the first question. The first question is if a newborn looks suspicious to have MPS due to hepatosplenomegaly, macroglosia, and macrocephaly, shall I test for MPS? I would not think of MPS if a newborn shows all these signs. We have very severely affected patients, but this you can even recognise in utero, it means they are born with hydrops fetalis , especially in MPS VII or IVA. But if a newborn looks very, very strange, I would think perhaps with Wiedemann or other diseases, not on MPS. It can also be a mucolipidosis type II, that can be, but not MPS. Another question is, can I find pathological results in the routine laboratory tests, such as hypoglycemia or hyperbilirubinemia or anything else? No. These diseases are metabolic diseases, but not metabolic diseases of the nutrition. These are metabolic diseases in the cells and therefore you cannot find anything in the routine laboratory results. The third question is, you told that MPS patients could be treated by hematopoietic steam cell transplantation. Until which age is this therapy an option? As I told you, the option is really good for MPS I, perhaps for MPS VI at the moment, but the transplantation has to be performed before the 18th month. So this means that you need a very early diagnosis, often not done. It is not an option at the moment in MPS II, in Hunter's disease. It is not at all an option in MPS III, Sanfilippo's disease, because all these diseases perhaps have the problem with the blood- brain barrier. This is also a problem even if you make a hematopoietic steam cell transplantation. I do not have more questions. I thank you all for watching this webinar and I hope that you will take the chance to look back to this webinar.
[00:30:36] Professor Susanne Gerit-Kircher : You... want and perhaps some of the pictures may be helpful in watching your patient and looking back what did she say, what did she show to us. I thank you very much and I thank the organisers very much for the opportunity to make this webinar. Bye- bye from Vienna. Bye- bye.