Dr. Christina Lampe: 00:00:00 Hello everybody, dear colleagues, I welcome you to this online course Challenges in Diagnosis and Disease Management of MPS and Alpha-mannosidosis. Extremely rare diseases, this I have to admit, but diseases that are treatable and this is why it is important to know about and to to be aware of. So we start the first module in introducing MPS and Alpha-mannosidosis challenges in diagnosis and disease management and my name is Dr. Christina Lampe.
Dr. Christina Lampe: 00:00:37 I'm the director of the Center for Rare Diseases at the University in Gießen at the Department of Child Neurology and now let's start the session. Just a few notes before we we start. Please do not take any screenshots. Please do not reproduce any slides or content of images. The format will be 60 minutes split into two parts. So 20 minutes for the first presentation, 10 minutes question and answers.
Dr. Christina Lampe: 00:01:09 You have a chat where you can answer all your questions you have and I will answer the first part after the first 20 minutes of presentation and then we have another second part and after that there will be a question and answer session again. So please submit your questions via text and not verbally and whenever there's time enough I will answer as best or on my best to have your questions. So let's start part one introduction and overview. What is MPS and Alpha-mannosidosis? How to diagnose MPS mannosidosis early?
Dr. Christina Lampe: 00:01:49 So the earliest signs and symptoms which is the most difficult part I have to say. Then exploring the latest diagnostic options that are available and the third part will be reviewing the pathophysiology. So we want to I want to start first with a lot of pictures so that you get an impression of this disease and why it is so important or difficult actually to recognize MPS is in practice and what you can see here on the pictures and these are some examples of MPS patients that this fast progressive or so- called classical MPS patients.
Dr. Christina Lampe: 00:02:23 It is in a way obvious that something is wrong with these children but they are already at an older age and it is something that you will start any diagnosis for sure. In other cases in these patients at the same age but in a more slowly progressing disease or non classical disease it is much more difficult to make a diagnosis because the there's not obvious immediately that something is wrong with these children and you may think probably they're just a little bit different from others.
Dr. Christina Lampe: 00:02:55 So but these have the same disease and if these patients are actually adults it is extremely difficult to make any diagnosis because then they are not under the care of pediatricians anymore and adult physicians are not that much aware of these diseases of childhood genetic diseases inborn errors of metabolism. So at this point these patients have often misdiagnosis.
Dr. Christina Lampe: 00:03:19 So it is important that you as a pediatrician diagnose this patient as early as possible and to show you that these patients are really very similar to other skeletal displacers here are some pictures of patients. Some of them are MPS patients, so mucopolysaccharidosis patients, metabolic patients but they are also part of the 460 skeletal displacers that we know and you see here how difficult it might be to diagnose. So how to diagnose early?
Dr. Christina Lampe: 00:03:50 The major problem is that if you see the earliest signs and symptoms of MPS and mannosidosis they are very similar to common complaints that you have to deal with as a pediatrician. For example you have a child visiting you with recurrent infections of the ears and airways or you have a child visiting you with hearing loss or with umbilical or inguinal hernia or a child that seems a little bit stiff in a way or has some developmental delay. So nothing really to be concerned about I think, correct?
Dr. Christina Lampe: 00:04:25 But how about if these infections are much more frequent or severe than usual or how about if this child has additionally a hearing loss or additionally an umbilical hernia or inguinal hernia or if this child additionally to this more frequent and severe infections it seems to be stiff or in a way delayed in diagnosis. So you have the impression that something might be wrong. So what do you think and what do you do actually?
Dr. Christina Lampe: 00:04:54 And to give you a very typical example of a patient with a mucopolysaccharidosis that might be a mucopolysaccharidosis but also from this earliest signs and symptoms a mannosidosis I will show you a video about one child. This is a child that is born from German and Spanish parents, normal height and weight at birth, uneventful pregnancy and he was dismissed from the hospital without any pathological findings besides a slightly enlarged head circumference. You see him here looking extremely healthy and as a like a normal baby.
Dr. Christina Lampe: 00:05:35 I'm sorry for that. I will start the video again. You see him here in his first week and he looks absolutely nice. Parents actually saw his first smile in his life at the second week. You see him here and please check a little bit if you see the parents in the background and compare it to the appearance of the child and also check how the child is moving if he looks a little bit stiff. With five months here the child had an umbilical, an inguinal hernia and needed an operating surgery to to solve this problem.
Dr. Christina Lampe: 00:06:20 With five months he was a seven months he was able to sit and with nine months he was able to turn around alone. With nine months he started to to speak with yeah yeah yeah yeah so the typical first sounds of a child. With ten months he had a severe infections of the airway he needed antibiotics and after two weeks he had an another infection and needed antibiotics again. With 11 months you see him here with the mother. He is a healthy looking child.
Dr. Christina Lampe: 00:06:52 The only thing was that his head circumference looked a little bit big and the mother was concerned that he was not really starting to speak. So he started here with his parents saying mom and dad but he was not really trying to speak properly even if he tried to communicate very much. Here with 15 months you see him walking his first steps so absolutely in time and here he said he wanted to take some some toy and you see that he had problems in moving his shoulder so in a way stiffness.
Dr. Christina Lampe: 00:07:24 With 18 months here he could stand up alone you see the enlarged abdomen and the umbilical hernia and with 19 months he was able to eat alone. The parents were very concerned about the fact that he had an enlarged head and also that he was not speaking and they were certain had the impression that he had an hearing loss.
Dr. Christina Lampe: 00:07:50 So he went to an ENT. The ENT diagnosed some fluid behind the eardrum and due to the recurrent infection that he had already the ENT had the suspicion that this child needs an adenoatectomy because he was also not sleeping properly had a lot of snoring and apnea during night and also some t- tubes. So they performed an hearing test and showed a severe hearing loss on both sides. The mother was pregnant that time so she was very concerned about the situation of the son and wanted to to to get a diagnosis.
Dr. Christina Lampe: 00:08:29 So this child had an ENT surgery with adenoatectomy and also t- tubes but unfortunately the child or the hearing test after was not really showing any benefits. So I just show you a little bit more pictures with 27 months he went to the kindergarten he was still not speaking properly and with 28 months look him here when he is moving very shortly he in a way he looks stiff the spine looks extremely flat and he's not really flexible and mobile that you would expect in a 28 months old child.
Dr. Christina Lampe: 00:09:08 He had at this point also the umbilical hernia making trouble and another inguinal hernia on the other side that needed a hernia repair. Just to go a little bit here he is on the beach the parents were concerned about his sleeping because he was waking up several times he was still snoring he had had apnea and he was not really healthy.
Dr. Christina Lampe: 00:09:39 So the parents went to a pediatrician and the pediatrician said that the head circumference is okay it's a little bit enlarged but nothing serious and she did not say any she did not saw any any reason for further diagnostics but the parents insisted on having some developmental delay testing and also to go to a neuropediatrician or child neurologist to understand what is going on with the child. This child neurologist had already seen once an MPS patient and due to that she started to make some diagnostics.
Dr. Christina Lampe: 00:10:15 Unfortunately it was summertime in Spain and the physician or the diagnostics took extremely long and for this reason it took quite long after until he had a real diagnosis. And with that picture I want to stop the video and just summarize for you the signs and symptoms that we had so far.
Dr. Christina Lampe: 00:10:39 The diagnostic was then done in Germany because there was a geneticist, also the neuropediatrician knew about the MPS disease and mannosidosis and the diagnostic was done. So just to summarize, the pregnancy and birth was absolutely normal in that child. He had just this slightly enlarged head circumference. His development was normal. He had with five months an inguinal hernia on one side, with two and a half years adenoidectomy in T-tubes and also an inguinal hernia repair on the left side.
Dr. Christina Lampe: 00:11:17 Additionally, at this time he had a delay in teething, enlarged head, language delay also due to the hearing loss and always recurrent severe infections of the airways. And you see also here on the pictures how he changed his face. And also the parents were concerned because he looked totally different from the family. I said already with 1. 7 years of age, an ultrasound of the head was done and the pediatrician saw no reason for further exams. And at the age of two and a half years, there was the first visit at the child neurologist.
Dr. Christina Lampe: 00:11:56 And the diagnosis at this time was global developmental delay, in particular language developmental delay. So extremely unspecific. But it could be also a multisystemic disease. And the child neurologist had already the idea. And she started to make some tests, some urine tests, I will explain later, to get an impression whether this could be an MPS or mannosidosis. She made some enzyme activity testing in blood because MPS and mannosidosis are diseases with a deficiency of a lysosomal enzyme and also a genetic confirmation of the disease.
Dr. Christina Lampe: 00:12:36 So what is this now so difficult to make an early diagnosis in children with MPS or mannosidosis? The major problem is the earliest signs and symptoms show overlap with very common complaints in childhood like frequent respiratory infections, ear infections, hernia, developmental delay, hyperactivity. It could also be a diarrhea or heart murmur. So what you have to do to get a diagnosis because there's no specific earliest sign and symptoms of MPS and mannosidosis. But the combination of these symptoms could lead to a suspicion.
Dr. Christina Lampe: 00:13:15 So a lot of children should be tested. To describe MPS and mannosidosis is very rough. It is a multisystemic disease. It is a genetic disease. It's chronic progressive. This is an important fact to have to take into consideration if you deal with these children. The appearance is extreme heterogeneous and it is life-threatening. But important is even if these diseases are so rare, we have for some MPS types and for mannosidosis a treatment available. And you don't want to miss any treatable disease in your practice.
Dr. Christina Lampe: 00:13:57 It is a multisystemic disease, I told already, and the signs and symptoms are here described with a lot of pictures of MPS and mannosidosis children. And what we see is the face has a coarse face. So you see it when they are older. The appearance is showing that something is wrong with the child. They have a hepatosplenomegaly, inguinal and umbilical hernia, sometimes swallowing problems. The lung has obstructive and restrictive lung disease, the recurrent infections that makes a lot of trouble.
Dr. Christina Lampe: 00:14:32 They have narrowed airways, take to anesthesia in these patients, very difficult topic. They have skeletal problems. And this is also why the MPSs and mannosidosis are part of the skeletal dysplasia, not only a metabolic disease, but hip dysplasia, kyphosis, contractures. A kyphoscoliosis in the torocolumbar spine could be the first symptom for an MPS disease. They have an eye involvement with the typical symptom, corneal clouding. The ears are affected with hearing loss and recurrent infections.
Dr. Christina Lampe: 00:15:08 But also the heart valves are involved, especially in MPS, not that much in mannosidosis. And the CNS in some patients, 60% of patients with mannosidosis and MPS have an involvement of the CNS due to the storage of material in the brain. And this is actually one of the biggest topic of these patients, 60% have a CNS involvement with the cognitive decline, but others don't have.
Dr. Christina Lampe: 00:15:40 I said already MPS and mannosidosis are extremely heterogeneous, which means the variability of signs and symptoms. Not all children show all or present all signs and symptoms that I showed before. They have a wide spectrum of disease severity, I will show you another picture, and the disease severity in specific organs may differ from one patient to the other. So it means MPS or mannosidosis patients have their own disease. Each patient has his own disease, and this makes it extremely difficult and variable in the clinical picture of these patients.
Dr. Christina Lampe: 00:16:19 And especially if patients have no cognitive involvement, it is even more difficult to diagnose. Here it is in the upper... an example from the literature of an MPS1 patient that has a very slow progressive disease. But what it shows that even if the child at the age of four years and the young lady at the age of 24 years look absolutely healthy, the storage had already begun. And you see with 31 years of age and with 54 she's in a wheelchair.
Dr. Christina Lampe: 00:16:54 So it means even if the disease is slowly in progression, she has the same complications of the disease than more severe patients. So this means also these patients should be diagnosed and treated. And actually in the lower part of the slide you see a six- month- old MPS2 boy looking absolutely healthy and fine, and at the age of 30 years you see the severe storage in the face. But this is not only in the face, but this happens in all organ systems, even if they appear normal at birth. And this is the way of this disease.
Dr. Christina Lampe: 00:17:32 To make it a little bit easier, before I tell you about the pathophysiology and how to diagnose these patients, you see a mannosidosis patient that is also called Hurler-like syndrome. Hurler is the severe form of MPS1. And you see also I divided them in the stiff ones and the hypermobile ones and also those with cognitive loss of cognitive abilities. The MPS1, 2, 6, and 7 patients, they look very similar in the yellow frame.
Dr. Christina Lampe: 00:18:04 And I call them the stiff ones because what you see are the contractures of joints and the enlarged abdomen with the umbilical hernia in the short neck. In contrast to them, the hypermobile ones, the MPS4A and B patients, they are the same group of disease, but they have a hypermobile joint and more musculoskeletal disease, while the MPS3 patients have a loss of cognitive abilities in childhood and have less severe physical involvement of the disease.
Dr. Christina Lampe: 00:18:39 And to show you some pictures of the more mild and severe patients for the disease severity, I will give you some short introduction to these diseases. For Alpha-mannosidosis, we have a very mild form with a very slow progression and juvenile onset. We have a moderate form with a juvenile onset and slow progression. And we have a severe form that starts in infancy and has an important CNS involvement and early death. And you see some pictures here. But there is a treatment available, the enzyme replacement therapy.
Dr. Christina Lampe: 00:19:17 So the missing enzyme is replaced with an IV infusion every week. The spectrum of the disease severity in MPS1 is shown here. And important is that MPS1 has one advantage in contrast to the other MPS types. The advantage is that if you diagnose an MPS1 patient with a severe disease under the age of two and a half years, there is a stem cell transplantation or bone marrow transplantation possible that is stopping the cognitive decline in these patients. So this is why it is extremely important to diagnose early.
Dr. Christina Lampe: 00:19:57 So stem cell transplantation is a treatment option for MPS1 patients if you diagnose prior two and a half years in life. And then you can stop the cognitive decline in these patients. But we have also patients in MPS1, the shyer patients, that are without any cognitive involvement. And actually in former times before the reason or the cause of the disease was described, the enzyme deficiency, they were thought to be another type of MPS, the MPS type 5.
Dr. Christina Lampe: 00:20:31 Now we don't have MPS type 5 anymore because the enzyme deficiency is the same from the severe and also the adenuated types.
Dr. Christina Lampe: 00:20:41 Another MPS type is MPS type 2, it's the Hunter syndrome. You see, we have patients with cognitive and without cognitive involvement. Important in this Hunter syndrome is that beside all other MPSs and also mannosidosis, MPS 2 is the only X-linked disease in this group of diseases. So MPS 2 is X-linked. The mothers are carrier and the boys are affected.
Dr. Christina Lampe: 00:21:10 And they have no corneal clouding, which is a very specific symptom for MPS. Child with corneal clouding, you should think to MPS. In MPS 7, an ultra, ultra rare type of MPS, you see here the spectrum of the disease. There is a treatment available as well, the enzyme replacement therapy, like in Hunter syndrome and MPS 1. And typical here is that some of these children have a hydrops fetalis when they are born. This should always lead to a suspicion to test on MPS 7.
Dr. Christina Lampe: 00:21:46 I told already Sanfilippo syndrome or MPS 3 is a group of four different enzyme deficiencies that have mainly progressive cognitive decline in childhood. So there's so far no treatment available, but there are some clinical trials on the way, and they have neurological problems, seizures, behavior problems. Now we are entering the Morquio syndrome. MPS 4 or Morquio syndrome is a mainly musculoskeletal disease. They have the hypermobility of joints in contrast to all other MPSs that are more stiff and have contractures.
Dr. Christina Lampe: 00:22:25 They have the specialty that they have an antelanto- axial instability, which makes anesthesia complicated as well. And also here, there's an enzyme replacement therapy available, at least for MPS 4A, I'm sorry. MPS 4B is not treatable. And spectrum of the disease severity of MPS 6, you can see here from fast progressive to slowly progressive. They have no cognitive involvement as the Morquio patients. MPS 4 and MPS 6 are the only MPS types where you have never a cognitive involvement. And I will explain to you a little bit later why.
Dr. Christina Lampe: 00:23:03 These patients have an enzyme replacement therapy as well. You see, due to this disease severity spectrum and the heterogeneity of these diseases, it is extremely difficult to diagnose. And what you can see that in literature, we have indeed a median delay of diagnosis of three years. In MPS 3 and 4 patients, you see here on the picture, it is also six years. So it is a big gap between earliest signs and symptoms in early childhood in the first two years of life and the diagnosis that is done much, much later. So how to diagnose these patients now?
Dr. Christina Lampe: 00:23:45 The screening test that is possible and easy to do is to measure the oligosaccharide excretion and the glycosaminoglycans for MPSs in urine. Unfortunately, this is not a really confirmation of diagnosis because we have false, in increased excretion, but also normal GAG or oligosaccharide excretion in urine, even if it affected children, which means this test is a good screening method, but it is not confirming or not making any diagnosis.
Dr. Christina Lampe: 00:24:21 The gold standard to diagnose these patients, because we are talking about rare lysosomal diseases, we are talking about enzyme deficiencies that are leading to storage in all organ systems. And this is why the enzyme activity testing in blood or fibroblasts is the proof of diagnosis. So whenever you have a patient and you have a low enzyme activity for different enzymes, you confirm the diagnosis of mannosidosis or MPS.
Dr. Christina Lampe: 00:24:53 We have a genetic testing which is confirming diagnosis and can also make diagnosis but not all mutations that are leading to MPS and mannosidosis are described in literature. So this is why you can have false negative results with genetic testing because not all mutations are found. The prenatal testing if you have genetic testing in one affected child is possible and the easiest option to diagnose MPS or mannosidosis is the dry blood spot testing.
Dr. Christina Lampe: 00:25:26 It is so far not available or not in all countries available for Alpha-mannosidosis but it is on the way and we have dry blood spot testing for MPS 1, 2, 3a, 4a, 6 and 7 and this is only five drops of blood on a filter cart you send it away and you get a result. It is extremely specific but it is, I'm sorry, it is extremely sensitive so you will not miss any patient but it is less specific so you have false positive testing. So this is why the real confirmation has to be done by enzyme activity testing in fibroblasts or blood or with genetic testing.
Dr. Christina Lampe: 00:26:05 So what is the pathophysiology? I talked so much about these diseases but I never said what it is the reason or the cause of the disease and actually we have 6,000 genetic diseases. We have 600 metabolic diseases, 60 lysosomal diseases or storage diseases and 11 MPS deficiencies leading to 7 types of MPS and Alpha-mannosidosis and you see here that all the lysosomal diseases, the red one surrounded diseases are diseases where we have treatment and the blue ones where we have treatment on the way. The pathophysiology is easy.
Dr. Christina Lampe: 00:26:48 It is the dysfunction of at least one lysosomal enzyme and this is leading to the accumulation of products that should be recycled or cleaned from the body but this storage of MPS, glycosaminoglycans or in mannosidosis oligosaccharides are leading to a cell dysfunction and cell death and since we have everywhere in our body glycosaminoglycans and oligosaccharides all organ systems are affected. For example, glycosaminoglycans are the main component of the extracellular matrix in the body.
Dr. Christina Lampe: 00:27:30 So glycosaminoglycans are everywhere and if you have a storage everywhere in your body it is clear that you have a multi-organ involvement and here on the picture on the right side you see a cell with all the white bubbles that is storage material and I think it is obvious if you see that cell that this cell is not working properly anymore. To show you the classification of MPS because in Alpha-mannosidosis it is one disease. We have deficiency of alpha monocytes and storage of oligosaccharides.
Dr. Christina Lampe: 00:28:05 In MPS it is a little bit more difficult because it is not one disease but these are 11 known enzyme deficiencies that leading to storage of different GAGs and to seven main types of MPS and as I said before not all of these patients have a cognitive involvement.
Dr. Christina Lampe: 00:28:27 So these patients where the glycosaminoglycans are stored heparan sulfate, one glycosaminoglycan that I here used HS to show it, we have it in MPS 1, 2, MPS 3 and also MPS 7 and these are the diseases that are storing heparan sulfate and for this reason may have or can have CNS involvement because the heparan sulfate is the cause of that. So again just to summarize we have the Alpha-mannosidosis that looks like a severe MPS 1 patient. We have the seven types of mucopolysaccharidosis, the stiff ones, MPS 1, 2, 6 and 7.
Dr. Christina Lampe: 00:29:13 We have in contrast to that the hypermobile ones, the MPS 4A and B patients that have the hypermobility of joints and we have the third group, the MPS 3 patients, four different enzyme deficiencies that are leading to a loss of cognitive abilities in childhood. And now to prove for you also to see whether everything I told you was clear before you can ask your questions, I would like to start with one question.
Dr. Christina Lampe: 00:29:49 So what is correct, mucopolysaccharidosis and mannosidosis are multisystemic diseases, are extremely heterogeneous, have always cognitive involvement, are due to different lysosomal enzyme deficiencies and are metabolic diseases and skeletal dysplasias. What do you think?
Dr. Christina Lampe: 00:30:13 I will show you the answer immediately. So what is correct was the question. For sure, they are multisystemic and extremely heterogeneous diseases. They have not always a cognitive involvement. As I told you, MPS4 in six patients never have, and there are also some patients that have sometimes an involvement and sometimes not. So not all patients have a cognitive involvement, but they are due to different lysosomal enzyme deficiencies. This is correct.
Dr. Christina Lampe: 00:30:49 And they are metabolic diseases, enzyme deficiency, but also skeletal dysplasias, as I showed you at the beginning. So number C is correct. Question two, what is wrong? The question, what is wrong? Mucopolysaccharidosis and mannosidosis have specific early signs and symptoms, are easy to diagnose, have kidney involvement, have something, sometimes hearing loss as first symptom, or symptoms overlap with common complaints in childhood. So what is wrong? So what is wrong? They have no early sign and symptom that is specific.
Dr. Christina Lampe: 00:31:36 This makes it so difficult to diagnose. It is not easy to diagnose. This is the next. And actually, nobody knows why, but MPS patients have no kidney involvement. For sure, they have sometimes hearing loss as first symptom, and the symptoms overlap with common complaints in childhood. This is correct. And the last question before you start your questions. And again, what is correct in mucopolysaccharidosis and mannosidosis? Glycosaminoglycans or oligosaccharide excretion in urine can be normal.
Dr. Christina Lampe: 00:32:11 Enzyme activity testing in blood is the gold standard of diagnosis. Genetic testing is useless. Dry blood testing is very sensitive, but less specific. And only from the appearance, the different types of MPS can be diagnosed. Make your guess. Okay, what is correct? For sure, glycosaminoglycans and oligosaccharides excretion in urine can be normal. This is what I explained, that it is only a screening test and not a confirmation of diagnosis. The enzyme activity testing in blood is the gold standard. This is correct as well.
Dr. Christina Lampe: 00:32:54 Genetic testing is useless is a stupid sentence for sure. And dry blood spot test is very sensitive, but less specific and need a confirmation of diagnosis. This is correct. And this is totally wrong that only from the appearance, the different types can be diagnosed, even for an expert. It is impossible. So now I'm waiting your questions and answers. I hope that a lot of people will be very interactive. And here I see already the first question.
Dr. Christina Lampe: 00:33:29 And the question is, do these children have the same facial appearance at birth or their facial features become more evident while they are growing up? And I think I showed you the MPS2 boy looking absolutely healthy at the beginning. And also the video showed the child being absolutely healthy at the beginning. And over the time you saw the face that was changing and you saw the storage in the face. So it is absolutely typical. An MPS child is healthy looking at birth, very proper, very nice children.
Dr. Christina Lampe: 00:34:03 And over the time you see the change of the face, the coarse face due to the storage. Next question. Any further question? The next question is, are these now metabolic diseases or skeletal dysplasias? And actually they are both. They are part of the skeletal dysplasias. The skeletal dysplasias are divided in 40 something groups of different diseases. And one group is indeed the lysosomal storage disorders with dysostosis multiplex. So dysostosis multiplex is the typical radiological signs and symptoms of MPS and mannosidosis patients.
Dr. Christina Lampe: 00:34:45 So it is the hip dysplasia, the thickened skull, the shortened long bones, the shortened and thickened middle hand and middle feet, the overweight vertebras. So these are typical signs of MPS. So MPSs are metabolic diseases because it's an enzyme deficiency disorder, but they are also skeletal dysplasias. Any further questions? Do have patients with cognitive involvement also benefit from ERT treatment, although the enzyme is not crossing the blood- brain barrier? This is the question I will answer a little bit later because I will explain first.
Dr. Christina Lampe: 00:35:30 So any further questions?
Dr. Christina Lampe: 00:35:32 Are there any specific genetic mutations or enzyme activity that correlate with a cognitive spectrum of MPS2?? There's no clear correlation between mutation and cognitive involvement in MPS2.. For sure very severe mutations or big changes or mutations make more severe phenotypes. But there's not like in MPS1, we have a better genotype- phenotype correlation in MPS. It is not completely clear, but there are some mutations that indeed lead to a severe phenotype. Any further questions: is there any test that can be done during pregnancy?
Dr. Christina Lampe: 00:36:23 Unfortunately you cannot make a diagnosis of for sure. You can measure in the amniotic fluid. You can measure the enzyme activity, but actually if you don't have any case or any patient in your family, it is so rare the disease that it is not part of the usual screening testing. But if you have one patient in your family, a cousin or a sibling of the unborn child, the best would be to make a chorionic billy examination if you have a genetic result of the affected child, because then you can look for this mutation. The amniotic fluid is also possible.
Dr. Christina Lampe: 00:37:04 You can measure the enzyme activity, but you have to grow the cells for a few weeks and also to weight the result, and so the pregnancy is already in a higher status. It's around the 20th week of gestation and then it is very difficult to decide what you want to do with the child. So the chorionic billy examination with the genetics, it's the best. Actually. Any further questions? What about the DBS for alpha-mannosidosis? This is already on board and so far as I know- I am in Germany- what I can tell you?
Dr. Christina Lampe: 00:37:50 That we don't have it by now, but we are waiting for that, so it will be possible. There's one lab in Germany that is already offering the dry blood spot test for mannosidosis, but not in general. But I hope and I think that it will come soon in a lot of countries because it's really the easiest way to diagnose. Any further questions: how is Morkio treatment executed? I don't understand the question exactly. If the question is, what is the expectation of Morkio for a treatment, I can say that there is indeed also in the trials that are over two years.
Dr. Christina Lampe: 00:38:37 There is a benefit in endurance, in pulmonary function, also in quality of life. But it is not. We have the treatment since 2014,, so it's only a short period that we are overseeing. Also, it seems that patients are growing better, which is another benefit. They have less infections. So it is a treatment that is indeed working but not available in all countries, unfortunately. Are siblings having similar clinical features?
Dr. Christina Lampe: 00:39:17 Yes, they have, although I have to say if you have siblings, one is always a little bit more affected than the other, but also in this case we have, since we have the treatment. One starts always earlier than the other or at younger age, and I will show you very soon an example how different it is if you start early or later. But for sure we don't have one very severe affected child and, with the same mutation, a very, very mild affected child.
Dr. Christina Lampe: 00:39:46 So they are similar but not absolutely clear because, as I said, every patient has his own disease and I think we have to go to part two, otherwise we will be longer than 60 minutes.
Dr. Christina Lampe: 00:40:04 And I will start with the next part, the red flags, signs and symptoms, the basis of diagnostic and when to suspect. So we start with examining the multisystemic features of the disease. I will show you a lot of pictures and a lot of slides. So just focus on the pictures that I show, reviewing how is the best follow up for these patients and what is the treatment that is available for these patients. So why we have to diagnose early? This is the first question I want to ask. And here it is, what does it mean for undiagnosed patients?
Dr. Christina Lampe: 00:40:42 Undiagnosed for a patient means looking always to get a diagnosis, to get a treatment, to link to an expert, to link to other affected families or patient associations, to think to family planning. If you don't know what disease that your child is suffering from, you don't know actually how will be the situation for further children. So you have an uncertainty. And also mistreatment is absolutely normal in undiagnosed patients because not all treatment options are the best for each disease.
Dr. Christina Lampe: 00:41:19 And also you cannot detect the life limiting disease complications if you don't know which these are and also the quality of life limiting disease complications you don't treat because you don't know what you have to look for. So for your patient, it has a big, and the families have a big, has a big benefit to have a diagnosis. The second reason is the storage begins prior birth as I told you before, and this is confirmed in human fetuses with MPS2. So it means even if the child is born and looking absolutely healthy and the storage had already begun.
Dr. Christina Lampe: 00:41:56 The third reason why to diagnose and also start treatment early in MPS and mannosidosis patients is that MPS and mannosidosis are progressive. And I showed you already these pictures and I would like to highlight again that this is happening in all organ systems. So if you start the treatment and you have irreversible organ damage, the irreversible damage is there, but what you want to do is to avoid any irreversible organ damage.
Dr. Christina Lampe: 00:42:26 And what we know for the treatment is here's an example for MPS2, but it is also published for MPS6 that we have in treated patients a better survival. And here it is demonstrated in 1, 000, almost 1, 000 MPS2 patients that they have in 54% a lower risk of death in the treated patients and a lifespan that is 10 years longer in treated patients than in untreated patients. And here's the case report that I was referring to. The patient one, he started at the age of three years of age with enzyme replacement therapy. So the missing enzyme was substituted.
Dr. Christina Lampe: 00:43:10 He had all organ systems affected, as you can see here before ERT and after three years he was checked again. And what you can see after three years, he stabilized in a lot of signs and symptoms or he improved also in hepatomegaly, for example, and not very much in the skeletal involvement, the dysostosis multiplex, which is obvious because it is a less vascularized tissue. But if you compare it with his brother who started at the age of four months, he was diagnosed because of the disease of the brother with enzyme.
Dr. Christina Lampe: 00:43:51 He had no signs and symptoms when he was born, as we said before. And after three years on treatment, you see that he still has almost in all signs and symptoms, no involvement beside the skeletal part, which shows that the earlier you start, you avoid irreversible organ damage and you avoid signs and symptoms. But now what treatments are available in these patients? Actually, you have to check all organ systems in these patients.
Dr. Christina Lampe: 00:44:22 I said already the life- threatening disease complications, the CNS, the respiratory system, and the heart, and also the quality of life- reducing disease complications in these patients, the skeletal, the eyes, and the ears, who cannot see properly and not hear properly, cannot develop properly, and they have a really limited quality of life. Also, mobility is a big issue, especially in more acute patients. So this is why we should really take care of that. And you have a lot of exams that could be done to check these organ systems.
Dr. Christina Lampe: 00:45:00 And I will show you later a recommendation how to do it. So what is needed is a lot of specialists to treat these patients.
Dr. Christina Lampe: 00:45:07 And now, let's see what quality of life- reducing disease complications we have in skeletal ENT eyes and gastrointestinal involvement. I would like you to now concentrate on the pictures, not very much on the text. So for the skeletal and joints, what we need is we need imaging, we need joint range of motion measurements, and we need orthopedics that are taking care of these patients. We need a lot of physiotherapy.
Dr. Christina Lampe: 00:45:37 There are some surgical procedures that are really helpful in these patients, but also orthosis or insoles or corsets that can really help these patients. But most important is the physiotherapy. From the craniofacial ENT eye and teeth point of view, we have to treat the deepness of these patients with hearing tests, T- tubes, adenoidectomy, hearing aids. The recurrent infections have to be treated very aggressive, also with antibiotics, inhalation, T- tubes if needed, and so on.
Dr. Christina Lampe: 00:46:19 Adenoidectomy, tonsillectomy, extremely frequent in MPS patients and needed also for a good sleep. And the eyes are involved with corneal clouding, visual impairment in MPS6, for example, also glaucoma, or in mannosidosis, strabism. Very obvious things. Gastrointestinal, we have the hepatosplenomegaly, but this has no therapy needed because hepatosplenomegaly is absolutely without any restriction in the function of these organs. So it is just big, but the function is perfectly fine.
Dr. Christina Lampe: 00:47:01 Umbilical and inguinal hernias need surgery, and the diarrhea needs to be treated with medication if needed. The behavior and cognitive decline in these patients that we have in 60% to 70% of patients that I said already, like hyperactivity, aggression, motor decline, abnormal gait, this is something we can try to treat with medication. The sleep disorders are a big, big problem in these patients and also lead to an impairment of the cognitive situation and the hyperactivity of these patients. So sleep is extremely important in these patients.
Dr. Christina Lampe: 00:47:40 So perform polysomnographies to detect sleep apnea and sleep problems to treat that. Also with medication or with CPAP ventilation during night, very important also for the behavior. And you know, children that don't sleep properly are not in a good mood the next day. Seizures are one topic that need to be treated, and also hydrocephalus or spinal cord compression are big topics in these patients. What is the life- threatening disease complication in these patients?
Dr. Christina Lampe: 00:48:14 We have the cardiac involvement, the pulmonary, the airway infections, and the CNS, the craniocervical stenosis. And as we said with the ENT system, also here the frequent infections of the airways need inhalation, antibiotics, physiotherapy, and also surgical interventions to solve the problem. We have the restricted lung disease due to the small and very stiff rib cage in these patients. I don't know whether you have seen, but most of these patients have a very short trunk and long legs and arms.
Dr. Christina Lampe: 00:48:47 So the rib cage is extremely small, and the enlarged abdomen also gives not very much space to the lung, and the lung cannot really work properly. So this is why these patients really need a lot of help and physiotherapy also to deal with the lung disease. And actually, the cardiorespiratory complications is the main cause of death in these patients. In MPL- 3, also the pneumonia. So this is why the pulmonary system has to be checked and has to be treated aggressively.
Dr. Christina Lampe: 00:49:21 Heart insufficiency is not that much often, but heart valve disease and heart valve insufficiency, and also arrhythmias. So you have to check regularly the heart in these patients. And I told already, and I would like to highlight again, be aware that MPS and mannosidosis patients have, due to the narrowed airways and the thickened tissue of the airways due to the gag accumulation, they have a high anesthesia risk in intubation, but also in extubation.
Dr. Christina Lampe: 00:49:55 So you need an anesthesiologist who is very aware of these complications and knows how to deal with these complicated diseases. We have problematic upper airways. We have in some patients, as I told already, the atlanto- axial subluxation or instability in the cervical spine. And we have also the heart involvement and the pulmonary disease and the difficult positioning. So the best would be a fibre optic intubation, awakened fibre optic intubation or local anesthesia.
Dr. Christina Lampe: 00:50:31 The CNS and peripheral nerve manifestations, I told already about hydrocephalus, spinal cord compression, atlanto-axial instability that need imaging for sure and sometimes surgical intervention. But we have also, and this is something very special for mannosidosis not, but for MPS, the carpal tunnel syndrome.
Dr. Christina Lampe: 00:50:53 Carpal tunnel syndrome is extremely rare in childhood, but if you find a child, as you see it on the picture on the left side in this boy, with the carpal tunnel syndrome, you should think to mannosidosis, to MPSs or mucolipidosis because this is usually a complication of middle-aged people. The carpal tunnel syndrome does not make the typical signs and symptoms like shaking the hand or tingling in the fingers or paresthesia. They are much more slow in progression, so it means the patients don't really feel the loss of sensitivity in their fingers.
Dr. Christina Lampe: 00:51:33 So this is why you need nerve conduction velocities in your patients to detect. So now what is the best follow-up for your patients and the immediate next steps? And actually, there is for sure, we are not talking about one disease, we are talking about mannosidosis and seven forms or types of MPS. So it is difficult now to show you all what is on the literature at the moment, but what I can recommend, and this is a new guidance to manage MPS for A in six patients, so the hypermobile ones and the stiff ones in the web.
Dr. Christina Lampe: 00:52:07 This is published this year and it is actually a consensus of experts dealing with MPS patients and this consensus due to online surveys and so on, it was a modified Delphi procedure that leads to a lot of very good key messages how to deal and how to treat MPS patients. And one of these is that a diagnosis and regularly after, patients should be followed to ensure that they are receiving optimal care. And this first step is whenever you have a patient, whenever you want to start a treatment, you have to perform baseline assessments.
Dr. Christina Lampe: 00:52:57 The baseline assessment should include endurance, growth, the urinary gag levels for sure, the respiratory function, quality of life questionnaires, but also evaluation of the upper and lower limb function and the cervical spine. This means whenever you diagnose a patient, you start from that, because then you can have, you have a good basis for regular follow- up examinations and you understand what is going on in these progressive diseases.
Dr. Christina Lampe: 00:53:27 And this recommendation that was recently published is also a list of all assessments that are needed and how often to perform them. For example, MRI of the whole spine in some cases, if there's a problem, you would do it every 12 months, but the six- minute walk test was the best test and also was primary endpoint in the clinical trials in combination very often with the pulmonary function. So endurance and pulmonary function were mainly the primary endpoints in the phase three trials to get approval for the enzyme replacement therapies.
Dr. Christina Lampe: 00:54:11 And these have to be done very regularly, every six months, for example. But you can see in the guidelines. They have also, the guidelines give some recommendations about which surgeries are good options for or optional for MPS patients. And they also give you some ideas when you send your patient to an ophthalmologist, what you have to ask this specialist for. So you have to ask for intraocular pressure. You have to ask for the retina.
Dr. Christina Lampe: 00:54:43 You have to ask for a split lamp examination to see the corneal clouding, because if the other physician is not aware of MPS, he doesn't know what to look for. So also these guidelines give you some ideas what you have to ask for when you send a patient to another physician. So now the latest treatment options. I told already that MPS1 is the one with the stem cell transplantation option under the age of two and a half years and stopping the cognitive decline and also some physical aspects. We have the enzyme replacement therapy.
Dr. Christina Lampe: 00:55:19 So giving the enzyme to the patient IV. We have the symptom based patient therapy that is important for each patient. And there are also some new therapies on the way, but I cannot talk about that in that frame today.
Dr. Christina Lampe: 00:55:35 So, the enzyme replacement therapy and I show you here the small vials of the treatments that are available in some countries. We have the decrease of urinary gag excretion and reducing of liver and spleen volume. This is both things have no impact on the patient's quality of life on ERT, but it shows you that the enzyme is given and it is working in the body because you have a normal gag excretion in most patients that receive enzyme replacement therapy.
Dr. Christina Lampe: 00:56:06 We have an improvement in joint mobility, which is true, but since this is a less perfused tissue, it takes quite long, but there are studies, long- term studies, especially in MPS1 showing how much improvement you can see over the years in joint mobility in these patients on ERT. The pulmonary system and endurance is improving. These were mainly the primary endpoints of the clinical trials and the skin and hair is improving and also there is seen, even if it is not statistically significant, of the quality of life and the quality of life question is.
Dr. Christina Lampe: 00:56:42 The enzyme replacement therapy has unfortunately, and this is one very sad aspect of the treatment, is not crossing the blood- brain barrier, which means patients have no benefit of their cognitive involvement. This, unfortunately, is a disadvantage or a handicap. To show you that, because I said the earlier you start, you avoid irreversible organ damage, that also older children or adults may have a benefit from ERT, I will show you this case. This is Heiko and he is born from German parents.
Dr. Christina Lampe: 00:57:20 He was of normal height and weight when he was born and the mother realized at the age of three to four months that he has a kind of stiffness of the shoulder and she was surprised about that. He was in each other developmental milestones he reached in time without problems. For two and a half years and three years, he had twice adenodectomy in T- tubes. With three years, developmental delay in language was diagnosed and at the age of three and a half years, he had an inner ear damage diagnosed. He needed ventilation tubes again and hearing aids.
Dr. Christina Lampe: 00:58:01 And the anesthesiologist actually had some idea of a lysosomal disease because he could not position him properly in the operating theater. And the diagnosis was done due to that at the age of four years with the urinary gag that was positive and some activity on confirmation on genetic testing. What you can see here between four and eight years, the symptoms were increasing. So the body height on the growth curve went down. He had a continuous progression of the joint contractures. He had hernia on the cause face.
Dr. Christina Lampe: 00:58:42 He had hepatomedialia all of a sudden. He had also at the age of eight years then a heart involvement. So progressive disease. And here you see the overview of this patient from birth to 12 years of age when he started treatment and you see the last blue box as the time before he started the treatment. And then six months, 18 months and five and a half years on treatment. On the pictures you see that in one year he improved in the shoulder mobility. You see in the six- minute walk test he improved also here.
Dr. Christina Lampe: 00:59:26 He improved or had stable results in the contractures of his joints and also his face improved. And I will show you later for sure he had also an improvement in the pulmonary function. But the most important for him and this is what is seen here is the height. He was born in the 95th percentile. He dropped down up to 12 years on the 10th percentile of growth. And then at the age of after five and a half years on treatment, I will show you the pictures very soon, he was on the 70th percentile again. So he was growing up to normal.
Dr. Christina Lampe: 01:00:06 And here you see him between 16 and 17 years of age. He's now an IT specialist in a big hospital. He has an improvement of his joint contractures, his eyes and also a stabilization of his heart, his ears and no hepatosplenomegaly anymore.
Dr. Christina Lampe: 01:00:26 And to show you that also severe affected Hunter patients can have a benefit from treatment, you see here one of my patients at the age of seven years and then 19 years, so nine years of ERT. And you see him even if he's severe affected with a severe cognitive involvement, he cannot eat alone, he has tracheostomy, he's sitting in a wheelchair. But you see him smiling, he's watching soccer and he has a good quality of life.
Dr. Christina Lampe: 01:00:50 And taken into consideration in literature, usually these severe affected Hunter patients would be without treatment, die at the age of 12 to 13 years.
Dr. Christina Lampe: 01:01:00 So, in summary, MPS and mannosidosis, we have the 11 enzymes leading to 7 types of MPS with a storage of glycosaminoglycans in tissues. Mainly, they are autosomal recessive except MPS2 that is X-linked. We have a multisystemic disease with dysautosis multiplex, so skeletal involvement and with neurological and without neurological involvement. While in alpha-mannosidosis, we have the oligosaccharides that are stored. It is an autosomal recessive disease. It is rare, for sure, but treatable.
Dr. Christina Lampe: 01:01:40 We have a multisystemic disease with dysautosis multiplex, meaning skeletal involvement. Also in mannosidosis, we have mild, moderate, and severe forms, and we have in some patients neurological involvement. And in both diseases, what we have is that the earliest signs and symptoms are unspecific with hearing loss, recurrent infections, hernia, and developmental delay, but in combination, it could lead to a diagnosis. And in conclusion, the best treatment of MPS and mannosidosis patients is the enzyme replacement therapy.
Dr. Christina Lampe: 01:02:17 For sure, it is not a healing therapy, but it is really improving the life of these patients. In combination with regular checkups and follow-up examinations to detect life-threatening disease complications and the quality of life-reducing disease complications, and for sure, an adequate symptomatic treatment, and this as early as possible. This is important to know. And I finish with another question. What is wrong? Makotopolysaridosis and mannosidosis are – need regular, standardized follow-up examinations, so what is wrong?
Dr. Christina Lampe: 01:02:55 Need a multidisciplinary team specialist to be followed up? Have life- threatening disease complications? Have quality of life- reducing disease complications? Have no treatment options? So, what is wrong? Actually, everything is correct besides the fact that they have no treatment option.
Dr. Christina Lampe: 01:03:17 we know we have the enzyme replacement treatment and even if in your country there's no enzyme replacement treatment available, the regular follow-up examinations and then the symptomatic treatment is also giving a lot of impact on patients' quality of life and also the survival of these patients. Another question, what is wrong? Enzyme replacement therapy is available for all types. Stem cell transplantation is the treatment option for all MPS types and mannosidosis. Symptomatic treatment is needed in all types and mannosidosis.
Dr. Christina Lampe: 01:03:55 ERT is improving endurance. ERT is crossing the blood- brain barrier. So what do you think? I give you the result. For sure, it is wrong that enzyme replacement therapy is available for all types of MPS so far. We have for the MPS3, we have no treatment available also not for MPS4b.
Dr. Christina Lampe: 01:04:30 For example, the stem cell transplantation is not a treatment option for all MPS types and mannosidosis at the moment, only recommended for severe MPS1. In some cases, in some countries also for MPS6. And for sure, it is wrong that ERT is crossing the blood-brain barrier because the enzyme is too big and will not cross into the brain, which means the cognitive decline is not touched by the enzyme replacement therapy, but the physical situation, which also leads to a better general condition of this patient.
Dr. Christina Lampe: 01:05:06 And last question from my side before you are asking questions. What is correct? Early treatment is improving the outcome. Early diagnosis has a benefit for families and patients. MPS mannosidosis may have anesthesia complications. Storage begins prior birth and treatment recommendations are available.
Dr. Christina Lampe: 01:05:33 So, all of these messages are correct and these are also the key messages I would like to give you and now it is your turn to ask some questions from your side. One question is what is the best option to diagnose these patients, urinary gag, or glycyrrhizates or dry blood spot test? And actually, in my point of view, it is the dry blood spot test because they are so sensitive that you will not miss a patient. It is not specific enough, so it means you have false positive and you have to test the enzyme activity in blood or the genetic testing as well.
Dr. Christina Lampe: 01:06:19 But you don't miss a patient, but you can miss patients because milder affected patients have less oligosaccharide or glycosaminoglycan excretion in urine or because the excretion is dropping down from the first year of life to adulthood. So you can have low gags, you can have oligosaccharides, you can miss some patients, but you can also have some increased gags, but no MPS because it is just unspecific related to other diseases. Any further questions? Should also adult patients should be treated although having already irreversible organ damage?
Dr. Christina Lampe: 01:07:05 Yes, and this is what I try to show you with a more attenuated case at the end. So even if you have patients that have already irreversible organ damage, what you can do is you stabilize these patients, and stabilizing is in progressive diseases a big, big benefit. So for me, if you have a progressive disease and you stabilize the patient and they don't have any further progression, you have a big, big positive effect. And this is why also adult patients should be treated. And I have a lot of adult patients that I'm treating and nobody of them stopped.
Dr. Christina Lampe: 01:07:46 So they are all very happy with the treatment and the stabilizing of their symptoms. Do we treat? Next question. Do we treat when symptoms are present or do we start before symptoms are present? So this is what I already tried to explain. We try with the enzyme replacement therapy to avoid organ damage. So the effect is much better in avoiding than in correcting. So this is why the earlier you start the treatment, the better it is. Any further questions? When do you start to see sleep disorders? Actually, we see that very early.
Dr. Christina Lampe: 01:08:31 The cognitive involvement usually starts in preschool age. But what we see due to the adenoids and due to the enlarged tonsils and the recurrent infections, we see a lot of sleep disorders in small children. And not always a polysomnography is possible in these children, but sometimes it is enough to measure the saturation in one night to... adapt. But also in young children, I would start immediately with diagnosis. I would start making some sleep tests to see whether this patient has some apnea, snoring during night and some desaturation.
Dr. Christina Lampe: 01:09:15 Because the nightly hypoventilation is some part leading to daily hypoventilation and to death of these patients. ERT for alpha-mannosidosis could be considered useful both for pediatric and adult patients and to be also associated with stem cell transplantation. So for sure, the alpha- mannosidosis treatment, the enzyme replacement treatment, is for children and also for adults useful because you stabilize, as I said before, also adult patients.
Dr. Christina Lampe: 01:09:51 The hematopoietic stem cell transplantation was used in former times, but actually is not the treatment option of the first choice. Any further questions? No further questions. So I would like to thank you for listening to staying this hour with me to listen about these rare diseases that are treatable. And I just want to finish with one sentence of a Belgian neurologist who said, it will not be diagnosed if you do not think of it. And you will not think of it unless you know of it.
Dr. Christina Lampe: 01:10:34 So I hope you will keep in mind the MPSs, the mannosidosis, whenever you see a child and you have an idea of a metabolic or a skeletal dysplasia, test on MPS. There's a treatment available. Thank you very much for your attention and I wish you a very nice day. Bye bye.