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[00:00:08] Dr. Bianca Link: So, hello everybody. We want to start now the case series concerning joint and bone manifestation of mucopolysaccharidoses. And first of all, there are some housekeeping points. The main points are, please do not reproduce any of these slides or contents or images or something like that. And if you want to post any question in between the presentation, you're very welcome to do so. And the rest you can read by yourself. It's a lot of text on this slide. This will get better in the coming minutes. So, starting with the main scene, just to get a short introduction to the MPSs you see over here, I will focus on mainly two body regions, which is the spine and the lower limb. And in all the MPS forms, you can see you have some kind of musculoskeletal involvement. Mainly it's deformity, it's stiffness. In MPS4, it's the instability. And all this leads over time to preterm arthritis or other degeneration problems, as well as neurological problems, mainly due to the spinal stenosis and myelopathy. You can see in nearly every form of MPS1, 2, 4, and 6. We haven't seen in MPS3 now, but maybe just we're not examining it. And on the lower limb, you see examples, clinical examples over here as well. You have mainly contractures in nearly all of the forms. Also in MPS3, maybe secondary to the CNS involvement. Of course, deformities of the lower limb, problems like hip dysplasia or femoral hip necrosis. And in MPS4, the instability is the leading phenomenon and also leading to early joint destruction or preterm arthritis. Now I want to step into, let me see, just shortly, the upper limb. You have the same features as mentioned in the lower limb, but one feature is a little bit special. And this is the carpal tunnel syndrome, which can occur in both sides and in early childhood. And this can lead to the diagnosis of MPS1 or 2, because in childhood, carpal tunnel syndrome is very rare. And if you see it in both sides, you can have the suspicion of MPS. And you see another feature in the hands, figured out here, that there are contractures in the fingers, especially in the distal joint of the fingers. And now I want to step in two main forms, MPS1 and MPS2. We start up with MPS1. And first of all, I want to show you this case. It's a female MPS1 patient, and it's a follow- up of the hip of 17 years. And what I want to point out is that you see already a femoral head necrosis over here on both sides and in an early age of life. But if you follow up over 17 years, it's just not really progressing. What is progressing is that the cartilage, you can see over here, is nearly gone. And this is in terms of the age of the patient, preterm compared to patients without any syndrome. But you can't get this as a prognosis for the patient, because it's, well, the dynamic is completely different, for example, in this patient. You see, this is MPS1. It's a male patient without any treatment, because it was not available at this year's. And you see here, the hips in the beginning, they are not completely developed already, look quite fine. But there is a part of hip dysplasia. You see the acetabulum is shortened. And due to this, the femoral head is not round only after three years anymore. And over time, this is progressing. And just after seven years, the femoral head is gone, more or less. So you have a hip dysplasia with a femoral head necrosis due to the pressure caused by the acetabulum. And this is less than half of the time, but it's the same syndrome. And the agenda doesn't make any influence on this. So if you have to judge, the main different feature is there's no dysplasia or nearly no dysplasia over here and a hip dysplasia over here. So this can change the outcome. The next case is a bit longer. It's MPS1 as well. It's the first case I had in Zurich when I changed from Mainz to Zurich. And it's a young boy with MPS1, and he was transplanted in the age of 18 months, which is just in time. And he had already the severe scoliosis. You can see over here with a severe curve at the Taroko- Limbo Junction, which was seen at the diagnosis. And if you have a two- year- old with such a severe scoliosis, this can raise the suspicion of MPS as well. And over time, the scoliosis, beside the fact that the transplantation was successful with a good engraftment and good enzyme levels, the scoliosis progressed. And when I came to Zurich, this was 10 years ago, they already planned a surgery for this patient. And they were really upset because I said, you have to stop the planning and first have a close look to the cranial cervical junction. Because if, as you see in the former picture, I tried to get it again, that there is a progression in the lower parts of the spine, the thoracic part and the lumbar part. You have to have a close look to the upper part, which is the cervical spine as well. And what you see here is a spinal stenosis in the upper part of the cervical spine. And this had no neurological impairment these days, but if you start to correct the scoliosis, you will produce tension over here. And this can cause tetrapleurosis, even though you don't touch the region at all. Therefore, we decided to decompress the stenosis. You see it mainly on the tissue over here that this procedure was made, and then take care for the scoliosis. And this part of the spine stayed more or less stable. In the last picture over here from this year, you see that the scoliosis is even worse. I will show you in the next slides. And this has an impact on the picture of the cervical spine, but the stenosis is still stable. And this is a very unfortunate, I should say, follow- up of the scoliosis. So because it was a small boy, we decided to make an instrumentarium, which allows growing in this child. You can see here, and the second benefit is that you don't touch the spine. You fixate it on the ribs and on the pelvis. Unfortunately, due to the body weight of the patient, he became some kind of pressure point over here with skin irritation, and we had to remove one of the instrumentarium because of infection of the skin over here, and implanted after recovering from the inflammation. So the shorter one, and then he had the same problem over here, and we had to expand this. And then the scoliosis you see was even getting worse. And the only solution was to take out everything. And this is, in a way, maybe a problem of the MPS as well, because the tissue is as stiff that you can't get along with your instrumentarium. And the second problem is he's still a walker, and he has less pain compared to the beginning, or he's nearly pain- free. But the problem is also the hips, as hip as well. So you... hip is in a really upright position, and the ectatelon should go down to here. And this is all cartilage in this age. We know this from MRI findings. But over time, the cartilage can't stand the pressure of the femoral head against the ectatelon. Therefore, the femoral head starts to rise, and there's nearly no head left in this year. And now we are discussing if it's possible and necessary to care for the hips to keep him walking, and especially pain is coming up now. So this is a typical case. And what I want to demonstrate with it is that a transplantation doesn't, I think, doesn't have a big influence on the bone, because the enzyme, which is produced from the cells implanted, is maybe not reaching the bone cells, but we couldn't prove this in the moment. This is another MPS1 patient, a girl, or now it's a young lady. She was transplanted three times because the engraftment didn't happen really good. And in the end, she had quite good enzyme levels. But in terms of the musculoskeletal system, she took a completely different way, even though the transplantation was not as successful as in the patient I showed you before. So this is in the beginning, so she was quite old. This is not before the transplantation, but you see the typical hernia over here, the genua vulga, the contraction of the elbow, a little bit of the facial features and a little bit of spine deformity. And this was the state of the status when she left the kinoshpital to transition to the adult hospital. There had been surgery for the hernia over here, the legs, I will show you, and the contracture were more or less stable and she's working in a bakery. And this is her course in terms of the legs. You see there's hip dysplasia as well, and the genu vulga over here, and therefore the orthopedic surgeon performed an osteotomy. I can't see the picture, let me check, yeah. An osteotomy of the femur to get the hip dysplasia addressed to prevent the femoral head from rising and destroying the cartilage and a correction of the genu vulga, which is mainly located in the tibia, as you can see here. Unfortunately, she had a problem with a compartment syndrome on the left side because the nerve or the compartment syndrome by procedures like this are quite common, and she still suffers from her instability of the ankle. But more or less, she is a very good walker, she is working, and she had an episode of knee pain in 2011, but it recovered with non- surgical procedures. So I try to get further. And another case of MPS, and these are very old pictures, as you can see, they are not in color. This is a case from Mainz as well, and this is one of the typical cases concerning an attenuated form of MPS1. It's a female patient, and ERT was not available for the entire childhood of the girl, but in fact, you see, the face is more or less not really obvious or not really giving us a hint to think of MPS or MPS1, and the hands, neither. But what you can see already is that she has a kind of thenar atrophy, which is typical for carpal tunnel syndrome. And this carpal tunnel syndrome already occured at the age of 10,. and this is typical with MPS1, that it's carpal tunnel syndrome on both sides in the early or in childhood. And she had a procedure, a deep compression of the carpal tunnel already before the diagnosis. This is a bit dangerous because if you don't have the diagnosis, you are not aware of the higher anesthetic risk in this patient. After four years, due to the ophthalmological features and the carpal tunnel syndrome, the suspicion of MPS1 was made and confirmed. But what I want to show you is the problem of differentiating between the features of carpal tunnel syndrome and spinal stenosis. And there's a long history in this young lady from carpal tunnel syndrome and spinal stenosis. So only five years after the decompression, she developed pain. not only in the upper limb, but also in the lower limb. She had dysthasia and she had an aggravation of the thena atrophy or hypertrophy, but the nerve conduction testing of the median nerve was stable. So there was no suspicion of a recurrence of the carpal tunnel syndrome. And it took one more year to figure out that her main problem with the symptoms was not the carpal tunnel, but the cervical spinal stenosis, which was mainly made to electrophysiological testing like SSEPs. Then a deep compression from the first cervical vertebral body to the sixth one was performed in mines as well from the neurosurgeons. And she had about eight years of time without any symptoms or with less symptoms. In 2003, there was the first recurrence of the spinal stenosis. You see over here, the tissue aggravation due to the surgery and the spinal stenosis, which occurred again. And there was again, a decompression of the spinal stenosis, but also the carpal tunnels was relapsed again in terms of pressure on the median nerve. In 2003, we had ERT available for MPS1 and approved by the insurance and we started ERT. And nevertheless, beside the fact that she had ERT already for two years, it was again, carpal tunnel syndrome. So I will shorten it up because in the end, she had still problems with the median nerve. And after several surgeries, we had to stop because it was not any more technically possible to decompress the spinal stenosis. And this is the young lady a couple of years later with the start of ERT and still, she doesn't look like an PS patient because it's an attenuated form. But this has a big impact on hand function, which is the residual of the carpal tunnel syndrome. Coming up to the MPS2, which is a bit different, but there are a lot of similarities. Yeah, I show you with the follow up of the spinal stenosis, the craniocervical junction and the upper cervical spine in PS2. And it's nearly the same picture as I showed you in MPS1. It's sometimes it's just a few segments, but it can a long distance like this one. And over time, you see it's slowly progressing. And that is the main problem because it's slowly progressing. Sometimes the neurological features are not striking. So you don't find loss of power, you don't find dysesthesia. So you have to do MRIs every year to figure this out before myelopathy is occurring. And in MPS2, as well as in MPS1, the history can be very, very different. So there's a broad variety how it goes. This are spinal pictures of MPS2 boys, all of them more or less in the same age. And you see it, they look completely different. And this one is the severe form in terms of definition that the severe form of MPS2 is the one with the CNS involvement, but you see it's a nice spine, it's quite straight. And this one is a more attenuated form. All of them had ERT, but you see the severe scoliosis mainly in the lumbar spine. And these are more or less in between, but again, all of them the same age, all of them have ERT and all of them have the confirmed diagnosis of MPS2 with no additional illnesses. And I'd like to show you a case from mine as well. It's funny, but these are the ones best documented with pictures I have. This is a male patient with MPS2. He started ERT in 2007, and you see this typical body features of MPS2. A severe contracture of the elbow, contracture of the hands, a flat spine with a hypereidosis over here. So he can't straighten completely the hip by walking. You see, normally the leg should be there if you have complete extension of the hip, contracture of the knee, and a shortening of the tendon. And if you know it, the feet are typical broadened in the middle feet part. And what I want to show you in this case is the hip. So a bit focusing on the femoral head necrosis. This is the right side. This is the left side. And beside the fact that in this picture, you can't really figure out a hip dysplasia. The tetabalum is here. It is nice and bony and covers the completely femoral head. But over here, you see this one, this is the necrosis. And in the, And in the MRI, you see the difference between the two sides. This is the necrosis. There's something missing. There's cartilage and bone. And this patient had really high pain levels. But the problem was to figure out what causes the pain. Because if you see the X-ray of the spine, it looks really nice. It's straight up. You don't have a kind of spondylolisthesis or something, some problem over here. The vertebral bodies are more or less nicely shaped. But if you see the MRI, it was in 2004. So it was still a young adult. And you see the discs of the spine. They don't look as in a 20-something year old man, because if they are black, they have less water in it. So the elasticity of the discs are like in a man or a patient normally in the age of 50 or 60. And he had also a disc herniation in this part of the lumbar spine. And this can cause pain as well in the same area as the hip problem. So if you want to decide what to do, you have to be very sure what is causing the pain. Then, because if the pain is mainly due to the hip, this procedure is the one to do. And if you have an adult, the best procedure to get rid of the pain is to do a hip replacement, which we did in this patient. And it was not simple because the bone had a different quality compared to normal bone. And maybe you can see that the bone marrow canal is really small. And we had really problems to get this part of the replacement into the bone. So I made it a bit short to give you the opportunity to discuss with me some questions. And so if you text, or I will try to answer whatever I can. Thank you. Let me see. So the first question is, are you able to identify the musculoskeletal signs of MPS1 from other MPSs when you first suspect? Well, yes and no. So sometimes it's not easy to get it in between MPS1 and 2 if you have a male patient. If you have a female patient, MPS2 is X-linked. So the suspicion will lead you more to MPS1. Concerning MPS4 and 6, it's a bit different. I didn't touch them in the presentation too much, but MPS4 is mainly the joints are instable and this does look completely different. MPS6, just from the musculoskeletal system, you will have similarities, but if you put all the systems together, so the eyes, the heart, the lung, then you will get an impression. Very problematic is it if you have the attenuated forms of MPS1, 2, or 6, because they have not these striking features. Other questions? Okay, so the next question is what differences does early diagnosis make for MPS and how would a 12-month delay in diagnosis impact on musculoskeletal science compared to starting treatment earlier? Actually we don't know. So first of all, it depends on the MPS form. So if you have MPS 1, for example, or MPS 2 with a CNS involvement, the early diagnosis of course is very important for the CNS treatment. Because if the kids are older than two years, the chance to address the CNS is very limited. Concerning the musculoskeletal system, the data, we don't have much data to really prove it. What I think is, or what we have seen is that the stowage in cartilage is as in all the other body cells. And what you have to take in mind is that the cartilage is the primary bone. So during fetal life, the entire skeleton is formed from cartilage and then due to ossification, it's developing to the adult skeleton till the end of poverty. And so the mistake is already there when the child is born. And you will not reach the cartilage with your therapy because you have a lot of extracellular matrix. And what we have seen, for example, by taking samples from cartilage in the knee, you see even though you have therapy or transplantation, you have still storage in the cartilage cell. And this disturbs the entire architecture of these tissues. And these tissues are very dependent on the architecture of the extracellular matrix to get their function and their development right. So 12-month delay for the diagnosis concerning the musculoskeletal system is actually not a long time because the system is developing very slowly. But you are already too late after birth, I think. And the other point is the bone, of course, is influenced by the function of all the other systems. So, for example, if you have CNS involvement, this will have a negative impact on the musculoskeletal problems the patient has already. So it's not easy to decide whether the treatment early or not. Concerning just the orthopedic treatment, for example, if you want to correct genua velga, then you are dependent on growth. If you just want to do a smaller procedure, as I have shown you, so just like eight plates or something like that, and then you have to take into account that the growth is limited in MPS and you have to start earlier with your orthopedic treatment. And therefore, it's important to have the diagnosis earlier. So the next question is, what is the earliest carpal tunnel surgery advised? So I think the question is, when should we do it? So we do the measurement of the nerve conduction testing every year, because in children, they will not claim about numbness, they will not claim about tickling. And if you see the thenography, it's already too late because they will not recover. If you see that the dynamic is that nerve conduction testing is getting worse, and still you have no neurological symptoms, then you should do it because then the function is still there. And the risk of the procedure of the carpal tunnel syndrome is not as big as the one in spine surgery. The next question, differentiate joint contracture from carpal tunnel syndrome. Yeah, these are two completely different points. So the joint contracture mainly is located in MPS1 and 2 in the distal joint of the fingers, which is this one. And the carpal tunnel syndrome may, yeah, the carpal tunnel syndrome show mainly two features. This is the sensitivity loss of these 3 and 1 1 fingers, so the first, the second, third, and the half of the fourth, and the hypertrophy, or the loss of power, of the thenar muscle. And the muscle is mainly responsible for oppositing the thumb to the other finger, so for the grip. It's very important. But carpal tunnel syndrome doesn't make contractures. Next question. OK, so the next question is, MPS patients often deny to perform MRI if general anesthesia is required because they are afraid of possible complications due to this procedure. What would be your argument for them to do MRI in a regular or frequent way? Well, actually, I didn't feature this problem too much. But, well, there are two points. For an MRI, you don't need complete anesthesia with intubation. So in the early age with the kids, we do sedation, which is a bit different. So the risk rises with terms, with the kind of anesthesia and the risk rises with the procedure itself. So the risk is higher if you have a spine surgery. The risk is lower if you have carpal tunnel surgery. And the risk is even lower with just an anesthesia for an MRI. And I think if the parents and the patients understand that the main risk of spinal stenosis is tetraparesis, they are willing to do it. And it should be done in a center which is experienced in anesthesia in MPS. It's a bit different if you have a severe case. Then sometimes you really have to discuss if you want to do an MRI. Because if you are not willing to take the consequences and perform surgery, for example, decompression of the spinal canal, then you should not do MRI. So it's a very open question. The next one, joint laxity in MPS4. Yes, there's joint laxity in MPS4 nearly in every joint except for the elbow. This is very short. But the main problems occurring in MPS4 are, of course, the severe genoa vulga. And they are relapsing after surgery. There is the severe deformity and instability of the hand and the wrist and the instability of the feet, which are even getting worse due to the instability of the knee and the hip. So the entire chain of joints in the upper and lower limb doesn't function together very well. And of course, the spine has a lot of little joints in it to connect the vertebral bodies one to another. And you have instability over there as well. And the problem is that the instability is not only due to the joint deformity. It's also caused by the tissue around it, so the ligaments and the capsules and everything. And therefore, the recurrence rate, if you try to stabilize or perform some kind of surgery, is very high. And therefore, we do a lot of technical procedures in terms of orthesis, braces, et cetera, to keep the patient walking. Next question. OK, I think time is over. And thank you, everybody, for listening. There are no further questions. And if you have questions, you are very welcome to contact me and to discuss patients. Hope all the best for you and stay healthy. Bye-bye.