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[00:00:00] Dr. Raymond Y. Wang: Good morning, good afternoon, good day. It's a pleasure to be here. My name is Dr. Raymond Wang. I am a biochemical geneticist. I practice in the United States, specifically in Southern California. I do clinical care as well as translational research in lysosomal storage diseases and especially mucopolysaccharidoses or MPS. And so today, I have the pleasure of talking to you today about how to recognize mucopolysaccharidosis in children. A few housekeeping notes. Very important. There are patient photos. While they've consented to have their photos as a part of educational material, they have not consented to screenshots. And please do not reproduce any of the slides or content or images. I'll be talking, we'll see, it's probably going to be closer to 30 than 25 minutes during the talk or afterwards. Please submit your questions by text and I will do my best to address them. We will go from there. Later on, the talk will also be available at this site. Let's get right to it. So, mucopolysaccharidosis or MPS, they are metabolic disorders. They are caused by deficiencies in lysosomal enzymes. And the function of these enzymes specifically is to break down step- by- step these highly modified sugar molecules called glycosaminoglycans or GACs. And here's a stylized cartoon of a cell sitting inside an extracellular matrix. And you can see that there are these stringy looking things with little bristles. And these are what are called proteoglycans. And when you zoom in on each of the individual little bristles of the proteoglycan, you'll see that there are these repeating chains of highly modified sugars, generally a sugar acid or a uronic acid with another glucose or galactose and sulfated or acetylated or various other things. And just like any compound within our body that's synthesized, it also has to be broken down and recycled. And there are many enzymes that participate in that. Because extracellular matrix is really present all throughout the body, when you're unable to break down glycosaminoglycans, you can potentially see symptoms all throughout. So, that includes the central nervous system, the eyes, the airways, heart valves, liver and spleen, and those points of the joints. So, we're going to try and go through each one of these today. Now, I'm a biochemist, but that doesn't necessarily mean that you have to memorize chemical structures. Really, the point of this slide is to show as we zoom into each of these various sugar polymers, that really every step is catalyzed by an enzyme and the breakdown is successive. And so, at any point in time, if you have a deficiency, say in this hydronidase, for example, which removes this hydronate, you're going to have a stoppage and you're not going to be able to break down this chain any further. The other thing you'll notice is some of these enzymes are present in the breakdown of multiple different species of GAGs. And so, when you have that deficiency, then you actually build up multiple different species of GAGs, which leads to symptoms, for example, predominantly in the central nervous system, if you're unable to break down heparensulfate, sort of the somatic rest of the body for chondroitensulfate or dermatensulfate, and then finally in the joints for keratensulfate. the large majority of the rest of the talk on MPS type 1, largely because what you see with MPS 1 is very common and shared in terms of symptoms, diagnostics, and potentially treatment. And so the enzyme that's missing in MPS type 1 is called alpha- idronidase. And as we alluded to previously, it's removes this hydronate sugar moiety from the ends of heparan and dermatan sulfate. And because heparan and dermatan sulfate are found throughout the body, if you are unable to break it down, you are going to have disease manifestations mostly everywhere throughout your system. Here's a slide that really demonstrates, and just like any other MPS or any metabolic disorder, any disorder, if you think about it, there is a spectrum of severity. And it ranges from the most severe, which is historically called Hurler syndrome, all the way to the most attenuated. I hesitate to call it mild because shape patients still face fairly significant disease manifestations. In between, there's an intermediate grade of MPS that's historically called Hurler's chain. The other thing that you're going to notice here is that generally, the level of residual enzyme that you can measure in white blood cells or in plasma correlates with the severity of the disease, such that if you really have zero residual hyaluronidase, typically caused by nonsense mutations or frameshift mutations in the gene, then you're going to have no enzyme which corresponds to severe Hurler. On the other hand, if you have some kind of missense or splice site variant, then you're going to have a more attenuated version. The other thing to point out, which we're going to revisit when we talk about treatment, is that it really doesn't take that much enzyme to prevent the severe central nervous system aspects of MPS1, such that shape patients really have about 3% of the lower limit of normal levels of hydronidase. So as you can imagine, when you have a severe enzyme deficiency, these children are going to develop symptoms very early on, typically in infancy. The symptoms are rapidly progressive, which leads to some kind of recognition and diagnosis, ideally before the first birthday. If untreated, there is neurologic regression, and the life expectancy is abbreviated in the Hurler's patients. There are some states in the United States and countries which are doing newborn screening for Hurler syndrome, which allow, or MPS1, which allow for identification diagnosis, even in the neonatal period, which can result in initiation of therapy and such. As you go down the spectrum of severe, notice that there's less and less cognitive impairment. Some Hurler's individuals can have some degree of learning disability, but typically not the regression that's seen in the severe cases. Okay, what are some of the initial symptoms that we see, especially in the Hurler patients? So if you think about it, you're accumulating glycosaminoglycans, and so organs and various different parts of your anatomy are going to become big. So here are a couple of our patients. This young lady is about six months old, this young man is about 10 months at the time this picture was taken. There's enlargement of the head, so the frontal lossing, so the head becomes big naturally from the brain storing gag material. We see what are called coarse facial features, so thick lips, again, sort of nasal, a depressed nasal bridge. And you'll see, as you see more patients' pictures, that there's kind of a common appearance to MPS1 patients. Other things you'll see, enlargement of the liver and spleen, there can be slowing of growth velocity as these patients are frequently ill, and there's also build up of gag material within growth plate cartilage. And so families before the newborn screen era would notice that their children were just sick all the time, they'd catch a virus, they wouldn't be able to heal up really well, and then they'd catch another one, recurrent ear infections, ear tubes to vent sort of the fluid build up. The other finding initially often times are hernias. So whether that's an inguinal hernia, umbilical, hiatal, all the increased sort of visceral contents tend to cause things to bulge out. And so many times, our Hertler patients have already visited an ear, nose, throat doctor, a general surgeon, other specialists before diagnosis is finally determined. Orthopedic manifestations are the other common initial presentation. So this young boy, the parents notice a bump in his back, a kyphosis, and will often get referred to orthopedics for this. And so again, many MPS patients before the era of newborn screening had seen multiple specialists before the diagnosis was provided. As we go to radiographs, there is a radiographic constellation of findings, which is called the testosterone multiplex. And so oftentimes, obtaining a scalable survey can serve as a helpful adjunct to diagnosis. We can see sort of this widening ribs on chest x-ray, or spatula ribs is the other term here, high convex or hook-like vertebrae, and so if you're on a lateral spine, you can see that instead of nice, you know, rectangular vertebral bodies, there's this weird lip or a hook, and this one is actually smaller. And so it's these dysplastic vertebrae that end up resulting in the kyphosis and gibbous that you see. Here you'll see something called proximal pointing, and so instead of having nice tubular metacarpals and metatarsals, there's a narrowing here, and all these findings together sort of constitute the testosterone multiplex and very frequently seen in MPS patients. In terms of other potential organ systems being involved, we've talked about the cognitive impairment in earlier patients. There can be hydrocephalus, and so crying and sort of hitting forehead or hitting their head on the wall, the inability to reabsorb cerebral spinal fluid will cause increased pressure in the brain, and untreated Hurler patients often require shunts to sort of take off the pressure. Cervical spinal cord compression is a major issue that many MPS patients face, and partially it's because the skeletal structure causes a narrowing of the spinal canal, and partially because gag buildup within the dura mater also further stenosis that area. Orthopedic, as we discussed before, scoliosis, kyphosis, contracted joints, it's like inflammatory osteoarthritis, stiff joints, inability or reduced ability to walk, carpal tunnel syndrome, all of these sort of combine to generate pretty significant impairment in activities of daily living. Here's a young man who, despite trying to do his very best to stand straight up, you can see their shoulder contractors, elbow, knee and hip. Finally, the ophthalmologist will often see corneal clouding and so there's storage of gag material within the cornea, which can, over time, result in reduced visual acuity. There can also be increased intraocular pressure, which eventually leads to loss of vision. We've touched upon upper airways and so buildup of gag within the upper airways can cause recurrent ear infections, sinus infections, obstructive sleep apnea, and between the spinal stenosis and the airway issues can result in a very challenging intubation. And so we want to make sure that our anesthesiologists and EMTs are well aware of the airway challenges before they go in and try to secure an airway for surgical procedures. Gag buildup within heart valves can lead to valve dysplasia, insufficiency, stenosis. There can be cardiomyopathy, which is seen fairly frequently in MPS1. And then before the era of therapy for MPS1, you would often see myocardial infarction. So there would actually be storage of gag material within the coronaries, which untreated would then lead to cardiac ischemia. And pulmonary disease were some of the most common causes of death in severe MPS1 patients before the era of treatment. We've touched upon the more attenuated forms of MPS1 previously. Patients with Shea syndrome are typically first seen by an orthopedist, an ophthalmologist, or a cardiologist. They see joint contractures, might be confused with rheumatoid arthritis seen by a rheumatologist, maybe a heart murmur, maybe corneal clouding. This does happen to be the rarest form of MPS. It's probably about 15 to 20% of all cases. And then the intermediate form, as we touched on previously, phenotypes somewhere in between the severe hurlers and the attenuated Shea's can be some learning disability and really cervical spinal stenosis becomes a real problem in these patients. This is a repeat slide. Apologies. Okay, now we get to diagnosis. So how do we identify a patient? And there are a couple ways to go about this. First, you can screen with quantitation of glycosaminoglycans in the urine. So you can do total GAGs and you can quantify that the total GAG levels are increased in the urine. Now with tandem mass spectrometry, you can actually even quantify heparan, dermatan, and keratan sulfate in the urine. And most specifically, there will be heparan and dermatan sulfate elevation in the urine, which makes sense because these are the two GAG species that can't be broken down. Eventually, though, we want to secure the diagnosis, confirm the diagnosis. And so we do that by measuring enzymatic levels, whether in white blood cells or plasma, and then ultimately doing sequencing of the IDUA gene. And whether this is targeted IDUA sequencing or through next-gen panels or through whole exome sequencing, all of those generally are going to be able to cover changes in I. geronidase. Some other MPSs, especially MPS2 and 4, may have deletions or rearrangements or intronic variants. And so we often depend on a combination of all of these to arrive at a diagnosis. As you can see, treating MPS is complex. There are a lot of different organ systems involved. It can be very overwhelming for a parent to take a child to all of these specialists. And so, our role as metabolic physicians, as lysosomal specialists, is to essentially guide the family through all the various different specialists that need to be seen and to provide family support because these diagnoses tend to really cause a lot of upheaval and stress. So, as we talk about just general multidisciplinary follow-up, I wanna talk about how to treat the condition, not just monitor. And so, the idea is pretty simple. You wanna have the enzyme put back in the body. But really, this was not, it says cross-correction. Sorry, the color doesn't come through very well. It wasn't until the discovery of this cross-correction principle that allowed for the knowledge of enzyme to actually go from the circulation outside of the body into the cells. The other problem that we have with MPS is this blood-brain barrier. So, you can have enzyme in the bloodstream, but if it can't get into the brain, then you're not gonna be able to treat the central nervous system manifestations of the disease. All right. Okay. Currently, we have two different approved therapies, one of which is intravenous enzyme replacement therapy. The other is hematopoietic stem cell transplant. And they've been around for a little over 20 to 25 years. Here's a young man who is actually in college at the moment. And when he was first diagnosed, he would get his enzyme infusions within the hospital. The enzyme is recombinant human alpha-idronidase. It underwent randomized double-blind placebo-controlled clinical trials, and it was approved by the United States FDA in 2003. And so, that's about 20 years ago. What does it treat well? And basically, what it comes down to is any organ system, which has a lot of blood vessels, which allow for a delivery of a lot of enzyme, is treated well. Conversely, any organ system that doesn't have a lot of blood vessels is not gonna be treated very well. So, the upper airways, lots of soft tissue, reduction of soft tissue storage, resulted in improvement in airway obstruction, reduced obstructive sleep apnea, due to sort of a general sort of improvement in health. A six-minute walk test, which essentially measures the distance a child can walk in six minutes, increased quite significantly. And there was an improvement in pulmonary function, a reduction in hepatocellular amygdala to near normal levels, if you think about it. The liver and the spleen are a place where ultimately a lot of enzyme ends up going. And generally, because these patients were beginning to feel better, be sick less frequently, there was an initial improvement in linear and weight growth velocity. And here are the references here to the original publication. And what doesn't it treat well? As we talked about before, any organ system that really doesn't have a lot of blood supply or any place that there's a barrier. And so obviously as we touched on previously, it's not going to be able to treat the central nervous system. The clinical trials were done in hermit shade patients who don't have neurologic disease and really not a whole lot of enzyme gets into the brain to be able to treat that. The cornea has no blood vessels and so patients would continue to develop corneal clouding. The cardiac valves would continue to get valve thickening and more insufficiency. And then finally, orthopedic problems. So reticular and growth plate cartilage is avascular and so really it's difficult to get enzyme into the joints. And so there's still progressive joint disease, no change in spinal cord compression. So definitely you have a treatment that's really changed the face of MPS, but there are still some significant limitations. Other limitations include the need for central lines because this is a weekly infusion. Central lines can break, central lines can become infected and need to be replaced. It's a five-hour infusion and oftentimes there can be infusion reactions as you're infusing potentially a foreign substance into these patients. The body can develop reactions which typically aren't life-threatening and typically can be premedicated with antihistamines or antipyretics, but they're still not very fun. And finally, from a sort of cost provisioning of limited benefits, private and governmental insurance agencies wrap up. Really right now, stem cell transplant is the current method alternative to get hydronidase into the central nervous system. And it's not because of any issues inherent to the bone marrow or anything like that with the patient. Rather, you're infusing stem cells that come from somebody who generates a normal amount of hydronidase. And these stem cells, most of them go to the bone marrow, but a small percentage does migrate into the central nervous system and become the immune system in the CMS. And the small amount of enzyme that these engrafted stem cells make in the central nervous system, if you recall, about 3% enables you to have attenuated MPS. That 3% is enough to cross-correct and prevent neurologic degeneration in bipolar patients. And as we've learned from our experience with newborn screening, generally the earlier you do these transplants, the better the subjects do, not just from a cognitive standpoint, but also from a somatic standpoint. There have been, by this time, hundreds of Ehrler patients that are transplanted. There is enzyme replacement therapy that we give before the transplant, which seems to reduce complication rates, such as engraftment or pulmonary syndrome. But strangely enough, doesn't seem to increase survival. Increasingly, umbilical cord stem cells are utilized. There seem to be higher rates of engraftment and less graft-versus-post disease. And then finally, we've learned over time that even though HLA matching is most likely with siblings, if the siblings are heterozygous for the same IgA mutations, the cap for the highest enzymatic activity that subject is ever going to be able to make is 50% normal. Outcomes tend not to be as... Finally, so there are risks, right? You have several weeks of immunocompromised that you're waiting for engraftment. There can be graft-versus-post disease. You know, occlusive disease, which is actually now treated with a medication called deferred time. And with all that, there can still be a 6% risk of fatal engraftment where you have to do another transplant or even death. What can it do well? Can it prevent the regression that otherwise would be seen in Herbler syndrome? There is still some residual learning disability and speech delay that is often seen. There is resolution of organomegaly, resolution of spatial features, reduction in upper airway issues, and somewhat improved joint mobility. This is a young man who, as you can see, has coarse facial features. Five years later, there is some subtle MPS features, but you can still see it's significantly improved. Just to wrap up with MPS1, what cannot transplant treat well? I would say that the outcomes are largely similar to transplant replacement therapy. claviclegia, are going to continue to have symptoms and issues. There is still some growth deficiency compared to what the genetic potential is with siblings. Just in the last few minutes, we will hit upon the rest of the MPSs. Hunter syndrome being the X-linked MPS, and the enzyme deficient being nitronic sulfatase. Very similar symptoms. There is a continuum of disease severity from attenuated to mild. There is some really subtle corneal clouding that is only visible on sweat lamp, but not enough to affect general vision. You can see, again, coarse facial features in individuals from multiple different ethnicities. Organomegaly in joint contractures. This is as high as the shoulder mobility can go. There are knee contractures and ankle contractures here. There can be some cognitive impairment, especially in the most severe forms of MPS2. Diagnosis is actually quite similar to MPS1. MPS... for one gene at a time. We have enzyme replacement for MPS2 with the same efficacy profile as ERT for MPS1. It appears that a stencil transplant, if performed early enough, may protect the cognition, but that's still in development at the moment. We're at about half an hour here. There are a few more slides that go over MPS3, which has primarily central nervous system involvement. This is a particularly problematic MPS at the moment because stencil transplant doesn't seem to preserve the cognitive involvement or prevent cognitive involvement. There have been attempts to get ERT, whether intrathecally or through a transcytost enzyme, but so far nothing seems to be approved or very helpful for Sanfilippo. I'm going to stop here because I'm running a little bit over time, and I will open up for questions. Again, just thank you for spending the time with us this morning, and hope you learned something about MPS. The question is, at what stage should enzyme replacement therapy be considered, and is it ever too early, and is it ever too late? Good question. MPS enzyme replacement therapy is a little different from, say, late-onset Pompe disease or Fabry disease, in that for those conditions, I tend to wait. The progression of the disease is pretty rapid, and you want to be able to provide therapy sort of as the child is growing and developing. If you recall, there's a significant amount of growth, linear growth, in the first six months, skeletal growth, and even within the first two years. We're noticing in the MPS1 children that are identified by newborn screening, starting ERT in those children as neonates has a tremendous effect upon sort of facial features, prevents all the EMT issues, and it's pretty early right now, so I think there should be some publications upcoming on the efficacy of early treatment. So my stance on ERT, specifically for somatic manifestations of MPS1, as early as possible. Is it ever too late? Well, better late than never, and I think being able to intervene and reduce ongoing storage is important. And just to recall that for CNS manifestations, especially for MPS1, that's one of the reasons why newborn screening was instituted, so that metaprotic stem cell transplant could be considered early on in the child's neurodevelopment, as opposed to after a period of time where storage has already occurred. Good question. Other questions? Can ERT or stem cell both be used in parallel? Which one to try first? Realistically, you're going to be doing both at the same time. So the process for a stem cell transplant is not immediate. You need HLA typing. It has to go to a stem cell bank to search for matches. And so while that is going on, you're going to want to introduce enzyme replacement therapy, if you will, to try and debulk or reduce the storage prior to the onset of stem cell transplant. So in reality, you're going to be doing both at the same time. Please explain more about the typical frequency of medicine infusion. How frequently do they need ERT replacement? Monthly or less? I apologize. It's not something that I specified. So the plasma half-life of most of these enzyme replacement therapies is less than four hours, which means probably after about 24 hours or so, you're not going to find any enzyme in the bloodstream. The cellular half-life is somewhat longer, but it's still not very long. And so because of that, the enzyme replacement therapies for MPS type 1, 2, 4a, 6, all of those are given every week. The only difference is the enzyme replacement therapy for MPS type 7, that's given every other week, but that's because the half-life of beta-glucuronidase seems to be quite a bit longer compared to the enzymes deficient in 1, 2, 4, and 6. Good question. Others? How is morcula IV treatment administered? So at the moment, there is one United States FDA-approved product, which is recombinant human galvanized enzyme. It is also given every week, but if you recall, it is an intravenous enzyme, and intravenous enzymes have those skeletal limitations. So really, in my clinical experience, enzyme replacement therapy for type 4 may improve some general activity levels, but it's not going to be able to reduce, say, the need for orthopedic surgery in the hips, knees, and up in the C-spine, which are the typical sort of problem areas for MPS 4a. Other questions? Okay, since that's it, I again wanted to thank you all for spending a bit of time with me, and I hope you learned a little bit about symptomatology and MPS. Always welcome to send us questions later on if they come up, and I wish you a good day and a good weekend to come. Thank you.