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[00:00:00] Prof. Elizabeth Braunlin: Good morning. This is Elizabeth Braunlin calling in from the United States for an online course in Challenges in Diagnosis of Cardiac Disease in MPS and alpha mannosidosis. I'm a professor of pediatrics at the University of Minnesota in the United States and have taken care of patients with storage diseases for about 35 years. There are some housekeeping notes here for the attendees which are shown here. I would like to move on to the talk now. So the objectives of this talk are to develop an understanding of the cardiac manifestations of MPS and alpha-mannosidosis. We'll go into that in just a few minutes. To understand the methods of assessing the cardiac manifestation of MPS and to understand the effects of treatment, enzyme replacement therapy and bone marrow transplant or hematopoietic cell transplantation on the cardiac manifestations of MPS. So there is really very little that is known about Alpha-mannosidosis and that is why the talk is mainly on MPS. MPS and Alpha-mannosidosis are lysosomal storage diseases. For MPS, the storage material is glycosaminoglycans or GAGs as we call them. There are several glycosaminoglycans, heparan sulfate, dermatan sulfate, keratan sulfate, chondroitin sulfate. For Alpha-mannosidosis, the storage material are mannose rich oligosaccharides. You might wonder what those compounds really are and if they're present normally in people or if they're something that is unique to these storage diseases. The answer is glycosaminoglycans and oligosaccharides are normally occurring compounds in all of us. GAGs and oligosaccharides normally occur in our bodies attached to proteins. For example, a glycoprotein is an oligosaccharide which is attached to a protein. An example is renin, which is a glycoprotein. Similarly, a proteoglycan is a GAG attached to a protein. And here's an example of a proteoglycan, aggrecan, which is a component of our joint fluid. So you can see that we all have GAGs and oligosaccharides. Well, what's the problem with the storage diseases? Glycosaminoglycans and oligosaccharides accumulate due to the deficiency of lysosomal enzymes in these diseases. And so these are normally occurring compounds that accumulate because of these enzyme deficiencies. The MPS disorders have a storage of glycosaminoglycans. The MPS disorders are inherited, progressive, systemic storage diseases affecting the heart. And the following features are important to determine what kind of cardiac issues the patient might have. The type of MPS is important. The specific mutation within that type is important, whether the patient has a severe or an attenuated mutation. The treatment status is important. It used to be that all patients were treatment naive, but that is not true anymore. Now patients have most often undergone bone marrow transplant or are getting enzyme replacement therapy. And finally, the age that treatment has begun is very important in understanding the cardiac issues for MPS. If we look at each of these factors individually, the type of MPS is important. There, as you know, are several types of MPS, and for a cardiologist, it's much easier and more useful to remember the GAG compounds that are accumulated rather than to try and remember the enzyme deficiency. So for type I and type II, that is Hurler's syndrome and Hunter's syndrome, heparan sulfate and dermatan sulfate are the GAGs that are accumulated. Type III, Sanfilippo syndrome, heparan sulfate is accumulated. In type IV, Morquio, Keratan, and Chondroitin-6-sulfate are those compounds that are accumulated. Type VI, Maroteaux-Lamy, dermatan sulfate is accumulated. In type VII, Sly syndrome, heparan sulfate, dermatan sulfate, and chondroitin sulfate are all accumulated compounds. So why is this really important for the heart? Well, dermatan sulfate is a very important component of the heart, and the heart valve is composed of about 20% dermatan sulfated proteoglycans. So how that becomes important is that MPSs that accumulate dermatan sulfate have cardiac valve problems more frequently than those that don't. So the types of MPS where you see valve issues are MPS I, II, VI, and VII, those that accumulate the dermatan sulfate. The specific mutation is important for MPS. There are hundreds of mutations that have been identified for the MPS disorders. There are severe mutations that tend to present earlier, and we think of them as having more severe disease. On the other hand, attenuated mutations may not come to medical attention until later, and by that time, significant change may have accumulated, and they too may have significant cardiac disease. The prediction of the disease phenotype is quite difficult from the genotype. There are many private mutations that involve only one or two individuals from a family, and a few have been found to specifically be associated with heart disease. MPS VI has a particular mutation found in Eastern Europe that is primarily associated with cardiac valve disease. So the take- home message from the mutation analysis right now is that the genotype- phenotype correlation is a work in progress and currently under study in all of the different types of MPS. The treatment status is important in MPS. Bone marrow transplant has been available for treatment of MPS I since Hobbs first reported it from London in 1980. There are problems that may be due to the effects of the bone marrow transplant procedure. In the early days of the procedure, radiation was given in high doses and the preparative drugs such as busulfan were quite stiff, and patients were generally older at the time of transplantation. These patients are now 20-30 years of age and the ones that were done that were transplanted back 20 to 30 years ago may show the effects of these procedures, the radiation and the preparative drugs, just as much as they show leftover or residual problems from MPS. Enzyme replacement therapy has been approved in the United States beginning in 2003 with the treatment for MPS I. Enzyme replacement therapy studies, the clinical trials, were all performed in attenuated patients, and importantly the subjects were more than 5 to 6 years of age in the clinical trials. We know now that the response is better the earlier or the younger the patient is who begins enzyme replacement therapy. Finally, age, as I mentioned before, is an important factor in the treatment of storage diseases. Storage diseases are progressive, and that pertains to the heart as well. Early recognition and treatment means less storage and less organ dysfunction. This is a classic picture from Giovanni Cappa in Italy showing two siblings, the girl on the left who has attenuated MPS 1, who was diagnosed and began enzyme replacement treatment at 5 years of age, and who has cardiac valve disease. As she was being diagnosed, her family... became aware that they were pregnant with the little boy on the right. He too was diagnosed with attenuated MPS , and in contrast to his sister, he began treatment at five months of age. You can clearly see the difference in their appearance. He is 12 and she is 17 now on this picture, and he has very little in the way of cardiac valve disease. This is an important finding, and because of that, newborn screening for MPS I has been recommended from the Health and Human Services of the federal government in the United States since 2016. There are several states that have already onboarded newborn screening, and what we are seeing now is patients being diagnosed within the first week of life with MPS I rather than being five years of age or even two years of age. So moving on to the heart, what parts of the heart are actually involved in MPS? First of all, the cardiac valves are the most familiar things that are involved in MPS. There are also problems with the coronary arteries in MPS. The heart muscle itself can be involved, and finally the aorta can be involved in MPS. What kind of valve disease is most common in MPS disorders? I've shown this slide to tell you that mitral regurgitation is the most common finding in all types of MPS, and that comes from a nice study done by Hartenbach and Witterman in 1995. Aortic regurgitation is the second most common, followed by mitral stenosis and aortic stenosis. It's very interesting that if you look at what the indication are for heart valve surgery, it turns out that when patients become adults, valve regurgitation appears to progress to stenosis with age. So that's an important factor to keep in mind for your patients who have cardiac valve disease. What I'm going to show you now is how you can determine mitral regurgitation with a two- dimensional echo. What you're seeing here is a picture of the left ventricle, and you see flow coming into the left ventricle, and you see turbulence, the blue, yellow, and green speckly signal, and that signal is mitral regurgitation. We're able to determine that mitral regurgitation is present, and we're able to quantitate mitral regurgitation using two- dimensional cardiac echo. A successful valve replacement has been reported of all types of MPS for the mitral valve. Aortic valve disease is also present in MPS and this is a short axis cardiac ultrasound showing you the aorta and the thickened aortic valve leaflets in the open position. Aortic regurgitation can also be seen in two-dimensional cardiac ultrasound, and again you see the left ventricle with blood going out to the aorta and regurgitating back into the left ventricle through the aortic valve. A successful valve replacement of the aortic valve has been reported in all types of MPS as well, and currently even transcatheter valve replacement has been reported in MPS patients. But what's the effect of enzyme replacement therapy and bone marrow transplant on the cardiac valves in MPS? Many studies have shown there's really no reversal of valve disease with treatments. Aortic insufficiency in some of the clinical trials has been shown to increase slightly with enzyme replacement therapy or after bone marrow transplant for MPS . And we know now that early treatment with either bone marrow transplant or enzyme results in less valve disease. Here are some references that will confirm these statements. Second thing that occurs in MPS disorders are thickening and occlusion of the coronary arteries. On the right you see a normal coronary artery in a three- month- old infant. You see the coronary artery and you see the lumen. In contrast is a 10- month- old child with MPS I who has a very thickened intima of the coronary artery, and this is what is left for the lumen. Coronary artery disease occurs primarily in MPS I and it can occur very early. It's difficult to diagnose because it's diffuse. It occurs on the epicardial coronary arteries. It's hard to find even with coronary angiography. It's unrelated to cholesterol. And specific mutations that have bad coronary artery disease are yet to be determined. It seems to be arrested by bone marrow transplant and ERT in MPS. The reason I say that is because bone marrow transplant has dramatically lengthened the life of individuals with MPS. And there's little post- mortem data to talk about the coronary arteries. This is actually good news that patients are still alive and still using their hearts and their coronary arteries. That being said, sudden death has been reported from coronary artery disease after initiating enzyme replacement therapy. And this was likely because there was significant coronary artery disease present in the patient when they began enzyme replacement therapy. Decreased heart function can occur in MPS. This is an important fact for you to know as doctors who care for babies with MPS. This is a picture of cardiac function in a one- month- old child who presented to us her treatment for MPS I. And you can see that her heart rate is very fast. And if you calculate what the squeezing fraction or the ejection fraction of the heart is, it's depressed at 30% where 55% is normal. Without any other treatment rather than enzyme replacement therapy, this is what I look like three months later with an ejection fraction of 50%. And she successfully underwent bone marrow transplantation. So it's important to know that enzyme replacement therapy appears to improve ventricular function in children with MPS I. And it's also been shown in MPS VI cardiomyopathy can occur in infants. Systolic function is maintained with both bone marrow transplant and enzyme replacement. The function that a patient comes into bone marrow transplant with is generally the cardiac function that they have 10 to 20 years later. Systolic function is improved in infants who present with cardiomyopathy. And there have been case reports of diastolic function where stiffness of the heart being improved in adults with enzyme replacement The conduction abnormalities that can occur in MPS, this is an EKG showing you that there is normal sinus rhythm going on until there is suddenly complete heart block. B waves with no QRS. This occurred in a patient with MPS I, 15 years after bone marrow transplant.
[00:19:30] Prof. Elizabeth Braunlin: It's been reported in MPS II, III, and VI. There appears to be no beneficial effect from treatment. And it's thought to be related to scarring of the conduction system. That's an important factor in follow- up of these patients. Finally, aortic root dilation is common to all types of MPS. And on this picture you can see a two- dimensional echo showing you the ascending aorta here with the valve sinuses, the sinotubular ridge, and the ascending aorta of a normal patient. Contrasted with a patient with MPS in whom the aorta is dilated, the sinuses and sinotubular ridge have fused, and there is no sinus anymore. There is no improvement noted with enzyme replacement or with bone marrow transplant. It's important to note that even though the roots are dilated, we haven't come across anyone who's needed aortic root replacement as you would find with someone, say, with Marfan syndrome. So now to move on to what we know about alpha- mannosidosis. Alpha- mannosidosis has the clinical features that can oftentimes be confused with Hurler's syndrome, and that is that there is mental developmental delay, mental retardation, there can be a coarse facial appearance, there's hearing loss, there are skeletal deformities, CNS involvement, and in contrast to MPS, there are immune defects with Alpha-mannosidosis . There are severe and attenuated types, and on the right is a picture of two brothers who were diagnosed with Alpha-mannosidosis, and the second picture is as they've grown up, and the third, frame C, is one of them as an adult. So you can see the coarse facial features can be confusing with attenuated MPS. There's very little that's known about the cardiac features of Alpha-mannosidosis. Dr. Brecht did a beautiful natural history study from four hospitals in the EU, Manchester, Prague, and Germany, and one other. There were 45 patients, and he found heart murmurs in nine of the 45 patients, but there was an abnormal echo in only five of them. Valve insufficiency was determined in two of the patients, and decreased ventricular function was determined in patients as well. There was not further description of what the valve insufficiency was, nor was there really good follow-up. There was an abnormal EKG noted in two patients, and again, it was not noted what those abnormalities were. So not a very high percentage, and quite poorly defined. Jolanta has recently published a paper looking at the cardiac and all of the clinical symptoms in MPS. There were 111 patients he found by scouring the literature from the early 1960s. The median age of onset of disease was 12 months, but the median age of diagnosis was 84 months. Among the presenting signs or symptoms that brought patients to attention, the most common was cognitive impairment. Virtually 100% of the patients had cognitive impairment, followed by coarse faces, hearing loss. Short stature was much less common, visual impairment was much less common, and cardiac involvement was quite low in the list, with only 4% of the patients having cardiac involvement. Again, the cardiac involvement was not defined, and this is an area of unmet need in terms of knowing what is the actual cardiac involvement in these patients. The treatments for alpha- mannosidosis, bone marrow transplant, or enzyme replacement. In the papers that discuss either of these procedures, the cardiac features are usually not described. I have taken care of patients with alpha-mannosidosis, and on the patients that I've seen, probably 6 to 10 patients, I've found no cardiac disease thus far. So if you're going to look for heart care for patients with MPS or alpha- mannosidosis, you really need to find a team that works with storage disease, understands the problems, is up to date, who knows who to ask if there are questions that arise for non- cardiac issues. Most importantly, work to advance the knowledge that we all have for these rare diseases. There are pediatric cardiologists who care for most of the patients, but with the advent of bone marrow transplant and enzyme replacement therapy, there's a growing need for cardiac care of adults with MPS and alpha-mannosidosis. We undergo cardiac evaluation at diagnosis, and based upon the initial findings, we have follow- up exams. We certainly have follow- up exams if there are new questions or concerns, such as syncope, shortness of breath, fatigue. And if there are upcoming surgeries that are big, such as orthopedic surgeries, it's a good idea for the patient to have an evaluation at that time. The things that we do, we examine them, measure blood pressure. The patient can have deposition of MPS in the aorta and present like a coarctation of the aorta. We listen to the patients, although the absence of murmurs does not mean that there's no cardiac disease. There can be valve disease and there can be decreased function without cardiac murmurs. Routinely, we get ECHOs and EKGs. We do 24- hour EKG monitoring. For lab work, we do troponin looking for muscle destruction. And we look at the NT-proBNP as a blood marker of systolic and diastolic function. And we measure a lipid panel. So now we've come to the questions. And I think that you will get them on the chat function. So here's the first question. Is there significant cardiac involvement in all of the following storage diseases except MPS I, alpha- mannosidosis, MPS VI, or MPS IV? So I'll give you time for your answer. This one ought to be easy for you. And of course, the answer is alpha-mannosidosis. We don't know as much as we should, but thus far, cardiac disease does not appear to be as important in alpha-mannosidosis as it does in the storage diseases. And you've noted that I put down the MPS diseases that have significant valve disease, MPS I and MPS VI, as part of the questions. There is disease in MPS IV as well. Here's your second question.
[00:27:58] Prof. Elizabeth Braunlin: One of the following statements is not true about cardiac disease in MPS. Decreased heart function can be found in infants with MPS I and MPS VI. No cardiac murmur means no cardiac disease in MPS. Mitral regurgitation is the most common finding in MPS diseases. And cardiac valve disease is most common in MPS I, II, VI, and VII. Well, as you know, no cardiac murmur does not mean there's no cardiac disease in MPS. So that is not true. You can have valve insufficiency that is mild, even moderate, without hearing a murmur. You can have decreased cardiac function. You can have coronary artery disease. And, of course, you can have aortic root dilation. And all of those can occur without a cardiac murmur. And finally, the question three, which of the following statements about the effects of treatment for MPS are correct? The age when treatment is begun does not matter to the outcome. Cardiac valve disease does not regress with either ERT or bone marrow transplant. Cardiac function is maintained with both ERT and bone marrow transplant. ERT and bone marrow transplant have favorably altered the natural history of MPS. And, again, you're right. The most important thing to know is that the age of treatment is very important to the outcomes. And so that statement is not true. And the correct answer is B, C, and D. So, in summary, our MPS, the heart valves, the myocardium, the coronary arteries, the conduction system, and the great vessels can all be affected by storage of GAG and MPS. Bone marrow transplant and ERT don't reverse existing valve disease. They may arrest coronary disease and preserve ventricular function. An early diagnosis of MPS can lead to better outcomes. For alpha-mannosidosis, cardiac disease appears to be uncommon in alpha-mannosidosis, but there are short follow- up times and small number of patients. And the treatment trials have not usually included cardiac outcomes as study endpoints. So continued cardiac studies are important as treatment improves. And with that, I conclude our session on the cardiac medical stations of MPS and alpha-mannosidosis. Thank you very much.