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[00:00:10] Prof. Barbara K. Burton: Hello, thank you for joining us today for our webinar entitled Mucopolysaccharidoses, Early Recognition and Management in Primary Care. My name is Barbara Burton. I'm a clinical geneticist and a professor of pediatrics at the Northwestern University Feinberg School of Medicine and the Ann and Robert H. Lurie Children's Hospital in Chicago. I'm really pleased to be joined for the program today by Dr. Joe Menzer, who's a professor of pediatrics at the University of North Carolina at Chapel Hill and director of the Menzer Research and Education Center for MPS disorders in Chapel Hill. I'm also joined by Kristin McKay, who is the president of Project Alive, an advocacy organization for MPS2, and also the mother of a patient with an MPS disorder. So I just want to begin our program today with a few comments. Please do not take any screenshots of anything you see. And feel free to enter questions for any of us into the question box at any time during the program. We'll take these questions at the very end, but you're free to enter them at any time. I just want to begin by speaking just very briefly about recognizing MPS disorders early by looking for subtle signs and symptoms. But before I do that, let me just comment for a minute on why we're concerned about early recognition. Why is that important? Well, we know that MPS disorders are progressive, multisystemic disorders. The disease manifestations continue to appear more and more over time. We have disease modifying treatment available for most of the disorders, and investigational therapies are under development for the others. In addition we know that symptomatic treatment is extremally important for all MPS disorders. Early recognition and early treatment regardless of the mode of the treatment is our best way to achieve optimal outcome in patients who are affected. Really, if we want to talk about early diagnosis, of course, whoops, I think that we all know that newborn screening is our best way to achieve early diagnosis for really any of our progressive metabolic disorders. That would allow us the earliest possible treatment. Fortunately, in the United States, this is now almost universal for MPS 1 and is expanding rapidly for MPS 2. And there are pilot programs ongoing in a number of states and other countries for these and other MPS disorders. However, in most countries, we still need to rely on early clinical diagnosis, and that's true also in the U. S. for our other MPS disorders. So this really is going to remain critically important for a good period of time before we achieve our final goal of getting to universal newborn screening for all of these conditions. So what are some of the common early findings of MPS disorders? One of the things I want to emphasize is that many of the early findings are things that are really common in the general pediatric population. So we'll talk about what some of those things are. This is one of the challenges to early diagnosis, but I think that if we see a combination of these findings, that can give us a clue to think about a unifying diagnosis such as an MPS disorder. This is something I try to emphasize with our residents in pediatrics all the time. If you see three or four different things going on in the same young child, it's always good to step back and say, is there some connection? Sure, it could be coincidence sometimes that a child has three or four different problems for different reasons, but many times there is a connection and there's a unifying diagnosis, and if you stop and think about it, you can achieve that early diagnosis, and that's really, really important in the MPS disorder. So many of the things that we'll talk about as early findings are common in the general population and by themselves maybe wouldn't suggest this possibility but in combination with other things really should. So some of the things we see are listed here. Recurrent otitis media, actually recurrent upper respiratory infections of many types but otitis media particularly kids with MPS disorders often needing tubes two, three, four times in a lifetime. Hernias are also common, inguinal and umbilical hernias. Some kids with MPS disorders will have chronic or recurrent diarrhea and then developmental delay. I think developmental delay you know tends to trigger thoughts of what's the etiology but oftentimes with the other things on the list you know it's common you wouldn't really think twice about it. okay some of the other more unusual features of MPS disorders include things like corneal clouding. Now this could be a very important early clue in MPS 1. We see it somewhat later in some of the other MPS disorders and this is obviously not something that would be common in the general population so should always result in suspicion. Sometimes kids with MPS disorders are recognized because a parent notices a lump on the back and they get referred for evaluation to a pediatric surgeon or maybe an orthopedic surgeon. This is lumbar kyphosis related to the underlying skeletal disease. It's a common presenting feature in MPS 1 but all also can be seen in other MPS disorders and some of these things Joe Menzer will talk about in a little bit more detail as he goes in more depth into diagnosis. Probably the thing that most commonly ultimately brings the kids to attention is the gradual change in the facial features that we see in many patients with MPS disorders that we call coarse facial features. Really thickening of the soft tissue resulting in that broader nose and some periorbital fullness, full lips, and it's a gradual phenomenon so often parents certainly don't think anything about it and it's very obvious if you look at the child on the left but the two kids on the right you know it's a little bit more subtle but if you start seeing something like this again in conjunction with some of the other findings I mentioned then that would be a really important clue. Progressive joint stiffness occurs a little bit later but also is an important clue oftentimes. Stiffening of the fingers, shoulder stiffness very very common but that one is less often appreciated unless you're really doing a full exam for range of motion but the finger stiffness is often noted early on. So with that I'm going to stop. This was just a brief little introduction to the clinical features. Joe is going to go into more detail but Kristen or Joe anything you'd like to add at this point?
[00:09:10] Dr. Joe Menzer: Barbara as you appreciate short stature associated with the mucopolysaccharidosis. Is that one of the early findings or not? Can you use that as a recognition since all kids get weight measured routinely in the first couple years of life?
[00:09:24] Prof. Barbara K. Burton: Yeah that's a good point Joe and no it really isn't a good early signal you're right it is common later on but these babies are typically a completely normal in size at birth and they grow normally for the first year or two typically sometimes actually rapidly you know and a larger head size might be an important clue. Occasionally you'll see a child referred for evaluation because the head growth has been excessive. There's macrocephaly even though there's no underlying hydrocephalus most of the time so that could be a clue but but the short stature is a little bit later typically. Kristen, anything you'd like to add at this point?
[00:10:09] Kristin McKay: Yes, I was, just it was very spot- on. I think that's something that many of our families in the MPS2 community experience: that they might go a couple of years with many symptoms, as you mentioned, a lot of ear infections, just constant illnesses, hernias, delayed speech, and often those things do seem to be kind of typical childhood ailments that they'll just grow out of. And often we also see it's the kind of physical features that will prompt the genetic testing, especially the larger head size and the coarse facial features, and then maybe even for more severe cases, you do start to see certain concerns with breathing or other organs, and that kind of leads people on this long diagnostic journey of trying to figure out what is going on, unless you happen to get lucky enough to run into someone who's familiar with maybe any of the MPS disorders to do further testing, and at that point, as we all know, there, as symptoms occur, that damage has already been done.
[00:11:23] Prof. Barbara K. Burton: Exactly, exactly, okay. Well, thanks for the great comments. Let's move ahead now and, Joe, share with us additional details related to the diagnosis of these important conditions.
[00:11:43] Dr. Joe Menzer,: Thank you, Barbara. We went to slides change here, so again, my presentation is going to cover some of the things that Barbara talked about but in addition some other issues and I just want to comment that Barbara alluded to that- you know- unique issue from an academic medical perspective. I established the Menzer MPS Research and Treatment Center in Chapel Hill. I'm currently director and that goal of that center is really to improve the well- being of MPS patients and their families. This slide is just my disclosures. I consult and serve on advisory boards for a variety of biotech companies and I'm a principal investigator for clinical trials for MPS 2 or Hunter syndrome. Again, I'm going to give Barbara gave a little bit. I'm going to give a little more overview of MPS again, emphasize some of her early signs and symptoms, really want to talk about newborn screening because that's really to me where the future lies because of the clinical challenges of recognizing these and the rarity. Just show one slide of the diagnosis, which we can do very readily if we have a chance to do that, and the current treatment options and then the rationale for early initiation of IV ERT in the MPS patient. So again, as Barbara alluded to, these are lysosomal enzyme deficiencies. In the MPS category there's 12 known enzyme deficiencies, 8 different clinical types. All are involved in the complex or the breakdown and recycling of these complex sugars called glycosaminoglycans, historically called mucopolysaccharides, or the name came to name. These are ultra rare, very heterogeneous, progressive and they're clinically characterized by somatic and or central nervous system involvement, with premature deaths, unfortunately for most individuals untreated. One of the key things Barbara and I have seen over the years. In general, the MPS patients appear normal at birth and I can't recognize or anybody else can recognize it, but they subsequently develop somatic and cognitive impairment. Every one of the individuals in the slide has an MPS- MPS2 attenuated, MPS1 attenuated- a her or child MPS1, a Sanfilippo, an MPS2, a morquio, an MPS1, a Sanfilippo. Just showing you the variability within each disorder and among disorders. This is one of the challenges. All these disorders, because they're enzyme deficiencies, really have a spectrum and it's really the amount of residual activity. If you have no residual activity, you have the severest form. If you have a little bit of activity, you have a more milder. And typically, if you have more than 2% or 3% residual activity, you never come to clinical attention. So there's a spectrum. But more importantly, there's also other issues in MPS1, 2, and 7, all have physical or multisystemic somatic disease and can have CNS involvement. But they never only have CNS involvement. For example, you don't see a child with these disorders who just have central nervousness involvement and no physical. That when you have that picture, that's SANSleep or MPS3, the primary neurologic disorder. And certainly mild forms are not likely detected clinically. And now in the days of DNA testing, we're actually seeing 10, 20, 30-year-olds with SANSleep who were diagnosed just because they had a DNA panel showing they had now two variants consistent with one of the MPS disorders or SANSleep.
[00:15:50] Dr. Joe Menzer,: In contrast to those disorders, MPS4, Morquio syndrome, is really a skeletal dysplasia. It's normal intellect, but with somatic involvement. And then MPS6, Naruto- Lame syndrome, has the same physical involvement as some of the others, but they're intellectually intact. In the US, one of the rarer forms of MPS7, or SLY syndrome, non- immune hydrocatalysis of common presentation. In other parts of the world where this disorder is more common, we see it more typically.
[00:16:21] Dr. Joe Menzer,: But the MPS7 patients have a lot of similar features to MPS1. I only show this slide not to go over everything. There's lots of different clinical manifestations, but what you don't see on this slide is renal disease. These patients never develop renal disease to our knowledge. And we never have liver failure. I've only seen a CITES and end stage of two MPS2 patients, but they were basically in the final few days of life of dying from their neurologic disease. But otherwise, most organ systems are involved. Some early diagnosis of MPS challenge the opportunity that Barbara alluded to. I think it's important to emphasize that, except for MPS7, MPS individuals appear normal at birth. And I've had the chance to examine half a dozen newborns picked up by prenatal diagnosis with MPS1 and 2, and I cannot be convinced they have anything, even though I'm biased knowing they have it. More importantly, storage starts in utero, as early as the first trimester. So we know they have storage, it just takes time for that storage to cause this damage. As Kristen alluded to previously, most MPS families experience a diagnostic odyssey. They go one to two years, sometimes even more, multiple subspecialty visits, sometimes incorrect diagnosis before the diagnosis of MPS is finally made. And I'll come back to that and talk about the differential. As you already heard from Barbara, some of the clinical features that can be seen early is this inguinal hernias, not so much umbilical, inguinal hernias typically occur early, hearing loss, recurrent ear infections, and then this very prominent within the first sometimes three or four or five months of life, that some of the severe MPS1 or her patients can get the kyphosis that can be actually a presenting sign, but typically is unrecognized until people really think about MPS. But here are some of the other things, if you see them, you should, again, as Barbara alluded to, again, delayed speech and or development, the coarse facial features, macrocephaly, large tongue macroglossy. One of the things that I have seen very consistently historically is clear, chronic, clear nasal discharge. They just, that fluid instead of going back, it just can't, because the turbinates aren't large, it comes out. Again, noisy breathing, you heard from Kristen, frequent respiratory infections. Apatomegaly tend to be there, but not a really early sign, but if you see a lot of splenomegaly greater than apatomegaly, that's not an MPS, that's a lipid storage disease, either knee, knee and hip or gout shape. And then if you saw a picture of severe joint range of motion from Barbara, but early on, what you see is, to me, the earliest sign, I'll be using Barbara to comment afterward, what I've seen is that supination, supination, that if you lock the elbow, that's some of the early decreased motion in terms of joint involvement. If you don't see that, it tends to be less likely to have an MPS, especially if you have other potential symptoms. So what's the differential diagnosis of MPS? It is really large, and this is one of the challenges because, again, patients with MPS can look like otherwise some of the storage disorders, such as mucolipidosis 2 or eye cell disease or mucolipidosis 3. Some of the glycoprotein storage disorders, not as sedosis, for example, can look like an MPS, and so that's important to be aware of that. But again, because of their bone disease, their dysostosis multiplex, skeletal aplasias can really sort of mimic the presentation of an MPS patient, and so they may get referred to orthopedics for that reason. Because of their current pulmonary infections, respiratory infections, in terms, they get referred to pulmonology. Because of heart issues and valvular disease and murmurs, you can maybe see a differential cardiovascular disease. Same way with developmental delay, it's very nonspecific, and a lot of times you'll get referred to neurology to work that out. I want to comment that it's not uncommon for autistic spectrum disorder label to be applied to our MPS patients before the diagnosis of MPS because they have some autistic features. And again, autism itself is a clinical diagnosis. It's really not the answer. There's lots of causes of autism, and certainly anybody with autism needs to have a genetic evaluation to rule out other things that can sort of mimic autism. And again, attention deficit hyperactivity, some of the San Filippo patients who have very little physical disease, but developmental delay, can be very hyperactive, and that can sometimes be your clue to that diagnosis. So the differential is really huge. That's why these patients get seen by a variety of referral specialists. Because of the rarity of diagnoses, it's typically not made until there's more progression. Sometimes, as Kristen alluded to, you can sometimes be very fortunate and somebody says, oh, yeah, I've seen that before. Again, with ENT, not uncommon for ENT people, but multiple septal tubes in a patient before they finally realize there's something different about this individual. Barbara alluded to, and I absolutely agree, why newborn screening for MPS? Again, most people don't appreciate how rare the MPSs really are. I estimate there's less than 2, 500 individuals total in the U. S. within all forms of MPS. Each of the three most common MPSs, MPS 1, 2, and 3a, I estimate there's less than 500 patients alive in the U. S. And so this is one of the challenges because they're so variable. It turns out in the U. S. there's roughly 60, 000 pediatricians. I estimate, historically, that the average pediatrician sees one or two MPS patients in a lifetime of practice that they recognized. They may have not even recognized one. And so that's one of the challenges. They're so variable and they're so heterogeneous. It's just not one form of MPS. There's lots of different forms. And each patient presents their own timeline. Each disorder, there's variable times of disease onset. The milder you are, the later you are. And the rate of progression can vary among the different MPSs. So these are all the challenges. In general, MPS patients appear normal at birth. You cannot recognize them except for MPS 7, alluded to before, nonimmune, and hydrophatality is a common U. S. presentation. So what's the status of newborn screening in the U. S.? As we already alluded to, MPS 1 was being screened to the Federal Recommended Uniform Screening Panel, so- called RUS, 10 years ago. They estimate that greater than 85 to 90 percent of the U. S. newborns are currently being screened for MPS 1. It turns out that Texas is the last major state not yet screening for MPS 1, but on their website they have announced they're going to actually hopefully start MPS 1 and MPS 2 in early August of this year. So hopefully very soon the vast majority of patients will be screened for MPS 1. So, what is the status of newborn screening in the U. S. for MPS2 and other disorders? MPS2 was added to the RUS in 2022, based on the reported benefit of pre- symptomatic treatment compared with the usual case detection, that is clinical diagnosis, and the feasibility of implementing newborn screening. The procedure to newborn screening for MPS1 is virtually identical for MPS2, and the same technology works for both. Fortunately, the uptake of newborn screening for MPS2 has been faster than MPS1, and I should allude that Dr. Burdin has been a pioneer in really getting newborn screening going in the U. S. Interestingly enough, West Virginia is currently screening for MPS4A or Morphia A, the only state in the U. S. that are doing that, and there's a local pilot project in the U. S. in the New York City area called Screen Plus, where they're screening for MPS2, 3B, 4A, 6, and 7 selected New York hospitals. So, what's the global status? Barbara alluded to this. Newborn screening for MPS is really limited to a few countries outside the U. S. There's been pilot and regional screening studies that she talked about in multiple countries, but newborn screening in Taiwan has been going on for a number of years for MPS1, 2, 4A, and 6. MPS1 has been included in the Netherland newborn screening program since March of 2021, and they had a very nice publication a few years ago showing that since early availability of MPS1 enzyme in 2003, there's still been a challenge to make the clinical diagnosis, and so newborn screening for them was the only way to go. And then more recently, South Korea started countrywide screening for MPS1 in January of 2024. So, the diagnosis, if you have to think about it to make it, so I use the clinical suspicion as really the key, but again, either x- rays can suggest a bone disease, clearly doing quantitative urine gag analysis and component analysis by LC- MS- MS clearly lets you tell you whether you have an MPS child. The MPS is all stored gag, we normally don't store gags at all, and again, the full standard is then doing lysosomal enzyme testing if your x- rays or urine gags are positive or your clinical suspicion is high. And so the diagnosis by a geneticist is pretty routine to do, but it's a question getting to somebody who thinks about it, has that clinical suspicion, because if you don't have the clinical suspicion, you know, they'll never make the diagnosis, and this is really the key. If you don't think about the disorder, you'll never make the diagnosis, and hopefully this webinar will help people make a more timely diagnosis, but again, the rarity and the heterogeneity makes it challenging, and newborn screening for the other MPSes hopefully occur in the future to allow us to obtain earlier diagnosis than we're currently doing. So what's the status of treatment of MPS? Enzymatic correction has been possible at the cellular level on MPS fibroblasts secondary with the following observations for probably greater than 50 years. Cultured cells release small amounts of lysosomal enzyme, and my mentor with Neufeld turned these correction factors before she realized what they really were. We also know there's a very efficient nanosec- phosphate receptor- mediated enzyme uptake that occurs, so there's a mechanism to get enzyme outside the cell into the cell through this. And more importantly, correction of the GAG metabolism may only occur with 1% or 2% residual enzyme activity, so you need very little additional enzyme in the cell to normalize that cell's GAG metabolism, and this ability to get an enzyme from outside the cell in is called cross- correction. So this is just a schematic showing that we know proteins are made in the rough endoplasmic reticulum, enzymes that are adjusted to the lysosome, and in the Golgi, a nanosec- phosphate is put on, and that basically directs that enzyme to the lysosome where it only works. These enzymes in all the lysosomal disorders are pH sensitive, they only work optimally at pH 4. 5, and so they really don't work outside this body, they only work in the lysosome. But again, this process is not 100% perfect. Some enzyme can escape, and you can either go back into that same cell in the clathrin- coated pits or the nanosec- phosphate receptor, which take it back, or a bi- center cell, and this is the rationale how transplant, which I'll talk about in a second, how transplant works. The macrophages make the enzyme and it can go to other cells nearby and get corrected. So, again, as I alluded to, we have two forms of treatment, hematopoietic stem cell transplantation and HSCT, intravenous enzyme replacement therapy. First patient was transplanted in the UK in 1981 with Hurwitz syndrome, a severe form of MPS1. There's been lots of success and lots of patients. I estimate over 1, 000 MPS patients have been transplanted. Successful and stable grafting in severe MPS1 patients has clearly resulted in clinical improvement of somatic disease. Unfortunately, the skeleton and the ocular disease have not changed and increased long- term survival. There's probably a function enzyme was generated in transplant. It's not a lot. And we know now from clinical trials going on with ex vivo gene therapy for MPS1, where the enzyme levels are much higher, we can actually potentially see skeletal changes improvement. So there's hope in the future we'll have improvements in transplant technology. So how did the brain be helped with transplant? It turns out the microglia cells in the central nervous system are of bone marrow origin and are the source of the enzyme in the brain after transplant. That process takes time, up to six months to a year, to really get enzyme in the brain to start slowing down the neurologic disease. And again, transplantation is really the treatment of choice for severe MPS1 or poorer patients under two years of age with normal development. If you're already cognitively impaired, transplant does really not help that much because, again, you can't correct an abnormal brain. The neuropsychological outcomes have varied widely after transplant for other MPS disorders. But there's some suggestion if you do it very young, you may have an improved outcome than you do with modern transplant technology. So as you'll see in the next slide, this is my overview of treatment options for MPS1 in terms of transplant. MPS1 recommend poorer patients all be transplanted sooner than later. It's unclear yet for MPS2 and 3A and B and 7 how much transplant. But the key is only if you do it early in an appropriate manner will you get the best result. And there's still some challenges. It's not clear what the difference is. And there may be an amount of enzyme actually delivered by transplant. In MPS2 or 3A and B patients, they need more enzyme. We alluded to that ERT is available. You can see here for MPS1, 2, 4A, 6, and 7, IV enzyme is really available and routinely used in the U. S. In general, you can say that ERT and MPS result in reduction of urine gag accretion and decreased liver and spleen size in almost all patients where they have it, improved joint range of motion, pulmonary function, and energy endurance occur in some patients after ERT, but it's limited. The lack of clinical progression should be considered a success in the MPS and reversal of clinical disease is usually not possible. Even though IV ERT is beneficial, it does not help unfortunately the brain disease because the MPS enzymes are a large glycoprotein which don't cross the blood- brain barrier. There's also limitations that I alluded to. Weekly infusions, three to four hours duration, enzymes are very expensive in terms of hundreds of thousands of dollars per patient, if not more, and it does not treat the brain disease if the patient has that. Also, some of the somatic tissues and clinical features listed here, synovium, trachea, bone, corneal clouding, carpal tunnel, are really not responding to either IV ERT or transplantation. I think that's really due to just not giving enough enzyme to these difficult tissues that are relatively avascular, and so hopefully with more enzyme in the future, we may see some improvement. Again, we're not treating the central nervous system except for MPS1, where patients with MPS2, 3A, Sanfilippo in general, and 7, all have neurological disease that can benefit from improvement for the brain disease. It's important to realize that the progressive storage of GAG results in irreversible tissue damage. These patients typically, when you're clinically diagnosed a patient, they already have damage. The rate of occurrence is not the same, so it's so variable.
[00:34:32] Dr. Joe Menzer,: Again, some clinical benefit improves, some benefit improvement occurs after ERT, but it's typically limited, and I'll show you a picture. The first MPS-1 patient ever treated, a patient of mine, Dr. Kakos treated, you can see pre-treatment, this is a Her-Lorche patient about 18 years of age. You see some improvement afterward in terms of joint range of motion. Yes, it's pathogenically disappeared, but he never got any better than this. This is basically the best you can hope for, and again, prevention is really the name of the game. It does not cure the disease. So what's the rationale for early intervention of ERT? As you already heard, I'll say it again, they're progressive disorders. There's early morbidity, premature mortality from cardiac pulmonary and CNS involvement. The long-term outcome of IV ERT has demonstrated that many disease manifestations are not reversible, and prevention should be the best expectation. So the earlier you can treat them before they have significant disease, the better. I've already alluded to the storage occurred already in utero, so it's not like it occurred after birth. And so now I just want to show you some case studies to sort of highlight early versus later IV ERT for MPS siblings. So Italian family, attenuated, young lady here at age five was diagnosed with MPS-1. Still intellectually intact, but you can see that core facial features. Some of the other characteristics, you can see her as a five-month-old. Unfortunately she had a five-month-old brother when she was diagnosed, and so he was actually started on ERT shortly after that. And you can see here five years later on ERT, the dramatic difference in terms of what he looks like compared to his older sister. Again, he doesn't have any cognitive impairment, but just showing you how. And there it suggests that maybe some of the bones can respond early on, but again, this is just a dramatic showing the improvement that can occur after starting much earlier than a sibling. The next slide shows two Japanese siblings. Picture on the left... with Hunter's syndrome and MPS-2. Picture on the right is at age 36, a similar age, but he was diagnosed at five or six months of age and been on ERT for a year, two and a half years. And you can just see he also, this includes his, you see his facial features, but his joints are also nowhere near as involved as his brother is, which you can see the hand is a very already abnormal hand at three years of age. I have one more case study to show. So this is now in a severe MPS-2 patient. So this patient's been still developing neurologic disease and IV ERT. But the older sibling, sibling O, was diagnosed at 4.3 years of age, and this shows his hand and a joint movement six months on ERT. So he has significant, pretty severe hand involvement, and he really can't raise his arm. His sibling, again, was diagnosed under a year of age because of his older sibling, and you can see here his hands are very different. This is a case of one and a half years of age, and he has, you know, reasonable shoulder sort of movement here. But if you now jump ahead to 13 years of age, you can see the older brother still really is not having any improvement in his joints, and his hands are still very involved. With the younger brother, who's now been treated for 10 plus years, or nine years almost, his hands are, yes, he has a skeletal disease, but he doesn't have any joint stiffness. And again, you can see here he has somewhat comparable shoulder motion, just showing you that we can prevent problems, but we can't correct issues. So, in summary, many lines of evidence, albeit with sometimes limited data since a lot of it is clinical experience, support the opinion that treatment of MPS2 should occur early and before the onset of significant clinical disease. Some people argue if you know it's going to occur, it should occur before you see any clinical disease. If you know that, I would agree with that. The take-home message is IV ERT is much better at preventing clinical disease than correcting or reversing clinical problems, and that's really one of the big take-home messages. And therefore, the earlier the diagnosis, the better you are. I just want to end the talk with some promising or potential new treatments in the U.S. for MPS. The FDA has approved for three companies to file a biological license application in the application needed for grant approval. This case, they're going to use the accelerated approval pathway, that is, instead of looking for clinical benefit, if they can show benefit of the heparin sulfate in the CSF, which we realize is associated with a disease in the brain, then that should be the basis for approval with collecting more clinical data over the next five to six, seven years to show clinical benefit traditionally. So, two disorders, MPS3A and MPS2, again, we have gene therapy, potentially for MPS3A, sometime next year, intrathecal gene therapy for MPS2, where they put the vector directly into the spinal fluid to treat the brain disease, hopefully this year, but early next year in the same way for IV ERT treatment using DNL310, so this is basically a drug that's taking the MPS2 enzyme, it's fused to a monoclonal antibody fragment that's recognized as a transferon receptor, and that goes across in the brain, and that works also very promising. Again, it would be weekly IV treatments. So, in summary, each MPS disorder is an ultra-rare or lysosomal steroid disorder with typical onset of variable clinical disease beyond the newborn period, except for MPS7. The rarity and the slow variable progression of clinical disease result in significant, typically irreversible disease at the time of clinical diagnosis. Individuals at risk for MPS should be diagnosed before the onset of clinical disease, if you can really improve their long-term outcome, if you can identify them, and that's one of the goals of this presentation, even though they're so rare and so variable, the signs, it's hard to be sure, and to me, newborn screening would be a way to go to dramatically improve outcome, as we've seen with MPS1. And again, improved therapies, ERT, HSCT, or transplant are available, but at best, stabilize the clinical features and may prevent progression if done once they have clinical disease. And I want to thank you for your attention, and we can take a couple of questions.
[00:42:09] Prof. Barbara K. Burton: Okay, well, thank you so much, Joe, for that very comprehensive discussion. I think we all agree that even though these are rare disorders, no disease is too rare to deserve treatment, and these patients with MPS disorders deserve our attention and our earliest efforts at diagnosis and treatment in the same way that any other patient with a common disease does. So I think it's really important for us to continue to focus on this issue, and you've done just a great job of highlighting, you know, the findings and really the therapies and the benefits of therapy early on. I think because we are running a little long on time, I'm going to defer any further discussion at this point, because it's so important for us always to hear the patient perspective, I think, and the perspective of caregivers. So I want to make sure we have time to hear from Kristen McKay regarding her experience, and then after that, we will take our questions from the audience and can discuss a little bit more among ourselves, assuming we have additional time. So Kristen, let me turn the podium over to you. Thank you for sharing your experience with us today.
[00:43:40] Kristen McKay: Thank you so much, both of you, for a great presentation so far, and I'm happy to be here to speak really on my personal journey that I think so many other families with MPS can relate to, to help highlight why it's so important to have early diagnosis.
[00:44:25] Kristen McKay: I am also a PS 2 sister. There we go, and this is my brother, Zachary. He had hunter syndrome as well. Zach was about two years old when he was diagnosed and this was back in the the 1900s. In 1996 he was born and diagnosed in 1998 and at that time there was certainly no newborn screening and there was also no enzyme replacement therapy or any other formal treatments for hunter syndrome. So my brother really experienced the typical progression of hunter syndrome as you can see here. He had the kind of clawed fingers, a larger head, he had a lot of the coarse facial features, very short stature and very developmentally delayed, as mentioned. Really until he was maybe a year and a half old or a year old he developed normally. He was very premature, but other than that he had developed normally until he started to have things like constant ear infections, always getting sick, the hernias and little by little that started to raise a red flag and as Dr Menzer actually mentioned earlier, it was an ENT that raised the flag for us and said: I think this child might have something called MPS and my brother was then diagnosed at 10 years old. He was able to receive enzyme replacement therapy once it was approved and available. But at that point his disease had already progressed pretty far. He had a lot of organ involvement, his heart enlarged spleen, he had lost his speech etc. So the enzyme replacement therapy did do some for him. It relieved some of his stiffness, he lost kind of the pebble skin that used to be so common and just kind of got a little bit more light to him. But it was only a short- lived experience as he continued to progress neurologically and eventually at 19 years old he passed, and that was far longer than we had been originally told. We were told he would live maybe until he was between 7 and 14 years old. So it felt like progress to us, but certainly not the ending that we had wanted. And if we can get the next slide up, there we go. This is my son, Charlie. He was diagnosed before he was ever even born. I knew to get tested for Hunter syndrome once I was pregnant- wish I would have done it before, but I hadn't- and we were able to get him started on enzyme replacement therapy at just 30 days old and he was able to have a stem cell transplant at four months old. So he really had treatment before he ever had any obvious symptoms and his transplant was completely successful. He had complications that caused other issues for him, hence the wheelchair, but in terms of his Hunter syndrome it worked well. He never lost the transplant. He's continued to have normal donor cell counts, he's had normal enzyme levels, normal gag levels and really has yet to show any major Hunter syndrome features because of that. So I'm able to obviously look at my brother and see the difference between my son and in terms of the Hunter syndrome it is drastic. He's now six years old and he doesn't have stiff joints, he has good range of motion, he doesn't really have the coarse facial features, he doesn't have an enlarged head, he's never had an ear infection in his life, his hearing is normal, and the list goes on, and it is just a really beautiful thing to see how early treatment can make a drastic difference. I think it's important to note that my experience is rather rare of having a child diagnosed so young and it will only be with newborn screening that that is possible for other families and to be able to treat at such a young age which is ideal. It's before anything has ever shown up clinically and that's what we really want to be able to treat before that happens and hopefully prevent or at the very least delay symptoms as long as possible and now with so many new therapies on the horizon it's even more critical for us to have that opportunity for early diagnosis where we may have hopefully very soon approved therapies that could be more effective and treat the neurological issues that we face in some of these PS types like Hunter syndrome and that's what we want to see as families. We will switch to the next slide too. Thank you so much. Okay these are some of our Hunter syndrome boys and actually as you can see on the very bottom left that's a family all three boys have Hunter syndrome and have had access to invest investigational therapies at different ages and with that you can see a very dramatic difference in their abilities especially cognitively. It's very apparent also with their behaviors and and whatnot with the baby having obviously received treatment the earliest and for us as families I think that it's important to know that we are living in a time where we finally have some hope. We never had hope before and we do with new investigational drugs hopefully on the horizon here soon and really noticing that for us any little bit of improvement means everything. I recently heard someone say instead of milestones it's inch stones and those inch stones mean the most to us and we don't necessarily need for it to be a cure and our child is just back to normal etc. We just want to see improvement. We want to see them continue to be able to do the things that they love like swimming and going to Disneyland and watching their favorite shows and have some I have heard some times that families have experienced different doctors saying you know because enzyme replacement therapy doesn't treat the neurological disease or the other limitations that it might have that it's not worth it and that's not true. It doesn't matter what form of therapy the different types of MPS disorders may have available. There's always something that you can do. First and foremost I think it's important to note that things like Dr. Menzer showed of increased range of motion that can actually decrease a pain that the patient is feeling. All of those things matter to us. It expanded my brother's life longer than we thought even though it didn't save him and you look at diseases like MPS 3 where we don't have a current treatment available but there are things that you can do. You can get into therapy programs. You can get connected to so many different resources and I think that's something that is important as a pediatrician or other practitioner that you get to be there to help connect families to resources. You get to help advocate for them because it's constantly an uphill battle especially with our insurance companies to access all of the resources available and the different modes of treatment that really could impact quality of life for our families regardless of if it's a disease specific treatment or not. So I really appreciate you all being here today having this taking this time to learn about these ultra rare disorders that you may never see but when you do it will mean so much to a family to know that you you already know you've already been here and you've taken the time to learn and that will really change that really hard conversation when you're making that diagnosis to know that the person sitting in front of you really cares. So thank you all very much.
[00:53:23] Prof. Barbara K. Burton: Oh, thank you. Thank you so much for those fantastic comments, Kristen. I think it's such a great reminder that, no matter what the disorder is, no matter what the diagnosis there may, even if there is no cure or no disease modifying treatment, there is always treatment. There are always things we can do to help the patient, to improve the quality of life, to help them lead as good a life as they can for as long a time as possible, while we wait for that cure that we all hope one day will come for all of these conditions. So thank you so much for those really important reminders of what's important to our families. Joe, anything you'd like to comment on at this point?
[00:54:19] Dr. Joe Menzer,: Inheritance: she had a brother with MPS2.. MPS2 is the only X- linked recessive disorder. All the other MPSs are autosomal recessive. So we wouldn't expect that. But if you hear this history of an affected, you know if a mother has a sibling that was affected or died, that should be a red flag to think about it as a genetic disorder. Think about an X- linked disorder. I think that's one important comment in terms of we didn't touch at all about it. Barbara, I have a question for you. We know the physical disease in MPS1 and MPS2 a lot of time makes their diagnosis more possible. But what about San filippo? What can you recommend in terms of what can the primary care providers identify? Again, if they don't think about it, you know San filippo disorder, they'll never make the diagnosis because once they get referred to genetics we're very good at making the diagnosis, but that referral needs to happen. So can you maybe just comment?
[00:55:17] Prof. Barbara K. Burton: Yeah, I mean, I think that that's a great question, Joe. San filippo is very tough because, as you pointed out, the somatic features are so much less obvious in San filippo than in the other MPS disorders so we may not see as much of the core spatial features, the hepatis, splenomegaly and so forth, although we can see some. Certainly patients with San filippo, some of them will have hepatomegaly detectable on exam and many over time will have some mild coarsening of the facial features, some more than others. Those two siblings I showed actually had San filippo type A and they had coarse facial features fairly early on. But I think you know, we know that most patients with San filippo will present first with the developmental delay, slowing of development, accompanied often with behavioral changes like hyperactivity or aggressive behavior, and so they do get referred more to neurologists or developmental pediatricians, maybe diagnosed with ADHD or autism, but I think in any patient you have in your practice who has those issues, look at the patient very carefully, you know. Say to yourself you know, okay, this is a kid now who's looking like she has some developmental delay and or, you know, hyperactivity. Did she have a lot of ear infections that maybe I just thought were you know nothing, or does she look a little bit coarse? Make sure you look carefully for any hepatomegaly, see if there are, you know, any suggestive findings on exam that would suggest the possibility of an MPS disorder. I think we all have seen recommendations from societies like the American Academy of Pediatrics and our genetic societies recommending that every child with developmental delay and autism have genetic tests like microarray and Fragile X testing. But I think increasingly we're also moving into the broader use of things like whole exome sequencing or whole genome sequencing as they become more economically feasible and they're being covered by more payers now, early in the diagnostic process. So I think that's a way of getting to a definitive diagnosis, including things like Sanfilippo but also other genetic disorders, as you know- early on, so that we can get the most effective therapy for the patient before we get to the point of newborn screening, which, of course, we all know is going to be really important for a condition like San filippo. As time moves on, what are your thoughts? Do you have any other other good suggestions?
[00:58:20] Dr. Joe Menzer,: You know there's a question in the chat bar, but I think you really hit it right on target. This is a challenging and with next-generation DNA sequencing- for anybody with developmental delays, behavioral issues, you know, autism, hyperactivity. They may deserve DNA testing to allow us to pick them up early.
[00:58:42] Prof. Barbara K. Burton: Yes, absolutely. And we do have a question coming from the audience that says: for a new diagnosis of MPS1, do you treat with IV ERT unless there is CNS involvement, in which case is the only treatment option HSCT? Well, I think when you have a new diagnosis of MPS1, the first step is to ask yourself: is this the severe or hurler phenotype which is associated with CNS involvement, or is this a more attenuated, milder phenotype? And part of that will depend on the timing of the diagnosis. If you're diagnosing a child with MPS1 at 10 months of age because you see corneal clouding and hepatomegaly and starting to see coarse facial features, that's the severe phenotype. You know any baby with manifestations in the first year, that's the severe phenotype. You're going to go to HSCT and we do most commonly use ERT right from the moment of diagnosis, as soon as we can get it up until the HSCT is performed and engraftment is complete. I would say that's not universal but most of the time that is the practice. Now, if you diagnose a patient you know at five years of age because of joint stiffness, mild coarse, negative facial features, cardiac valve disease and the child is developmentally perfectly normal, that is an attenuated form of the disease and the treatment would be ERT, we would not send that child for HSCT. So, yes, we use HSCT when we know there will be CNS involvement or there is CNS involvement, but hopefully at an early enough time that you can get the benefit. Because, as Joe pointed out in his talk, you know once you have very significant neurologic disease you're not going to see the neurologic benefits. So then you have to look at the risk-benefit equation a little bit differently than you do early on. And HSCT is currently the only option for treating the CNS disease that is readily available. But, as we also heard, there are some investigational therapies that will hopefully also treat the CNS, both the lentiviral-mediated stem cell therapy using the patient's own cells- that is like transplant but safer because it's the patient's own cells and with more enzyme activity- but also the blood-brain barrier-crossing enzymes that we also heard a little bit about. So there are a number of investigational therapies in development for the brain in MPS1, but for now it's HSCT, with earlier ERT and ERT up to the time of engraftment, and for the attenuated patients without CNS disease it's ERT.
[01:01:56] Dr. Joe Menzer: So these are exciting times for the MPS community, as you alluded to all sorts of new therapies the next 5 or 10 years, we're going to see, hopefully, a dramatic change in the landscape, with more newborn screening and therapies to treat the brain disease.
[01:02:13] Prof. Barbara K. Burton: Absolutely, it is really an exciting time, with things changing and so much hope for our patients, who are currently alive today, as we heard from Kristen, and with newborn screening even more so. So with that, I think, I'd like to close our session today. I'd like to really thank both of the other speakers: Dr Menzer, who's one of the world's experts in the MPS disorders- I'm so grateful that you shared your time with us today- and also Kristen McKay, who really, in a very meaningful way, brought us the perspective of someone who has lived the life with a patient with MPS, both as a sibling and now as a mother, and really contributed so much to our understanding. So thank you all for participating. It's been our pleasure to be here today and thank you all.
[01:03:21] Dr. Joe Menzer: Thank you, Barbara.