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Multisystemic Manifestations of Underlying Metabolic Diseases

Authors: Barbara K. Burton, MD​; Roberto Giugliani, MD, PhD​; Martha Solano, MD​​; Klane K. White, MD, MSc​​Faculty and Disclosures

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Activity Transcript

CHAPTER 1

Barbara K. Burton, MD: Hello. I'm Barbara Burton, a professor of pediatrics at the Northwestern University Feinberg School of Medicine and an attending physician in the Division of Genetics, Birth Defects and Metabolism at the Ann and Robert H. Lurie Children's Hospital of Chicago. Welcome to this series of presentations called "Multisystemic Manifestations of Underlying Metabolic Diseases." In this series, experts from around the world will address various topics related to the diagnosis and treatment of mucopolysaccharidosis.

I would like to start this series of five presentations with an overview of both classical and non-classical presentations of some of the mucopolysaccharidoses (MPS). Just as a reminder, the mucopolysaccharidoses, or MPS disorders, are a subset of the larger group of disorders referred to as lysosomal storage disorders. There are 11 known enzyme deficiencies which comprise seven distinct clinical MPS subtypes. In all of these, there is increased tissue storage of glycosaminoglycans or GAGs. These are progressive disorders with multi-systemic involvement, and there's a wide range of clinical involvement in each of the MPS disorders. Although, these disorders are individually rare, collectively it's estimated that their incidence is approximately one in 25,000 births.

While symptoms affecting multiple organ systems are the rule, skeletal and joint abnormalities are a prominent feature of many of the MPS disorders. This is particularly true of the non-classical or more attenuated forms of the disorders in which osteoarticular abnormalities are often the initial symptom. These patients generally have clinical manifestations presenting at a later age, and symptoms affecting cardiac and pulmonary systems may be less pronounced than in the classical presentations. While symptoms affecting multiple organ systems are the rule, skeletal and joint abnormalities are a prominent feature of many of the MPS disorders. This is particularly true of the non-classical or more attenuated forms of the disorders in which osteoarticular abnormalities are often the initial symptom. These patients generally have clinical manifestations presenting at a later age, and symptoms affecting the cardiac and pulmonary systems may be less pronounced than in classical forms of the disorder. The diagnosis is frequently delayed in these patients. Therefore, an important message is that patients presenting with osteoarticular abnormalities in the absence of inflammation should be evaluated for the presence of an MPS disorder.

We are going to focus our attention today on two of the MPS disorders, MPS IVA and MPS VI. Morquio syndrome is the common name for MPS IVA. This disorder is the result of deficient activity of the enzyme, N-acetyl-galactosamine-6-sulfatase or GALNS for short, an enzyme that catalyzes the breakdown of two glycosaminoglycans, keratan sulfate and chondroitin 6 sulfate. In the disorder, there is progressive accumulation of these GAGs in tissues. The incidence of the disorder varies across geographic regions but is estimated to be approximately one in 500,000 in North America. Patients with MPS IVA, unlike patients with some of the other MPS disorders, have preserved intelligence, and skeletal findings are often the prominent features of this disease. However, there's wide variability in the clinical presentation and disease severity.

Here you see a patient who has what I think of, and I think most physicians think of, as the classical presentation of Morquio syndrome with very severe short stature and prominent skeletal deformities. But it's also important to note that we see other manifestations as well, including ocular findings like corneal clouding, pulmonary findings, obstructive sleep apnea and others, hepatosplenomegaly, ear, nose and throat issues, dental abnormalities, and cardiac valve involvement, much like we see in other MPS disorders. And I also want to stress that the disorder is clinically heterogeneous. So, while the patient you just saw and who is in the center of this set of photographs has the more classical presentation, we see a wide range of severity. The woman on the left would appear to have a more intermediate phenotype, while on the far right, you see a patient who is of normal stature and doesn't have obvious skeletal deformities. But all these patients have MPS IVA. MPS IVA or Morquio nonclassical phenotype was reported in an international study to account for approximately 25% of all Morquio patients. And as more patients with nonclassical features are diagnosed, the fraction of patients accounted for by this phenotype may be considerably higher than this. The nonclassical patients typically have less overt skeletal involvement, their stature may be normal, and hip stiffness and pain are very often the chief complaints.

In this slide, you see x-rays of a patient reported in the literature with the nonclassical phenotype, who first presented with hip pain at 11 years of age. And at that time, the presumptive diagnosis was a bilateral Perthes-like disease. The patient continued in life and over time had more significant hip pain, which led him to an orthopedic surgeon at 27 years of age, at which time, the diagnosis of MPS IVA was established. And you can see that there are some findings of dysostosis multiplex like the mildly dysplastic capital femoral epiphysis, there's some scoliosis and some humped vertebral bodies. But overall, the findings are much less obvious than we see in the classical patient. And we know that misdiagnosis is extremely common in MPS IVA, in this attenuated phenotype, with the most likely misdiagnoses being various types of skeletal dysplasia, such as spondyloepiphyseal dysplasia. But some patients are just followed with a particular symptom like kyphosis or scoliosis or the patient with the Perthes-like disease that I just showed you. So, this is certainly something that leads to delayed diagnosis in those cases. So, if you have a patient who appears to have findings that might be consistent with one of those skeletal dysplasias, spondyloepiphyseal dysplasia (SED), or multiple epiphyseal dysplasia, or bilateral Perthes disease, but genetic testing, for example, has not confirmed the diagnosis, or you haven't had genetic testing, then certainly consideration of MPS IVA would be very important.

Now, I mentioned that we were also going to touch on MPS VI. And here, you see photographs of several patients at the same age with MPS VI, and you see that there is quite a bit of heterogeneity and variability and severity in this disorder as well, with the lady on the left having the rapidly advancing severe form of the disorder associated with very short stature. But some patients like the one on the right can live into adult life with MPS VI with normal stature and much less severe skeletal abnormalities. And we see everything in between. Like all lysosomal disorders, there is a spectrum of severity. This disorder also has a reported incidence of about one in 500,000 with thematic features very similar to MPS I and II, particularly in the severe form, but with no cognitive involvement. It's the result of a deficiency of N-acetylgalactosamine-4-sulfatase or arylsulfatase B, which leads to progressive accumulation of dermatan sulfate in the tissues. Here you see photographs of another patient with MPS VI at various ages, showing the evolution from what appears to be a very normal looking young infant in the first slide, to a patient who over time develops the coarse facial features associated with MPS VI, and although it's not visible in this slide, short stature, and skeletal abnormalities as well. So, we really see a similar phenomenon in MPS VI as we see in MPS IVA, and we know that all the MPS disorders are progressive. So, the findings become progressively more apparent over time but at variable rates in different individuals. With this, I'd like to thank you for your attention, and please continue to listen to my colleague, Dr Klane White, who will discuss a number of clinical case scenarios related to what we have just reviewed.

CHAPTER 2

Klane K. White, MD, MSc: Hello. My name is Klane White. I'm a professor of orthopedics and sports medicine at Seattle Children's Hospital in the University of Washington in Seattle, Washington. Welcome to this case presentation, Clinical Case Scenarios, Differential Diagnosis of MPS versus other Skeletal Dysplasia.

I will be discussing a 7-year-old boy who presented to us quite a while back now, August 2008, but I think this is a very typical presentation for this scenario. This is a boy who had been limping off and on since age 4 and even had symptoms of knee pain since age 5. Now presenting to us at age 7, he was seen by one of our advanced practice providers, our physician assistant (PA), who obtained an x-ray and diagnosed him with Perthes. He had no associated joint swelling, and his height was within normal CDC measures. If you look at his picture here, there's nothing dysmorphic about this child. This is the x-ray that was obtained that day, and you can see, as the arrows point out, that there are some changes to the proximal femoral epiphysis. Now this was read as bilateral Perthes disease, and this is how the child was diagnosed, and this is not an uncommon situation.

A couple years later, after continuing to be followed, it became apparent to this physician assistant that maybe this child had something more going on than just bilateral Perthes disease, so he was referred to our skeletal dysplasia (SKD) clinic. He had urine screening for mucopolysaccharides (MPS), but these were normal. So, at that time, it was determined that this child did not have MPS, and no further workup was pursued. I should say that he is a very active child, played soccer, hockey and was swimming, all without difficulty at this time despite some of the symptoms.

His history is relatively insignificant. He is full-term delivery, vaginal, normal weight, uncomplicated pregnancy. He was walking at 10 months of age so met all normal developmental milestones with perhaps maybe a slight speech delay. I can tell you now that he's not only an excellent student in, well, at that point, he was an excellent student in grade school, but now he's graduated from college with a degree in engineering. Family history was not that significant. Father had some toxic synovitis of the hip, which resolved. Mother had known myopia. He had a half-sister who was hypothyroid. So, some of these things you could think hypothyroidism associated with epiphyseal dysplasia, myopias associated with type II collagenopathies, and then just hip problems in the father, but nothing that really gives us a lead.

He was seen again at this time at age 9. His height was still within normal limits for CDC standards. His arm span was maybe a little long relative to his height, but not abnormally disproportionate. Again, no other findings at this skeletal dysplasia visit that would be suggestive of a significant or obvious skeletal dysplasia, no palate defects so that would lead us more towards a type II collagenopathy. But he did have a mild scoliosis without any significant gibbus deformity. He had some flexible flat feet. This is part of his skeletal survey. You can see his foot films there, which are, I would say, relatively unremarkable. You can see the persistent epiphyseal dysplasia of the femurs. And if you look at the spine film, there might be a little bit of endplate irregularity or platyspondyly. Skull film and flexion and extension cervical spine films were also unremarkable. There is no flattening of the sella turcica, so what we call a J-shaped sella turcica, which is often seen in more severe forms of MPS was not present here. He has no cervical instability. So, if you are thinking Morquio syndrome, classically, we think of cervical instability, particularly by the age of 9. This time, we repeated his urine GAGs just to make sure that it wasn't a lab error and, again, they were relatively normal, so he was sent for molecular testing for other skeletal dysplasias. As we can talk about at some point during this meeting, type II collagenopathies are going to be top on our list, and I will share an x-ray later that shows the similarities with this child's x-rays.

Other forms of Stickler syndrome also can have some epiphyseal dysplasia. Spondyloepiphyseal dysplasia tarda can present with delayed growth at this pre-pubertal age and looks a lot like type II collagenopathies. Then there are some forms of TRPV4 mutations, specifically spondylometaphyseal dysplasia Kozlowski type (SMDK), which can have endplate irregularities and epiphyseal dysplasia but again, as the name would imply, would have more metaphyseal changes. So those were all normal.

He was seen back in a year for continued evaluation, perhaps developing some chest wall deformity, so some pectus carinatum is what we decided this was. We had another patient who had urine GAGs that were negative, and that patient ended up having Morquio syndrome. So, at this time, we decided to send an enzyme panel on this child, which was abnormally low with GALNS level of 3.29 nanometers per the appropriate units. He did have an attempt at confirmational molecular analysis, which only demonstrated one copy of a change in GALNS. It had normal deletion duplication studies as well and so the second hit was not identified at this time and has not been pursued.

So, this patient we felt to have Morquio syndrome type A and certainly is a non-classical presentation. As you can see, the physical findings are subtle. The radiographic changes in the spine and hips and ribs are most reliable in this patient, not ribs, but spine and hips. A diagnosis of bilateral Perthes should always be an indicator of evaluation for skeletal dysplasia, and most importantly, a form of MPS. So, in our clinic, when in doubt, when we see bilateral Perthes disease, we always test for MPS.

A little discussion on non-classical Morquio patients will show that these patients are typically normal stature that this child was. But as you follow him later in life, you'll see that he'll eventually start falling off the growth curve. Progressive hip and chest wall deformities are common in these, and they can have progressive spinal deformities. This child ended up developing scoliosis requiring surgery. I think urine GAGs are typically normal in these attenuated forms of MPS. So, in MPS type IV and MPS type VI, most commonly you can see normal GAG levels or urine mucopolysaccharides by age 7 or 8, and so this should not be used as a end-all, be-all test.

Looking at growth curves for Morquio, there is the classical growth pattern, but then there is a large scatter of patients who have normal or certainly more growth than you would expect for a classical Morquio patient. With that said, most adults end up being of short stature, less than 120 centimeters in height. But there are many who end up in that even 5-foot or 5.5 feet range, but most are going to be in the high 4 to low 5-foot range. You can see this child's growth chart as he went on, he never actually truly fell off, but he ended up at the sort of fifth percentile for age. Most commonly, though, you would see these children fall off at an older age so it can be very mutation dependent. With that said, just going over this case again, you had normal GAGs, but enzyme testing was abnormal and molecular confirmation, I think, these days is important. Sometimes you can do the molecular testing first, but if you have an abnormality in molecular testing, you always must confirm with enzyme levels when we are talking about MPS.

So, there are some, what I call, radiographic red flags for MPS. In this case, it was bilateral hip osteonecrosis. Idiopathic osteonecrosis of the hips is called Perthes. This is, in this case, not idiopathic. It has a perfectly good explanation. We just need to find what it is. Vertebral body abnormalities, including hypoplasia of the vertebral bodies, but in this case, just platyspondyly is something that should be a red flag and a tip-off for MPS. We have published on this, and if you look at hips in attenuated MPS, they often look like this. But don't be too myopic about it because there are other forms of skeletal dysplasia, again, particularly type II collagenopathies where the films can look very similar.

Spine films also, to the uninitiated, can look very similar and there are many phenotypic similarities and radiographic similarities between skeletal dysplasia syndromes, including pseudoachondroplasia, achondroplasia, metatropic dysplasia and Morquio. So, to round this out, vertebral body abnormalities, bilateral hip osteonecrosis, you really should be ordering enzyme or molecular testing to rule out MPS.

In summary, I will say that mild MPS can be normal. These patients can have normal stature, but they typically start to fall off the growth curve in late childhood. They have progressive hips, spine, and chest wall abnormalities. And if you see bilateral Perthes disease, again, test for MPS. The differential diagnosis, again, includes spondyloepiphyseal dysplasia tarda, type II collagenopathies amongst others.

So, I appreciate your time, and I thank you for participating in this activity.

CHAPTER 3

Martha Solano, MD: I'm Martha Solano. I am a neuropediatrician from Bogota, Colombia. I direct a special program for degenerative diseases in Fundación Cardio-Infantil and I am the principal investigator for Colombia in patients with MPSII, III, IV and VI.

For all of us in Latin America, who work with patient with MPS, the last 18 years provide us convincing evidence about the benefits to start the therapy in our patient with MPS early. This evidence has been built through the natural history of the disease, by the knowledge about the burden of the disease in MPS IV, burden of the disease in MPS VI, early interventions, and the effect that enzyme replacement therapy (ERT) has had in this [condition]. At the beginning, our patients with MPS were diagnosed late. Therefore, they received the ERT late, but as we become aware about the root of the disease and its impact in their quality of life, our therapeutic goals change. The sum of experience between countries in Latin America, such as Brazil, Colombia, Argentina, Mexico, allowed for a multidisciplinary approach for our patient focusing on their quality of life.

However, the World Health Organization in the last international functioning classification questioned us about the focus and approach and measurement of these results in patients with chronic disease. It’s not enough to improve the structure or function affected if this is not done together with an active participation from our patients in their basic daily activities. For this reason, is very important to know what exactly the burden of the disease for MPS VI is, which focuses on the cardiopulmonary system, sense [organs] system and the spinal cord compression. And on the other hand, is very important to know what the exact burden of the disease for MPS IV is, which focuses on the musculoskeletal system, sense system and spinal cord compression too.

Likewise, it is very important to say that early intervention is composed by pharmacologic treatment and nonpharmacologic treatment. In addition, early intervention using a multidisciplinary team approach has 4 big therapeutic goals. One of them is the sensory organs, especially auditory system, which is impacted by ERT. The other one is the cardiopulmonary system, the early intervention upon which has an impact on morbidity for both diseases, MPS IV and MPS VI. Not less important is the timely correction of spinal cord compression. And finally, the muscular system is very important to keep our patient mobile.

A multidisciplinary approach with orthopedics and rheumatology is very important to ensure the participation of our patients on their basic daily activities. Their basic daily activities are impacted by their mobility, upper extremities, fine motor deficit, pain, fatigue, and range of motion.

In our experience, patients with MPS IV who started therapy before 5 years of age have shown improvement in their respiratory and sleep pattern. At the same time, they have shown improvement in their mobility. So better results in the medullary decompression surgeries. In the same way, patients with MPS VI who have started therapy before 5 years [of age], as published by Dr. Dafne Horovitz in Brazil describing 34 patients with MPS VI who started therapy before 5 years [of age] showing not only the safety, but also the effectiveness in these populations. Similarly, Dr Mc Gill and Dr Leiro demonstrate the safety of ERT.

I would like to show you a patient with MPS VI, with a mutation for severe and fast disease who has started therapy at 13 months of age. At 4 years old, she showed low progression disease and improved cardiopulmonary system and mobility.

In conclusion, early treatment with ERT in patient with MPS IV and MPS VI has shown an impact on cardiac and pulmonary function. Additionally, the impact of ERT in other systems, such as musculoskeletal system, pain, cardiac improved the impact on the daily activity for our patients and therefore their quality of life.

Thank you very much for listening. And I invite you all to continue and listen to my colleague Dr Roberto Giuliani, who will discuss diagnosis algorithms.

CHAPTER 4

Roberto Giugliani, MD, PhD: Hello, my name is Roberto Giugliani. I am from Porto Alegre, Brazil, and I’m here today to discuss the diagnosis of mucopolysaccharidosis (MPS) diseases.

So, when should we consider MPS? In a child who usually is born normal and who has a slow progressive course. Presenting coarse facies not always, but very frequently, corneal clouding may be present, is very common to have visceromegaly like liver and spleen enlarged. Joint stiffness is also quite frequent. Bone dysplasia, it's one of the hallmarks of these diseases. They may present respiratory infections and respiratory distress, also heart valve diseases frequent. And many times, patients are submitted to previous surgery for herniatosis. And some of these patients present cognitive decline, in some of these MPS diseases. So, the first take-home message is that clinical suspicion is important, but you need the labs to make a diagnosis of MPS.

So, I will talk about the importance of establish an early diagnosis. And I will just mention this paper published several years ago, where they studied two siblings. One sib was diagnosed late and started therapy with 3.5 years [of age]. The boy on the right was diagnosed early, because of the family history and was treated since birth. At 3.5 years, he was evaluated. Comparing the sister and the brother, you see that the spine is completely different. These pictures were taken 3.5 years, one [sibling] untreated at that time and the other treated since birth. We see the different in the importance of early diagnosis, and of course early treatment. So, the second take-home message is that efforts should be made to diagnose the MPS patient early in life.

Now let's talk about evaluation, how to make these diagnoses? And we usually start with evaluation of urinary glycosaminoglycans (GAGs). And if an MPS is suspected, test for urinary GAGs. Patients with MPS usually present increased urinary GAGs. But to evaluate these, you need to have age-related reference levels. You should consider that a diluted urine specimen may give false results. Very important, avoid these qualitative screening tests like spot tests, which are colored in blue, or the turbidity tests. They give many false positive, which is not a major problem, but they give also false negatives. So, the third take-home message is increased total urinary GAGs suggest MPS but does not provide the diagnosis. This is important.

If urinary GAGs raised, you suspect MPS, but you do not know if this is true or not and which kind of MPS you have. And if you have normal levels of total urinary GAGs, this does not completely rule out the disease in a patient with a strong clinical suspicion. So, if you have a strong clinical suspicion of MPS and normal GAGs, consider repeating the assay or doing other tests. If you have the increased urinary GAGs, you should look at what their profile is. Maybe you may have heparan sulfate, dermatan sulfate, keratan sulfate, so these can be very helpful for thinking which type of MPS the patient presents. For instance, if you have an increased dermatan sulfate, this is typical of MPS VI. If you have increased keratan sulfate, this is typical of MPS IV, which may be IVA or IVB. So, the fourth take-home message is in a patient with increased excretion and abnormal pattern of urinary GAGs and suggested clinical picture, diagnosis of the MPS is very likely.

But a confirmation is still needed, and this confirmation comes usually by enzyme assays. Because we know all the enzymes which are deficient in the MPS, so that we have now 12 MPS types, each one with one specific enzyme deficiency. For instance, if you have Morquio disease type A, you are in the presence of a deficiency of the N-acetylgalactosamine 6-sulfatase or GALNS. In MPS VI patients are arylsulfatase B deficient. So, finding the specific enzyme deficiency you have would give specific diagnosis. And this is important, because the GAG degradation pathway, there are several enzymes that acting in a stepwise manner. And if you take the example of N-acetylgalactosamine 4-sulfatase or GALNS when it is deficient, there's an interruption of the breakdown of GAGs. There is a GAG accumulation, and you have the MPS. Which samples are being used for the enzyme assays? In the past we used skin fibroblasts. But this is invasive, you need to cultivate the fibroblasts. So, we replaced these by leukocytes, which is much simpler. And presently, we are doing most of these assays in dried blood spots. Dried blood spots are very convenient, a practical sample for the assay of MPS enzymes. There is also of interest in countries with the difficult-to-access areas, like Brazil and where regular sampling and mail are limited. Also, it's easy to ship across borders when you need to send the sample to another country. You still use these tests, these enzymes, but as a screening. You prefer to confirm in leukocytes or using a molecular analysis for, to have a final confirmation of diagnosis. So, how you do the assay of the enzyme activity? Usually, you use artificial substrates and mix it with the sample of the patient, where it may be dried blood spots (DBS) or leukocytes, where you have the enzyme. And then if the enzyme is present, the breakdown of these artificial substrates occurs, and you have usually a part of the substrate that is fluorescent. And you go to the fluorine, determine you have the fluorescence. In the red column, you see the cohorts with high fluorescence. In the blue column, your blue column you see the patients that have a very low fluorescence, and so the very low enzyme activity. So that for fifth take-home message, our patients have very low enzyme activity irrespective of having severe or attenuated from low enzyme, is important to confirm the diagnosis. But it does not mean that the patient has a more attenuated or a more severe phenotype. And it's very important in the cases specifically when you have a sulfatase deficiency, you should assay other sulfatases. Because there is one condition named multiple sulfatase deficiency (MSD), where there are several sulfatases affected, and this is different from the MPS IVA or MPS VI that have a sulfatase deficiency. So, it's important when you have a sulfatase deficiency, the activity of another sulfatase must be measured to rule out this other condition that is multiple sulfatase deficiency. And these enzyme assays, they are very good to identify patients. Here in the left you see the controls, in the right you see the patients, varying, different activities. But it's not suitable to identify carriers. For carriers, it is not reliable to use the enzyme assay, you should go for molecular analysis. So, the sixth-take home message is the enzyme assay is useful for patient diagnosis, but it's not reliable for identifying carriers.

For these, you need molecular genetic analysis, now we will know all the genes involved in the MPSs. You can sequence them using maybe standard sequencing or next-generation sequencing, and you have all the sequences. And this is very important, because identifying the molecular defect of MPS IVA or MPS VI of the MPS. That then you have a final confirmation of the diagnosis. And importantly, it is the seventh take-home message, in most cases a molecular genetic should be performed to identify carriers.

But if the mutation in the index case is known, the lab should be informed to perform mutation-palliated genetic investigation, saving time and savings costs. So do not need to sequence maybe all the genes, because you already know that in that panel you are looking for a specific mutation. And the eight take-home message is that you, a molecular genetical analysis may be helpful for phenotype prediction.

So usually, it is the patients with nonsense mutations or frameshift mutations who present with more severe disease. And usually in these patients with missense mutation look, may have a more attenuated phenotype. So, this may be helpful, for this. Then regarding those charts, what do we usually do? We start from clinical suspicion. We do the GAG analysis, the GAG the quantitation and the GAG the evaluation in which GAG species is present? Then you do the enzyme assay, and finally do the molecular analysis and have the full picture. But what is now occurring is that you are more and more using the molecular analysis as a first laboratory approach to MPS, so you have the clinical suspicion and then you do the molecular analysis. You can do a targeted mutation detection if you already know the mutation in the family. You can do the gene sequencing of the disease you suspect. You can do gene panels where you can assay, analyze several genes at the same time. Or even you can do the whole exome in some cases if you have a specific suspicion. Then with these results, you should confirm if there is an enzyme deficiency, and if there is also an increase of GAGs. Because if you have an abnormal genotype but you have low enzyme activities, and you can have the deficiency.

I will say if there is a consequence, this is both a functional consequence and a biochemical consequence that is the accumulation of urinary GAGs. And the one thing that is now very interesting is that there are some specific signatures in urine that you can identify specific MPS. And this is a very interesting development, in that we can have analyzed by thermal mass spectrometry the urine of patients with mucopolysaccharidosis. According to the pattern, you can say if it is MPS I, MPS II, MPS VI, MPS VII. So, this example is particularly interesting, that you see a specific pattern for MPS VI. You can do this, even before the enzyme assay and have a very good idea about the final diagnosis. When you test patients with clinical suspicion, you can usually diagnose most cases with suspicion. If you perform screening, for instance in patients with joint stiffness or with skeletal dysplasia, you can find more patients. And that you can, of course you test more patients, then you diagnose more patients. If you test all the population as you do in newborn screening, you will find all patients. Maybe these will be used in the future to diagnose all MPS patients very early in life. So, I think that the diagnostic laboratory in the future will have basically two approaches, the thermal mass spectrometry to assay the GAGs and maybe the profiles of oligosaccharides that would help in the diagnosis and the enzymes. You have the next-generation sequencing to do the molecular analysis and gene panels, and gives you all things you can do in dried blood spots, which is very convenient.

So, summarizing, that if you suspect of MPS, measure urinary GAGs. If GAGs are normal, think of non-normal MPS levels lysosomal diseases​. If GAGs are increased, further tests should be performed. Identification of GAG species together with clinical and radiological findings could suggest potential diagnosis. Detection of the enzyme deficiency is recommended for diagnosis. And molecular genetic analysis is useful for diagnosis confirmation, carrier identification and also prenatal diagnosis. If molecular genetics analysis is performed before biochemical tests, enzyme assays or urinary GAGs are still needed to confirm the diagnosis. And the identification of the correct MPS type will enable therapeutic decisions and correct guidance to the family.

I thank you very much for your attention.

CHAPTER 5

Barbara K. Burton, MD: Hello, I'm Barbara Burton back again, and it is my pleasure to welcome you to this global overview of newborn screening with a focus on mucopolysaccharidoses.

Just to review newborn screening in general, many of you know that this is often referred to as the Phenylketonuria (PKU) test, because PKU was the first disorder for which we had widespread newborn screening, but now, over 35 different disorders are included in most states in the United States with more being added with each passing year. Newborn screening for at least some disorders is also done widely throughout the developed world, although there's tremendous variation in terms of the specific disorders that are included in individual countries.

Newborn screening in the U.S. is a state health department initiative, and each state decides which disorders will be included. The Secretary's Advisory Committee on Heritable Disorders and Genetic Diseases in Infants and Children makes recommendations to the Secretary of Health and Human Services regarding which disorders should be included on what is referred to as the Recommended Uniform Screening Panel or RUSP. Most states follow federal recommendations, and eventually implements screening for disorders on the RUSP. But in addition, some states may choose to include disorders that are not on the RUSP. There are currently 35 disorders on the RUSP, including one MPS disorder, MPS I, which was added in 2016. In addition, the Advisory Committee voted to add MPS II to the RUSP in February of 2022, and this recommendation has been forwarded to the secretary of Health and Human Services. If it is ratified, then we will have 36 disorders, including two MPS disorders.

There are some general requirements for adding a disorder to the newborn screening panel that really apply to any condition that is added to the RUSP in the United States. First of all, the disorder should be one that is serious. There must be a test that will reliably detect the condition using a dried blood spot without an unacceptable number of false positives. There should be treatment, and there should be evidence that initiation of treatment prior to clinical diagnosis is beneficial. We need to have some pilot data showing that screening can be accomplished, and typically, some pilot data from the U.S. is required, although data from other countries can also be included and considered. Why would we think about newborn screening for the MPS disorders? First of all, it would avoid the diagnostic odyssey that is so common for patients with this disorder, where there are symptoms and patients see three, four, five different physicians before a diagnosis is ultimately established. It would allow early initiation of treatment before permanent irreversible damage occurs and would also allow genetic counseling to provide families with information on their reproductive options before having other affected children.

MPS disorders really meet all the criteria to be good candidates for newborn screening. They are certainly serious. We have tests now available for virtually all of them that can be performed on the dried blood spot. We have approved therapies for MPS I, II, IVA, VI and VII, and there are investigational therapies in the pipeline for MPS IIIA, B, and C. There is certainly some evidence that treatment of the disorders prior to clinical recognition is beneficial. Intuitively, of course, we know this will be true because the disorders are progressive. At some point, there is irreversible damage to cells and tissues that we could prevent with very early treatment. Pilot data from the state of Missouri were the basis for the addition of MPS I to the RUSP, and pilot data from Illinois and Missouri supported the application for MPS II.

Now that MPS I is on the RUSP, newborn screening for this is becoming very widespread in the United States. This map shows in purple all the states that were doing MPS I newborn screening. As of a few months ago, this changes all the time, so there may very well be other states now that should be colored in purple. It shows, excuse me, the two states in blue that are also doing newborn screening for MPS II. There are three primary methods in use for newborn screening, all of which are methods that measure enzymatic activity. This can be done by tandem mass spectrometry through the digital microfluidic method or the standard fluorometric method. It may be possible at some point in the future if the technology improves to use measurement of gags in the dried blood spot as a primary screen, but this is not currently possible because there are way too many false positives. This would be desirable in allowing detection of all the MPS disorders, but currently, they're diagnosed individually through measurement of the deficient enzymatic activity. False positive results can be reduced by using a second-tier screen on the dried blood spot measuring gags. This is done in some of the states that are doing MPS I newborn screening. For example, MPS I newborn screening for the state of Kentucky is done by Mayo labs. And if the enzyme activity is low, dried blood spot gags are measured. In a publication regarding their early experience, it was shown that in over 130,000 infant screens, using this two-tier method, only two positive screens were reported, and one was affected with MPS I, while one was a carrier, so it does very substantially reduce false positive rate. In other states where we are measuring enzyme activity alone, many of the false positive seen are the result of pseudodeficiency for the iduronidase enzyme. We know that pseudodeficiency occurs for all lysosomal enzymes that have been studied.

Pseudodeficiency is a condition in which enzyme activity is low, but there's no evidence at any time of any clinical disease, and there is no GAG storage in the tissues. But the enzyme activity in patients with pseudodeficiency can, in some cases, be as low in the test tube as that measured in affected patients. This is the reason why we have false positives in many cases. Pseudodeficiency for iduronidase is very common in patients of African descent. So, in states with a high African American population, we see many false positives resulting from this issue. Diagnosis in an asymptomatic newborn because of this issue requires both demonstration of enzyme deficiency, and evidence of substrate accumulation obtained through measurement of gags in either dried blood spot or urine as we commonly used for diagnosis, or in some cases by demonstration of a genotype that is definitively linked to disease. We often, however, find genotypes that are not previously reported unique variants or variants of unknown significance, and this can lead to difficulties in phenotype prediction, attenuated versus severe. The same phenomenon occurs in MPS II. We also see pseudodeficiency there, and we have some of the same issues with phenotype prediction when we have a mutation that is not previously described.

Newborn screening for other MPS disorders is not currently widespread, but testing for MPS IIIB, IVA, and VI is ongoing in Taiwan. In addition, there is a pilot screening program evaluating several different conditions not currently on the RUSP, ongoing in New York state called the Screen Plus Program. That includes screening for MPS IIIB, IVA, VI, and VII. Hopefully this will provide us with pilot data that is needed to enable a RUSP application, and more widespread screening for some of these treatable disorders. Screening for MPS VI in a high-risk community has also been reported in Brazil and is ongoing.

So, to summarize, newborn screening for MPS I is becoming widespread in the U.S. and allows treatment to be initiated at a very early age, improving outcome and avoiding the diagnostic odyssey. Newborn screening for MPS II is beginning, and hopefully will soon become more widespread. Screening could be done for all the other MPS disorders. The technology is there, and with the data from pilot programs ongoing, it is likely that this will become common practice in the years to come.

So with this, I would like to thank you for participating in this activity. I hope you have enjoyed and benefited from the individual presentations and gained new insights on the recognition and treatment of MPS disorders. As we attempt to improve outcomes in patients with rare disorders with multi-systemic manifestations through earlier recognition and treatment. Please continue to answer the questions and complete the evaluation of the program.

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