Identification and Referral of Mucopolysaccharidoses (MPS)

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Introduction

Dr. Christina Lampe: Good afternoon, good evening, everybody. My name is Christina Lampe. I'm working at the University Hospital of Gießen in Germany. And I'm very honored to speak in a row of very famous lysosomal persons like Paul Harmatz, Maurizio Scarpa, and Roberto Giugliani. And I would like to present today MPS case studies, practical examples of an effective identification and referral process.

And I hope you forgive me that I have a lot of slides. And I kindly ask you not to take any screenshots, not to produce any of the slides. And please submit your question at any point via the question panel. And I will answer the question at the end of the webinar. So if you want to see the presentation again or the others, they will be also online available on https:// mps. spot- early- signs. org.

So here are my financial disclosures. Paul Harmatz gave already a very nice introduction to the MPSs. And I just want to remind you again that we are talking about seven types of mucopolysaccharidosis caused by 11 enzyme deficiencies. And to make it a little bit easier to speak about cases and also diagnosis, I usually group them a little bit in MPS I, II, VI, and VII that are showing mainly joint stiffness.

And I call them the stiff ones. In contrast to that, we have MPS IVA and B, which have more musculoskeletal symptoms than the other types, but they have hypermobile joints. So a little bit different. And MPS III, I will not focus on that today, which has not that much somatic signs and symptoms of the disease, but more a cognitive involvement.

MPS: the spectrum and how it presents

We all know that MPSs are multisystemic diseases with signs and symptoms of almost all organ systems with a very high variability on heterogeneities in symptoms and organ involvement. We have cognitive involvement in all MPSs besides MPS IV and MPS VI, actually. And just to give you a very brief overview, we have the MPS IV, the hypermobile ones that have classical cases, but also with a wide variability of signs and symptoms, non- classical cases with more subtle disease complications.

We have MPS VI from very severe to attenuated. And this is for all MPSs the same. Important to know is that with the wide spectrum of disease severity, the disease can also be very specific in some organs in patients, but not all organs are affected. So the disease itself is very specific or individual for each patient. What we know is that they have all a storage of glycosaminoglycans.

We know they can be slowly progressive, they can fast progressive, but nevertheless, it is a severe disease and not a mild disease at all. To show why it is so important to diagnose patients as soon as possible is that we have enzyme replacement therapies for many MPSs. And you see here the table of all MPS types, and in red and bold, the ones where treatment is available.

And actually, it is beside MPS III, IVB and IX, we have treatment for almost all MPSs. And since we are talking about progressive diseases, it is extremely important to diagnose and start treatment as soon as possible in that patients. And actually, many promising clinical trials are ongoing also for MPS III. So this is why it is extremely helpful and beneficial for the patient to diagnose early.

Diagnosis and treatment options

The diagnostics Paul mentioned already is the screening with the glycosaminoglycan excretion in urine. We have this gold standard, it's the enzyme activity measurement in blood, but also dry blood spot tests are available for the treatable MPS types and the genetic testing. We have the enzyme replacement therapy for many MPS types, as I have shown in the last slide.

But we have also hematopoietic stem cell transplantation in MPS I Hurler patients, if they are under the age of two and a half years. And this is why it is so important, because with this treatment, we can stop the cognitive decline in MPS I patients. So the earlier you perform the transplantation, the better it is. So, now coming to case reports and the earliest signs and symptoms, and I will start with the stiff ones, so MPS I, II, VI, and VII, but I will focus a little bit on MPS II because all these diseases, the stiff ones, are quite similar in presenting early signs and symptoms.

Case series: recognising the early signs

Here you see four boys between two and three years of age, and if you look at them, in a way, they look similar, although they have different faces. And I go fastly through these cases, but what you, if you see the pictures, you cannot see that this patient is suffering recurrent infections of the upper airways and ears, but you see a kind of stiffness of that patient, you see this enlarged abdomen, and you see the face that seems that he cannot breathe properly through the nose.

The next patient here, recurrent infections of the upper airways as well, inguinal hernia on both sides, an abnormal gait, a kind of general stiffness of that patient, and a macrocephaly was found in that patient. The third case you see here as well was suffering of recurrent infections of the upper airways and the ears. He showed contractures of the fingers.

He's the oldest one with three years in that group. He had inguinal hernia, a developmental delay, hepatomegaly, a general stiffness, and macrocephaly as well. And if we go to case four, you see the boy here. You see as well the same story, recurrent infections of the airways and ears, inguinal hernia due to the infections, also hearing loss, adenodectomy was needed.

He had a kind of developmental delay at the age of two and a half years, was diagnosed as a hyperactivity, macrocephaly that needed a shunt, and a general stiffness. And you see the big umbilical hernia and the enlarged abdomen. So this was very quick, but if you see these cases all together and the symptoms we saw, what we can see is that some symptoms are present in almost all these patients.

And this is actually here, the recurrent infections were present in all these patients. The inguinal hernia, the skeletal stiffness, and also the macrocephaly. The inguinal hernia was not present in that case. It came later, but actually it shows that these are really the main earliest signs and symptoms in these patients. So the first conclusion is early signs and symptoms, recurrent airway and ear infections, hernia, inguinal or umbilical hernia, skeletal stiffness or general stiffness, and macrocephaly.

These are all unspecific signs and symptoms, but the combination of these symptoms can really lead to a diagnosis. But as I said, it is unfortunately very unspecific. And this is also the reason why patients are diagnosed much later than they should. So here, 44% is the median age at symptom onset, but one third or more than one third of patients are diagnosed older than 10 years of age.

And this is actually present for true for all MPSs. We have in general, in all MPS types, a median delay to diagnosis of almost three years, and in 20% of cases, a delay of more than 10 years. And you see here that MPS II is the median, the median diagnostic delay is four and a half years. In MPS IV, the hypermobile ones, six and a half years.

So it's quite a big gap between the first signs and symptoms and the diagnosis at the end. Another case here, and this is why it is so important to listen to parents, the mother noticed, since she had already two older daughters, a stiffness of shoulders at the age of three to four months in her son. And you see him here on the picture, and he cannot really move his arms in front of him.

So he was never able to crawl, but he was suffering recurrent airway infections. He had several ENT surgeries. He had a language developmental delay diagnosed due to a hearing loss. And actually here, and you see him here on the picture, that he is in a way stiff as well, and he has contractures of the fingers, and an anesthesiologist recognized the contractures because he was not able to position him properly in the operating theater.

And he was suspecting storage disease, and this is why at the age of four years, even if he was already showing the first symptoms at the age of three to four months, he was diagnosed as an MPS II patient. You see here the progression of the disease. You see that he had also at eight years an heart involvement.

So it is a multisystemic disease, although in him the first sign was the stiffness of the joints. And you see here on the first picture with the green shirt, he wants to perform a peace sign with his fingers and you see the severe contractions. And here also the contracture of the shoulder at the age of 12 years.

So actually this is a typical non- neuropathic case. So he has no cognitive involvement, but you see the long distance between the first symptoms, the diagnosis, then the long time of symptomatic treatment until he started ERT. He is actually on treatment since 2011. He is doing very well. I saw him yesterday, but still the irreversible organ damage cannot be returned to normal.

And this is why it is so important to start early. Another MPS II case, and you see here, even if pregnancy and birth are normal in most cases, in some cases there's a Hydrops Fetalis present, but mainly the pregnancy and birth of MPS children in general is normal. And the children look extremely healthy at birth because they have normal height, they're even bigger than usual, they have a normal weight.

And the first time of life, the first weeks and months are usually absolutely normal. And with the disease progression, and you see it here also in the child on the pictures, you have continuous symptoms that are added. So he had a mild developmental delay. Actually, he was also not crawling because of the contractures of the shoulders, and the parents were never able to hold him on his hands and walk with him because he was too stiff in his shoulders.

He had inguinal hernia as well, recurrent infections, an enlarged head and a hearing loss. And it is like repeating myself, these are different cases, but they have all the same actually history behind this child actually. The parents were very concerned about his enlarged head at the age of 1. 7 years, but they went to a pediatrician. The pediatrician said, no, everything is fine, there's nothing behind this enlarged head.

This is just because he is like he is. At the age of two and a half years, the parents insisted in visiting a child neurologist. He received an MRI of the brain actually because of his hearing loss. And as a side diagnosis, there was found white matter lesions. He had, at this time, he was clumsy, he got tired quickly.

He had this enlarged abdomen, enlarged head, and also the coarse face was really, the parents said he's looking totally different from us. The mother was pregnant at that time, so this is why she was really insisting on having a diagnosis. And they tried to find, but the diagnosis was global developmental delay, in particular language developmental delay. But due to some lucky circumstances, they got in contact with a physician who knew about MPS.

And this physician started a urinary GAG measurement, then had the suspicion of Hunter syndrome or differential diagnosis alpha- mannosidosis, which looks very similar. They made an X- ray which showed scoliosis and hip dysplasia and also cardiomegaly. And for this reason, at the age of two and a half years, it was the diagnosis made of Hunter syndrome. And this is a typical neuropathic case.

So here this case is: usually the children are having a kind of developmental delay maybe, but then they continue in developing, slow but normal. So as we saw in the first case, now in this case you see that in with ages three years he's losing fine motor skill, has a poor attention span, is very impulsive. With four and a half years he has a lot of loss of intellectual abilities and his mobility.

With five years he has a loss of interest in people and the attention span is dropping down as well. With five and a half years he's incontinent, has an aggressive behavior, severe sleep problems and a loss of cognitive skills. And this is very, very typical, not only for MPS II but also for MPS I, that the development is a little bit slow but then at a certain time, mainly preschool age, they drop down and they really lose abilities on cognitive abilities they had before.

A closer look: MPS VI and its mimics

So what is my conclusion? The conclusion is the heterogeneity of the disease. Patients with MPS I, MPS II and MPS VII can present cognitive involvement. Actually, 70% of these patients, patients with MPS IV and MPS VI, don't have any cognitive decline, and here's a case that I presented last year already. But I think it is a very good case because I have many pictures and you see this child from Turkish parents with two healthy siblings, after an uneventful pregnancy, normal height and weight at birth, and with 18 months you see that she has dropped down from her percentile of height from 40 to 10 percent.

She was suffering recurrent infection of the airways. She showed umbilical hernia, the thoracic kyphosis, which is always a suspicion of MPS. Whenever you have a child with thoracolumbar kyphosis or so- called gibbus, you have to think to MPS and to exclude at least. She's also showing some pectus carinatum here, hip dysplasia, macrocephaly and you see also a stenosis of the cranial cervical cord.

So she has no really joint stiffness at this time, but a general stiffness. So now is the question, if you heard all these symptoms already, so what kind of MPS is it? MPS IV is more a hypermobile disease, so we can exclude MPS IV.. She has quite a lot of somatic signs, skeletal signs and symptoms, so MPS III is unlikely as well.

Why it is not MPS II? I mean, she looks exactly like MPS II.. The reason is MPS II is X- chromosomal, inherited, while all the other MPSs are autosomal, recessive so, and she's a girl, so MPS II is unlikely as well. MPS IX is so rare that I would like to exclude it here, but we have MPS I, VII and VI that she could suffer from.

So the diagnostic was done. The urinary GAGs showed only dermatansulfate, while in MPS I we would expect dermatansulfate and heparansulfate and in MPS VII as well, also chondroitin sulfate. There was done an enzyme testing in blood and there was shown an arylsulfatase B deficiency in that patient. The genetic showed the mutation in the specific MPS VI gene.

And actually why it is so important to make pressure in diagnosing these patients so early is that if it would have been an MPS I patient- and she could really be an MPS I from all the symptoms she showed, then we would perform immediately the hematopoietic stem cell transplantation. Because if MPS I Hurler syndrome- so the severe type of MPS I, we would expect a cognitive decline and this we can stop with the stem cell transplantation, but only if you perform it up to the age of two and a half years.

So this is why it was so important to have a diagnosis as soon as possible. So it is an MPS VI finally, but it could have been an MPS I as well. This is her at the age of four and a half years. You see, she is on treatment and she is better, but she has still some problems in walking.

The girl has also a cousin that was born in 2018 and you see him here. He had actually quite a lot of difficulties during birth, which is uncommon for MPS, but you see him here that he started treatment in the first months of life and you see him here at the age of four years and he is absolutely less affected than the cousin who started much later.

And here another case, what diagnosis would you find? This boy showed recurrent infections, umbilical hernia, enlarged abdomen, developed mental delay. He was diagnosed as a patient with hyperactivity. He showed the macrocephaly and the skeletal stiffness that you can see here and he had also these small pebbles on his legs and also shoulders, but nobody was thinking to MPS.

Actually, he had also a coarse face, which is maybe difficult to see in him, but he had this, in contrast to the parents, this strange face and actually he was diagnosed at the age of five years, even if the symptoms started in the first year of life. And this is actually a pity because it is quite late.

But what I would like, wanted to show with the MPS VI and all the MPS II cases, the clinical differentiation between the subtypes, especially this stiff ones, is extremely difficult and can be a challenge. So it is always needed to perform enzyme activity in blood or dry blood spot and genetic testing for confirmation in order to start the correct treatment in these patients.

And there is one case from the literature showing how important the early diagnosis and also the early start of treatment is. This is a child that was diagnosed with MPS I at the age of 4. 4 years and she started the enzyme replacement therapy at the age of five years, while her brother was diagnosed immediately. He is younger, so it was known that he is suffering from MPS and he started ERT with five months of age.

And she had quite a lot of signs and symptoms of MPS. And if you see here, the comparison came after five years of treatment. At the age of five years, you see his hand skeleton looks almost normal, while in his sister, she was diagnosed at the age of 4. 4 years and started treatment later. You see the skeleton of the hand that shows the typical disostosis signs of MPS.

And these are the two siblings at the age of 15 and 10 years. And you see these two and the sister that is much more or severely affected than the boy, even if they have the same mutation, the same parents, but the boy started five years earlier his treatment. So the conclusion three is early treatment. The earlier you diagnose and treat the patient, the better is the outcome.

And this is why it is so important that you find and you diagnose these patients. Now, this was the part of the stiff ones, the stiff MPSs. Now to the hypermobile ones, the Morquio A and B patients. But here I would like to focus on Morquio A. And you see here the disease severity. We have almost normal looking guys, but we have also patients with severe skeletal involvement.

Cases across the MPS types

And this case actually was born in November 11 from after normal pregnancy, normal height and weighted birth. He was diagnosed very early at the age of 1. 5 years. You remember the median delay of diagnosis in Morquio patient is six and a half years. And he showed that time a kyphoscoliosis and recurrent infections of the airways. He had inguinal hernia repair.

He had ENT surgeries. So very much similar to the other MPS types, but a hypermobility of his joints. So with one and a half years, he was diagnosed. He started treatment at the age of three years because the ERT was not available until he was three years of age. And I just show you a small video of how he is behaving.

You see the hypermobility of the joints. You see especially the hands in that case. And he's making some physiotherapy here at home. And you also see that he has, even if he has this hypermobility of joints, he has contractures of his shoulders and the short neck. That is very typical. Here he is at the age of three years or four years, and what you can see is that the symptoms were progressive as well.

He has craniocervical stenosis, very typical for MPS. You see the gibbus deformity of his back. You see the pectus carinatum. He has hip dysplasia, actually knock knees, and he lost his growth percentile because dwarfism is a typical sign of MPS in general as well, but that starts at the age of three to four years. So this is why you can miss it if you have a patient that is younger than that age.

And he started the ERT at three years of age, and you see that he dropped down from the 50th percentile to the third percentile of his height. And then after ERT, he started growing parallel to the third percentile. So actually this is a very severe, a classical MPS II, MPS IVa case. And in contrast to this very classical ones, the more attenuated cases like the non- classical MPS IVa cases have much more difficulties in being diagnosed.

This child here was born at normal height and normal pregnancy as well. I repeat myself, this is typical for MPS. She has a younger sibling that is healthy, and she received the cognitive and motor milestones on time. At the age of two years, she had a strange uncertainty of running and tiredness, and the physicians recommended sports. She had recurrent infections of the airways and needed ENT surgeries as well.

And at the age of four years, she had indeed a very suspicious gait, a wide- based gait with external rotation of the right knee, and all other examinations were normal. And I show you here how she's running. The child is this one with the white shirt and the red trousers. And you see here, I'm sorry for the noise, but you see her here coming in the video, how she's running, which looks very much strange.

The parents were very concerned about this strange gait, and they tried to find some diagnosis. So they went from one hospital, one physician to the other in order to receive a diagnosis. There was performed at the age of five years, a gait analysis, and you see her here walking, which is not a normal gait for a five years old girl, but actually the diagnosis was a clumsy child.

And you see the longer she's walking, the more waddling the gait is, but in all other signs and symptoms are not present in that child. Actually, we have also some x- rays of her, and you see the typical radiological signs like the ovoid vertebras in that child, but nobody was thinking to an MPS. She lost her growth percentile from the 50th to the second percentile at the age of eight years, you see here, now she was growing along her percentile, then she was dropping down to the third at a certain age.

She had hip dysplasia. She was diagnosed as bilateral aseptic hip necrosis and an epiphyseal dysplasia. We saw the hand, but nobody was thinking of MPS, but at the age of 10 years, she was diagnosed with urinary GAG excretion, enlarged GAG excretion in urine, and also enzyme activity measurement as a Morquio patient, and so she started treatment. But between starting to walk at one year of age and 10 years, it's a nine years delay.

And the non- classical case here also with another Morquio patient, just to show you her pictures and the hypermobility of her joints, even if she does not look like a typical one. So the conclusion for is MPSs are not only metabolic diseases, but also skeletal dysplasias. And the typical signs, skeletal signs are called dysostosis multiplex. So whenever you read that on a result of a radiologist, you should think to MPSs.

Here are some skeletal dysplasias and you see how similar they look like. For most of them, there's no treatment available, but for MPS it is, and this is why you have to really sort them out. And here in the red boxes, these are patients with an MPS. So how to narrow this gap? Actually, there's one publication that made a systematic literature review and included almost 200 papers out of 1613 and an online physician survey asking 200 physicians in 16 countries about the first signs and symptoms that was triggering to screen for MPS and for this consider MPS tools were performed and I would like to show you a few of these results here and 859 MPS cases were described by the surveyed physicians and what you can see is that more than 50% of MPS VI patients showed a short stature, but also more than one- third of the patients.

We have the skeletal abnormalities that were seen in 50% of almost all MPSs beside MPS III that has no real somatic signs and MPS VII. So actually skeletal abnormalities and short stature are quite often or any joint abnormalities are quite often symptoms. So MPS is indeed not only metabolic, but also a skeletal dysplasia and in patients under the age of four years old commonly presented with skeletal malformations.

This is what we said after the earliest signs and symptoms like hernia and recurrent infections but also the dysmorphic features, the developmental delay, growth delay, psychomotor retardation were very very common symptoms and what the survey and literature review is that the juvenile arthritis was the most common misdiagnosis for MPSs. So conclusion number five is more specific signs of MPS is the skeletal involvement, the dysmorphic features are very common and the juvenile arthritis is a common misdiagnosis in MPS patients.

A final case and a diagnostic tool

And now at the end I would like to make a test with you. I will present you a case, a boy at the age of three and a half years, first child of German parents, he has a younger sister that was born with macrocephaly. Everything was uneventful, pregnancy and birth. At the age of three months, he had hydrocele hydrosceles surgery, developmental milestones were normal.

With 18 months, he suffered from pneumonia. At the age of three years, he had a speech development and recurrent ear infections and with three and a half years strabism and macrocephaly. In the x- ray of the skull, because he developed macrocephaly as well, he was born with the 92nd percentile, the sister. He was born with 90th percentile head circumference, but now his head was growing.

So they decided to make an x- ray and to find diagnosis and they had the suspicion of a lysosomal disease. At the age of almost four years, you see him here, height and weight are absolutely normal, but the head circumference was 54 centimeters, so extremely big and you see him here on the picture. He had also a coarse face, totally different looking from his family.

He had claw hands, he had this square head with frontal bossing, you see in another picture better, pectus carinatum, in a way straight and stiff spine, an umbilical hernia with a weak abdominal wall and hepatomegaly and unclear speech and a mild developmental delay. What do you think and what would you do in this case? Actually, you do a routine lab, which is normal, often illogical.

He has no specific signs, some astigmatism and hyperopia, ENT, chronic middle ear infections on both sides, but hearing test was normal that time. He had in the skeletal assessments typical signs of dysostosis multiplex, an abdominal ultrasound with slightly enlarged spleen, heart, lung, EEG, MRI, everything normal, but in the skin biopsy they found enlarged lysosomes. The developmental testing showed a mild developmental delay.

So what do you do now? Diagnostics. You think to MPS, you have the typical signs, you measure the glycosaminoglycan excretion in urine. That was negative. This does not mean anything, because you can also have MPSs, especially milder patients that have normal glycosaminoglycan excretions and also in adulthood you may have normal gag excretion in urine. So you are not concerned about that and you make an enzyme activity testing in blood.

Actually, MPS IIIb probably not, because he has a lot of somatic signs and symptoms and not a severe cognitive involvement. MPS IVA probably no, because he's more stiff. So you think maybe to MPS I, II, VI and VII, but unfortunately the enzyme activity test for these MPSs is negative as well. So what do you do in genetic testing now?

Or any idea, any differential diagnosis in that patient? Actually there was an additional urine result that you did not read at the beginning because you were so convinced about MPS, but there were some oligosaccharides in urine that were increased. He looks like MPS, has the same early signs and symptoms of MPS like recurrent infections, hernia, developmental delay, macrocephaly, so all the signs and symptoms that you already learned that are typical for MPS.

You have the same skeletal signs like MPS, so the dysostosis multiplex, and you have also a coarse face like MPS. So any idea what it could be? I help you. It is actually the enzyme activity in blood that was found in deficiency of the alpha mannosidase, so the diagnosis is alpha mannosidosis, and there's also a dry blood spot testing available for alpha mannosidosis, and there's an enzyme replacement therapy available for alpha mannosidosis, and there's also the option of hematopoietic stem cell transplantation in some mannosidosis patients.

So this is him just to give you an overview of his life. I know him since a few years. He's now 33 years of age, I guess, or 36. So at the beginning in the first years of life, between three to five years, he was suffering recurrent infections. He needed hearing aids at the age of five years.

At 14 years of age, he had several infections of the airways, enlarged head circumference, the coarse face, an ataxia, which is very typical and different from MPS, and a mild mental retardation. So actually this is him. He's on treatment, and he's very happy. And why do I show you an alpha mannosidosis case in the mucopolysaccharidosis? Because in earlier times, when it was not clear that an enzyme deficiency is the reason for the MPSs, the alpha mannosidosis was called Hurler- like syndrome, and Hurler is the severe form of MPS I .

So actually it's very similar. It's a different disease, but it has a lot in common. So most important, after you saw all these pictures, is MPS shows an overlap with common complaints of childhood. But the combination of these signs and symptoms may help to raise the suspicion of MPS or mannosidosis, and you would test, and you can start treatment early.

There is a diagnostic tool developed that is very nice, so short stature or decreasing growth velocity, especially in the milder patients, recurrent ENT- related symptoms, infections, hernia or recurrent hernia repair, hepatosplenomegaly or developmental delay for some MPS besides MPS I and VI, and any additional features like cardiac valve disease, coarse face, corneal clouding, this peau d’ orange that I showed you in one case, or skeletal involvement, then please think to MPS and test.

It is easy and you will help the patients quite a lot in not only having a name for the disease and avoiding jumping from one physician to the other, a physician to the other in order to find diagnosis, but also to start the treatment as soon as possible. And with this, I thank you for your attention. I know I was speaking quite long and fast, but I hope you could see the pictures and you will diagnose patients very easily now. And now I'm open for questions. Let me check how I can open the chat. Let me check. Okay, so.

Questions and answers

Could strabismus be a sign of MPS? Could it be related to a specific MPS type at which age? Actually, no. Strabism is not a typical sign of MPS, but if in some patients have a hydrocephalus, for sure the strabism can be due to that.

Actually, the ERT is not crossing the blood brain barrier, the enzyme replacement therapy that we have approved now. But there are some clinical trials with enzyme replacement therapy in combination with an antibody that is linking to a receptor on the blood brain barrier in order to to cross. So there are some clinical trials available in Japan. There's one ERT that is able to cross the brain barrier already on the market, not in US and in Europe or South America at the moment.

The hematopoietic stem cells crossing the blood brain barrier, and this is why they can stop the cognitive decline. And this is why we use it in MPS I if they are diagnosed very early, because then we can really stop the cognitive decline. And we have some transplanted patients that are going to the university. So actually, it's really successful if you do it early.

For MPS II, it is also mentioned in some cases and some countries are doing that. But unfortunately, I think due to the older age when they are diagnosed, we don't have the success that we see in MPS I. Would macrocephaly be accompanied with white AF? Actually, this is intraventricular spaces probably. And the macrocephaly is sometimes indeed combined with a hydrocephalus.

Sometimes it is it's a real hydrocephalus so that you really need a shunt system. But sometimes it's also in the enlarged intraventricular spaces because of because of the atrophy of the brain that you have in the neuropathic patients. So the patients with cognitive involvement.

Until what age is ERT effective for MPS? Actually, it is, in my opinion, I would start all patients immediately when I diagnose them. But since it is not a healing treatment, what I usually do is I plan for one year. I discuss exactly what the parents and the patients can expect from treatment. If whenever there's irreversible organ damage, for sure, we cannot return to normal, but what we can do is we can slow down the progression of the disease.

So we know that the joint contractures need quite a long time until they improve. We know the heart needs quite a long time, but they improve over time. And this is a stabilization of the disease. So actually, I would start each patient. There are some countries that have special programs, so they start treatment, and they check after six and 12 months, and there must be some improvement seen so in order to continue the treatment.

And I think every patient has the right to start unless the patient is severely affected, is bedridden, has a severe cognitive decline and cannot move anymore. I mean, then I would not start, but in all other cases, I would start the treatment, discuss what is our goal, and then to see what is going on with the patient on treatment and how he improves or not.

Is there any renal tract involvement in MPS? No. Actually, this is the only organ that is really excluded from the multisystemic organ involvement in MPSs. I have two MPS II patients with some blood in urine since a long time, but we don't find a cause, but it is not typical like in Fabry's disease. We have no renal involvement in these patients.

Also, hematopoietic stem cell transplants are available in which countries and available since when? Hematopoietic stem cell transplantations are available in quite a lot of countries. In Europe, for sure, in US, but also in Middle East. I know that a lot of MPS patients are transplanted also in Brazil, for example, but probably much more countries that I don't know at the moment.

And it is available much longer than the ERTs. The ERTs are available. The first ERT for MPSs in 2003, it was MPS I, but I have patients that are transplanted 23, 24 years ago, MPS patients, and they're doing very well beside the skeletal involvement that is not solved by the stem cell transplantation.

How about Sanfilippo treatment? Have you found organomegaly in them? Yes, in some Sanfilippo patients, we find hepatosplenomegaly. We find also sometimes some skeletal involvement in these patients, but at an older age. And about treatments, there are some treatments in clinical trial at the moment. For example, there's one study for MPS IIIB, or there was a study for MPS IIIB with the intrathecal ERT, so the enzyme given directly to the brain, or CSF.

There are some gene therapies on trials ongoing, and also one which is very promising in MPS IIIA. In UK, this is a kind of ex vivo gene therapy, so the child is giving their own stem cells. The stem cells will be genetically transformed with the correct gene, and also a kind of speed up gene, so that more enzyme is produced, and then these stem cells are re- transplanted to the patient.

And I enrolled one patient in that study in Manchester, and the child is doing very well. But there are a lot of new trials ongoing at the moment. So there are no further questions. Thank you so much also for your active participation and asking questions.

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