A Step-By-Step Approach To Early Signs Of Mucopolysaccharidoses (MPS)

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Introduction

Prof. Maurizio Scarpa: Hello everybody. I'm Maurizio Scarpa and I welcome you to the third webinar of this series. As you know, in the previous two webinar, Professor Paul Harmatz and Dr Christina Lampe were making a very good and very outstanding webinars regarding mucopolysaccharidosis, of different aspects and tonight I will speak about mucopolysaccharidosis but in a different way how to understand why the mucopolysaccharidoses have so many different symptoms, signs and phenotypes.

I am Italian. I work at the Regional Coordinating Center for Rare Diseases at the University Hospital in Udine, which is a northeast city in Italy, and what I would like to remember you is actually this very simple housekeeping note: do not take any screenshot, please do not reproduce slides. We will have about 30- 35 minutes of talking and the important thing is the questions that you are very welcome to do, and you can actually put your question in the in the chat panel.

At the end of this of this webinar, I will read and answer directly to you. A recorded webinar will be available at this website after my talk. So these are my disclosures. As you see, I work quite a lot of with quite a lot of different companies and but I don't have any interest in the market of these, and all the presentations and the pictures are with permission.

So let's start with the first part of my talk, regarding a summary of what it is a rare disease. I think that not all of you have followed, probably, the two previous webinars, so it's better to have a summary. What is a rare disease? Rare disease is a life- threatening chronical disease. We count about six to eight thousand distinct rare diseases, according to different classification, but about 250 new described disorders are per year described in the literature.

What rare and lysosomal diseases are

The definition is for a rare disease is to affect less than five people every 10,000 citizens and globally let's say that from six to ten percent of the global population is affected and in Europe is about 30 million people. 80% of the these disorders are inherited as genetic mutation. 70% of them affect a neurological system, 50% of the rare diseases affect children and 35 of these children do not live more than one year and 30% of the children do not live more than five year after birthday.

The most important thing is also that most of these diseases cannot be treated because 95% of them do not have approved the drug treatment, and for this it is important to work on the search for orphan drugs. Let's say that the definition of an orphan disease is a disorder which is not been adopted by a pharmaceutical industry to provide a therapy, because of lack of interest in the market and little financial incentives and for this term that is being used is orphan, because nobody is thinking to them.

So there is no actually satisfaction in definition an orphan disease, because it is not really this kind of definition that is presenting the entire meaning of this disorder. In the different continents, you see that the description of why we call a disease a rare disease is different. For example, in the USA you have a disease with less than 200,000 patients, in the EU, as I said, less than 5 per 10,000, and in Japan and in Australia, but you see that more or less they are very similar.

They are lysosomal disorders, and as you know, lysosomes are in all the cells of the body besides the red blood cells, so I mean all the cells of the body are affected by the storage. Indeed, for this case, the accumulation is affecting all the different organs, the CNS with mental retardation, and we will see some, then deafness, corneal clouding, and then the skeleton, rather the ENT, the lung, the heart, and the abdomen, and 70 to 80 percent of them involve the central nervous system.

The clinical spectrum of MPS

If you know the disorder, it is very easy to diagnose because, I mean, you can take just a drop of urine, and the disease itself is just easy to diagnose because with the concentration of the dermatan sulfate, you can even start thinking when you have a urine analysis, so if you really know this disorder, you can suspect by the phenotype, and you make in a few hours the right diagnosis.

These diseases, as you saw from the previous webinar, share and have commonalities in features. You see here a panel in which you see that there are different features like the intelligence, the behavior, the cause- effect features, the cardiac problem, the short stature that can be present at different levels, but more or less, they are present in all the different MPSs.

As a matter of fact, indeed, if you group all the patients affected by the different type and subtype of these diseases, you see that they can all come from the same family because they have all of them beside the different enzyme deficiency, very similar features in terms of skeletal, in terms of abdomen, in terms of facial features with the different grade of CNS involvement like in the MPS I Hurler, in the MPS II type A, in the MPS III Sanfilippo disease, and in MPS VII.

However, inside even the same disorder, you can have a different spectrum of disease severity. This is, for example, the MPS II, the Hunter syndrome, in which patients having similar enzyme level and genetic disorder may have a different spectrum for a very severe and neuropathic phenotype to, let's say, attenuated and non- neuropathic, so with a full alteration of periphasomatic and central problems to just somatic and totally spared CNS activity.

This is very typical of this disorder, and so it is very difficult to understand exactly which kind of spectrum the child might have just at birth and with a genetic and enzyme level.

You can also have the distinction of this disorder in the stiff ones and the hypermobile. Usually the MPSs are having all joint stiffness beside one, which is the MPS IV type A and B, because this disease is actually very much affecting the skeleton, but the joints are much softer than in the other kind of disorder. The only disease which is affecting the CNS in all the different types is the Sanfilippo.

We have four kinds of Sanfilippo diseases due to four different enzymes, but all of them have a very severe CNS involvement. The clinical course of this disorder in the severe phenotype is very, very important because the facial dysmorphia, the corneal clouding, the cardiac, the musculoskeletal, and the hepatosplenomegaly are affected in the first decade of life, and the life expectancy is at the maximum of the second decade.

In the slowly progressing MPSs, the same features are much slower in progression. The life expectancy is reaching adulthood up to 60 to 70 years of age.

Of course, these are so- called more attenuated phenotype, but of course to live also with this disorder is not easy due to the fact that this progression is in any case altering the quality of life of these patients. Just very quickly to remind what already has been said by Christina and Paul regarding the typical joint stiffness of the skeleton, and so the claw hands, which is really a typical sign of the MPSs together with the tiptoes walking, and the rigidity of the joint.

Cardiac, corneal and carpal tunnel involvement

I remember you that the joint stiffness is also followed by an alteration of the spine with scoliosis, with the flattening of the kyphotic, and then a lordosis, which is very, very accentuated, and then here you have problems of the hips that can bring the patient to have a prosthesis and a hip replacement. One distinctive sign that you need to be very careful is actually a lordosis, kyphotic lordosis, which is present in the lumbar part of the spine.

You see here due to the alteration of the genesis of the vertebral bodies with big scoliosis and hip dysplasia. The accumulation can also affect soft tissues, like, for example, the larynx. And this is a feature of the larynx with a lot of GAG. And also in the ear, you see how infiltrated can be the middle and the inner part of the ear.

You can have also accumulation of GAGs in the cornea, which is very typical of the MPSs and very minimal in MPS II. And this feature, especially in the MPS larynx accumulation, it's a nightmare for anesthesiologists and is really a risk for any kind of anesthesia that the child can require, even for minimal surgery procedure or even for an MRI.

The cardiac signs and symptoms is very common in this disorder, and with specifically a valve disease which is present mostly in the mitral, aortic, tricuspid, and pulmonary valves in this exact level. So the first valve which is affected is the mitralic valve, and then you have the other two. This kind of alteration can give to pulmonary hypertension and ventricular hypertrophy with cardiomyopathy.

And you can have patients affected by arrhythmias and abnormalities of conduction, which can be sometimes fatal and also giving congestive heart failure in the very late stage. At the central neurological problem, you have a very typical cervical stenosis, which is also giving a peripheral neurological sign very important to the patient. And then different levels of enlargement of the ventricles with the enlargement of the Virchow-Robin system.

And also the carpal tunnel is very frequent in these children. Remember that carpal tunnel is not a pediatric disease, and if you have a carpal tunnel in a child, the first thing that must be done is to rule out a lysosomal disease. Okay, so I was going through very quickly with the most important sign and symptoms of this disorder, but do we know why these children have this kind of sign and symptoms?

The pathophysiology of lysosomal storage

Let's say that these are lysosomal diseases. So they are storage diseases. You know that these disorders are due to a genetic defect of lysosomal genes. So you have a defect of a protein which is degrading the glycosaminoglycans and the glycosaminoglycans are stored in the lysosome in the cell.

So in the 1976, Bob Desnick was saying that these metabolic disorders were the simplest metabolic disorders because they were done by one gene defect, one protein defect, one compound which is stored in the body, and for this, the accumulation of the stored material in the lysosome was giving apoptosis to the cell, and for this reason, the cell was dying.

So very simple. Everything is due to the stored material. But if you see, for example, the different organs, you see that indeed in the liver, you can even stain very nicely the GAG storage, and you can see even with a low magnification. In the spleen, you can see the stored material in the tissue. But if you go to the brain, actually, which is very much affected in 70% of these patients, you don't see very much deposition of glycosaminoglycan.

And actually, you don't think that with such a deposition, you can have such a severe CNS disorder. So after this description, the idea that the stored material is the unique responsible for such a terrible disorder starts to be not so sure anymore. Up to, let's say, the 80s, 90s, the lysosome was supposed to be just a garbage tank.

All the material that needs to be recycled or destroyed goes directly to the lysosome where there are about 100 enzymes. Each enzyme is working in an industrial chain, so they are degrading the different molecules in monomers. And that's it. That was, indeed, the idea that the lysosome was the end part of the metabolic pathway of a molecule.

But in the middle 90s, what has been shown is that the lysosome was in strict contact with a lot of other pathways in the cell, with endocytosis, with, for example, chaperone- mediated autophagy, with ubiquitin-proteasomal system, with microautophagy, with mitochondria, with a Golgi, even with the nucleus. So at a certain point, the lysosome was not considered anymore just a garbage tank, but a central part of metabolism and the welfare of the cell.

So what we do here is to go very quickly through these five points, that the lysosomal storage is not a homogeneous process, that you might have a problem due to the lysosomal problems due to the endocytic events, that there is also alteration of other systems like calcium homeostasis, endoplasmic reticulum stress, and other parts, that the lysosomal disorders were also very important to rediscover the autophagic system, and that it is a problem of recycling, which is important for lysosomal disorder.

Let's say, for example, that in the lysosome, you don't have only material that is recycled due to just endocytosis, but you can have, especially in the neurological system, alteration of the endocytic trafficking, and so for this reason, the alteration of the lysosome can have a result in the entire architectural structure of the brain and the brain tissue.

And this is particularly true, because if you make a biopsy in the brain of this patient, you see that the neurons have actually this kind of very strange phenotype, with ectopic dendrites and creation of new synapses, and if you go and make a detailed analysis of one of these ectopic dendrites, you see that there are some spheroid neuroaxons, which are totally dystrophic, with a lot of bodies that are actually causing the death of the cell.

And if you see also the flow of the axonal transport of the different materials inside the neurons, you see that there is an alteration of what is the normal transport. So the entire activity of this, not only the accumulation of the lysome, is affected by a lysosomal storage, and this is present in all the different neurological cells, in the Purkinje, in the basal ganglia, in the non- pyramidal cell or the cerebral cortex, so the alteration of this storage is really generalized.

Another important thing is that the engulfment of the lysosome with stored material does have some important effect, not only inside the lysosome, but also in other metabolic pathways, and this is present not only in the MPSs, but also in Gaucher, in the Niemann-Pick, in the GM1 gangliosidosis, in Niemann Pick C, and in the infantile NCS. And this is because there is a sort of communication between the lysosome and a lot of other systems that are present in the different membranes, like the ryanodine receptor, rather than the calcium depletion due to alteration of the calcium receptor and channels.

It is also important to remember that also cholesterol is affected inside this cell affected by a stored material in the lysosome. So the primum movens is indeed the stored material, but that the alteration of the lysosome is causing also alteration of other system in the cell. Let's say that this is also important to understand because since we have calcium alteration, we can use some calcium blocker as therapy.

Since we have endothelial reticulum stress, we can have also some blockers working. We have calcium modulators. We can even have other cholesterol therapy that can be done. Of course, this kind of knowledge can really start understanding about the cell death, which is a very complex pathway and not only the alteration due to the stored material. So at a certain point, what is also important is that there is a system, which is the autophagy, which is very important in our science because we are producing continuously material that are not usable in the metabolic system and these are labeled and then they are destroyed.

But it has been seen that in the lysosomal diseases, the fact that there is an accumulation in the lysosome is altering also the autophagy. So at a certain point in all the different diseases and the NPSs rather than other lysosomal disorders, what has been seen is that the material that needs to be destroyed are not properly recognized.

So the ubiquitin part is really not working very well. For this reason for example what has been seen is that in the different brain tissue you can have not only glycosaminoglycan storage, but even amyloid are stored for the reason that I just said. So amyloid can be found. You can find even synuclein, which is typical of the Parkinson disorder and you can find even prion protein, which is not, of course, a glycosaminoglycan, but you can be found in the brain of MPS animal models.

Why diagnosis and multidisciplinary care matter

The nice thing is that whenever you are able to put inside the enzyme or to produce, to express the enzyme which is missing, you know, also this material is cleared. So these are further aggregation, further storage, which are the effect of a secondary cascade of events following the original gene defect and the original GAG accumulation. So the proposed model is that it is indeed the lysosomal enzyme, a sort of easy disease because it is due to an enzyme deficiency.

There is indeed a lysosomal storage disorder, but this is not enough. The lysosomal storage is indeed increasing an impairment of autophagy. The impairment of autophagy is responsible for accumulation of toxic proteins. And then there is an alteration of important organs like mitochondria. So there is also an energy depletion in the disease. At a certain point, all these processes result in a cellular disgrace, particularly in the CNS phagocytosis by microglia and activation of microglia, a chronic inflammation with a disease of cytokine, and after all this cascade, of course, the cell at a certain point goes in apoptosis because of different toxic effect.

This is something that is extremely important because also for therapy reasons, at a certain point what we want is not just to give the missing enzyme, but we need also to understand how to intervene to correct also other aspects like inflammation in this disorder when the patient has already a diagnosis and is not treated asymptomatically. This is what you have seen important for the brain, but you see here that there is another organ which is very much commonly affected by these diseases, which is the skeleton.

For example, in this disorder which is the mucopolysaccharidosis type IV, the even Morquio you see that here there are different grades of severity and the skeleton is very much involved and this is the only disease that is totally sparing the CNS. So these are perfectly normally and intellectually normally children with different severe skeleton deformities. This is a typical sign, and if you remember, this is the disorder which is not having a joint stiffness, but actually hypermobility and laxity of joints.

The disorder is distributed, as you see, in all the different parts from the small bones to the larger bones, so it is responsible for a dysostosis multiplex. The defect is always the same.

They need to work together, because these patients need to be followed, with or without therapy, from a lot of specialists, because they require to be seen at 360 degrees. One important thing is whenever these patients are diagnosed or are suspected, also all the other different colleagues can be involved and must be involved in their treatment, because at any age, at any time, you need to follow and to manage these patients as a whole system, not only at the level of the different topics.

Questions and answers

Well, this is a very nice question. The MPS IV is a typical skeletal disorder. So, differently from the other MPSs, you don't have hepatosplenomegaly, very, very minor hepatosplenomegaly, you don't have cornea, clouding cornea, or you don't have neurological problems. So, indeed, the skeletal problem is the key point of the MPS IV. So whenever you see a child with some alteration of the bones in the first year of age, with a little bit of scoliosis, with a genu valgum which is present together with some laxity of the joint, you have to rule out absolutely the MPS, really to concentrate on the question of the skeleton.

And for this reason, children with recurrent airways infection, with airways infection that are not even seasonal, or they are not treatable with normal treatments, and possibly coupled with a hernia, a hernial hernia, which are not resolving the first year of age, they are quite at risk to have MPSs. So these two signs, the recurrent infection and hernias, might lead to a suspect of MPSs.

There is another nice question. Can we have vertebral anomalies, fish mouth or bullet finger in some types, in 100% of cases, and when we label as vertebral anomaly, fish mouth? Well, this is really a question, I mean, this is really a sign that you can see particularly in MPS IV. You can have alteration of the vertebral bodies in all the MPSs, but of course not in attenuated phenotypes, at least up to a certain age.

If we concentrate in the first year of age, these kinds of signs can be seen in MPS I, MPS II, particularly in MPS IV and MPS VI. In MPS3, a little bit less, because in the MPS III, all the four phenotypes have minor skeletal problems. But in MPS I Hurler and MPS II and the neuropathic, and MPS IV and MPS VI, for sure these kinds of problems can be seen.

Remember that all the children affected by skeletal abnormalities have a kyphosis in the lumbar space, and the kyphosis, the lumbar kyphosis, is really a sign that should ask for a lysosomal or an MPS suspect. There is another nice question. In MPS X can the GAGs be normal? Thank you for this question.

As a matter of fact, GAGs are usually accumulated in the urine Indeed, in MPS X you can have a normality of GAG. But you can have also normality in other MPSs. Because indeed, the GAGs are not always present in the urine of these children. In particular, if you have a very, let's say, attenuated form of the disease, or whether you are in the adolescent age.

As a matter of fact, the concentration of GAGs decrease with age. And even if the patient might have had an abnormal accumulation of glycosaminoglycan during the infancy, in the adulthood period, the GAG can decrease. Because if you make the hematopoietic stem cell transplantation in the first year of life, you can really alter the neurodegeneration. And you can modify the history of neurological development in these children.

Another nice question is, is newborn screening for NPS on the horizon in the timeline? Thank you very much. The newborn screening for this disorder is something that is becoming more and more closer. There are already different pilot testing in different countries. Taiwan was the first country with a very big screening. What is important is not only to make a newborn screening as a newborn screening.

The newborn screening is not a test only, the newborn screening is a system. You need to identify the patient, but you need also to make a prognosis. You need also to understand what to do with the therapy. So what is important in the pilot programs is not only whether you are able to identify a defect in the enzyme level, but what kind of phenotype you can make as a prognosis.

Because sometimes with the newborn screening you are not able to understand whether the disease will be severe or not. And so I think that what is important is to really make all this pilot testing and to understand and to make some flowcharts that could really navigate the physician in understanding what is the prognosis in order to choose the right therapy for these children.

We have another question. In a resource-limiting setting, we usually go for urinary gags. What do you recommend? As you said, it can be normal. With high index of suspicion, if it's negative, and can we request for a specific enzyme? Well, yes, I mean, it depends from where you are writing from. Let's say that now the quickest way is to make a urinary GAG analysis, but now more and more we can make at least a screening or a few drops of blood for a lot of different enzymes, even in multiplex.

So in my lab, for example, but not only my lab, from the same spot we can do different analysis at once and to have a, with a very, very limited cost. Then whenever you have done this analysis, this enzymatic analysis, you can go on the genetic analysis to try to understand if there is a sort of prognosis or not, and also to help the family with genetic counseling.

So I think that the combination of urinary GAG and enzymatic analysis in MPS is mandatory. At least this. And then whenever you have a suspect, you can go directly to the genetic analysis. Now there are also cheap testing with panels of hundreds of different mutations and genes for lysosomal disorders. there are panels of NGSs for lysosomal diseases.

So these are very useful, but I think that the best, the best test at the moment to start the diagnosis is indeed GAG and enzymatic assay. Okay. I think that we don't have questions anymore, and I thank very much for these questions because they were very much complemented in my talk. So I would like to thank you for participating to this webinar.

I want to remind you that in one week's time, you will have an outstanding presenter, which is Roberto Giugliani. Roberto Giugliani is from Brazil. He's one of the major experts worldwide in lysosomal disorders. He's a geneticist from Porto Alegre in Brazil with a huge center and an incredible experience in patients. And he will close this series of webinars.

So please try to be on the 20th of April at 6 p. m. Central Europe summertime to complete this webinar and also to hear what Roberto Giuliani will tell, which will be for sure very interesting and outstandingly talk. So thank you very much. Happy Easter and looking forward to meeting you next week with Roberto Giuliani.

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