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[00:00:00] Dr. Florian Lagler: It's my pleasure to welcome you to this spot. The early signs of alpha-mannosidosis webinar today. As you may know, this is a series and this is training three. My name is Florian Lagler. I'm a pediatrician by training and a pharmacologist, and I work at the University Pediatric Hospital in Salzburg, Austria, Paracelsus Medical University Salzburg, and it's my pleasure to talk today about understanding what happens next, from diagnosis to early treatment of alpha-mannosidosis. Let me start with some short notes, housekeeping notes. We need to ask you to: please do not take any screenshots. Please do not reproduce any of the slides, content or images without the express written permission of the speaker. We will have this presentation that is going to last around half an hour and this will be followed by question and answers. You can submit your questions or comments via the chat function, by texting us via the chat function, so you may submit your questions at any point and we will then, in after the presentation, discuss it together. There is no option to verbally address a question. However, of course, I will answer your question orally. As many as as many questions as possible will be answered, but we cannot guarantee that all of the questions can be done today, as we have a very hard time planning for this webinar and it may. It will be recorded so you may come back later and replay this presentation of this webinar. So thank you very much and I want to thank Excellence in Pediatrics for providing the opportunity to speak about alpha-mannosidosis today, and in my presentation I would like to cover the following aspects.
I will give a short introduction so that the ones that could not follow the first presentations, the first webinars in our series, get a short update on alpha-mannosidosis, and then we will explore patient management of alpha- mannosidosis and the latest therapeutic options available. We will also go on multisystemic symptoms and treatment of all the children and the transition to adult therapies, as well as exploring the need to start treatment as soon as possible and optimizing the therapeutic outcome for pediatric patients. And, as I already said, you will have an opportunity to raise your questions after that. To start with, alpha-mannosidosis is an autosomal recessive deficiency of alpha-mannosidase and it's occurring approximately one in five hundred thousand. So even in the field of lysosomal storage diseases or inherited metabolic diseases, as such, it is a very rare disease and, as you can appreciate on this slide, the, it's a multisystemic disease and it involves several organ systems. So we will find mild to moderate intellectual disability and psychiatric symptoms, coarse facial features, immunodeficiency, clinical and or radiographic skeletal abnormalities, aseptic destructive arthritis, metabolic myopathy, hepatosplenomegaly and the central nervous system is involved, as well as the hearing in terms of impaired hearing, and you may also appreciate corneal opacity.
As a matter or as a result of the enzyme deficiency and the accumulation of the metabolites. So, if we speak about the clinical pattern of the disease, it is important on the one hand to have an overview on the most common symptoms and as you can appreciate on this slide, based on the very nice publication of Zielonka, cognitive impairment is present in almost 100% of patients. Bone abnormalities in 81%, coarse facial features in 70%. Hearing loss is very common, 67%. Respiratory tract infections, around half of the patient and then followed by dysmorphism, organomegaly, hernias, ataxia, short stature and muscle hypotonia. Secondly, it's important to know when the clinical signs occur and there is really a broad spectrum as I will highlight a little later after that slide. And the diagnostic delay, so the gap between the median onset in the first year of life, second year of life to the diagnosis may well be five years or even longer. So, there is a very long diagnostic gap between the first initial signs and the diagnosis of alpha-mannosidosis. And as we will discuss a little later when it comes to therapy of the disease, it's very critical to make an early diagnosis and make the correct diagnosis early in the disease course. So, as I pointed out earlier, the symptoms can differ between different types. However, I have to say that the clinical symptoms and the rate of progression occur in a spectrum rather than in very strictly separable types. Still, in the classification, we consider a type 3 patient with a severe course of disease, rapidly progressive and leading to an early death, typically from the central nervous system involvement or infections that you appreciate. That's considered type 3 alpha-mannosidosis. A very mild type on the right-hand side shows symptoms only after the 10 years of age with mainly myopathy, slowly progression, and the absence of skeletal abnormalities.
And within this spectrum, in the middle, we have the moderate form, the type 2 form, which has symptoms before 10 years of age with myopathy, slow progression, and presence of skeletal abnormalities. So you can see that besides the multisystem symptomatic symptoms, there can be a broad range of different courses of disease. We can say that hearing impairment and speech delay are more common in severe and moderate forms, whereas motor impairment and psychiatric forms are typical for mild forms. But as I pointed out earlier, this is a spectrum, and it's not strictly separable between the different types. So once the clinical suspicion is raised and we consider alpha-mannosidosis as the underlying cause of the clinical symptoms that were observed in our patient, the diagnostics are very straightforward. As in most of the lysosomal storage diseases, it is based mainly on enzymatic testing. So the activity of alpha-mannosidase is measured in peripheral blood leukocytes and other nucleated cells, and the genetic testing in the MAN2B1 gene confirms the diagnosis. The urinary excretion of mannose-rich oligosaccharides can be used as a kind of a screening test, which is straightforward and easy to be done. So incidental diagnoses sometimes are made when vacuoles in lymphocytes are detected from peripheral blood smear.
But first of all, we need to think of alpha-mannosidosis, and this is most important because otherwise the diagnostics cannot be done with the enzymatic and the genetic testing that confirms alpha-mannosidosis in the patient. Now, it is obvious that an early diagnosis is always important if there is treatment available and this is definitely the case in alpha-mannosidosis and I will shortly strife about hematopoietic stem cell transplantation as one therapy and enzyme replacement therapy as the second therapeutic option. Hematopoietic stem cell transplantation has been reported as an effective treatment for alpha-mannosidosis as it is the case in other LSDs as well. And the situation is pretty much comparable, for example, to other lysosomal storage diseases like mucopolysaccharidosis. So the challenges and risks of hematopoietic stem cell transplantation in alpha-mannosidosis patients is on the one hand the hematopoietic stem cell transplantation may slow down the progression of the disease, but it may have only minor effects on already present manifestations. So it's obvious that an early diagnosis and an early transplantation is of benefit. The potential risk of engraftment failure and the potential risk of graft versus host disease, of course, has to be taken into consideration. But clearly the risk for these have been reduced in the last couple of years. So overall, there is a clearly positive risk-benefit ratio for hematopoietic stem cell transplantation in alpha-mannosidosis. Of course, this is also dependent on how well the donor matches in terms of HLA and maximum of HLA matched fit is recommended for the hematopoietic stem cell transplantation.
But of course, this is true for all hematopoietic stem cell transplantations, not only for alpha-mannosidosis. So the data which we can use for assessing the risks and benefits of hematopoietic stem cell transplantation in alpha-mannosidosis mainly come from a retrospective study of 17 patients. And in this work, it's clearly shown that all patients made developmental progress, but they still remain below the age average or the average of age-equivalent children and patients. Hearing improved as well, but not in all patients, only in some of the patients. So the 5.5 years survival rate was 88 percent. So 15 patients in total survived the full follow-up period of five and a half years. Two patients died, and this was within a five-month time frame upon transplantation, as a complication towards the complication rate. So it's obvious that age matters. Early age at transplantation leads to superior outcome over transplantations in later age. As a second treatment option, there is enzyme replacement therapy with Velmanase. Efficacy and safety of Velmanase has been studied in adults and young patients with alpha-mannosidosis and the safety has been confirmed in both studies. I will only highlight the results on efficacy of the studies in children below six years. That's a very recent publication published in this year by Guffon and colleagues. And it nicely showed that upon long term treatment of with Velmanase, the patient showed significant decrease of the metabolic biomarkers and a slight increase in six minutes walking test and three minute stairs climbing test, which are the standard tests for assessing improvement in energy in enzyme replacement therapy studies. So there is a beneficial efficacy confirmed in these children.
The other study with elder children and adults, failed to show a significant improvement in terms of the efficacy outcome parameters beyond the biomarkers. And that is in part due to the study design and in other parts due to the fact that irreversible symptoms can hardly be reversed upon enzyme replacement therapy. So another confirmation of the obvious fact that early diagnose and early start of treatment is crucial for an optimum of treatment outcome. On the right hand side of this slide you can see the safety data and it was a clearly excellent profile of Velmanase and this is in line with data from other enzyme replacement therapies for mucopolysaccharidosis or other lysosomal storage diseases that have been approved many years ago. So I further want to put your attention towards a very, very recently published case report which reports on or which is the first report on a combined therapy with Velmanase and hematopoietic stem cell transplantation. And as you can appreciate in these figures you can for example see here the time point of enzyme replacement therapy when it was started, eight weeks of age. So the diagnosis, eight weeks after diagnosis it was very early treatment and enzyme replacement therapy was conducted until hematopoietic stem cell transplantation was possible. And as you can see on this slide the urine excretion of mannosyl-rich oligosaccharides shows a significant decrease towards almost normal levels and also in the plasma. So clearly a very good response.
On this figure here you can see that upon hematopoietic stem cell transplantation the patient observed a clear increase of alpha-mannosidase activity as expected in beneficial course of the treatment. The authors conducted a comprehensive clinical testing of the patient including the general appearance, cardiac ultrasound, brain MRI, abdominal ultrasound, brain stem, auditory evoked response, neurological and motor development assessments, skeletal findings, immunological status and you can see that in most of these tests there was a clear improvement in this patient observed.
This is only a case report, but I selected it anyway because it nicely shows that in alpha-mannosidosis, the strategy that has been recommended, for example, also for a mucopolysaccharidosis type 1, to start with enzyme replacement therapy until hematopoietic stem cell transplantation is possible, obviously leads to excellent therapy outcome. The comprehensive discussion of all follow-up measures in alpha-mannosidosis patients is beyond the time frame of this presentation but I want to continue with this visualization of an optimal setup for providing a comprehensive care and follow- up for these patients. So it is clearly a multidisciplinary approach needed. On the one hand, on the physician's side, but also on the therapist's side, as we have a multi- organ and progressive disease, it's obvious that we need the specialists for all of these organ systems and symptoms, starting with the orthopedics and together with physiotherapy, due to the skeletal and joint problems, a pain specialist is often needed, the immunodeficiency and increased rate of infections benefits from strong immunology support. We need regular eye testings and therefore ophthalmologists, we need neurologists and as well as neuropsychiatric testing facilities available, we need the imaging specialists as well as cardiologists and respiratory specialists, ENT, endocrinologists and speech and language experts to provide the best possible care for these patients and their multi- systemic disease involvement. On the one hand, this is the basis to provide best care, on the other hand, this is the basis for treatment, evaluation and improvement of these patients.
As you have appreciated earlier, this is a disease that can have an onset in adolescence or even in adulthood and therefore we need the structure and procedures for transition, so a transition specialist or transition program to hand over the patients from pediatrics to adult medical specialists is additionally needed. And for time reasons, I want to sum up this very short presentation in order to receive your questions. So in conclusion, I hope that I could make clear that early diagnosis is based on the knowledge of the clinical pattern. Most of the clinical symptoms as such are very unspecific and can be found in other genetic or even other diseases, so it needs the knowledge of the clinical patterns that at least should direct towards a rare disease and once the suspicion for a rare disease is made, the patient should be referred to a rare disease center and can undergo a systematic workup and hopefully the correct diagnosis. The diagnosis is then confirmed as in other metabolic and lysosomal storage diseases by enzymatic and genetic testing and once the diagnosis is made, early treatment should be started, which is critical for the treatment success. Hematopoietic stem cell, this is true for hematopoietic stem cell transplantation as well as enzyme replacement therapy, both show good efficacy and safety, but for both we need to say that already manifest disease complications that are mostly irreversible, which underlines that an early diagnosis and treatment start is of paramount importance.
With an early diagnosis and a combination of enzyme replacement therapy until the hematopoietic stem cell transplantation with the HLA matched donor is possible, most probably leads to the optimum of clinical outcome in these patients. So I hope that with that I could stimulate a lot of interesting questions and I'm looking forward to answer your question now. Please use the chat function to address your question. So, there is a first question coming in and the question was, what is the common spread of prevalence per type in type 3, 2 and 1? So, type 3 is the very severe type with a very rapid progression of the disease which occurs in the first years of life, however, it's not clearly defined in terms of month of life or years of life, but rather defined via the rapid progression and the severe symptomatics. The separation between type 2 and type 1, so the intermediate and the mild form of the disease is by the presentation of clinical science before, this would be type 2 and after the 10th year of life in type 1. So next question would be referring the diagnosis, the best order of tests to be done, lab enzyme then genetic or another order, any tests in parallel.
So, it depends a little bit on the situation. If you have a clear suspicion of the disease, for example, if you have a positive family history, you would go for all the tests right away, meaning that you expect the disease to be either confirmed or ruled out, then you go for the enzymatic test and the genetic test at the same time. If you, however, have a patient that shows some signs that could be in line with alpha-mannosidosis, but also in line with mucopolysaccharidosis, for example, or serolidosis or other lysosomal storage diseases or other rare diseases, then you may prefer to start with a screening test and in this case, the analysis of oligosaccharides in urine together with, for example, the glycosaminoglycans, which are increased in mucopolysaccharidosis together with other metabolic screening tests may be the preferable route of diagnostic workup.
So, it depends on if you clearly focus on confirmation or exclusion of alpha-mannosidosis or if you have a combination of unspecific symptoms that may be explainable by alpha-mannosidosis, but also for other diseases. Well, and thirdly, I have to say that nowadays, in which our whole exome sequencing and other methods that are rather broad in their approach are really feasible and possible for many centers, the decision to go for a whole exome is rather low. So, in cases where you have a strong suspicion of a genetic disease, but you have no differential diagnostic route that you prefer, you may also go for a whole exome sequencing to find these patients. We have to have in mind that the incidence of alpha-mannosidosis is really, really low, so even in comparison with other rare diseases, it's a very rare disease and therefore, in many cases, we rather go for a broad approach, which may include either metabolic screening tests like urine analysis and other blood analysis tests or, nowadays, more and more whole exome sequencing.
Okay, very interesting question as well, hematopoietic stem cell transplantation and enzyme replacement therapy together. The combined therapy, is it dependent on the type of alpha-mannosidosis or other factors? So as we know mainly from other lysosomal storage diseases, but also from the retrospective study that I've highlighted, hematopoietic stem cell transplantation is most effective if it's done early in life. So patients that are diagnosed early in life, they should definitely be considered for hematopoietic stem cell transplantations. And this is true particularly because we know very well that enzyme replacement therapy does not cross the blood- brain barrier. So as hematopoietic stem cell transplantation can reach out to the CNS, this is a clear advantage of the hematopoietic stem cell transplantation. So there's a very clear picture that patients that are diagnosed in early years of life should be considered for stem cell transplantation. There is some discussion if stem cell transplantation is still useful in patients after third, fourth, fifth year or even in adolescent or adult patients. And as we have learned also from other lysosomal storage diseases, the evidence that the stem cell transplantation improves the outcome is most clear in the early lifespan and then it goes more and more, then it's less and less clear in older age. So it's mainly dependent on the time point of diagnosis and you also referred to a question towards the combination. Once hematopoietic stem cell transplantation has been successful and we observe a good response, there is no evidence that indicates that the enzyme replacement therapy needs to be continued. But preparing the patient for the stem cell transplantation and throughout the transplantation period and shortly after it, obviously it has some benefits. And again, this hypothesis or this approach is mainly based on experiences with other diseases. But as you have seen in the case report I presented, this seems to be the case in alpha-mannosidosis as well. Next question, please. OK, this is also a very good question. It starts with a comment.
So the diagnostic delay is much higher than in MPS. As this disease progression is slower. I think that's one factor. Another factor is that today, alpha-mannosidosis is still less well known in general as compared to mucopolysaccharidosis, which may also contribute to a late diagnosis. So the question is, how can we move to diagnosis before the age of three years? Of course, like in other lysosomal storage diseases, newborn screening is highly discussed. So on the one hand, there is some technical approaches available to do newborn screening. On the other hand, we need to provide evidence that the newborn screening diagnostics is superior in terms of treatment benefits as compared to the situation we are facing now. So newborn screening is one approach for earlier diagnosis. Awareness-raising activities, and you may consider this webinar as well as an awareness-raising activity, are another option to highlight the importance of being aware of alpha mannosidosi as a cause for the respective clinical science. But we have done a study conducted in patients with Pompe disease and other lysosomal storage diseases, which clearly indicated that once a patient goes on the diagnostic odyssey. So in other terms, once physicians outside of the center setting start to try and work up the patient, maybe by sending from the family pediatrician to a neuropediatrician outside a rare disease center, the diagnostic odyssey or the diagnostic gap doubles at least. So, we were discussing this with the aim to come up with good suggestions for shortening the diagnostic gap and actually I believe that we should try with awareness- raising activities to highlight how patients with a high risk for a rare disease, a high rare genetic disease can be identified and we should encourage the referral of these patients to a center for rare diseases for a systematic workup. And one reason why we are convinced that this may be the way to go is because there is almost 10,000 rare diseases known in our days. There is more and more treatable diseases and it's really a challenge to be aware of all the clinical patterns of all the rare diseases that benefit from an early diagnosis and have an effective and safe treatment available. So, the third column of trying to improve clinical diagnosis in young ages is maybe the use of symptom checker platforms and there is a number of symptom checker platforms out there. I work a lot with symptoms. Mainly, I work with symptoms in a research setting but I always recommend the use of symptom checker platforms in which you can enter clinical symptoms and then you get a suggestion to which group of diseases you should focus on in your diagnostic workup. But let me underline this once more.
I strongly believe that the process of finding the correct diagnosis of a rare disease should be have a suspicion in the non-expert setting and refer the patient to a center quickly thereafter rather than trying to spread the information on how to clinically identify these patients with alpha mannosidosis or another disease in the non-expert setting. So, I would be very happy if the non-expert setting is very good in identifying patients with high risk for a rare disease. Next question please. We get a last question. There is a question with regard to the newborn screening for alpha-mannosidosis in Europe. I think we are quite close but I have to admit that I am not a newborn screening expert. So, in newborn screening for lysosomal storage diseases, we always are facing the problem that whether or not we are able with the screening test to separate cases that benefit from early treatment from cases that may be non-cases or show a mild progression of the disease and therefore might not have a substantial benefit from providing the early diagnosis.
This is in most of the lysosomal storage diseases the case. So, what is needed is a clear genotype, phenotype correlation and an exact testing methodology that allows us to identify and approach the patients and their families which have substantial benefits from early diagnosis and early treatment. I am informed that there is no further questions and with that I want to thank you for your interest in alpha-mannosidosis and what follows the diagnosis in terms of treatment and multidisciplinary patient care. Thank you very much. Have a great day.
[00:42:24] Dr. Florian Lagler: Looking forward to meet you soon.