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[00:00:12] Dr. Martin Magner: Ladies and gentlemen, good morning or good afternoon to all of you who joined our session. I'm very glad and it's my great honor. We will spend half an hour together. Today's topic is alpha-mannosidosis clinical manifestation. And we'll focus more on CNS involvement in this disease. Without further ado, let's have some messages. The basic message is you may submit your questions at any point via the questions panel. The questions may be submitted only via text and not verbally. And I do really please you not to take any screenshots or reproduce anything.
[00:01:06] Dr. Martin Magner: What's alpha-mannosidosis? It's a rare lysosomal storage disorder. So we got a mutation in a DNA. Based on this mutation, we got a deformed protein or enzyme with a low activity. And this enzyme should normally catabolize the oligosaccharides in lysosomes. And when they are not metabolized, they are stored there. And then we have lysosomal storage. And based on that, we got the whole myriad of impaired cellular functions. The incidence of alpha-mannosidosis is said to be very low. The first estimates that are old, more than 10, 20 years, are talking about the incidence of 1 to 500,000 to 1 per million. But I may share the situation from the Czech Republic, where I'm based. We had three patients that were diagnosed in 1991. And that was a really long time gap. And since 2017, we have diagnosed five more patients. So you see it's kind of a rare disease. But instead of originally said incidence of 1 per 500,000 or 1 per million, now maybe because of greater awareness, the incidence is much higher. And I estimate it to be between 1 to 100,000 to 1 to 150,000. As all other lysosomal storage disorders, alpha-mannosidosis is also a multisystemic disorder. And the systems which are mostly affected is the CNS, hearing loss, there is a skeletal involvement, there is a problem with the immune system, with recurrent infections, so immunodeficiency. Again, historically, there was a classification of three types of alpha-mannosidosis, mild form, moderate form, and severe form. Again, this alpha-mannosidosis clinical manifestation is rather continuous. And all of the extremes, like in type 1 or type 3, are really rare. So the most common or the great majority of the patients could be classified as type 2. What are the initial symptoms? And now we are touching also the topic of the differential diagnosis. Because alpha-mannosidosis itself resembles in its clinical manifestation other lysosomal disorders, namely mucopolysaccharidosis type 1 and type 2.
And also the initial symptoms are pretty the same. As we can see it, what is in alpha-mannosidosis in our cohort from Czech and Slovak and American patients, development to delay is the first sign, coarse facial features, hepatomegaly, macrocephaly, hearing disorders, and recurrent respiratory infections. And this is pretty the same as we see it as in children with MPS I or MPS II. And this is also published by Zielonka et al., who has collected 111 patients from PubMed, from various clinical studies, all patients who were published. And he found that the cognitive impairment is the most common initial sign. And together with coarse features, I mean, we will see it in the pictures, it's not like coarse features that would be totally expressed. It might be really a mild expression of this. So there is some dysmorphia and you will see it in the pictures. And hearing loss, that is the most common, I would say, triad. And if anything, and you want to make me a happy lecturer, so please remember from this lecture at least this one message, this is the main message of this lecture. If you see a child with a cognitive impairment, hearing loss, and mild dysmorphia, always remember or consider the diagnosis of alpha-amino. Again, as it was described for mucopolysaccharidosis, it's the same for alpha-mannosidosis. I said this is a multisystemic disorder. So many times we see symptoms that may be mild, that may be unspecific. But altogether there has to be a question. Can not be there anything that joins all of these symptoms together? And these symptoms are recurrent otitis media, chronic rhinorrhea, facial features, hepatomegaly, hernia, joint stiffness. So anytime we see, for example, a child with otitis media, it's a very common symptom and it's a normal thing. But if the child has mild hepatomegaly or hearing disorder, we have to watch out for cognitive delay. This could be some disease. There could be some reason behind this. In general, as we said, we should talk a bit about the differential diagnosis.
So the mucopolysaccharidoses are the most similar to alpha-mannosidosis. So what do they have in common and what not? So in general, and I will repeat it later, alpha-mannosidosis is like mucopolysaccharidosis in many, many ways. But still, its progression is usually much slower. It's a milder disease. And patients live longer than patients with neuropathic forms of MPS. So what do they have in common? Organomegaly, umbilical and inguinal hernias, development delay, coarse facial features, hearing disorder, macrocephaly and recurrent respiratory infections. What's different? Patients with alpha-mannosidosis do suffer from some infections. They are uncommon in mucopolysaccharidosis, like repeated pneumonia. Psychosis or any psychiatric symptoms, we will talk about them later, as I said, a slower progression.
What is also typical for alpha-mannosidosis is ataxia, especially from the second decade of life. Carpal tunnel syndrome is not typical for alpha-mannosidosis. And also, there are some changes in the cervical region of patients with alpha-mannosidosis, but I'm pretty sure they are not so severe as in patients with MPS. And now, when do these diseases manifest? And again, it's very similar. If you are a very careful physician, you usually notice something the first time, already in the first year of life, as it was in our cohorts. You see that in our cohort of patients with alpha-mannosidosis, we had the first symptom already in the median in 9 months. And it corresponds also to the literature, to this mentioned publication of Zielenka, where we see the first symptom was already in the median at the age of 1 year, but the diagnosis was done pretty late, with the delay of approximately 5 years. Now, we see some facial features of alpha-mannosidosis, and again, they resemble some of those in mucopolysaccharidosis. We also can talk about Hurler-like facials, especially macrocephaly with prominent forehead. But this may not be over 97th percentile, but we just have a feeling that the forehead is prominent. What I would stress in alpha-mann is really arched eyebrows. We will see it in the pictures, also in this picture C, but also in all of these children, I think.
And again, what is also quite characteristic is depressed nasal bridge and quite broad nasal root. Macroglossia and widely spaced teeth not always. And you see, these are patients from my follow-up. The boy on the right side was 11 years when this picture was done, and the girl on the left side at the age of 5 years. And you see, you have to be very careful when considering coarse facial features, which may be really mild, as I said before. These are really more affected patients. They are 3IV and 32 years of age and you see, I would express or emphasize here, and boy on the right side, it's his name's Marek and typically here we can see this depressed and broad nasal root and high arched eyebrows. I would say that's quite typical, which is not so typical for mucopolysaccharidosis. And we got these two boys to these brothers again here and now. It's a little test for you. So we got four children with lysosomal storage disorder and you can make the diagnosis or you can guess, okay, so for first child has an alpha-mannosidosis. The second, it's a severe form of mucopolysaccharidosis, type 2, but the child is still young so the features are not so expressed. Again, we want to do the diagnosis as early as possible. So please do not wait until the whole signs and symptoms, including coarse feature features, are expressed, because it will take a long time.
[00:11:17] Dr. Martin Magner: So we got four children with lysosomal storage disorder and you can make the diagnosis or you can guess, okay, so for first child has an alpha-mannosidosis. The second, it's a severe form of mucopolysaccharidosis, type 2, but the child is still young so the features are not so expressed. Again, we want to do the diagnosis as early as possible. So please do not wait until the whole signs and symptoms, including coarse feature features, are expressed, because it will take a long time. And those two others are children with MPS IV with Morquio, as it was for other symptoms also: bone disease, dysostosis multiplex, which is present in MPS, in mucopolysaccharidosis. It's also present in alpha-mannosidosis. Again it's mild to moderate dysostosis multiplex. There are many symptoms of this and if you have an experienced radiologist he should recognize all of these. But I would show you the other slide when it is easily to compare. Again, on the left side we got a healthy child and then we got a child with MPS II, where we see mild proximal tapering of the metacarpals and minimal slenderness of distal phalanges. And when we see now the X-ray from the child with the alpha-mannosidosis, we can see it's not fully normal, but it's not fully expressed as in MPS II.
So again and again it's about alpha-mannosidosis is usually slowly progressing than MPS. How about growth? And this was a large study done by Professor Beck at the time and consortium of authors, sponsored by European Union. The project was called HUE-MAN and it was done in the first decade of this century and we can see there that I mean 43 patients were involved in this study. They were observed over two years. And there's interesting thing which is also in the SPARC registry, where patient with alpha-mannosidosis are input and this is the ratio between males and females, which is 2 to 1 in this case. But of course it's an autosomal, recessive diseases. So it doesn't make sense. And what is the explanation for this? It's highly probable that in girls and females the alpha-mannosidosis is underdiagnosed. So we should remember alpha-mannosidosis, especially in girls as well. Let's get back to the growth and we see the majority of patients are in normal growth curves, both males and females, and this is again kind of A difference to mucopolysaccharidosis, when we often see an overgrowth in the first, first or second year of life, and then majority of these patients do have growth failure or short growth. What about immunodeficiency and recurrent infections? Immunodeficiency and recurrent infections are not a constant sign. If I ask my patients, some of the mothers said that some of those kids were very sick many times in the first decade of life, but then it went away. The other kids were absolutely healthy. Some of them do have lower levels of immunoglobulins, some not. But then, at the adult age, I may refer that some of those patients really do have like atypical infections. For example, I have a patient with chronic skin infection, or hidradenitis suppurativa, or endocarditis, or gonitis, purulent gonitis. So, these are not the infections that would be really common and maybe probably explained by this immunodeficiency. The theory explaining immunodeficiency in alpha-mannosidosis is an older theory. It's related to the hypothesis that oligosaccharides with five and six mannose residues bind to IL- 2 receptors, and they block T- cells, B- cells, and atriocular cells. And I think there is a lot of space to do research in this area. When we compare the 6- minute walking test, which is normally used in lysosomal storage disorders, to assess the performance of children and adults with such disorders, we see that they are decreased. Again, this is the natural course of cohort of Beck. And the same is for pulmonary functions, functions measured by the FVC or FEV1. So, also lung function, we see that the decrease is about 30% of the mean in both. Hepatomegaly and splenomegaly. It's just a remark that when I look for definitions of hepatomegaly, like something that would be unified all over the pediatric world, still there are many definitions.
And what I always say, especially to young colleagues, and I'm sorry that I'm saying that, but it's the experience, because I have experienced it many times, that the children were sent to our hospital without detected hepatomegaly, and these children had massive hepatomegaly. Only one explanation is that the doctor started his or her palpation right under a costal ridge. And he was moving with his hand on the surface of the liver or the spleen, not detecting its edge. So, he couldn't say that there was this enlargement. But anyway, beside this, again, conclusion is hepatomegaly in alpha-mannosidosis is usually mild. And it's really only in severe forms exceeds 3, 4, 5 cm. It usually is somewhere between 2 or 4 cm. So, again, let's not wait until the hepatomegaly will develop. And when we talk about hepatomegaly, it's rather the opposite, because in alpha-mannosidosis many patients with their growth do not have their liver palpable anymore. I wanted to talk more about CNS manifestation in alpha-mannosidosis this time. And we see in this new publication that there is much of it such as cerebellar dysfunction, development to delay, absent tendon reflexes, spasticity, development to delay, impaired speech, hearing impairment, psychosis, cognitive impairment and so on. There is a whole range of various mechanisms and many of those are still unclear in the matter of research.
[00:19:39] Dr. Martin Magner: So let's start with the development and cognition in alpha-mannosidosis and again, just to compare, we got three diseases, MPS I, MPS II and alpha-mannosidosis and again, we see that the progress in alpha-mannosidosis is much slower. So the typical course in MPS I or MPS II is these children do suffer when they have neuronal pathic form of this disease or in case of MPS I, they have Hurler disease. So they have a very early developmental delay and according to the severity of disease, they suffer from regression in their development which takes place from two and a half to let's say seven years of age in the milder forms of MPS II. When there's a non-neuronopathic pathic form of MPS II, non-neuronopathic pathic form of MPS I, so Scheie syndrome, the development might be normal. When we compare it to alpha-mann, we see that the majority of patients in the first decade of life have IQ around 75 and then somewhere between 50 and 75. And many times these children may be clumsy, they may have problem with concentrations, but still many times they can enter the school and they are still borderline and no one really say that they are like severely developedly delayed. But this developmental delay progresses, especially in the second decade of life and the majority of patients are in the area of IQ between 25 and 50 in the third and fourth decade of life. Unfortunately or fortunately in this case, this is not constant. There are some exceptions and there are some case reports of adult patients with a normal or borderline development living independently.
Or of course patients after alpha-mann or after transplantation of hematopoietic stem cells may keep their cognitive performance. So if we conclude the neurocognitive decline is generally slower and patients live longer in a patient with alpha- mono compared to neuropathic forms of MPS. This is the work by Line Borgwardt which assessed also the Visualization and Reasoning battery, Memory Screen and the raw scores for Attention Sustained compared to normal range and we see all of them are decreased. So the attention is the greatest problem as we can see here. Last year, thanks to the company Chiesi which supported this project, there was an initiative in alpha-mannosidosis creating some Delphi recommendation. And I'm showing this slide here because these are the answers of renowned experts from the whole world who follow up the patient with alpha-mannosidosis and this is the way they answered, they shared their personal experience in the topic of cognitive manifestation and I thought that that would be a good way to present it further. So we see the first answer, many patients do have speech delay, other mental retardation with learning difficulties.
So as I said, these children may go to the school, but many of them do have learning difficulties before borderline or mild mental retardation is diagnosed. Again, what is here, speech delay, short- term memory and attention. It's in line with the publication of Line Borgwardt. The next answer, developmental delay, cognitive decline in adults, as we saw that into the severe mental retardation and psychotic episodes in adolescents and adults. We will talk about that later. We see some behavioral changes in the personal experience of other experts, lack of communication, aggressiveness, inability to raise their concerns, new onset of psychosis and again what we see, learning difficulties and social problems. So let's move to psychiatric manifestation. And, again, this is common, especially from the second decade of life, and again, aside from the personal experience of these experts. So, what do they say? Anxiety and depression are common and should be monitored. Even psychosis may occur. It's the very same or similar as in the second question as second answer. Anxiety, depression, behavioral change, or depression, acute psychiatric episodes, and physicians should be aware of it. Again, anxiety and depression, changes in behavior, agitation, combative behavior, psychotic changes were also reported. So, let's go to the publication.
This publication was done by Malm in 2005, and he had 9 patients with psychiatric problems. And we see the average age of the first psychiatric disturbance was 18 years, but it was in the range from 14 to 31 years. Some of those children and patients had recurrent episodes of psychiatric disturbance, and the duration of the longest episode was even 24 months. So, it was really, really long, and we see it's episodic, it may last a long time, but also a short time, but it may come back after retraction. And behavior and general symptoms, so we see the most common was reduced abilities in several areas and peculiar behaviors. We will continue in this study. So, presence of alternate symptoms reported by the observers. So, memory difficulties, difficulties in finding their way, unfamiliar surroundings, even in their houses. They may get up during the night, stand up from the bed, and they are disoriented in their home. What's next? Difficulty in understanding communications from others. Difficulty with producing coherent verbal communication. Symptoms during night time we see in all 9 patients. Unfortunately, also depression is quite common. Reduced interest and endurance in usually pleasurable activities. Reduced appetite or loss of weight. Reduced sleep during the night. Tendency to be silent or speak a little or slowly. I got the same experience in my adult patients who are otherwise very well-tempered, but sometimes they have really like a depression episode that may last for several months.
So, let's conclude the psychiatric manifestation. It may affect more than one quarter of the patients. They might be some physical or psychological stressors. And these episodes typically last for 3 to 12 weeks, may be recurrent, and that's it. What is absolutely clear that in patients with intellectual disability psychiatric symptoms form part of a more diffuse clinical picture with systemic cognitive or motor neurological signs. And what we should remember when patients do have psychomotor delay, they may also have depression which should be treated. I have to emphasize ataxia as well, because it's an important sign. The development of motor functions in affected patients is generally slow and the children appear clumsy already in the first decade of life. Caused by a combination of factors like muscular weakness, joint abnormalities, ataxia due to cerebellar atrophy and cerebellar demyelination. The impairment is by nature progressive with gradual worsening in the second and third decade of life. And this is very important because these children or these adults fall often and they are not able of the independent gait anymore because of this. Further findings include dysarthria and dysmetria. Now, I'll do a short comment on characteristic brain MRI findings in alpha-mannosidosis. And I think we got some time limit already, so I will just refer to the publication of my PhD student Litka Majewska.
But just to point some hallmarks, it's the thin corpus callosum. But what is really like the major combination of the signs are white matter changes as we see here in the periventricular area. And the second is cerebellar atrophy. It's very similar here in these pictures. We even see the retrocerebellar cyst and this is for those who have some graphic memory. This is just for comparison. We see the changes in the white matter located perimetrically, but the whole white matter when we see it as more contrasted and there is a less contrast in between great and white matter when we compare patients with alpha-mannosidosis to controls. These pictures were taken at the level of basal ganglia and these pictures, which are pretty similar in their message, were taken at the level of central semi-ovale. Just very shortly, MRI in other selected lysosomal storage disorders. So this is a very expressed, severely expressed findings in the mucopolysaccharidosis when there is a hydrocephalus, which is not so common. It's really rare in alpha-mannosidosis. We can see some changes in the white matter periventricularly as well, but otherwise white matter is not so changed diffusely as in alpha-mannosidosis. And what is typical for patients with MPS are these enlarged perivascular spaces, Robin Virchow spaces, adjacent to the ventricles as we can see it here. And picture E, we can see the narrow wing of the spinal channel. Very mild findings like this might be also in alpha-mannosidosis, but the spinal compression is really, really rare. I would like to show one other lysosomal disorder, which typically manifests in the second or third decade of life with psychiatric manifestation as well. These children also might have this atria, ataxia and proximal nerve weakness. So there are some similar symptoms like in alpha-mannosidosis, but the majority of these patients have normal cognitive performance. And the disease name is Tay-Sachs disease. And why I'm saying this, because it's a differential diagnosis to also in MRI, there is a cerebellar atrophy as well. But this cerebellar atrophy in Tay-Sachs disease, in late-onset Tay-Sachs disease, is a bit different. There is also an atrophy of the pons. So we should talk about pontocerebellar atrophy. The last slides are about hearing and vision in alpha-mannosidosis. I said hearing impairment is almost constant, but again, don't wait for the hearing impairment until it's present. The last patient we had diagnosed the last month, it's a girl. She had mild course feature features at the age of 20, one month. She still doesn't have an independent gait and she has no progressive speech in the sense of any words. But her hearing is still normal. So let's not wait until the symptoms are fully expressed. We see objective data from the study of Beck again, and we see the average loss of the hearing is about 70 decibels. And there are also some retinal changes, usually not causing any blindness or so. And if I just highlight the main findings, there might be some optic nerve atrophy, but no pigmented deposits. And when we do optical coherence tomography, there is a periphoreal thinning of the outer retinal layers and retinal pigment epithelium. One slide on diagnostics.
Of course, the most important thing is to make a suspicion and as idea you can refer the patient to the specialist or you have to do the diagnosis on your own and then there are several methods. Biochemical methods is you can do oligosaccharide screening in urine or in serum, but it's quite challenging. The same enzyme studies in some places or centers, also dried blood spot screening is available, then a measurement or analysis of the enzyme in leukocytes or fibroblasts, which is usually not done anymore. It's done in leukocytes or dried blood spot and also molecular testing. Either you have an aimed testing on alpha-mannosidosis or you have an NGS. It's very important to stress that for patients with possible MPS, but with a negative MPS test result, subsequent alpha-mannosidase should be considered and the testing is strongly recommended. There are several cases like this that MPS was suspected, but was excluded and afterwards alpha-mannosidosis was confirmed in this patient. I would await one more comment. If you have NGS panels, just be sure and check out that the gene for alpha-mannosidosis is also involved. What's the outcome and mortality? The average age, according to the publication of Julia Hennermann, in 2022 of survival was 45 years, but it may be much longer. Some patients survived till the sixth decade of life. The most common prevalence of death was pneumonia, 46%, but I find interesting that three deaths, so it means 20% of the whole group, were associated with a cancer. Colon carcinoma, breast cancer or leukemia. And I think this might have something to do with the immunodeficiency or impaired immunology in these patients. So we are coming to the summary and there are three summary slides.
Alpha-mannosidosis and MPSs have many common features including organomegaly, hernias, development to delay, coarse facial features, hearing disorder, macrocephaly and recurrent respiratory infections. Additionally, the immunodeficiency ataxia and psychosis are present in alpha-mannosidosis. However, cervical cranial instability and carpal tunnel syndrome are missing. The progression of alpha-mannosidosis is generally slower and patients live longer than patients with neuropathic forms of MPS. Alpha-mannosidosis is a rare but probably still underdiagnosed disease. And I want to repeat one more, especially in females, very probably. The disease may be diagnosed on biochemical, enzymatic and genetic level and the ideal approach for the diagnosis may differ based on local experience or possibilities. Before the era of neonatal screening, the clinical suspicion remains crucial, of course. Watch out, some NGS panels do not involve MAN2B1 alpha-mannosidosis gene. So let's be careful about that. And now let's talk about the CNS manifestation a bit. Let's conclude this topic. So nearly all patients suffer from progressive and mental deterioration. Developmental delay is usually only borderline mild in the first decade of life. Various psychiatric manifestations develop in the second decade of life. Progressive ataxia and frequent falls are the main reasons for the independent gait loss. Hearing disorders develop gradually in all patients. And brain MRI features involve white matter changes and cerebellar atrophy. And I do really thank you for your attention. And now I'm open for your questions. Please submit your questions via text on the questions panel. Now I will stop sharing my screen, which was done yes, now. And I can't see any questions.
[00:40:05] Dr. Martin Magner: So I would just remember, or I would just like to stress one more time, if you don't have any questions, the basic thing: if you want to make me a happy as a lecturer, please remember: always suspect alpha-mannosidosis in children who have cognitive delay, they have hearing disorder or some hearing problem and they have less typical facial appearance. I think this is the most important and this is the most important message. So we got the first question, which it says: how much slower on average are the newer signs of alpha-mannosidosis compared to MPS? It is always up to a decade or longer later compared to MPS. This is a very complex question because there are many types of MPS and also the involvement of neurological involvement is quite various. But in general I can say that the majority of children with alpha-mannosidosis in the first decade of life they may have from the beginning slight mental retardation or developmental delay which may be still borderline. They're a bit clumsy, I would say more clumsy than really severe ataxia would be. I would be present and the regression or the progression of this dementia or loss of the cognitive functions is really much slower than in MPS. In MPS, in majority of types, either you have neuronepathic forms and you have the regression or progressions within the first five or eight years or you're in the normal level or low normal level. But in alpha-mannosidosis it seems like these patients and children in the first decade of life. They are nearly normal or have only slight development to delay and the progression occurs only in the second and the third decade of life.
So which means when we compared the alpha-mannosidosis and neuronopathic forms of MPS, the decline is really much slower. Are there bone changes, as in MPS? It's a similar answer as we saw the x-rays. There are bone changes, but majority of them are not so severe and as we have, for example, many surgeries in patients with MPS IV and MPS II due to deformed genua vulga or coxarthrosis and so on, these patients require surgery. It's much less common in patients with alpha-mannosidosis that they would. Of course it might happen that they need replacement of their hip joint, but it's much less frequent than in MPS, so it's not such a burden like in MPS. Next question is: psychiatric symptoms and depression are occur in 25% of cases. But at what age is this most likely? I would say in which age? It's not likely. It's not likely in the first decade of life, but from or since the second decade of life. It may occur any time and it's really challenging also for the diagnostic and for the treatment, because many of this, you never know when there is a change in the mood in severely affected patient, if there's, if this is caused by some organic problem, some chronic pain, or this was just a psychiatric thing that should be treated by the psychiatric medication.
[00:44:36] Dr. Martin Magner: I think I don't have more questions and therefore I would like to thank you so much for your attention and for having you here today. I wish you a great day. Bye.