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[00:00:00] Professor Martin Magner: Ladies and gentlemen, cordially welcome to the first lecture of alpha-mannosidosis series with the title "The importance of spotting the early signs of alpha-mannosidosis. My name is Martin Magner. I'm a pediatrician and a geneticist and I work at the Department of Pediatrics and Inherited Metabolic Disorders in General University Hospital and First Faculty of Medicine, Charles University in Prague. Several notes, please do not take any screenshots and please do not reproduce any of the slides content on or images without the express written permission of the speaker. The lecture will last about 30 to 35 minutes and then there will be a Q& A section. Please submit your questions at any point via the questions panel and questions can be only submitted via text and not verbally. As many questions as possible will be answered and the end and recorded webinar will be also available on the online AM resource centers, a link we can see. So let's move first slide. What's alpha-mannosidosis? It's a lysosomal storage disorder. So we got some mutations or variants in the gene in this case called MAN2B1 that is encoding the enzyme with the name alpha- mannosidase. And this enzyme is really important for the degradation of macromolecules for cleavage of N- linked oligosaccharides. And due to decreased activity of this enzyme, these oligosaccharides then are getting stored in lysosomes which cause the impaired cellular function. This disease was firstly described by the Swedish physician Öckerman in 1967 and it has also other names like lysosomal alpha-D-mannosidase deficiency or alpha-mannosidase B deficiency. The inheritance is autosomal recessive.
About the incidence of the disease, it's considered to be an ultra- rare disease with an incidence estimation of one to half million to one million. But to be honest, I strongly believe that the incidence will be much higher and this disease is underdiagnosed. About the clinical presentation, it's a multisystemic disease and the main features include hearing loss, skeletal involvement, cognitive impairment, immunodeficiency with recurrent infections. But there are also other signs like ataxia, coarse facial features, cardiac involvement, muscle weakness and so on. And now during this lecture, we will discuss the signs and symptoms one by one. Traditionally, there is a classification with three types of alpha-mannosidosis based on the severity of the clinical phenotype. Type 1 is the clinically mild form with the symptoms after the age of 10 years. Type 2 is a moderate form recognized before 10 years of age and type 3 is like a neonatal phenotype. It's more true that the phenotype is represented by a continuous spectrum. So this classification, this original classification should be probably omitted. And as I said, the majority of patients would belong to the type 2. How to teach, or how to talk about alpha-mannosidosis? Maybe it's a good comparison with mucopolysaccharidosis. The majority of doctors are more familiar to because they are more common.
And although alpha-mannosidosis and mucopolysaccharidosis do not have biochemically too much in common, their phenotype is similar, especially to the types MPS I, MPS II, and MPS VI. And these are the signs and symptoms I will repeat several times during the lecture. So it's the variable development of delay, recurrent upper respiratory tract infections, hearing disorder, coarse facial features, organomegaly, valve disorder, dysostosis multiplex with scoliosis. So, what do alpha-mannosidosis and mucopolysaccharidosis have in common and what not? So in common, it's organomegaly, umbilical or inguinal hernia, developmental delay, coarse facial features, hearing disorder, macrocephaly and recurrent respiratory infections. What is different and specific for alpha-mannosidosis? It's the immunodeficiency, psychosis. Alpha-mannosidosis is usually with a slower progression, ataxia, and what is not typical for alpha-mannosidosis is carpal tunnel syndrome or craniocervical stenosis or instability. So we may say, in general, the progression of alpha-mannosidosis is slower, and patients live longer than patients with neuronopathic forms of MPS. What are the initial symptoms? Again, very similar with MPS. Here we can see three studies which we participated in. The first study is 44 patients with MPS II from four Central and Eastern European countries and we see it's inguinal hernias like a first symptom, developmental delay, macrocephaly, recurrent respiratory infections. We're similar with the Czech cohort of MPS I patients, umbilical and inguinal hernias often already in neonatal age, coarse facial features, hepatomegaly.
And the last cohort of patients with alpha- mannosidosis, 13 patients, the first symptom, developmental delay, coarse facial features, hepatomegaly, macrocephaly, hearing disorder, and recurrent respiratory infections. So these are our experience and these are very similar to the review paper of Zielonka who reviewed 111 patients with alpha-mannosidosis and their first symptom, which was cognitive impairment in 97% of them, bone anomalies when there is an experienced radiologist, coarse facies, hearing loss, respiratory tract infections, and so on.
When do mucopolysaccharidoses and also alpha-mannosidosis manifest? So it really depends on our awareness and whether we consider the symptom as a part of the phenotype. But if we go really into the detail, the majority of patients with MPS I, MPS II, but also with alpha- mannosidosis manifest their first symptom already in the first year of life. In alpha- mannosidosis, in our study, the median of the first symptom was nine months. In Zielonka's review, it was the one year. But we can see the diagnostic delay here, which was five years. So that's the problem, that the signs may manifest very early, but until the manifestation is typical or there is a combination of the symptoms that lead to diagnosis, there is a great lag. So we have to be very careful about mild symptoms that occur very early. So let's go to the facial features of alpha-mannosidosis. And we can see there are children, it's very variable. In some children, there is nearly not any affection of the appearance. In some children, coarse facial features are really strongly visible. Typically, there is Hurler-like facies or coarse facial features. So these include macrocephaly with prominent forehead, arched eyebrows, depressed nasal bridge, macroglossia, widely spaced teeth, and prognathism. Here we can see two siblings from my follow- up from my department and we see that if we are not aware about their coarse facial features we could easily overlook them. The girl on the left side is now six, the boy on the right side is now 13 and this is two years earlier and we see the coarse facial features are really mild. And there are two brothers on the left side aged around 8 to 10 years and on the right side aged 30 and 32 years. And we see in there's Marek and Adam. In Adam they are much milder than in Marek although they are brothers. Okay the same picture or next picture of the same guys and this is a little test for you. So if you see the dysmorphism in MPS and alpha-mannosidosis, you may say, or you may make the diagnosis. Just consider what could be the diagnosis. So the first girl has an MPS II. It's a very rare case of a child of a girl with X- linked MPS II but there are about 20 girls with the severe phenotype caused by skewed X chromosome inactivation. The boy in picture B has typically pectus carinatum and knock knees. We see the coarse facial features are very mild and this is typical for mucopolysaccharidosis type 4. In image C there is a boy with alpha-mannosidosis and D, mild phenotype of MPS II. Another test. So the first boy has alpha-mannosidosis then B, very typical appearance of MPS II. Nearly no facial features in the boys at picture C and D with MPS IV. What about development? In the first two pictures there is development in neuronopathic forms of MPS I and II and if we see the scales we see that within the first six years of life they have regression and they progress to the moderate or severe mental retardation. If we compare this to patients with alpha-mannosidosis where the scale is in decades we see that the majority of the children still have normal or just normal development or mild cognitive decline in the first decade and then they progress to moderate to profound mental retardation in the second or third decade of their life.
So the neurocognitive decline is generally slower and patients live longer in patients with alpha- mannosidosis compared to neuronopathic forms of MPS. We already see that the alpha monocytosis is very difficult to diagnose but if there is really a constant sign it's a hearing disorder. It has usually an early childhood onset. It occurs in most of the patients and it might be complicated also due to fluid accumulation in the middle ear and reduced hearing due to untreated infections may also contribute to disturbed speech and mental function. So the hearing impairment or loss may lead to delayed speech initiation, limited vocabulary, difficulty to understand pronunciation. This is the cohort describing the natural course of alpha-mannosidosis by Beck and we see that the alpha- mannosidosis multiplies. Mild to moderate. What we can see is thickened calvaria, ovoid configuration flattening and hook- shaped deformity of the vertebral bodies, hypoplasia of the inferior portions of the ilia, mild expansion of tubular bones in the hand, asymptomatic osteopenia, focal or sclerotic lesions, osteonecrosis, knock-knee contributing to gait disturbance, brachycephaly and poor pneumatization of the sphenoid body. The picture we can see cleft scoliosis with skeletal abnormalities of the vertebrae and coxarthrosis already at the age of eight years. Again, in comparison to mucopolysaccharidosis, this dysostosis multiplex is milder. In the left picture, picture A, we can see a healthy child, X-ray of the hand of a healthy child . Picture B, the child with MPS II, and we see the mild proximal tapering of the metacarpals and minimal slenderness of the distal phalanges. When we compare it to the child with alpha-mannosidosis in picture C, we see that these changes are mildly expressed. About the growth, children with mucopolysaccharidosis do usually manifest an overgrowth in the first two or three years and then they go to growth disorder, so the final height is low. It's usually not the case of patients with alpha- mannosidosis.
Again, the study on natural course by Beck when we see that the majority of patients are still in normal range. Immunodeficiency and recurrent infections. This immunodeficiency is probably caused by oligosaccharides, which bind to IL- 2 receptors on immunocompetent cells and deteriorating their functions. From the experience, some children, especially in preschool age or younger school age, manifest bronchitis, pneumonia, repeated otitis. Other children do not manifest recurrent diseases, so it's variable and it's not constant. Psychiatric manifestations in alpha-mannosidosis. It may affect more than 25% of patients. It may be in episodes and it typically comes in adolescence, in the second or third decade of life. And it may be modified by the intellectual disability that is present. What is quite typical are the acute or recurrent attacks or confusion, sometimes with anxiety, depression, or hallucinations. These children may wake up during the night and they get lost, they are disorientated, they don't know where to come back to the bed. Sometimes even the psychosis may be present.
Other typical symptoms are motor functions, deterioration. Patients learn to walk later than the other individuals. Impairment progresses with age. The real problem is ataxia, which comes in the second or third decade of life, with frequent falls. And because of these, patients are then wheelchair- bound and they are not able of independent gait. Other symptoms may include enlarged spleen and liver, cardiac and renal complications, typically aortic regurgitation. So we see also the six- minute walking test is about a 50 to 60 percent of normal. So what's the diagnosis and prognosis? So all those symptoms typically present from an early age. The disease is usually diagnosed in early childhood and adolescence. There is often a delay in diagnosis and the majority of patients are diagnosed by urinary tests for oligosaccharides, enzymatic analysis of alpha-mannosidase in leukocytes or by genetic analysis. The disease is typically diagnosed by different specialists. It's not about so much specialization but about awareness of that doctor.
The thing is we should always think of the combination of these symptoms. When a child has macrocephaly or mild organomegaly isolated, and we focus on this and omit that the child has recurrent otitis media or other symptoms that are consistent with alpha-mannosidosis, we may easily miss the diagnosis.So all the time we have to do detailed medical history and look for the combination of signs and symptoms. Two more slides on pulmonary function in alpha-mannosidosis with decreased forced vital capacity and forced expiratory volume. The thing about hepato- and splenomegaly, it's always a problem with the very general things and there are many, many definitions of hepatomegaly. We talk about hepatomegaly in alpha-mannosidosis but majority of patients do not have liver larger than two centimeters, which is on the limit of the American Association of Pediatrics definition, but we should be always very careful. There are also retinal changes in alpha-mannosidosis where typically there may be a partial optic nerve atrophy and there may be the shift of the pigment in retina. What we found as characteristic brain MRI findings, so these are white matter changes, delayed maturation of the white matter, which can be misinterpreted sometimes as an accumulation of iron in basal ganglia because of the contrast to white matter, and the other very typical sign is cerebellar atrophy, which may be progressive over time.
What's the outcome and what's the mortality? There was a very nice study by Julia Hennermann, who identified 15 patients and the cause of death and the median age of death was 45 years. There were deaths due to pneumonia or infections, but it's quite interesting that three patients died because of oncological reason, and this might have something to do with the immunodeficiency. So again, the chart to the same study with a cancer, pneumonia, respiratory failure, septicemia or other course, and now just to illustrate the variability of the phenotype even in the same family. This is a consanguineous family from northern Tunisia, and let's take the first family from this publication. There were five patients with alpha-mannosidosis. We see that the age when the diagnosis was done was very different from 2 to 33 years. Age at onset of hearing impairment, it was very early, usually lower than two years in all patients, and the hearing loss was 60 to 100 decibels in all patients. This is very interesting about dysmorphic features. As it's a very subjective evaluation, there may be really big differences, and sometimes the description is really not an objective. So we can see coarse facial features or a large broad forehead, which are typical coarse facial features in patients 3, 4, 5, but not such a typical description in first two patients. What is quite interesting are the musculoskeletal abnormalities like pectus carinatum in the first and in the third and fourth patient, which are not very typical for alpha-mannosidosis, but there is a lumbar kyphosis, short neck, thoracic deformity, spondylolisthesis, all of them may occur. What is also interesting is for alpha-mannosidosis, macrocephaly is the characteristic, but here in the girl, patient number three, we see microcephaly. So even if this symptom is not consistent with alpha-mannosidosis, we cannot exclude whether there was some perinatal asphyxia, congenital infection, or whatever, what caused the microcephaly instead of macrocephaly. Also interesting, the variability in cognitive decline. We see the first child at the age of nine years, and his developmental performance is described as learning difficulties. And in the second child, aged three, there is no cognitive decline. There are also some autistic features in the girl, number three, at age seven. And we have to say, many times autism is mixed with the children, with the other cause of mental retardation. There are memory impairment learning difficulties in patient number four, and mental retardation in patient number five. I just want to say, there are also exceptions. I know about one adult, nearly 50- year- old patient with alpha-mannosidosis who runs his own business in Hungary, and he's got a shop with the bicycles. So there may be also very mild forms.
And psychiatric symptoms or behavior, there is a hyperactivity and heteroaggressive behavior. About the immunodeficiency, so first child had recurrent serous mucosal otitis. The other, bronchopulmonary infections, and it was the same in the third patient. But as we see, patient number four and five, the first one had only adenoid hypertrophy, and there is no information about recurrent infections. Also about abdominal sonography, as we said, organomegaly might be only very mild, and it's detected typically in younger children. It may disappear in older children. That's why the hepatomegaly may be seen only in the first two children. And what's quite interesting is the Mongolian blue spots or hyperpigmentation on the back, which is quite common in Arabic population in this disease. So again, when to raise a suspicion on alpha-mannosidosis? And I will name the list of the signs and symptoms one more time. And we should always say, this could be a lysosomal storage disorder, either alpha-mannosidosis or mucopolysaccharidosis. When I see the combination of at least two or three of these symptoms, coarse facial features, recurrent respiratory infections, chronic rhinorrhea, upper airway restriction, recurrent otitis media, hearing loss, heart murmur, hepatomegaly, umbilical and inguinal hernia, recurrent watery diarrhea, joint stiffness, and developmental delay and or speech delay. When or how to make a diagnosis? If we have MPS phenotype and we don't have the diagnosis of MPS, we should always consider whether or exclude alpha- mannosidosis.
There was a study of 1, 010 individuals with MPS- like phenotype and more than four patients with alpha-mannosidosis were found in this cohort. So summary, alpha-mannosidosis and mucopolysaccharidosis are rare multisystemic disorders. alpha-mannosidosis and mucopolysaccharidosis have many common features, including organomegaly, umbilical and inguinal hernias, developmental delay, coarse facial features, hearing disorder, macrocephaly, and recurrent respiratory infections. Additionally, immunodeficiency, ataxia, and psychosis are present in alpha-mannosidosis. However, craniocervical instability and carpal tunnel syndrome are missing. The progression of alpha-mannosidosis is generally slower and patients live longer than patients with neuronopathic forms of MPS. It's an extremely rare, but probably under-diagnosed disease. The diagnosis may be set on biochemical, enzymatic, or genetic level, but there will be other lectures from this series focusing on diagnosis. The ideal approach for the diagnosis may differ based on local experience or possibilities, and before the era of neonatal screening, the clinical suspicion remains crucial. Thank you for your attention. This is my email if you have any other questions. Now we've got Q&A section. Thank you very much.
[00:31:11] Professor Martin Magner: The first question is, you mentioned you feel it's under-diagnosed. What do you think the true prevalence is? It's hard to estimate the number. I can just tell you that in the Czech Republic, the situation was that we diagnosed four patients in 1992. And from the time until 2018, there was no other patient diagnosed. But in the last five years, we have diagnosed five other patients. So it's really the question of whether this is a bias of rare diseases or this was caused by increased knowledge or awareness. Anything is possible, but I know about a higher diagnosis of these diseases in other countries as well, especially in the last five years. It might have something in common that the therapy for this disease is available, and so that the information and awareness of this disease is higher than it was before. The next question is, alpha-mannosidosis develops slower than MPS in general. Is that the case throughout the development or just the early signs? It's not only about the early signs. The early signs, the time of their occurrence or manifestation is very similar to MPS, but generally they are milder and they are more difficult to catch, I would say in this word. Again, if we have a toddler with recurrent ear infections, there are many of such children. But if the child has a hepatomegaly of one or two centimeters, we may easily overlook it and we don't think in our practice that it is important because it's unspecific and it's very mild. In severe form of mucopolysaccharidosis, the liver would be much larger, so it would raise our awareness much faster. And that's the art of diagnosing alpha-mannosidosis, that we have to really spot the very mild signs and to ask if there is combination and to really search by ourselves to other symptoms, whether they are present or not.
So not just to overlook the signs and symptoms, but to concentrate and search for other signs and symptoms. I just did a study on another metabolic disease, and I may say that it was also a multisystemic disease, that the percentage of the signs and symptoms, which were noted by the sending doctor, were about 30% lower than they were then found at the metabolic center. The doctor who knows what to look for will find many more signs and symptoms than the doctor who is not so familiar with the disease. Thank you. There is a question about newborn screening for alpha-mannosidosis. So there are already methods for screening of alpha-mannosidosis, but it really depends on the policy of the countries. Still, it's a very rare disease, so there are different approaches to this problem, and the opinions on this might be different. I just say methods are available, but the screening in European countries is not widely introduced. What about enzyme replacement therapy? Enzyme replacement therapy is available for this disease. It was approved by FDA and also EMA, and another approach is hematopoietic stem cell transplantation, but it would be for a longer discussion, and I would leave that for another lecture from this series. But alpha-mannosidosis is a treatable disease. When we have the patient with suspect of MPS, but the tests are negative, should we exclude also mucolipidosis? That's a question, which tests are negative, because in majority of mucopolysaccharidosis or Hurler disease type 2 or 3, at least glycosaminoglycans in urine should be elevated. But still, if we got a strong suspicion on LSD, lysosomal storage disorder, and even we don't have any biochemical changes, like on the level of excretion of glycosaminoglycans or oligosaccharides, but we have other signs like organomegaly, cognitive decline, hearing disorder, all of the clinical signs, and dysostosis multiplex, and we don't have more biochemical methods, we should skip to NGS panels.
The next question is on the siblings. When is it best to test the younger siblings for alpha-mannosidosis? On the first suspicion of the older sibling or on firm diagnosis? So, it really depends on how long the diagnosis will take. If we have the diagnosis in 2 or 3 weeks, we can wait, but if it would take longer time, everybody will be curious about whether the younger child does or does not have the diagnosis. Just for the therapeutic reasons, as in any other disease, also in lysosomal storage disorders, especially alpha-mannosidosis, the effect of the therapy depends on early introduction. So, when there is a delay of 2, 3, or 4 weeks, it's not a big deal, but if it would be longer, then we should make the diagnosis as soon as possible. Please explain more about DBS testing for alpha-mannosidosis. When it should be used in the diagnosis and the referral process? I would say in the testing in dry blood spots, again, there are different methods that may be used in some labs. There are genetic methods available in some labs, enzymatic level methods, but generally, we should always indicate screening for alpha-mannosidosis. Any method and DBS is especially suitable and easy when we get a suspicion on MPS or lysosomal storage disorders and the screening for MPS is negative. So, this was the last question. I would like to thank you for your attention and it was a great pleasure for me. I would like to wish you a great day. Goodbye.