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[00:00:00] Dr. Christina Lampe: So welcome to the Shine a Light on Alpha- Mannosidosis webinar of today, Spotting the Signs. I'm very happy to welcome you all to this webinar, which is sponsored by Chiesi in collaboration with and hosted by EIP. And I will introduce my two colleagues a little bit later on, and we'll make some introduction first. So actually, this is an educational webinar, and actually, it is disease- state focused, and we present only disease- focused information, not including any information about specific treatments or medications. So please do not take any screenshots or reproduce any slides. Your questions can be submitted via text, so we will have a long question and answer session at the end of this webinar. So please ask a lot of questions so that we have a fruitful discussion at the end. And this webinar will be recorded and will be available on demand. The learning objectives of today will be to identify the symptoms associated with alpha-mannosidosis and to understand how to differentiate this condition from other lysosomal storage disorders. We will also show you a real- life case report to explain or to show how the path to diagnosis could be improved for individuals and their families. And we would like to discuss about how to understand the importance of an early diagnosis, the barriers to diagnosis, and how they can be overcome. So after this welcome and a short introduction about alpha- mannosidosis, Dr. Stepien will talk about spotting the signs of alpha- mannosidosis and also showing a patient journey, a case report discussion, then Dr. Ficicioglu will talk about translating clinical concerns to time of diagnosis. And at the end, we will have a question and answer session.
So now I would like to introduce my colleagues, Dr. Karolina Stepien from the Salford Royal NHS Foundation Trust in the UK, and Dr. John Ficicioglu from the Children's Hospital of Philadelphia. My name is Christina Lampe, and I'm working at the University Hospital in Gießen. Here are our disclosures. So, shining a light on alpha-mannosidosis. Why is there a delayed recognition and under-diagnosis of alpha-mannosidosis? For sure, because it is a very, very rare disease with an estimated prevalence at 0.1 to 100,000. But not only this, it is also a disease with a very variable severity of the disease that presents clinical challenges in our patients. If we see the prevalence in different countries, we see it as very heterogeneous, and it varies quite a lot. However, we think that a lot of patients are under-diagnosed due to the rarity of the disease, but also because of the fact that the clinical signs and symptoms are so variable. So the evidence suggests an incidence rate significantly higher than 1 to 500,000. What is the cause of the disease? It's a gene defect that is causing a deficiency of the lysosomal enzyme alpha-mannosidase. This enzyme actually is usually degradating glycoproteins, and so they can be recycled or degraded. If this enzyme is missing, we have a storage of oligosaccharides in several cells, and so often in different organ systems. The inheritance is autosomal recessive. It is actually both parents are carrying the mutant, one mutant of the MAN2B1 gene, and around 25% of children are affected by this disease or could be affected. To date, we know around 155 variants of this gene that have been identified so far. However, it is very difficult to find a genotype-phenotype correlation at the moment.
[00:04:44] Dr. Christina Lampe: And with this short introduction, I hand over to Dr. Karolina Stepien talking about spotting the disease symptoms in alpha- mann.
[00:04:57] Dr. Karolina Stepien: Thank you, Christina. We have heard that alpha- mannosidosis is highly heterogeneous and symptoms and disease severity as well as disease progression varies widely from patient to patient and clinicians should be aware of the red flags of alpha-mannosidosis symptom presentation that may hasten diagnosis and therefore maximize the opportunity for intervention at the earliest stage possible. Early identification of patients is essential to ensure early treatment. So, most patients with alpha-mannosidosis manifest with mild to moderate learning disability with an IQ varying between 60 to 80 with a declining tendency over later decades. Most follow-up observations suggest gradual impairment of their mental and motor function as well as speech decline with age. Psychiatric symptoms typically are presented, manifested in their adolescence but also in their adult life. Symptoms such as anxiety, such as delusions may be also a classical feature. In addition to that, behavioural problems and sleep disturbance may be manifested in young adults and later on in their life. Hearing impairment is another classical feature of alpha-mannosidosis and it may lead to moderate to severe sensorineural hearing loss. The diagnosis is made with audiometry in cooperating patients with alpha-mannosidosis but can be difficult in young children and adult patients with learning disability. For speech therapy to be effective, hearing aids should be provided and we know that these patients require hearing aids in their childhood, young adolescence, the stages of their life and later on in their life. Skeletal abnormalities can vary from patient to patient and complications progress over time. They may be marked to moderate dysostosis multiplex, scoliosis and deformation of the sternum. Kyphoscoliosis is commonly seen and can be corrected with orthopedic surgery. Some patients develop genovagal deformity which can be treated with epiphyseal stapling in growing children but must be performed early in their life to be effective. Foot bone deformities have been observed in our patients. We know that these patients require orthopedic intervention and the requirement for that increases over time, so in adult patients is more common. The generative changes in large joints often limit their mobility and their quality of life and patients may require analgesia and hip replacement long term. The facial traits include large head with prominent forehead, rounded eyebrows, flattened nasal bridge, macroglossia, wildly spaced teeth and prognathism. Slight strabismus may be common and the clinical variability is significant among these patients representing a continuum in severity. There's an overlap in terms of their symptoms with other lysosomal storage diseases such as Hurler's Syndrome in terms of their facial features and interestingly patients with attenuated forms of alpha-mannosidosis may have subtle facial features which we will present later in one of our cases. One of the main features of the condition is immune deficiency manifested by recurrent infections especially in their first decade of life. In 2000, Malm and his research group found that post-immunisation levels of antibody were much lower in patients with alpha-mannosidosis, proving a decreased ability to produce specific antibodies after antigen presentation.
[00:09:50] Dr. Karolina Stepien: One of the main features of the condition is immune deficiency manifested by recurrent infections especially in their first decade of life. In 2000, Malm and his research group found that post-immunisation levels of antibody were much lower in patients with alpha-mannosidosis, proving a decreased ability to produce specific antibodies after antigen presentation. It was shown that in mannosidosis, oligomannosides with 5 and 6 mannose residues bind to interleukin-2 receptors, disturbing the interleukin-2 dependent responses and interleukin-2 activates cells such as T-cell, B-cell, NK-cells. It can therefore be speculated that blockage of this receptor is the mechanism causing immune deficiency seen in this group of conditions. Myopathy and ataxia may become prominent in childhood, adolescence and even more in adulthood and it may progress over time. Interestingly, in some late diagnosed cases, ataxia can be misdiagnosed as a neurological condition, neurological symptom of a completely different condition and as a result, sadly, patients may experience falls, they may experience and develop dependence on their working aids over time. In summary, alpha-mannosidosis is a neurodegenerative condition and the children are often born apparently normal and their condition worsens progressively over time. The sequel of symptoms may differ from patient to patient but they all develop neurological, neuropsychiatry and orthopedic related problems. Alpha-mannosidosis is insidiously progressive as shown by some cases diagnosed as late as in their 6th decade of life. The long-term prognosis can be poor unless they are diagnosed earlier in their life. This slide presents three different categories, three different forms of alpha- mannosidosis. Type 3 is the more severe form presenting in childhood with skeletal abnormalities and obvious disease progression, results very often in early death due to CNS and involvement in myopathy. Individuals with the milder phenotype have mild to moderate intellectual disability, impaired hearing, characteristic cold features, clinical and radiographic skeletal abnormalities, immunodeficiency and primary central nervous system disease, mainly cerebral involvement causing ataxia. Periods of psychiatry symptoms may be common and may be more pronounced later in their life in attenuated forms. There are also other associated medical problems such as cornea opacities, hepatosplenomegaly, aseptic destructive arthritis or metabolic myopathies. In the survey published in 2019, it was shown that alpha-mannosidosis has a considerable impact on the quality of life of patients and their carers and their families with patient awoken ability as a key factor. The increased dependence of patients who are wheelchair dependent or severely mobile on their carer for all aspects of daily life results in a high level of strain related to care provision for the carer and poor quality of life and poor quality of outcomes for the patient. Caring for a child or young adult with alpha-mannosidosis has a negative impact on the health and quality of life of carers, particularly regarding to their mental health. And the stress and anxiety caused by the disease put pressure on family relationships and family dynamics. Alpha-mannosidosis also impairs social integration of patients, their carers and their families.
[00:15:07] Dr. Christina Lampe: Thank you so much, Karolina, for this very comprehensive overview of the signs and symptoms. But what can we recommend? Which particular red flags can we see in alpha- mann? What should lead us to think to an alpha- mannosidosis? John, do you want to start?
[00:15:36] Dr. Can Ficicioglu: Yeah, I think we heard that this disease is affecting multiple organ systems, but a couple of them are actually quite striking. I think hearing loss and intellectual disability and bone disease are the two, three main symptoms for these patients. I think, but the key message here, I think we need to see the whole picture instead of just focusing on one symptom. It's important to see the other symptoms that might be subtle when these patients present, but see the patient as a whole and then put all the symptoms together to be able to make diagnosis. But the three main symptoms I think is kind of striking.
[00:16:31] Dr. Karolina Stepien: Yeah, I fully agree. Alpha-mannosidosis is a highly heterogeneous condition, as I said before, and often patients have atypical presentation. So they may not have all symptoms I've just listed, presented, but if they have two or three of the symptoms, they should be red flagged for the condition and they should be screened and considered for screening for alpha-mann.
[00:16:58] Dr. Christina Lampe: And if you decide between, or if you divide between pediatric and adolescent patients, what would be the red flags for the pediatric patients? John, do you want to?
[00:17:10] Dr. Can Ficicioglu: Yeah, I think the red flags for pediatric patients, developmental delay and hearing loss. And sometimes coarse facial features and the coarse facial features could be very mild and it is, you know, not all patients have it, but, you know, some of, you know, facial differences of patients from their parents I think could be a red flag. But sometimes I feel like these patients come to us with just one symptom. It's the striking, you know, hearing loss, speech delay, but the other symptoms are very, very mild. And then, you know, it is very easy to miss these cases.
[00:17:49] Dr. Christina Lampe: Adolescent patients, Karolina.
[00:17:54] Dr. Karolina Stepien: Adolescent, so they may have mild, only mild learning disability. They don't necessarily have severe learning difficulties. And also in adolescents and young adults, ear infections are not that common. But what we see commonly is neuropsychiatry problem, so psychosis, and behavioral problems, agitation. So these patients may need to be referred to neuropsychiatry for their intervention. And what we see is the progressive pain in the joints and deteriorating mobility over time.
[00:18:33] Dr. Christina Lampe: Okay, so the best would be to see a real case. Karolina, I think you have a case that you can show us so that it is more clear what
[00:18:43] Dr. Karolina Stepien: Sorry. So diagnostic delay in rare diseases is a problem for our patients and their families, but the society as a whole. And we know that the average time to the correct diagnosis is estimated as four to five years, but in some cases it may take longer, up to a decade. And these patients face diagnostic odyssey and often undergo extensive and expensive investigations, very often in several institutions. But it's worth distinguishing between delayed diagnosis and the late onset diagnosis. So delayed diagnosis may result in the condition worsening into a serious illness or disease. And while a delayed diagnosis refers to the condition which is undiagnosed for an unreasonable amount of time, the late onset diagnosis refers to a medical condition occurring relatively late in their life for the first time. So in case of patient I would like to present, a diagnosis was clearly delayed. And although symptoms were mild, one may argue that it was a late onset form of alpha- mannosidosis. It was a female patient born at 10, her birth weight was 2. 6 kilograms. And in her childhood, she just developed a meconium swallowing, but otherwise she had normal early childhood until the age of three when she required hernia surgery. In primary school, she was noticed to struggle with her speech. And as a result, she had to be moved to a special needs school. She always had difficulties with hearing and indeed for the investigations confirmed sensory neural hearing loss. And eventually she required a hearing aid fitted at the age of five years. Her mother mentioned that she always struggled with infections. She gets easily a cough and cold and she required her adenoids to be removed in childhood. She had several ear infections and required grommets in childhood. She had multiple episodes of tonsillitis. She had short stutter and the most recent recorded height is 148. 5 centimetres. She may have prognatism, she may have a low set ears and possible mild pest cables, but there's no evidence of peripheral neuropathy. In her adolescence, despite some health problems, she had normal quality of life. Her mobility has started to become an issue. She had problems with turning and she had very broad based gait. When she was in her twenties, she noticed that she started stumbling over things. She had recurrent falls and her gait has become more unsteady. Her walking has deteriorated over the next few years. She started bumping into things and she required a follow- up in a neurogenetic clinic to screen for various genetic and neurological causes of ataxia. And despite several metabolic genetic investigations, her condition has remained undiagnosed over the next four years. When she was 27, she developed a problem with her left hip. It became a problem, it became painful and she was referred to a local orthopedic team for their scans and intervention. And her symptoms initially were managed with steroid injections, but she stopped responding after the first few injections. In the meantime, she was enrolled into a 100, 000 Genome Project and she was found to have two mutations previously described in the literature. And so she was compounded a heterozygote for mutations causing alpha- Humanozygosis. Following on from a genetic diagnosis, the biochemical workup was completed. Urine oligosaccharides confirmed three saccharides bands and a ladder formation on oligosaccharide chromatography. And is the top row, the third band from the left is our patient. Her alpha- mannosidase activity was almost deficient, and chitotriosidase activity, a non- specific biomarker, was raised. The pain and mobility were results of her left hip osteoarthritis with dysplasia of the left hip, genu valgum, and her left knee. The range of movement in her left hip was very limited and restricted due to the pain. The patient had previous corrective surgeries of her toes in both feet, which was only a fully corrective of any bone deformities on one side, in one foot. So all this resulted in limited physical activity and limited quality of her life. These are his x- rays and the CT scan. The x-ray on the left and the further right shows the left hip and pelvis with present subarticular cystic changes. The CT scan on the image in the middle showed severe osteoarthritis with further obliteration of the joint space and there was swelling of some soft tissue, which was in keeping with synovial hypertrophy. So in summary, her severe osteoarthritis, left hip dysplasia, and large cyst in the acetabulum led to severe pain and reduced mobility. So in summary, I presented a case of an adult patient who has developed symptoms of alpha mannosidosis over a period of 30 years before she was diagnosed with the condition at the age of 31. She had mild coarse facial features, hernia, sensorineural hearing loss, recurrent infections in childhood, and skeletal abnormalities leading to chronic pain and mobility problems and ataxia. And only recently, she also developed secondary amenorrhea and swallowing problems. She's been currently investigated for mild to moderate aortic regurgitation as well. So subtle and non-specific symptoms of mild alpha mannosidosis may result in a delayed diagnosis. And the diagnostic pathway is often very long and the data regarding the challenges faced by these patients and their families is very limited. In terms of the management of these cases, they often require highly specialized multidisciplinary team approach. And we know that an early diagnosis maximizes the opportunity for early treatment beyond best supportive care alone.
[00:27:44] Dr. Christina Lampe: So thank you for this. And I think it illustrates very much that the first signs and symptoms are extremely unspecific and this makes it so difficult to diagnose patients. That is what we also know from the mucopolysaccharidosis. But what are the key factors in this underdiagnosis and delayed diagnosis? John, you want to start?
[00:28:12] Dr. Can Ficicioglu: Yeah, this is a very interesting case. You know, we heard that this patient actually had symptoms in early childhood, but they were not very specific and no one really combined all and asked the question, what is going on here? So I think the focus was much more on specific symptoms, but not the all symptoms. So it is tough. And I found that this patient had some facial differences. She had some facial dysmorphism, it's important to look at the parents as well. But I think the problem is that the subtle, nonspecific symptoms in an ultra rare disease I think is the reason we are not able to make a diagnosis in a timely manner.
[00:29:07] Dr. Christina Lampe: Karolina, what was the age when you think the first signs and symptoms were present that the child could have been diagnosed?
[00:29:15] Dr. Karolina Stepien: So the hearing impairment and delayed speech in childhood, it might have had been picked up early if she was referred to community pediatricians and the metabolic team many years ago. But it's the diagnostic pathway. Patients may not be referred to the right team on time.
[00:29:37] Dr. Christina Lampe: But do you think also the recurrent infections are one of the key symptoms of alpha-mann?
[00:29:47] Dr. Karolina Stepien: Yes, recurrent chest infections, recurrent ear infections are classical features, especially in childhood.
[00:29:56] Dr. Christina Lampe: How can we support the physicians in sending these patients with these very unspecific signs and symptoms to a metabolic centre? Because these signs and symptoms that we know, a little bit delayed speech, hearing loss, recurrent infection, it's very common in childhood. So how can we lead these patients to a metabolic centre?
[00:30:23] Dr. Can Ficicioglu: I think it's important to ask the question, what is unusual? So I think it is unusual to see more than one organ system involvement. I think it is really important to look at all patients and all symptoms together. I think it is the key. But if you are not able to do that, maybe the question should be, patient has hearing loss and speech delay, what is causing that?
[00:30:53] Dr. Christina Lampe: But if a patient has always recurrent ear infections, it is obvious that he has a kind of hearing loss at a certain point. So it is very difficult. So do you think that parents should insist on these things, that they feel something strange or that physicians should listen to parents if they say, well, he's always sick, he has the hearing loss, he's not speaking? I mean, things that we should listen to the parents and their feeling that something might be wrong?
[00:31:22] Dr. Karolina Stepien: I think it's a very good point, especially if the parents have more than one child and they can compare that something is not right with hearing of this child as compared to other children, which can be also a red flag. And I agree with Dr. Ficicioglu that actually there's more than one symptom. So there's a hearing problem, there's infection, there may be a speech delay, there may be a myopathy also in childhood. So more than one symptom, which is suggestive of a metabolic condition.
[00:32:03] Dr. Christina Lampe: Yeah, I think we need more explanation. John, would you talk a little bit about translating clinical concerns into timely diagnosis, please?
[00:32:14] Dr. Can Ficicioglu: Sure. All right. So we heard that this is an ultra rare disorder. And, all right, and heterogeneous, there is variability in symptoms and patients may present with different symptoms at different time points. So there's diagnostic odyssey. And based on published papers, we know that the median onset of symptoms is 12 months. So these patients present early. And most of the time they go to their primary care physicians, and they remain in that practice for one to five years before they are referred to a specialist. Once they are referred to specialists, most of the time specialists focus on the symptom they have expertise, and they do not see the picture. Again, based on the paper published in 2019, there is a median diagnostic delay is six years for alpha mannosidosis. So there is diagnostic odyssey. Early diagnosis is very important to start disease specific treatments, and of course, supportive care, and early diagnosis, early treatment will improve the outcomes and quality of life. So how we can make this happen? So, one option is, of course, to educate healthcare professionals and increase awareness about red flags of alpha-mannosidosis. This is very important, but it may not be enough. And another approach is, you know, implementing MAN2B1 gene in certain gene panels, such as hearing loss panel or developmental delay intellectual disability genetic panels. So, when there are patients with hearing loss or intellectual disability, many physicians nowadays send genetic test panels to see what the underlying cause is, so alpha mannosidosis can be diagnosed through this way. And, of course, for all rare inherited metabolic disorders, newborn screening is the way to go if you really want to make a diagnosis as early as possible. So, if you look at the frequency of presenting symptoms, this paper was published in 2019 and they presented 111 patients published in the literature. And what they found is 97% of these patients had cognitive impairment. It's very common. Bone abnormality is 81%, coarse facial features 70%, hearing loss 67%, recurrent respiratory tract infections 53%. So you see that there are multiple symptoms here, and some of them are quite common in presentation. So we can focus on that. Again, a group of experts published diagnostic algorithms in 2019. In this slide, you see diagnostic algorithm for children less than 10 years of age. If you have a patient with hearing impairment and speech delay, and the second question you should ask is if that patient also has other symptoms, if that patient has two manifestations among the following, cognitive delay, motor disturbance, impaired balance, facial features, coarse facial features, then the chance that that patient has alpha mannosidosis is very high and those patients should be referred to metabolic centers. And this algorithm basically tells us that if there are no other symptoms, just keep monitoring patients for those symptoms. So we can discuss what else can be done in this type of algorithms. So the second algorithm is basically for children older than 10 years of age, and then in this group, intellectual disability and motor impairment or regression or psychiatric manifestations are the primary symptoms. If you have a patient with the symptoms, you should ask the question if the patient had other symptoms such as hearing impairment, motor disturbance, ataxia, skeletal disorders or joint disease, if the patient had two of them, the likelihood of alpha mannosidosis is very high and that you should refer that patient to a metabolic center as soon as possible. If not, and I think, you know, basically algorithm tells us that we should keep monitoring if there are any signs of alpha mannosidosis signs in box to appear. So once you suspect the diagnosis, we have tools to make, to diagnose alpha mannosidosis. So one of the laboratory tests is urine oligosaccharides. It can easily be sent in some countries, it cannot be done, but if it is, so it's a simple test. It shows monos rich oligosaccharides and it is an abnormal test for alpha mannosidosis. Enzyme test is easily available. It can be measured on dry filter blood spots as well and it is an important test to confirm the diagnosis. Genetic test nowadays is easily available. You can send the targeted genetic test for MAN2B1 and it confirms the diagnosis. I added histopathology here because it could be an important way to diagnose alpha mannosidosis. If you have peripheral blood smears, you may see what goes in lymphocytes. It's not specific to alpha mannosidosis, but it increases suspicion for storage disorders. One of my patients about 20 years ago actually, she had a TNA tonsillectomy and the ENT surgeon sent tonsils to pathology and the pathology found storage cells in tonsils and referred that patient to us and we diagnosed with alpha mannosidosis. So histopathology could also be another way to go.
[00:38:58] Dr. Christina Lampe: Thank you so much. Do you think that this diagnostic algorithm that you showed are robust to diagnose patients early?
[00:39:07] Dr. Can Ficicioglu: I think the diagnostic algorithm is great, but we also talked about that there is variability and there is heterogeneity and that not all patients have the same symptoms when they present. So in that algorithm, instead of waiting for two other symptoms to appear, I would go with, if I have a patient with hearing loss and speech delay, I will suspect alpha mannosidosis. If I have a patient with intellectual disability, I will probably roll out many other disorders, but include alpha mannosidosis. I think it's an ideal slide, but you may not be able to see all other symptoms.
[00:39:52] Dr. Christina Lampe: Yes, I think this is true. I mean we are thinking first to the more often diseases instead of the very rare ones. Nevertheless, we should include them in our diagnostic thinking, I guess.
[00:40:07] Dr. Christina Lampe: Karolina, anything to add before we start the question and answer session?
[00:40:12] Dr. Karolina Stepien: I just wanted to say that these diagnostic algorithms are widely available and they are available in different settings for community pediatricians, neuropediatricians, general practitioners, but it's our role to educate doctors about alpha mannosidosis and to making them consider alpha mannosidosis as a differential diagnosis. And as we've seen, the algorithm may have hearing loss or cognitive impairment as one of the differential, but a patient needs to have at least two more other symptoms so that the patient is sent for screening for alpha mannosidosis as per the algorithm.
[00:41:01] Dr. Christina Lampe: Yeah, probably ideal would be the newborn screening that is unfortunately not available in most countries, but I think this is something to work on. To start the question and answer session, I invite all the attendees to ask a lot of questions that we can hopefully answer. Are there any questions by now? Actually, before waiting, there's a question. What are the main challenges in distinguishing alpha mannosidosis from other LSDs and how can these be overcome? John, start.
[00:41:44] Dr. Can Ficicioglu: Yeah, I think there is definitely overlap with other storage disorders because, you know, MPS patients may present with speech delay and hearing loss as well and coarse facial features could be part of that MPS disorder. Sometimes, you know, when we suspect and we may not be able to say that this is alpha mannosidosis, but we should include it among the other storage disease screening panels when we send tests. Sometimes we do send more than one test to roll out multiple storage disorders.
[00:42:19] Dr. Christina Lampe: Karolina, you want to add something?
[00:42:25] Dr. Karolina Stepien: I agree there's overlap in terms of the clinical features and also facial deformities, facial features, but the bone deformities as well. And as long as a clinician considers screening for lysosomal storage diseases as a whole, I think it would be a big success. And we know this alpha mannosidosis is included in the Y cell enzyme panel and it could be diagnosed as part of the facial diagnosis. But the clinical features, I think clinical presentation may not be that helpful in terms of diagnosing alpha-mann based on the clinical manifestations. Yeah.
[00:43:16] Dr. Christina Lampe: What are the typical neurodevelopmental abnormalities in alpha mannosidosis? Do they overlap with other LSDs or genetic disorders? If so, which ones?
[00:43:25] Dr. Karolina Stepien: So, I think if I may start. So, I showed it on... I presented a case who presented with speech delay and a hearing problem and some children may have, probably a pediatrician John could add, but children may have problems with meeting the developmental milestones. So, it depends if it's type 3, type 2, type 1 alpha-mannosidosis, depending on the severity of the condition. But in general, meeting the developmental milestones may be a problem and can be again a red flag for neuropediatricians.
[00:44:20] Dr. Christina Lampe: Can, do you want to add?
[00:44:20] Dr. Can Ficicioglu: Yeah, I completely agree. I think, you know, it is also important to do neurodevelopmental tests to be able to catch the mild intellectual disability, in these cases, to see if there is an impairment in neurocognitive functions. I think the neurocognitive, you know, intellectual disability and hearing loss, I think two main things in alpha-mannosidosis. So, it is really important to look for other symptoms when you have patients with hearing loss and, you know, neurocognitive impairment.
[00:45:01] Dr. Christina Lampe: So, where's the difference between alpha-mann and MPSs? I mean, they could be confused because the signs and symptoms are quite similar, especially the unspecific signs and symptoms at the beginning, but where's the difference between alpha-mann and MPSs in your opinion?
[00:45:21] Speaker 4: Right.
[00:45:21] Dr. Can Ficicioglu: In the beginning, I think it might be difficult if patients presenting early, it might be difficult, especially if they have coarse facial features, but many MPS disorders, MPS I, MPS II, I think they have much more striking symptoms than alpha-mannosidosis in terms of coarse facial features, corneal clotting, or more bone abnormalities, kyphosis, in the beginning of presentation, but those are a miss too. There's diagnostic delay for MPS disorders too. But it's tough. I think, you know, sending, you know, certain tests, if you're not sure, I think sending a lysosomal panel enzyme test or, you know, sending urine oligosaccharides and both urinary GAGs at the same time, if you're not sure about the storage, which storage disease this could be, is the way to go.
[00:46:14] Dr. Christina Lampe: It makes sense. I mean, it makes sense to test both at the same time.
[00:46:19] Dr. Can Ficicioglu: Absolutely, yeah.
[00:46:20] Dr. Karolina Stepien: I agree. The only thing I see, the MPS developmental delay is more heavy than in alpha-mann and it is much quicker. So alpha-mann patients have a delay, developmental delay, but it is very prolonged in contrast to MPS, at least in my experience, and slowly progressive.
[00:46:41] Dr. Can Ficicioglu: Exactly. I completely agree with that. The progression rate is much slower.
[00:46:46] Dr. Christina Lampe: Yeah, yeah. There's another question. You described three types of alpha-mannosidosis given the heterogeneity of the disease and likely overlap in symptoms between the types. How do you find that this classification works in clinical practice?
[00:47:03] Dr. Karolina Stepien: So it's probably a question for me. I think so. So it's probably easier to classify a patient with severe form into the type three category because it's a very extreme case, whereas type two and type one, where there's a cut-off of 10 years of age, it may vary in some cases. And I think we need to be sometimes flexible. We know that patients may not present exactly below the age of 10 or above. The symptoms, as we mentioned, are being developed over time and they progress gradually. So depending on the severity of the condition and the onset of symptoms, we may have, I'm not saying a problem into categorizing into moderate or very mild form. But patients, as is shown in my case, they may have a typical presentation sometimes. And probably my patient will meet the criteria for type two because she developed hearing problems in childhood, whereas all other symptoms have gradually been developed over time when she was an adolescent and young adult. So just to answer the question, so probably the classification is useful. And from the pediatric point of view, you may also add, if you diagnose alpha-male in childhood, in terms of the late diagnosed case or late onset case, it's probably less useful. I think.
[00:49:04] Dr. Christina Lampe: And I mean, I think also the French are fluent, so it's very difficult to classify clearly in type 1, 2, or 3. There's also one classification telling if their bone involvement under the age of 10, it's more severe than if you have bone involvement after the age of 10. But I think it's just an idea to say it is more this or more that. But in most cases, I think it's very difficult to classify in type 1, 2, and 3. And the next question is, is it needed to classify so strictly in the types? John, what do you think?
[00:49:46] Dr. Can Ficicioglu: Yeah, probably no. There is lots of overlap. It will be very difficult, I think, to make, especially as Carolina said, type 1 and 2s. So they will overlap. Is it needed, right? The question, I think it's a spectrum. We all know that they fall into somewhere in that spectrum. Maybe it's easier to make the classification as severe and attenuated type thing. But then, again, how we define severe, how we define attenuated is different, right? Yeah.
[00:50:23] Dr. Christina Lampe: So there's another question. Which is the proper timing for hemiepiphysiodesis and alpha mannosidosis? I'm a surgeon. Maybe I can answer. I think, I mean, it depends on the severity of the deformity that you have. I mean, whenever you want to use hemiepiphysiodesis to correct, for example, the knees, you should do it before the patient is not growing anymore. So in my opinion, or this is what we know from MPS, is that we usually recommend at the age of seven years or a little bit older, a little bit younger, depending on the severity. But John, do you have a different opinion on that?
[00:51:15] Dr. Can Ficicioglu: Yeah, I think I agree. I don't have much experience on that, to say anything else.
[00:51:21] Dr. Christina Lampe: I don't see a lot of leg deformity in alpha-mann. We see quite a lot of scoliosis in older patients, but not that much leg deformity. Karolina, what is your experience?
[00:51:42] Dr. Karolina Stepien: In terms of deformities?
[00:51:44] Dr. Christina Lampe: Yeah, that need hemiepiphysiodesis.
[00:51:50] Dr. Karolina Stepien: So as I mentioned when I was presenting the red flags of the disease, it's recommended to correct the knee deformities in childhood when a child is growing. But we see that corrective surgeries are required in adult patients as well. Foot surgery, hip surgery, and knee surgeries are often required in our adult patients.
[00:52:19] Dr. Christina Lampe: But then there are no hemiepiphysiodesis anymore, but more hip or knee replacements or real osteotomies.
[00:52:30] Dr. Karolina Stepien: Yeah.
[00:52:32] Dr. Christina Lampe: So diagnosis delays of four to five years on average, late-onset case study at 27 years old, how common is such a long delay in diagnosis?
[00:52:42] Dr. Karolina Stepien: This is a very good question and well-timed because currently we are looking for late-diagnosed cases and late-onset cases. So anybody who was diagnosed about the age of 16, we are collating cases around the world. And if you delegate such cases, please do get in contact with us. We've identified several cases and the plan is to analyze them in terms of the diagnostic odyssey. We would like to see who was looking after them in their childhood, adolescence, before the diagnosis was made. So it's a very relevant question and very well-timed currently.
[00:53:30] Dr. Christina Lampe: But Karolina, since you are working on that, are these patients indeed developing such late symptoms or are the symptoms in childhood were not.
[00:53:47] Dr. Karolina Stepien: So this is why I started from defining late diagnosis versus late onset. So most likely my patient was, the diagnosis was missed in my case. And she might have had subtle symptoms throughout their life, but the diagnosis was missed until she was enrolled in 200,000 genome project. And so late onset is less likely to be relevant to this particular case or I would say any lysosomal storage disease because these patients have a degree of some bone deformities, even carpal tunnel syndrome throughout their life. So it's most likely a late diagnosis, not late onset case.
[00:54:43] Dr. Christina Lampe: You agree, John?
[00:54:47] Dr. Can Ficicioglu: I completely agree, yeah.
[00:54:48] Dr. Christina Lampe: Yeah, me too. There's one more question. What are the subtle symptoms that should be red flag in terms of facial features? John?
[00:55:00] Dr. Can Ficicioglu: Yeah, I think some of these patients have coarse facial features, but they are much milder than MPS patients. And some patients do not have coarse facial features. You know, they do not have it. So, or they might have very mild facial dysmorphism, but it is not well defined, you know, what it is, you know, long philtrums or, you know, or short nose and that type of things. But, you know, it could be tricky to, you know, some patients may not have it, but they usually, they are different from their parents and they can have a little bit, you know, coarse facial features and then jaws and, you know, some coarseness, but it may be difficult to, you know, recognise that in the beginning. Once diagnosis is made, you know, you may say that, oh yes, coarse facial features, but when these patients present, it might be difficult to pick that up.
[00:55:58] Dr. Karolina Stepien: Yeah. So just to add, they may look slightly differently from their parents and their siblings as well.
[00:56:04] Dr. Can Ficicioglu: Right.
[00:56:04] Dr. Christina Lampe: Yeah. This is my experience as well. They are not looking like MPS patients, but if you see a lot of mannosidosis patients, they look similar to each other, like siblings. So there is something different, but I think the best way is to decide whether these children look like the parents or if they look different. Another question, how do you see the diagnostic journey for people with alpha-mann changing in the future?
[00:56:33] Dr. Can Ficicioglu: Well, I think, you know, the diagnostic journey is changing for many lysosomal disorders. You know, MPS I is in the newborn screening panel. MPS II is in the RUSP in the United States and many other LSDs are screened. I think alpha-mannosidosis hopefully will be in the newborn screening panel at some point. In the UK, they are just starting a genome project. So I think, you know, lots of, I think, screening will be done to make diagnosis as early as possible, but newborn screening is the way to go.
[00:57:12] Dr. Karolina Stepien: Yeah, I fully agree. We have better access now to whole genome sequencing, which is stemming from 100,000 Genome Project and access to the metabolic laboratories, which are excellent. And the diagnostic odyssey will improve. And we hopefully will see very few late diagnosed cases in the next few years.
[00:57:39] Dr. Christina Lampe: I think also the dried blood spot test is making diagnosis much, much easier and quicker, and also the awareness problems like the seminar today. And I thank you both for your excellent talks and discussions. I thank the audience to be part of this webinar today. Please keep in mind, we have a second part of it next week, same time, same day. And we will go a little bit more in detail in some issues. So I hope we will see you all next week again. And thank you very much for the questions and the participation.