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[00:00:00] Dr. Karolina Stepien: Welcome to our second webinar, Shine a Light on Alpha-mannosidosis, It's a Matter of Time. This is an educational webinar, which is brought to you by Chiesi. As all content is disease-state focused, the presentations will not include information on specific treatments or medications. This webinar is for healthcare professionals only. Please don't take screenshots. We would like to ask you to do not reproduce any of the slides, content or images without express written permission of the speaker. We would welcome any questions from you at the end of the webinar, which will be very helpful during the discussion. As many questions as possible will be answered at the very end. And the recorded webinar will be available on demand as the webinar one. So the main learning objectives of this webinar are listed on this slide. So we aim to understand best practice, multidisciplinary care in the long term management and mannitoring of our patients with alpha mannosidosis. We aim to explore how care and management can be enhanced, including barriers to appropriate care and how to overcome them. And we aim to discuss how to support the transition from the pediatric to adult care. So at the beginning, I would like to introduce my colleagues, Dr. Lampe and Dr. Ficicioglou. We will have several presentations discussing the multidisciplinary approach to care of our patients with alpha mannosidosis, which will be illustrated by case presentations from our colleagues, the speakers. And it will be followed by brightening the future in alpha- mannosidosis presentation from Dr. Lampe. As mentioned, we would welcome questions from yourself, which can be posted in the chat. So I would like to introduce my colleague, Dr. Christina Lampe, who is a metabolic clinician from Gießen in Germany. And she looks after pediatric and adult patients with alpha- mannosidosis. Dr. Professor Ficicioglu is a clinician from Philadelphia, and he looks after pediatric patients with alpha-mannosidosis. And while I work in Salford in Greater Manchester in the UK, and I look after adult patients with this condition. These are our disclosures.
So last week we had a webinar one. And just to summarise, we've learned that alpha mannosidosis is an ultra-rare lysosomal storage disorder caused by several mutations affecting the gene MAN2B1. And it results in alpha- mannosidosis deficiency. The condition has a very broad spectrum and the clinical presentation may vary from patient to patient. We know that there is a classification of different types. In general, they may be classified into mild, moderate and severe forms. The broad range of clinical manifestation places a high burden on patients and caregivers. And the overlapping non- specific symptoms of lysosomal storage disorders such as MPS conditions and lack of awareness amanng healthcare professionals can lead to delayed diagnosis or misdiagnosis. And we know that there are diagnostic algorithms which have been developed to support a timely diagnosis. And research suggests that high- risk population- based or newborn screening may enhance early recognition of this condition. Patients may present with the whole spectrum of different symptoms and the severity of these symptoms and age when they develop the symptoms may vary. But in principle, most of these patients developed learning difficulties. They may have coarse facial features, but we know that mild forms, attenuated forms of alpha-mannosidosis, may not necessarily have very coarse features. They may present with immunodeficiencies, some autoimmune conditions and they may be at risk of recurrent infections. We know that their bone and skeletal system is severely affected. Their joints may be particularly painful and it affects their mobility. It affects, causes ataxia and results in myopathy. They may have cornea opacities. They have impaired hearing early in their childhood and the central nervous system in principle is affected, which results in declining cognitive function over time. They may have hepatosplenomegaly mainly in childhood. So now I would like to hand over to my colleague Dr. Ficicioglu to present his first presentation.
[00:06:12] Dr. Can Ficicioglou: As we heard last week and today, alpha-mannosidosis is a multi systemic disorder and patients present with different symptoms and it is very important to have a proactive approach to care. When these patients present with certain symptoms such as hearing loss and they need hearing aids and we know that these patients are at risk for certain complications such as bacterial infections due to immune deficiency, it is important to start antibiotics as early as possible to prevent at least the severity of bacterial infections and treat them early. Due to immune deficiency, it is also essential to complete their immunizations in a timely manner. So ongoing surveillance is very important in this multi-organ disease like many other storage disorders. These patients should be seen at certain time intervals and certain tests should be done to assess the progression of their disease. Of course, it's a recessive disease as we all know. There is risk for recurrence and these patients should receive genetic counseling. If they are younger siblings, it's important to test them and it's important to also guide parents to understand the future risks in other pregnancies. So we talked about the multisystemic nature of this disease. So of course the patients are in the center but there is need for an expert geneticist or metabolic physician to guide these patients and help them during their journey to receive the best care. As you see here on this slide, there are multiple subspecialties involved and some of it can be quite overwhelming for families to go and see all of them. Sometimes it is necessary to prioritize which subspecialty is more important than the others but all have roles in the care of alpha mannosidosis.
Of course, patients most of the time come to us with hearing loss or hearing aids, you know, speech therapy, audiology, ENT are extremely important. These patients are at risk for learning disability and neurocognitive impairment and sometimes psychiatric symptoms, neurology, psychiatry are extremely important. You know, they do need physical and occupational therapies and this is a chronic disorder. Lifelong treatment is required and case managers, social workers are very important in the care of these patients. It's very important to remember to include primary care physicians in the care of this complex disease. Primary care physicians should be kept in the loop and they are definitely very important in the management of these patients. Sometimes, of course, depending on the age of diagnosis and severity of the cases, if bone marrow transplantation is an option for treatment, transplant team also gets involved in the care of these patients. Now, I will discuss the first case. This is a, I think I need to get the slides back. All right, this is one of the cases we saw in our clinic. So this patient was born full-term via C-section. There were no complications prenatally or during delivery and she was perfectly fine in the first year of life and walked at one year of age. So parents did not have any concerns in the first year of life. And during the second year of life, this patient had increased weight gain. And the parents also noticed that speech was delayed and hearing tests was done. At around two years of age, she was diagnosed with hearing loss. So speech delay and hearing loss was the main problem and weight gain, increased weight gain during the second year of life. And this patient was followed by a primary care physician at some point seen by a gastroenterologist due to reflux, but it didn't require medications. At around four years of age, this patient was referred to clinical genetics and seen by a clinical geneticist. And at that time, she did not have any dysmorphic features and the weight was at 100 percentile and head circumference and height was also at the upper end of normal limits. But again, she was seen by a dysmorphologist and the physician did not appreciate any dysmorphic appearance. And the only thing abnormal on the exam was white spaced teeth. So this patient, at the time, the clinical geneticist thought that this could be predatory because of obesity, but there was no hypotonia at birth or hands and feet were normal. So it was also not high on the differential diagnosis, but they chose to send SNP array and methylation- sensitive PCR for Prader- Willi syndrome and they all came back normal. So this patient lost the follow- up, basically went back to PCP and followed by a primary care physician. At around eight years of age, four years later, she was referred back to genetics and she was morbidly obese, head circumference was at 97th percentile. And at that time, it was noted that she had mild down- slanting palpebral fissures and myopia. She had sensorineural hearing loss and speech delay, which was present at two years of age as well. And she had nocturnal enuresis, speech delay, and this time at eight years of age, she also had learning disability. The father also had a history of learning issues, and he couldn't graduate from high school.And ear tips were placed in that time in the past and tonsils were removed due to snoring and difficulty sleeping. So this was, you know, this was when she was seen at eight years of age. So the clinical geneticists had concern and couldn't really come up with any specific diagnosis, obesity, learning disability, speech delay, hearing loss, and there was family history of learning issues as well. And they chose to send whole exome sequencing and whole exome sequencing showed that patient had two likely pathogenic mutations in MAN2B1 gene, which is consistent with alpha mannosidosis. And this patient was immediately referred to metabolism, to us, and we measured the enzyme level, which was zero. We sent urine oligosaccharides, which showed grossly elevated mannose-rich oligosaccharides , and we did neurocognitive testing and the patient's IQ was 76. So this patient did not have any history of recurrent infections and on our exam we didn't appreciate coarse facial features and skeletal survey was done and she did not have any bone abnormalities such as dysostosis multiplex. Now I will hand over Dr. Lampe for another case.
[00:15:09] Dr. Chirstina Lampe: Thank you very much John. I would like to present the case of an early diagnosis. Actually this child was born in 1987. So he's around middle of 30 now. And actually he was born after an uneventful pregnancy spontaneously without any complications at normal height and weight. And at the age of three mannths he received surgery on both sides. The developmental milestones were quite in time. He was walking a little bit late with 15 mannths and he suffered his first pneumannia at the age of 18 mannths. So at the age of three years he had some speech delay and also recurrent infections of the airways and the ears especially. So he received an adenoidectomy and T- tubes. At three and a half years he developed a strabism and a macrocephaly. So being on the fifth percentile with height and weight he had circumference at the 97th percentile. So due to that he received a CT scan and there were no signs of craniosynostosis or hydrocephalus. But in the x- ray of the skull there were signs of a dysostosis multiplex and this actually was leading to the suspicion of a lysosomal disease.
So the diagnostic started. So actually the patient was presented with a coarse face like MPS, a flat nose, a squared head and frontal bossing. He showed some kind of claw hands not as severe as we see it in MPSs but nevertheless kind of claw hands. He showed pectus carvinatum and a very stiff and straight spine. The abdominal wall was very weak and he had a small umbilical hernia and the liver was palpable three centimeters under the ribs. The heart and lung were normal and also the neurological examination was without pathological findings. His speech was a little bit unclear and only a few words and the developmental testing at 45 mannths of age showed actually only a mild developmental delay mainly in speech and body control. The first idea of the colleagues was that it might be a mucopolysaccharidosis and the glycosaminoglycan excretion in urine was tested but this was normal. He received quite a lot of other examinations. I don't want to go in detail but it shows actually how important it is to have a multidisciplinary team to take care of this patient. And also the MRI was without any pathological findings. And finally the colleagues decided to perform a skin biopsy and in the electron microscopy they saw enlarged lysosomes. So at this point the patient was tested on alpha mannosidosis and the enzyme activity in blood was almost zero. So this diagnosis was for sure confirmed by genetic testing. And at this time the awareness of alpha-mann was not that as it is nowadays but this patient actually was not under metabolic care but went from one specialist to the other according to the symptoms he developed and showed. So between four and five years he had recurrent infections of the airways mainly pneumannia. At the age of five years he received hearing aids which leads to an improvement of speech, a better concentration and also that he was able to speak in full sentences. Now he had hypertrophic tonsils and the head circumference was still quite high. With 14 years of age, so adolescent age, he went to a school for handicapped people due to his mild mental retardation. He had still his enlarged head circumference and he developed an ataxia without any other neurological findings. With 18 he started working in a company for handicapped people and he developed some or he had some fractures of the metatarsal bones. He had a hip dysplasia and suffered from knee pain. With 23 years of age, he had some teeth extraction because of cysts. With 26 years of age, he had an MRI which showed some leukencephaly at the cerebellum, an unsteady walking, but no medication at this point. With 28 years of age, he had a, or he showed a progression of his unstable gait. He was falling very often. He had a loss of balance. And in the neurological examination, it was described as severe ataxia, standing on one leg for less than one second, not possible. Standing on one leg for less than one second. He was not able to jump on one leg. He had a mild loss of his fine motor skill. He could read letters, but no words. He was writing a few words in capital letters, but the reflexes were normal and the muscle tone and strength as well. With 31 years of age, he showed a progressive dysostosis multiplex in his X-rays. And at the age of 33 years, so actually very late, he showed the typical lysosomal signs in the MRI, the periventricular lesions. Then in later adulthood, he was living in a house for handicapped people, working. He loves to drive a cat car and is flag bearing, but his mother reported a deterioration of his gait. So the increased use of a walker, less endurance and less sensitivity of pain, but he was always complaining about pain in his joints. He had hearing aids, glasses. Due to a hypertension, he received medication for his heart. He had no incontinence, less infections than in childhood and adolescent ages, no pulmannary problems and also no psychiatric problems. So no psychosis. In the clinical examination, he spoke very loudly. He had hearing aids, glasses, a very coarse face, as you can see in the picture. He was very straight and stiff in his spine and he showed a severe ataxia without any pathological reflexes or pyramidal signs. And here's a video showing him with his ataxia at the age of 36 years. To see the wide-based unbalanced gait in this patient. I think this case illustrates how many specialists are involved in the treatment of these patients. Thank you.
[00:23:24] Dr. Karolina Stepien: Thank you. Thank you very much to Dr. Lampe and Dr. Ficicioglu .Really interesting cases with some learning points. They illustrate the natural history progression and symptoms development over time. Just looking back at these cases, are there any symptoms which were a red flag for alpha-mannosidosis?
[00:23:55] Dr. Chirstina Lampe: If I can start, probably, John, you agree both of these patients had a macrocephaly. Maybe this could be a red flag. I don't know, but a lot of my alpha-mann patients have a macrocephalus. So maybe this could be a red flag as well.
[00:24:17] Dr. Can Ficicioglou: I think it is a red flag. The only problem, I think, as I presented my case was she was all in all big. And the obesity, I think, was confusing. And then it was included in the differential diagnosis of, you know, and it's not part of alpha-mannosidosis, but obesity is kind of more striking symptom. And which definitely, I think, distracted from the other symptoms the patient had. But a macrocephaly could be the first one, like many other storage disorders, right? So it could be one. In the case that I presented, I think hearing loss is the first symptom and remain is the main symptom for a long time. So sometimes, you know, that's why I think I was trying to, you know, highlight that, you know, algorithms are extremely important, but on the other hand, some patients may not have everything, you know, more than a couple of symptoms, and then one symptom might be the leading and the most striking symptom. So it makes it, I think, much harder to suspect alpha mannosidosis.
[00:25:39] Dr. Chirstina Lampe: One thing that I also noticed, right, sorry, but… No, my case had a hearing loss as well. I mean, it was a little bit later, but actually the hearing loss was leading to the speech delay, and this was also one sign, and the coarse face, actually.
[00:25:56] Dr. Chirstina Lampe: But sorry for interrupting you.
[00:25:58] Dr. Can Ficicioglou: Yeah, it is very striking, you know, last week, Dr. Stepien presented one case. I see very similarities in facial appearances of both cases. Do you agree? I think they do have some very similar facial features.
[00:26:18] Dr. Karolina Stepien: Facial coarse features, yes.
[00:26:20] Dr. Can Ficicioglou: Yeah, right.
[00:26:22] Dr. Karolina Stepien: Coming back to the hearing impairment, so we know that children with alpha mannosidosis, as well as other LSDs, present with hearing impairment quite early in their life, and we know that it's included in the algorithm, diagnostic algorithm, so it can be one of the red flags. But just looking back at these cases, if you were to change anything in their management, would you change anything to make the diagnosis earlier in these patients?
[00:26:55] Dr. Can Ficicioglou: I think in the case that I presented, a hearing genetic panel should have been sent at the time when she was diagnosed with hearing loss. And if you can include multiple genes that cause hearing loss, I think alpha mannosidosis could have been diagnosed at two years of age, in my case.
[00:27:20] Dr. Chirstina Lampe: My case was lucky. I mean, this patient was diagnosed due to the macrocephaly, and they found signs of dysostosis multiplex, so the thickened skull, and this was leading to actually more thinking about other signs and symptoms. So actually, probably not a real typical case, but he had at the end all the typical signs and symptoms that we can use at red flags in his life.
[00:27:50] Dr. Karolina Stepien: And we know that a diagnosis of alpha mannosidosis has a significant impact on our patients, their families. And in your cases, what was the impact of the delayed diagnosis on the patients and their families?
[00:28:10] Dr. Can Ficicioglou: I think the case I presented is not the most severe case. She didn't have many other symptoms and findings of alpha mannosidosis. But I think I will say that the stress and anxiety of not knowing what is causing hearing loss and so forth is, I think, the big impact on this family. Eight years, they lived without knowing what the problem was. And of course, it's important to start surveillance as soon as possible to look for possible complications of alpha mannosidosis in a timely manner, and it wasn't done in my case. There was a delay.
[00:28:55] Dr. Chirstina Lampe: They cannot link to a patient association. They cannot go to a specialist if they don't have a diagnosis. I mean, family planning is another topic, and also maybe treatment that is not useful for these patients, like hip surgeries and hip dysplasia or something. I think it's leading to quite a lot of mistreatment if you don't have a diagnosis.
[00:29:24] Dr. Can Ficicioglou: Or not receiving certain important services, even in the school.
[00:29:31] Dr. Karolina Stepien: Yeah.
[00:29:32] Dr. Chirstina Lampe: Yeah.
[00:29:33] Dr. Karolina Stepien: So it only emphasizes that the earlier they are diagnosed, the better, because they can be treated by different teams, multidisciplinary teams, and we know that they have multisystemic complications. So thank you very much for these presentations. Now, I would like to invite Dr. Lampert to present her presentation on brightening the future in alpha mannosidosis, optimizing care globally.
[00:30:00] Dr. Chirstina Lampe: Thank you sorry for this. So what we know is that most of our patients now surviving above the age of 20 and the estimates suggest that more than 50% of people with an inherent metabolic disease are adults. So what we need is it's not only a disease of childhood, but it is also a disease of all ages and we have to keep that in mind when we take care of, also, alpha-mann patients. So there's the development of long-term age-related complications, there's the metabolic progression of the underlying condition, but- and this is probably our, our big complication is that there is a lack of data on the natural cause of the disease, because we are not, we don't know about the complications of the disease in adulthood or in adult patients, since these patients are not really under regular care by now. So what it is needed for our patients is an appropriate transition from pediatric to adult services, and actually this is also true for the ultra-rare diseases. Transitional care is defined actually as a purposeful, planned movement of adolescents and young adults with chronic physical and medical conditions from child-centered to adult-oriented healthcare systems. But this is actually not very easy in most countries. So here in the survey monkey of two metabolic specialists of the EU and the 63 experts were answering, from 20 European countries, and the most challenges in managing transition was mentioned: the lack of time, the lack of adult metabolic physicians positions vacancies, the knowledge gaps amongst medical staff, lack of reimbursement, lack of interest, poor communication between pediatric and adult centers, and around 10% of alpha-mann or metabolic patients in the EU never transition from adult care and remain in pediatric care their entire life, which means there's really a need of adult physicians taking care of these patients. So the principles of a successful healthcare transition is for sure that a transition coordinator is needed- and I think paulina is the best to talk about that- to provide specific metabolic training for adult physicians and ensure adult metabolic positions.
As we said already, there's a financial gap for these positions, but also there's no defined training in some countries for adult physicians. There's also that it is needed to ensure an individualized transition plan, so not one model fits all. It means every patient needs in a way his own or her own transition plan, but nevertheless there must be some standardized protocols for transition and also for the documentation. If sometimes in some hospitals, like in my hospital, it is not possible to perform transition because there's no adult metabolic care team, at least it is important to start planning for transition to adult care in early adolescence, so meaning that the patients are encouraged to speak alone and be able to manage their disease on their own, if it is possible, but at least to know that they have to speak and to take care of themselves and be self-responsible. Then the next point is to involve family and caregivers, and this is something that is not very common in adult medicine but nevertheless in rare diseases. The parents or patients are mainly experts for their disease and it is important to listen to them and to involve them in the care of patients and also to empower the people to be part of the planning and organization of the transition and also the care of the patient, and it is important to personalize the transition to the individual needs of a patient. We have some patients with severe mental retardation, we have patients without, and this has to be individualized.
So what can we do or what is important to fill this gap and to improve the multidisciplinary work up with our patients? Actually there are quite a lot of differences between healthcare systems and physicians training in different countries, but nevertheless the international collaboration is recommended to optimize the care of patients, especially with this ultra rare diseases, because every one of us has a few patients, but all together we have a bigger group and we can understand better the needs of the patients, the red flags, the complications of the disease we have to expect. This is for sure sharing expertise and information like in the European reference networks. So to collaborate, to share information and share experience with these patients. It's also sharing best practices on diagnostics, medical care, healthcare transition, education and social care. It is optimizing the training and education for healthcare providers so that we are raising awareness for rare diseases and resources that are available and for sure the development of guidelines for diagnostic tests or also the screening for the diseases. We saw this slide and John presented in the last webinar, but I think it shows very well the journey of our patients. It's the importance of improved awareness that is leading to a timely specialist referral since we heard already that we have a big gap between the earliest signs and symptoms and the diagnosis and patients are running from one physician to the other. Everyone is a specialist for his own specialty, but nobody is really seeing the patient as a whole and this is leading to a delayed diagnosis. The referral to a specialist center is quite important, first for an early diagnosis, but also to start the multidisciplinary care that the patient is needed. And at least the multidisciplinary care of our patients, that is the best supportive care, ongoing specialist consultations, surgeries, etc., that is needed. And after being an adult, also the transition or starting in adolescence, starting the transition to adult services so that the patient is in optimal care at the end.
[00:37:57] Dr. Karolina Stepien: Thank you. Thank you very much, Dr. Lampe. This was a very comprehensive overview of the transition care and our experience based on this data from this survey. I have a question. How can we best handle the transition of alpha-mannosidosis patients from pediatric to adult care? And who should lead this process? And common problems in the transition process to look for, to avoid?
[00:38:32] Dr. Chirstina Lampe: Karolina, you are the best to answer this question. I'm sorry.
[00:38:40] Dr. Karolina Stepien: So, the transition, I must say, the transition process is pretty unique and we are lucky that we have it well set up in the UK. One of the reasons is that we have two separate specialties, pediatric metabolic specialty, where pediatricians look after patients with rare diseases from the age of 0 to 16, and adult metabolic specialty. So, we, me, myself, with my team, as adult physicians, we look after anybody above the age of 16 up to the age of 90. above if possible. So because there are two separate specialties and different setup often in different hospitals, so it led to the development of various guidelines, protocols and how we can support these young people and their families throughout this process. So the question is how can we best handle the transition of patients with alpha-mannosidosis from pediatric to adult care. So ideally the more complex case, the sooner they should start attending the transition clinics and we, at least in Manchester, we hold transition clinics in the pediatric hospitals. So the adult team with a clinician, with a physiotherapist, with learning disability nurse, we attend these clinics in the pediatric hospital where we jointly with the pediatric team review these patients. It may be intimidating as you can imagine as there are several people in the room, but we try to build up rapport with the young adult and their family. So one of our nurses or the dietician for other conditions make sure that they can have a one-to-one conversation with the young adults as well. And as I mentioned, the more complex case, the sooner they should attend this clinic.
So from the age of 13, 14 and when they are ready around the age of 16, but definitely before they reach the age of 18, they should really transfer, the care should be transferred to our adult metabolic centre and it's not just from the transition and the transfer of care, it doesn't apply to the pediatric and adult metabolic specialty, it applies to any other specialty. So we know that patients may remain under the care of orthopaedic surgeons, there may be a weighting, hip replacement, correction of the foot or knee deformities. They may require input from psychiatrists, neuropsychiatry team, psychologists and these clinics or the care from these clinics should be transferred accordingly to adult equivalency in our hospital. So we have care coordinators and it's crucial to have a nurse on the pediatric side, but also a specialist nurse on the adult side who coordinate the care, the follow up appointments and any documentation which needs to be prepared during the transition process and any information required for us to look after these patients long term. And in terms of the common problems in the transition process, so there may be challenges, but it's, you can imagine that after 16 years of being under the pediatric team's care, it may be difficult for young adults and their families suddenly to switch the hospital, the team, clinic, nurses, physiotherapists. So they keep phoning the pediatric team, they keep phoning them if they have any queries because especially in between the transition clinic and the first clinic appointment in the adult hospital, it may be confusing for them whom they really, they should contact. So they keep going back to the pediatric team. So it takes a while for them to get used to the adult team's care. So this is the transition process in a nutshell. Anything else, Christina, you would add? No, John, how is it in your hospital?
[00:43:07] Dr. Can Ficicioglou: Yeah, I mean, here in the United States, it's a little bit complicated. First of all, biochemical geneticists are trained to see both pediatric and adult patients, but most of them are trained in pediatrics. So they are pediatric, they, you know, board the individuals and then they have biochemical boards as well. But the problem here is access and insurance. It is not that we do not have the same system that UK has. You know, once patients become adults, they have insurance, and then the insurance companies dictate them which hospital they can go. So when they are pediatric, I think there is much more flexibility to see these patients in pediatric hospitals. But once they become adults, if they live in another state, and if they have, you know, special insurance that will allow those patients to be seen in that state, and in that state, there may be no biochemical geneticists available. So I think shortage of providers, access, insurance issues are main barriers in transition. So we do not have the same system that UK has.
[00:44:20] Dr. Chirstina Lampe: In Germany, it's very difficult as well. I mean, we have only a few centers with adult metabolic specialists, so that these patients really stay with pediatricians or at least in the under pediatric care. What I try to do is at least to change the specialists. So I am a kind of coordinator, I see the patients, I make the plan for all the assessments, but they switch from the pediatric cardiologists to the adult cardiology, pulmannologists, etc. So this is a kind of transition due to the lack of metabolic adult physicians that we have.
[00:45:05] Dr. Can Ficicioglou: You know, we do the same thing. The main issue is that is, you know, when they see those subspecialties and most of the time, they can go and see a cardiologist in Children's Hospital of Philadelphia. So everything is more integrated in one place, but once they become adult and we refer them to an adult cardiologist, then the insurance company doesn't allow them to come to the next door hospital. So they need to go to another hospital. The cardiologist in one hospital, nephrologist is another hospital. So then the multidisciplinary care is definitely, it's not perfect when they become adults. And, you know, the other thing is, of course, the adult providers always think these disorders as a pediatric diseases and they don't have much knowledge about this and then it becomes a big challenge.
[00:46:00] Dr. Karolina Stepien: Yeah, I fully agree. It's really important to have the multidisciplinary team in the same hospital. Simply, if we have an electronic patient record, they can all access this electronic patient record. So it facilitates the communication between the various teams. Right, so now I would like to open the Q&A session and would like to invite questions from our delegates. The first question came through, what about the dried blood spot test for alpha mannosidosis? Is it really, or is it already on board and where?
[00:46:44] Dr. Can Ficicioglou: Well, the alpha mannosidosis enzyme can be measured on dried blood filter papers and it was published as a newborn screening test as well. And it can do multiplex in all those things. But the majority of laboratories, I think measure the enzyme in leukocytes and they request the whole blood. Maybe in the United States, there is only one laboratory doing the dried blood spot, but most require whole blood and measure the enzyme in leukocytes.
[00:47:16] Dr. Chirstina Lampe: Right, and in Germany? We have the dried blood spot test, but there's one laboratory that is measuring the enzyme activity and also the genetics in a dried blood spot test. Otherwise we have to send blood as well, full blood.
[00:47:37] Dr. Karolina Stepien: Yeah, it's similarly in the UK. The dried blood spot cards has been more utilized during the COVID pandemic and we continue using them as well as a diagnostic method. The next question, which diagnostic method is best to use? Which one to use first, genetic, lab, MAN2B1, in which other?
[00:48:05] Dr. Can Ficicioglou: So the question- I think it's a good question. As a biochemical geneticist, I will say probably biochemical tests is the first and genetic is the second. But sometimes depending on the situation, it's much easier to send the genetic test. It could be just a buccal swab type thing, you can send it. Or sometimes genetic test is included in a panel test that you would just send it. I think it depends on the circumstances. I think either is fine.
[00:48:33] Dr. Karolina Stepien: There are advantages- I agree. There are advantages and disadvantages to that. So the turnaround time is probably longer than the enzyme activity method, the costs to that. But also the LSD panel tests may not cover rarer mutations, especially for late diagnosed cases, attenuated forms. So if only one mutation is found, then we still need to repeat it and look for rarer variants, right?
[00:49:04] Dr. Can Ficicioglou: That's correct, right. I think both are needed, right? If enzyme is low, you need the genetic test. If genetic test is abnormal, you need to confirm that the enzyme is low.
[00:49:14] Dr. Karolina Stepien: Yes, I agree. What needs to be done to increase the number of, the numbers of metabolically trained physicians to keep pace with the demand for this specialty?
[00:49:32] Dr. Can Ficicioglou: Well, I think, you know, it is just, you know, compared to other subspecialties, I think there are some limitations in this field, you know, financial or many, but I think, you know, metabolics probably is in good space now because there are many clinical trials. We are able to treat more and more patients' disorders now, so it's becoming more attractive. But, you know, I think it's hard to, you know, if you compare with cardiology or there are some other subspecialties, I think there are some disadvantages, but, you know, you need to have a special interest in taking care of patients with genetics and, you know, in head metabolic disease. So it's a good answer to a good question. There's no good answer.
[00:50:22] Dr. Karolina Stepien: Yeah, I fully agree. So in the UK, we have a training for adult metabolic physicians, but also we encourage doctors from other specialties to develop an interest in rare diseases such as cardiology, neurology. In particular, that there's a proportion of patients with rare diseases who may have either neurological complications or cardiac complications or others. So they are very welcome to work with us as well.
[00:50:47] Dr. Chirstina Lampe: But in Germany, we don't have subspecialty metabolic physicians. They are mainly internal medicine specialized on endocrinology, for example, and then they are taking care also of metabolic patients, but there's no clear educational program. There's one from the SSIEM, I guess, but it is not in the German regulation. There's no subspecialty metabolic physician.
[00:51:21] Dr. Karolina Stepien: And we as clinicians, we need to really reach out to Royal College of Physicians or pediatricians to make sure that rare diseases program is incorporated in the curriculum, in medical school curriculum. Because once medical students have exposure to rare diseases in their medical school, it may encourage them to consider the specialty in the future. What does effective international collaboration look like in real life? How can healthcare providers in different countries share best practices?
[00:52:05] Dr. Can Ficicioglou: I think there are two things important. For rare disorders, there should be registry and then registry data should be published. So we learn from those registries. I think at the meetings, there should be, you know, at international meetings, you know, organizing some, you know, workshops for these disorders will probably bring people together so they can share their experience. I think we should also publish more guidelines for best practices. Based on what we know, of course, guidelines should be renewed.
[00:52:42] Dr. Karolina Stepien: Yeah, I fully agree. And apart from meetings, conferences, now we have virtual meetings, as well as various adult metabolic groups where we can share difficult cases and we ask for advice from other colleagues, because some conditions are ultra rare, where there's only one or two cases per center. And we often seek advice from colleagues from other centers by this group. What are the most significant barriers to improving the care pathway for people with alpha-mannosidosis? How can this be addressed?
[00:53:20] Dr. Chirstina Lampe: I would say it's that these diseases are so ultra rare. So we don't have a lot of cases. And as we said before, if we are not creating a network and sharing expertise and also the signs and symptoms, like in a registry, it is very difficult to take care in the best way because we don't know what we have to expect, especially in adult patients. We don't know what a 70 years old alpha mann patient will present as symptoms by now. And as John said, everyone has one case, but this doesn't mean that we know about the disease, because someone can have common diseases plus an ultra rare disease. And to see what is really the disease complications in patients should be collected by data from everyone who is taking care of patients.
[00:54:21] Dr. Can Ficicioglou: And we also discussed the multidisciplinary team and then, you know, sometimes it is quite challenging and it is a huge burden for patients to go from one subspecialty to another. So ideally, you know, there should be nurse navigators, complex schedulers to help these patients. And then the care pathway probably will be improved if these patients get more assistance, like, you know, a nurse navigator, complex scheduler, and those things. I think, you know, we need to also improve, I think, diagnostic pathway, right? I mean, the early diagnosis is the key and early diagnosed patients hopefully will be receiving the best care and have better outcomes. But, you know, it is difficult for these, you know, families to go to multiple subspecialties. Yeah, one question, yeah, go ahead.
[00:55:26] Dr. Karolina Stepien: I think one important step would be to have guidelines so that also families know what assessments are needed, what they have to, which specialists they have to go to. I fully agree, fully accessible guidelines for healthcare professionals, but also the families. So we should also put our patients and families in contact with patient organisations as they may provide support and put them in contact with other families. Regarding the same topic, there's a question from our delegates. How do you prioritise this specialist and ease the stress on the parents, families in real life?
[00:56:18] Dr. Can Ficicioglou: One thing that we did not for specific to alpha-minus-I doses but for other storage disorders, we create a specific clinics, for example, MPS clinic, and we bring subspecialties to that clinic. So patients, families do not need to schedule separate appointments. They schedule one appointment and they are seen by multiple specialists at the same visit. So it definitely decreases burden on families.
[00:56:43] Dr. Chirstina Lampe: I totally agree. Yeah. But for this, we need a coordinator that is planning and organising this.
[00:56:52] Speaker 4: Yeah.
[00:56:53] Dr. Karolina Stepien: So we also have several specialties involved in the care of our patients with alpha-mannosidosis and other LSDs. And we have joint clinics with cardiologists, ENT specialists, orthopaedic surgeons, neurologists, and it does work, especially for patients who live two, three hours driving away from our centre. There's a question, I think, referring to one of the cases. Is weight gain normal in the early development of alpha-mannosidosis as in the case presented?
[00:57:27] Dr. Can Ficicioglou: I have not encountered any other patients with morbid obesity. I don't know if you have had any patients. I don't think it has been reported before, right? I mean, there are no... Obesity is not a problem.
[00:57:45] Dr. Karolina Stepien: So in obesity, from an adult metabolic point of view, I can say that obesity is not a problem, but the significant weight gain, we notice in patients whose mobility has significantly decelerated and who developed independence on walking aids and awaiting hip surgery, for example. So because of limited mobility, there was a significant weight gain in a couple of patients. There's a question regarding speech delay. Are delays in speech a sign to look for along with hearing, or is speech not always such a clear sign?
[00:58:28] Dr. Can Ficicioglou: If I understand the question correctly, I think that speech delay definitely triggers hearing tests, right? You know, it comes first. You know, patients have speech delay. They cannot catch up. And then so we order hearing tests. So I think speech delay comes before we know that patient has hearing loss.
[00:58:51] Dr. Karolina Stepien: Okay. I think we need to wrap up. So I would like to thank to our speakers. I would like to thank to EIP for giving us the opportunity to host this webinar today. I would like to thank our delegates and for all the questions which came through. If we didn't answer any of your questions, please do get in contact with the EIP and we will be able to answer your questions later on. I would like to remind you about the feedback form to be completed. And just to say that both webinars from last week and this week will be available on demand on the EIP website. Thank you.