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[00:00:00] Dr. Christina Lampe: Hello everybody. I would like to welcome you to the Spot the Early Signs of alpha-mannnosidosis series and this will be the last one from four trainings. Three very fantastic speakers have already gave you some insights in alpha-mannnosidosis and today I would like to talk about what every pediatrician needs to know about the alpha-mannnosidosis patient's journey. My name is Christina Lampe. I'm working at the University Hospital in Germany at the Rare Disease Center and I'm focused on lysosomal diseases. Please do not take any screenshots or please don't reproduce any slides, content or images. We will have a talk about 30-35 minutes followed by a question-and-answer session. So whenever you have any questions type it inside the question panel and we will answer these questions at the end of the webinar. Whenever you want to see this webinar again or you want to send it to a colleague, here is a website where you can find these presentations again.
[00:01:33] Dr. Christina Lampe: Also my potential conflict of interest and the outline for today is that we or I would like to understand the important role of a multidisciplinary team in Alpha-Mannosidosis patient's journey, the management of MPS and Alpha-Mannosidosis in daily practice and to explain or to discuss a little bit the ways to support these patients and families and after that we will have the question- and- answer session. So the first topic understanding the important role of a multidisciplinary team and what I would like to do today is to guide you with one of my patients through this presentation which will be actually quite a little bit a summary of the other webinars you heard with focus on the patient's needs. So when you see this child at the age of two years, what disease would you suggest? The child has hernias, a mild developmental delay, mainly speech delay, recurrent infections, macrocephaly and dysostosis multiplex and probably this information is not enough. So what I can also tell you about this patient is that there was an uneventful pregnancy and uneventful spontaneous birth. He has a sister that is three years younger and at the age of three months, he had a hydrocephalus surgery on both sides. The developmental milestones were reached in normal time, but at the age of 18 months, he had a severe pneumonia and needed antibiotics. So what do we have here? We have hernias, the mild developmental delay and recurrent infections. And what would be your first suggestion if you hear that? And everybody who knows me knows that I'm always talking about lysosomal storage diseases. So to give you more information about this child, at the age of three years, he had an adenoidectomy and ear tubes due to the speech developmental delay and recurrent ear infections. At the age of three and a half years, he developed strabismus and macrocephaly, so his head was at the 97th percentile. And for this reason, he received a CT scan of the skull and this showed no signs of craniosynostosis or hydrocephalus. But there was also performed an x- ray of the skull and the radiologist described signs of dysostosis multiplex. Dysostosis multiplex is a radiological term for different skeletal abnormalities like shortened long bones, thickened skull, ovoid vertebrae, very horizontal ribs that are widened and hip dysplasia. So actually when you hear the word dysostosis multiplex, you will probably think to MPS and also if you google dysostosis multiplex, the system will lead you directly to mucopolysaccharidosis. And speech delay, recurrent infections, macrocephaly, dysostosis multiplex could indeed be leading to the diagnosis of MPS. And here you see the seven types of mucopolysaccharidosis caused by 11 enzyme deficiencies. As we know in lysosomal diseases, we have a deficiency of different enzymes. And if you see here, and you compare these pictures with the picture of the patient that I showed you in my first slide, you see here the stiff ones, the patients, MPS patients with contractures of bones and joint stiffness, are very similar to the patient I have shown you. The MPS IVAB patients, the hypermobility of joints is not fitting that much, and also the MPS III with the neurocognitive involvement and less physical involvement is not fitting perfectly.
So probably your first idea of a diagnosis could be mucopolysaccharidosis, and this was also in our case here. So the glycosaminoglycan excretion in urine was measured, but it was in normal range. So several LEDs may show similar signs and symptoms. So we have not only the mucopolysaccharidosis, but probably also multiple enzyme deficits or oligosaccharidosis like alpha-mannosidosis and mucolipidosis that could have the similar signs and symptoms. And indeed, alpha-mann was previously called Hurler- like syndrome because it was quite similar to the MPS patients with the stiff joints. The first description of alpha-mannosidosis from Öckerman in 1967 says, a generalized storage disorder resembling Hurler syndrome. So this is why there's a quite big connection between MPS and alpha-mannosidosis from the clinical point of view. So he described two patients with infections, psychomotor retardation, gargoyle- like face, tallness of stature, hepatosplenomegaly, hypotonia, abnormal bone structure and features, widely spaced teeth, cloudy areas in the capsule of the lens, storage cells in bone marrow, vacuolated lymphocytes, and hypogammaglobulinemia. The two children died at the age of, or this child died at the age of four years. And in the histology, they found ballooned storage cells leading to a lysosomal storage disorder. In the liver, greatly increased amounts of a mannose-containing component, at this time not identified. So the activity of alpha- mannosidase was low in the liver, spleen and the brain. And he said that this may present a disease not previously described. And you see the pictures of the child here. So how do we diagnose alpha-mannosidosis? So we have the, in contrast to the MPSs, where you can find glycosaminoglycan excretion in urine, you find elevated excretion of mannose-rich oligosaccharides in urine. So this is a screening test, but not a confirmation of the diagnosis. So to confirm the diagnosis of an alpha-mannosidosis, you need to measure the enzyme activity in blood or in dried blood spot tests, as it is seen here. And you would measure the alpha-mannosidase deficiency for sure. To confirm the diagnosis, you can also use genetic testing of the MAN2B1 gene. In some countries there are dried blood spot tests available, where you can test the treatable MPS types and also the alpha-mann in one. So coming back to our patient. So the mucopolysaccharide excretion in urine was normal. He had still chronic ear infections, T- tube, but a normal hearing. He had the signs of dysostosis multiplex in his skeleton. He had mild hepatomegaly. And in the skin biopsy, they found electron microscopy in large lysosomes. Heart EEG and MRI were normal. But what they found in the developmental testing is that he had mild developmental delay, mainly speech and body control. Thank you. Height was normal, weight as well, head circumference quite high, still over the 97th percentile. He had a coarse face with a flat nose, claw hands, a quite squared head with frontal bossing, pectus carinatum, a very straight and stiff spine, a weak abdominal wall with a small umbilical hernia. The neurological examination was quite normal, but his speech was unclear with only a few words. It was measured the enzyme activity of the alpha-mannosidase in blood, and he showed a deficiency. So, after confirming, or genetic confirming, the diagnosis of alpha-mann was made. The patient was born in the 80s, so at that time there was no treatment available. And for this reason, the patient was just treated symptomatically. alpha-mannosidosis, in fact, I don't want to go very deep into this slide, since we had heard from Professor Manger, from Professor Langler, from Professor Guffon, already about the cause of alpha-mannosidosis. But important to know is that the median onset of symptoms is around 12 months, and the median diagnostic delay in these patients is 6 years. We have a multisystemic involvement in alpha-mannosidosis, also this we heard from the previous speakers, with cognitive impairment in 97% of patients, bone abnormalities, coarse face, hearing loss, respiratory tract infections, organomegaly, hernias. But in contrast to MPSs, we have an ataxia that is in particular developing in adolescent patients, and we have a real immunodeficiency, which is not common in MPSs. We have also some muscular hypotonia, and in some cases a short stature. But if you focus on the main first signs and symptoms of alpha-mann, our patient is really representative for a typical alpha-mann patient, with the cognitive developmental delay, with coarse face, and the respiratory tract infections. So Dr. Guffon already showed you this algorithm for diagnosis, and I don't want to go too much in detail, but what I would like to highlight is that the hearing impairment is always a red flag to think to alpha-mannosidosis, especially if you find also some cognitive delay, motor disturbances, impaired balance of facial features that are commonly milder than in MPS. In patients that are older than 10 years, you have probably more a mental retardation or motor impairment, the regression and or psychiatric manifestations that are more prominent. And for these patients, you should also have a combination with hearing impairment, motor disturbances, ataxia, intellectual disability, skeletal disorders or joint disease. In these cases of hearing impairment, mental retardation, recurrent infections, and skeletal disease or facial features, you should think to alpha-mannosidosis. So how do we manage these patients now? And what is the treatment options we have? To follow with our patient, between four and five years of age, she suffered from recurrent infections of the airways.
[00:14:05] Dr. Christina Lampe: At the age of five years, he had a hearing loss and needed hearing aids, or the typical sign of alpha- mann. Mainly, it is more early than at the age of five years. But this is what we see in all our patients, that we have a wide spectrum of disease severity and heterogeneity. So it means not all patients show the same symptoms at the same time. So at the age of five and a half years, he had an improvement of speech due to the hearing aids. He could concentrate a little bit better and start to speak in full sentences. He had hypertrophic tonsils and needed tonsillectomy. And you see the head circumference is still high. The adolescent time of this patient, you see with 14 years of age he went to a school for handicapped people, he had still several severe infections of the airways. In the examination you see that he had all facial features more prominent than before and he developed an ataxia and a mild mental retardation. With 18 years he started working in a company for handicapped people. At the age of 19 years he showed a fracture of his fifth metatarsal bone and with 20 years again he had now quite a lot of pain in hip and knee and he showed a hip dysplasia. And also here we should mention that the patient had no ataxia at the beginning but now he developed this ataxia. Also the fractures of the bones, it is not the most important sign and symptom of alpha-mannosidosis but in particular in adolescent and adult patients we should indeed test the bone density from time to time. Our patient here in early adulthood you see that he was living in a house for handicapped people and working there and his mother reported that he had a deterioration of his gait, he using more frequent his walker than before, he had less endurance, less sensitivity of pain when he hurt in a way but he had quite a lot of pain in his joints. He had only as a check- up or follow- up of his disease, he had ENT check- ups for his hearing aids, he had annual check- ups for his eyes, an MRI was performed three years ago when he presented here with white matter lesions, he had infections but not as many as he had in childhood and in clinical examination he had a height of 176 centimetres, quite tall and a weight of 90 kilos. The patient showed a loud speech, he had hearing aids as I said, glasses, coarse face and a very straight and stiff spine and an ataxia and I hope the video will work and you see here that he has a typical tactic gait with wide spread legs when he's walking. Let's see him again and this is something that is untypical for alpha mannosidosis, for MPS patients, MPS patients don't show an ataxia.
[00:17:51] Dr. Christina Lampe: So the natural course of alpha mann and what you also could see in this case is that there is in the first decade of life a high incidence of recurrent infections, in the second and third decades the infections diminish a little bit and the ataxia and the muscular weakness are more prominent. At any time alpha maln patients have a risk of acute necrotizing atritis or acute hydrocephalus and what it is not mentioned here but what we also see in alpha mannosidosis patients is that patients can show psychotic episodes starting in adolescence. If we see the intellectual functional survival and mortality in alpha mannosidosis patients we see that the intellectual functional variables but the patients show the decline in IQ with age particularly during the first decade of life and this is also shown here in the first picture. The survivor is at the age of 41 years and 73% of patients are still alive. So alpha mann patients are indeed reaching adulthood and patients with an onset above 7 years survive significantly longer than patients with the age onset below or equal to 7 years. Also this is very common in our MPS patients. The mortality was described that the most prevalent cause of death was in 46. 7% pneumonia at a mean age of 49 patients. But patients that were examined here were between 21 and 56 years. So what are the pillars of therapy of alpha-mannosidosis? We have a specific enzyme replacement therapy. In some cases, hematopoietic stem cell transplantation is possible as well. We have the symptomatic treatment for our patients. We have physiotherapy, respiratory therapy, speech therapy, etc.
[00:20:20] Dr. Christina Lampe: And we have the general care, like vaccinations, respiratory hygiene, social medical care, and so on. So what we need to follow our patients in a proper way is a multidisciplinary team. Unfortunately, my patient was born in a time where alpha-mannosidosis was not very well known. So the patient received only symptomatic treatment whenever he had any kind of problems. There was no regular follow-up or standardized follow-up that could prevent any disease complications. So what we know now is that our patients need for sure one specialist who knows the disease and can send the patient to all the specialists needed, is collecting the results afterwards, analyzing them, and discussing with the patient and the family. But beside the metabolic specialists, these patients need ophthalmologists, cardiologists, respiratory specialists, EMT surgeons, endocrinologists, and speech and language therapists. They need physiotherapy, immunology, neurology, radiology. I don't want to read all these specialties now, but it is extremely important that the patient is taken care of in a holistic way and not only organ by organ. So if we now have an alpha-mann patient and we have to take care of him, we have for sure talk about the hearing loss. We have to analyze the infections that the patient is suffering from. We have to ask about irritability, depression, and psychosis that, as I mentioned before, is starting in adolescent ages. We need to know about change in social or work- related activities of our patients, the change in walk distance or the endurance, diarrhea or incontinence, muscle bone pain or joint aches, and reduced range of movement in our patients. The physical examination contains ear and eye examination, liver and spleen size, heart and lung examination, the neurological status, including the gait, but also All these patients need orthopedic evaluation of bones, bone density, as I mentioned before, and in children, for sure, growth, height, weight, and head circumference. Sometimes CT scan or MRI of the brain are needed to analyze the size of the ventricles to exclude a hydrocephalus and to see the shape and the size of the cerebellum. Some blood tests are also quite useful beside the routine lab, meaning here the immunogenic tests, and also to exclude a lupus erythematosus, as we see sometimes in our patients. Beside these examinations, we also need to understand what can we do to improve the quality of life of our patients. So, is it needed that the patient needs to learn sign language with a significant hearing loss, for example? and of social skills is needed, so speech therapy to improve speech, special education to maximize learning, and also planning how. Since a few years, there's, in some countries, an enzyme replacement therapy available, Velmanase Alfa. And what can we expect from this treatment? What we saw from the clinical trial outcomes is that there was a significant reduction of serum oligosaccharides in our patients, an improvement in the three- minute StairClimb test, and an improvement in serum IgG, and an improvement in forced vital capacity. There were also shown in clinical trials improvements in the six- minute walk test, in the quality of life questionnaires, improvement in daily life activities, and in the fine motor and gross- motor developmental skills that were measured by the BOT-2. In particular, in pediatric patients, this was seen. Pain reduction was also described in all groups. In summary, the safety profile across the ages was good, and the infusion- related reactions manageable. So going back to our patient, as I said, the patient is now 33 years of age, and he started the enzyme replacement therapy at the age of 30 years. The infusions were very, very tolerated. The caregiver quality of life report showed that he had an improvement of quality of life. He was able to perform his daily life activities more than before. He was less fatigued. He was much better. He had much better endurance, and he was less tired. From the clinical improvement, he showed stabilization of pulmonary function, stabilization in the six- minute walk test, and an improvement of balance, so meaning a tiny little bit of less ataxia. So how can we now support our alpha-mann patients and families? To improve, we need to know what is available for our patients, and there's one publication showing the social and medical needs of rare metabolic patients. This was a survey from MetabERN, and 924 centers participated, and here there's the table of coverage of medical expenses by national healthcare systems, and what we can see is here not covered by the healthcare system was in one- third to one- fourth medical services, food supplements, integrators, and speech therapy, and in particular, speech therapy is extremely important in our Alpha mann patients. Also, psychological assistance was not covered by the healthcare system in 21 percent. Free educational and developmental programs need to be offered to our patients, and what we see here in Europe is that special needs schools are available for over 50 percent of our patients, but free educational services are not widely accessible, so home educators only in 30 percent, and daycare centers in 45 percent, psychomotor skills development in 34 percent, and if we look to the social workers, social worker services, only 28 percent respond that social workers services are guaranteed.
[00:28:30] Dr. Christina Lampe: An exception of this is Denmark, where the social worker service is performed in almost 80 percent, and the majority reported that there's no guaranteed service or no knowledge about this matter.
[00:28:48] Dr. Christina Lampe: For the psychological support for our patients and caregivers, we can see here that for patients the availability of psychological assistance is present in 36. 3%, but the need of psychological support is in more than 66%. In parent and caregiver's point of view, the availability of psychological support is almost 30%, but the need is more than 70%. So there's quite a lack of social support that our patients need. So how can we provide optimal care in our patient? The first step is an early diagnosis for sure. The management and optimal care does not mean only medical treatment, but it is also the psychological care, the medical legal care, the social care that our patients need. And we need quite to do much more to provide daily assistance to our MPS and Alpha-mann patients in order to minimize the burden on caregivers and to allow patients to become independent and productive adults. So there's quite a lot to do still. In order to understand better the disease and also the patient's needs and the disease complications, there was the SPARKLE registry developed and established in December 2019. And at this time, 18 patients were enrolled. The registry is multi-center, multi-country, non-interventional prospective study that is including patients with alpha-mannosidosis despite any treatment. And this is important because we also get a lot of knowledge about patients that are not on treatment. And the data that is collected is from the routine clinical practice. So no further assessments needed. And the goals are to understand the treatment effect by improvement, the treatment effect by stabilization if the patient is on enzyme replacement therapy, but also the natural history of non- treated patients. The endpoints are defined as the global treatment response model. And you can see here it's the pharmacodynamic, functional, and quality of life assessments that are collected. We also collect the musculoskeletal impairment and the respiratory limitation in these patients. In terms of safety, the rate of adverse events is collected. And secondary endpoints are the IgG, IgM, IgA measurements, the hearing test, and quality of life questionnaires, the infection rate, and the psychotic rate. There's also the collection of some more rare disease complications like acute renal failure or loss of consciousness. And as I said, it is also in characterization of untreated patients. In order to take care in a proper way of our patients, it is extremely important to connect our patients to patient organizations. And you see here a map and also a link to a website where you can find a patient organization that is taking care of alpha-mannosidosis patients. Patient organizations are extremely helpful for patients in particular in such rare diseases.,because patients can share experience, that can speak with others that are affected in the same way, and so feeling more stabilized in in their arm situation. So, in summary, what do we have in alpha-mannosidosis? We have a rare genetic chronic progressive multisystemic and life- threatening disease that is quite similar in some aspects to mucopolysaccharidosis, but in a way also different. We have the psychotic episodes, the ataxia, and also the immunodeficiency that is completely different from MPSs. We know that we have to perform a diagnosis as early as possible. We need regular follow-up examinations for our patients to detect life-threatening and quality-of-life-reducing disease complications as early as possible. And there's, at the moment, Delphi methodology ongoing to understand and to standardize the follow-up assessments that we need for our alpha-mann patients. Symptomatic treatment is needed. Enzyme replacement therapy is available in some countries, but another option would be hematopoietic stem cell transplantation. Patients and caregivers need psychological, medical, legal, and social help, in particular in patients with cognitive involvement, and it is extremely important to connect to a patient organization. So, whenever you have a patient with hearing loss, recurrent infections, different appearance, and developmental delay, think not only to mucopolysaccharidosis, but also to alpha-mannosidosis. With that, I thank you for your attention. Here you see the patient that I, or who guided us through this presentation from birth to adulthood, and I thank my patient that he was giving me the chance to present him today. And with this, I open the chat and wait for your questions. So, the first question is, how does the healthcare-provided team of specialists differ from alpha-mann to MPS, as disease progression is typically slower, it is more emphasis on certain specialists for alpha-mann than MPS and vice versa? Indeed, the team is quite similar, but what is different is that we have the psychotic episodes that needs psychiatric care in our alpha-mann patient that is usually not needed in our MPS patients. It's all the psychological support that is needed in our mucopolysaccharidosis patients. The endocrinologist is discussed whether we need endocrinologists for alpha-mann patients, but due to the fact that these patients have an immunodeficiency, he would be also part of the multidisciplinary team. I think these are the main differences in the teams that are needed for alpha-mann patients. Any other question? Will all main signs and symptoms have presented and started to be treated by 18? Do new ones follow in the second and third decades? Indeed, the main focus or the main signs and symptoms in younger patients, so pediatric patients, are the recurrent infections, the developmental delay, the hearing loss. These are the more common symptoms. In older patients, so over 18, we have the ataxia that is more present and sometimes the psychotic or psychological problems. Patients that start early with the treatment have for sure a better outcome due to the fact that there are less irreversible organ damage that you can develop without treatment. But also in adult patients, we see an improvement on treatment because these patients stabilize, these patients feel better, the quality of life is improving and also a stabilization is a positive result in chronic progressive diseases. Any major side effects of ERT that we should be alarmed. As all enzyme replacement therapies, we have infusion- related reactions also in alpha-mannosidosis patients, but they are mainly mild to moderate and they are very similar to our other allergic reactions that we know. So nothing very special. Ataxia developed later. In the case you shared, 14 plus. Is this the norm or only in this type of alpha-mann? The ataxia can also develop earlier. So there are different types or severity forms of alpha-mann. So we have very severe patients that have signs and symptoms at birth and we have others that have a more mild disease and the symptoms start later. So it is extremely difficult to say that a symptom is starting always at the age of, but I would say that the ataxia is more over the age of 10 years instead of earlier. Overlapping nonspecific symptoms- herder-like signs, as you mentioned, makes it hard for general pediatrics- are the main physical signs that indicate IM at the early stages? Hearing loss, close face, cognitive decline. Actually yes, as we see it in mucopolysaccharidosis and a lot of lysosomal other lysosomal diseases, we have quite unspecific signs and symptoms that each symptom could have a very common reason. So recurrent infection at the age of two years is nothing unusual for a child that is going to the kindergarten.
[00:40:40] Dr. Christina Lampe: So I think that important is to combine these very unspecific signs and symptoms together, so it is not only the macrocephaly or the hearing loss or the hernia or the developmental delay, but it is the combination that should lead to the suspicion of a genetic disease and, in particular, in alpha-mann or in MPS patients. How can I better support alpha-mann patients and families? Psychological support, you mentioned, but how can we help in practice? I think extremely important is to be there for these patients, meaning that they have a physician that is taking care of, who knows the history- they don't have to come- and to explain the N plus one time that, what this disease means and what this disease is. I think extremely important is to follow these patients and they know they can ask questions whenever they have some questions and they have someone they trust. I think this is the most important. These patients need for sure therapies like physiotherapy, speech therapy. They need to find a good school or place to live when they are adults. So I think what we can do is to take care of these patients, to be always ready for questions and to follow up these patients in a standardized way and also- and this is why I also showed the registry today. It is extremely important to learn more about this disease, because it's such a rare disease that we don't have a lot of knowledge, and so it is, I think, also needed to learn as much as possible about the disease. So there are no further questions.
[00:42:56] Dr. Christina Lampe: I thank you for listening, for the questions and the interest for this rare diseases. Thank you very much and goodbye.