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[00:00:00] Dr Nathalie Guffon: Hello, everyone. I am happy to welcome you to the second webinar in series two, Shine a Light on Alpha- mannosidosis, about Illuminating the Patient Voice. This is an educational webinar sponsored by Chiessi in collaboration with and hosted by Excellence in Pediatrics. As the content is disease- focused, presentation will not include information on specific treatments or medication. This webinar is for healthcare professionals only. Before starting, I will give you some messages. Please do not take screenshots or reproduce any of the slides, content, or images without the permission of the speaker. We will have a question and answer session at the end of this webinar, and we will do our best to answer as many questions as possible. You can submit your question at any time via the question button. Your questions can be submitted only by text and not verbally. This webinar will be recorded and available on demand. Concerning the main learning objectives of this webinar, we will reflect on the Delphi Consensus study recommendations on practical care in alpha-mannosidosis and illustrate their implementation through care studies and discussion. We will review patient- reported outcomes on quality- of- life measures and consider how this can influence clinical practice and guide care. Then we will consider how approaches to monitoring symptoms, clinical practice, and available resources may vary, and how barriers to care could be overcome.
[00:02:26] Dr Nathalie Guffon: After this welcome and a short introduction, Dr. Can Ficicioglu will talk about personal care in alpha- mannosidosis, and I will present a case study to open the discussion. Then Dr. Christina Lampe will give a presentation on patient- reported outcomes on quality of life in alpha- mannosidosis. Finally, we will have the question and answer session at the end. Please do not forget to ask your questions througout the webinar via the question box. Now it's my pleasure to introduce my colleagues. We are all involved in inherited metabolic disorders and lysosomal storage diseases. Dr. Christina Lampe comes from Gießen in Germany, Dr. Can Ficicioglu is from Philadelphia in the United States and I am Nathalie Guffon from Lyon in France. Here are our disclosures. Now let me briefly summarize what we learned in Webinar 1 last week.
[00:03:44] Dr Nathalie Guffon: We have heard that alpha-mannosidosis is an ultra-rare underdiagnosed lysosomal storage disease caused by lysosomal enzyme alpha-mannosidase deficiency due to pathogenic variants in the MAN2B1 chain. We have learned that alpha-mannosidosis is a progressive multisystemic disease with heterogeneous symptoms and a continuum of clinical severity ranging from severe to attenuated phenotypes, and that it is very important to distinguish the severe form from the attenuated ones. We have heard that the wide range of clinical manifestation places a high burden on patients and caregivers. The overlapping nonspecific symptoms and the lack of awareness among health care professionals can lead to delays in diagnoses and contribute to further the patient and caregiver's burden. Then, we have discussed key red flags for alpha-mannosidosis. Clinical features include macrocephaly with some cross-facial features that can be very subtle, hearing loss, recurrent infection, learning difficulties, develpmental delay and motor impairment, especially balance, coordination, and fine motor disturbances. Radiographic features may include asymptomatic disostosis multiplex and later focal lytic or sclerotic lesion, osteonecrosis, and osteopenia or osteoporosis. Sometimes hematologists can phone you because of vacuolated lymphocytes on a sample for urinary oligosaccharides show an increase in mannose-rich oligosaccharides. Affected siblings and parental consanguinity can also be an orientation element. Then, we have discussed the rationale and objectives of the Global Delphi Consensus. This consesus provides the first best practice guidance for its care providers on three care areas of disease management, assessment in newly diagnosed individuals, routine follow- up care, and treatment- related follow- up. Now, I would like to hand over to my colleague, Dr. Can Ficicioglu, who will present the Global Delphi Consensus recommendation for monitoring and care in alpha-mannosidosis with an emphasis on a personalized approach.
[00:06:51] Prof Can Ficicioglu: Thanks very much, Dr. Guffon. Hi, everyone. In this part of the presentation, I will provide you with guidance on how to follow up patients with diagnosed alpha-mannosidosis. So, let's move to the next slide. Okay. So, hearing loss, as you may all know, is one of the red flags for lysosomal storage disorders, and especially when you see a patient with hearing loss and a few other symptoms, such as developmental delay, developmental regression, or coarse facial features, or hepatosplenomegaly, hernias, or recurrent respiratory tract infections, it's important to suspect lysosomal storage disorders, including alpha- mannosidosis. So, hearing loss is a common symptom of alpha- mannosidosis. The majority of patients develop hearing loss, severe or moderate, at some point in their lifetime, and most of the time it is a presenting symptom. So, how do we follow up, monitor patients' hearing function? So, as I said, hearing loss is a common symptom of alpha-mannosidosis , so it is very important to monitor patients for hearing function regularly. So, we do recommend audiology evaluations every one or two years. If you have a pediatric patient with hearing loss and bearing hearing aids, those patients should be monitored every six to 12 months by an audiologist. And both pediatric and adult patients should have regular ENT evaluations. In many countries, audiologic evaluations and ENT visits are combined, and patients should be seen by ENT for routine evaluations with otoscopic evaluations and hearing tests every year, and more frequently as needed. Patients with alpha- mannosidosis also have frequent infections. We know that a weakened immune system and immune dysfunction is a common finding in these patients, and these patients may be at high risk for bacterial and viral infections and frequent respiratory infections, gastrointestinal infections and it is important to monitor these patients for infection throughout their lifetime. We also know that pediatric patients are prone to this type of frequent infections more commonly. When they get older, the frequency of infections actually gets less. How do we monitor immune function in patients with alpha- mannosidosis? So both in pediatric and adult patients, it is important to do some routine laboratory assessments once a year, and we listed them as complete blood count, erythrocyte sedimentation rate, and immune workup. These patients should be monitored for infections, and additional evaluations and testing should be done as needed. These patients are at risk for autoimmune disorders, such as autoimmune thyroid disorders or systemic lupus erythematosus. When there are signs, symptoms of these autoimmune disorders, it's important to refer those patients to immunologists or rheumatologists for further assessment and follow- up. Patients with alpha-mannosidosis should receive their vaccinations. Every year, they need to get influenza vaccine. If they have lung disease, pneumococcal vaccine is also recommended. If we go to the next slide. So in this slide, we discuss patients' psychiatric manifestations. About 25% of patients with alpha-mannosidosis present with neurobehavioral and psychiatric manifestations. Psychiatric manifestations is actually more common in late puberty and early adolescent years. It's really important to monitor these patients for these type of symptoms, and sometimes there are physical or psychological stressors that trigger a rapid onset of symptoms, such as confusion, delusions, hallucinations, anxiety, and often depression. It is important to ask certain questions and monitor behavioral problems, psychotic episodes, depression, insomnia, anxiety, hallucinations, and delusions, confusion, aggressive behavior, hyperactivity. So these are the common symptoms that we see among psychiatric manifestations in this disease. So these are the recommendations for behavioral and psych manifestations. In pediatric patients, every one or two years, it is important to assess psychiatric manifestations using certain tests. Child behavior checklist is one of the recommended tests in the Delphi consensus study. Both in pediatric adult patients, assessment of psychiatric manifestations based on patient history or using certain tests, such as general anxiety disorder assessment or EQ5D5L or adult self-report questionnaires are important. In different countries, different tests may be used. Pediatricians or geneticists may not be familiar with this type of test. I think it's important to work with a psychologist or neuropsychologist to perform this test every one or two years. Again, patients who have psychiatric symptoms, it's important to refer those patients to psychiatrists or psychologists, and brain imaging may need to be done as needed in these patients. Alpha-mannosidosis also cause CNS symptoms. Cerebellar atrophy, the myelination of the brain, is common, and muscle fiber degeneration can also occur. It is important to regularly monitor potential neurologic symptoms. Ataxia is a common neurologic symptom, falls and changes gait, cognitive impairment, developmental delay or regression, intellectual disability, hydrocephalus, seizures, hypotonia, headaches, are common neurologic symptoms.
Both in pediatric adult patients, physical and neuro exams should be done every year to assess CNS manifestations of this disease. Head circumference is recommended for pediatric patients. Brain imaging or EEG should be done as needed in both in pediatric and adult cases. Patients with alpha mannosidosis are also at risk for pulmonary involvement. There are a few papers published on that, and in one paper, three out of five patients developed parenchymal lung disease, and all five patients had abnormal pulmonary function tests and reduced peak oxygen uptake. In another study, they identified pneumonia as the primary cause of death in individuals with untreated alpha mannosidosis. So lungs can be affected in this disease. So important to monitor respiratory functions at every visit. Important to rule out respiratory infections and look for them. Sleep could be impaired, so important to ask questions about that. Shortness of breath, exercise intolerance, or reactive airway disease questions should be asked. So a pulmonologist is an important team member in the care of these patients. We recommend pulmonary function tests in pediatric and adult patients every year, and more testing should be done, such as sleep study, or if there is a respiratory infection, more workup should be done to understand, to diagnose and treat those respiratory infections. So like in many other storage disorders, eyes are also affected in this alpha mannosidosis cases. As you see here, patients may have optic neuroprophy, strabismus, abnormal eye movements, nystagmus, less opacity, retinal degeneration, and corneal haze. And important for these patients to be seen by an ophthalmologist. So it is important and recommended these patients be seen by an ophthalmologist every year, and both general ophthalmologic exam, including retinal and slit lamp examination, should be done. And of course, if patients have symptoms, every six months or more, a follow- up is needed. Heart is another organ that is involved in this disease. So valve abnormalities, such as aortic regurgitation, stenosis, or mitral stenosis, or regurgitation, are seen. And dilated cardiomyopathy has also been reported. So we do recommend these patients be seen by a cardiologist every two to three years. And echocardiogram EKG should be done. As needed, cardiac MRI can be done. If patients are at risk or if there is concern for cardiac arrhythmias, whole- term monitor may need to be done as well. So I think these are all points that I wanted to make. Dr. Guffon, I think you are taking over at this point.
[00:18:09] Dr Nathalie Guffon: Thank you so much. This is a story of a boy who is the third chid of non- consanguineous parents. He was born after normal pregnancy and delivery with normal clinical examination. His medical story begins with recurrent otitis and renal pharyngitis since his first months of age and finally led to adenoidectomy and T- tube placement at 21 months of age with no clear improvement. He developed speech delay and was diagnosed with hearing impairment at two years of age. Parents reported musclar weakness compare to other children He was able to walk at 18 months but remained clumsy. A mucopolysaccharidosis was suspected at two years of age because of ENT manifestations associated with progressive macrocephaly, some cross-facial features, and accelerated growth velocity during the first years followed by a decline. Next, please.
[00:19:44] Dr Nathalie Guffon: Urinary GAGs were normal and ruled out the diagnosis of mucopolysaccharidosis. Urinary oligosaccharides shows a typical pattern of alpha- mannosidosis with elevated mannose- rich- oligosaccharides and the diagnosis of alpha- mannosidosis was confirmed at 2 years of age. He has regular follow up and during his early childhood he had recurrent ENT infection with spontaneous otorrhea every two weeks requiring multiple antibiotic treatments and repeated T- tube insertions. He began with speech therapy at 3 years of age and required hearing aids since age 5. He was hospitalized and treated with antibiotics for several months for septic arthritis of the right knee at age 12. Despite my learning difficulties, he attended normal nursery and elementary school. During his childhood, he started wearing glasses at age 7 because of hypermetropia with strabismus for which he had surgery at age 9. He continued to suffer from recurrent ear infection and had a bone infection of the right scaphoid at the age of 10. the age of 14 years. He had some difficulties in school and social life because of clumsiness, abnormal gait, balance problems, coordination difficulties and slowness. In adolescence, despite some motor difficulties, he was able to ride a bike, play ping pong, ski and swim. At the age of 13 years, he He repeated his 8th grade, then tried 9th grade at a technology school high school followed by horticultural training but failed to be a graduate. At the same time, he developed anxiety attacks, periods of depression due to difficulties with school and relationships. He continued to suffer from ENT complications with cholesteatoma and had a left tympanoplasty at 14 and the right one at 15. He also presented recurrent urinary infection complicated with renal lithiasis crisis with hospitalisation at 14 and 16 years of age. At 15, he was hospitalised for ulcerative gastritis. Next please. Finally, he left school at the age of 18 years and worked at his village council for 18 months on a solidarity employment contract. He had trouble with temporal spatial orientation, difficulties with attention and memorisation, fatigue, slowness and the loss of school level which was evaluated in 4th grade. At 21 years of age, he had his first psychotic acute crisis with hyperactivity, visual and verbal hallucination, hetero agressiveness, running away, mood disorders with alternating laughter and crying. All medical examinations including brain and spinal cord MRI were normal. He was hospitalized in a psychiatric unit for 3 months. At 22 years of age, he worked in a work assistance establishment for 2 years but had to stop because of a psychotic crisis. He had a new urinary infection with lithiasis crisis at 25 years of age and was also hospitalized for a basal pneumonia at the same age. Next please. He also developed lower back pain with sciatica episodes and shoulder stiffness. As a young adult, he was socially isolated. From 24 years of age, he went to an occupational establishment one or two days per week with integration difficulties. Despite the psychiatric medication and follow- up, he had four acute psychotic episodes at 23, 24, 25, and 27 years of age. He had to be hospitalized again in a psychiatric unit at the age of 24 for two months and at the age of 27 for four months. He was under guardianships, he lived with his parents and could not sleep outside the parental home because of his psychiatric status. He started enzyme replacement therapy at 28 years of age. He reported, and his parents reported also, no more significant infection and improvement in well- being with reduced pain. He has no more psychotic disorders with a progressive decrease of his psychiatric medication and no more anxiety or depressive crisis. His social integration improved, and he participates in occupational activities with others. He sleeps two or three nights a week in a home for disability adults. His entourage noted better autonomy in daily life. He has less need for medical and paramedical care, with only a nurse for home infusion and yearly visits to my center for multidisciplinary follow- up. Tolerance is good without any treatment related reaction. He is now 39 and a half years of age. He has no stereoarticular complication. His pulmonary function remains almost normal with a forced vital capacity 77%. Cardiac evaluation is completely normal. He is able to walk 480 meters in six minutes and climbs all the stairs of my hospital in less than three minutes. His psychological status is good. His cognitive abilities are better probably because he is in better health and no longer has psychiatric disorders with only a very low dose of neuroleptic. He has no longer any notable infection with normalization of his immunoglobulin G levels. Next, please. Now, we will discuss how care is adapted in daily practice for alpha- mannosidosis patients who may have different needs, different symptoms, and different situations. So, Christina, do you want to start?
[00:27:33] Dr. Christina Lampe: Thank you very much, Nathalie. I think it shows quite well that it is a disease progression and that we have different ages with different symptoms that are in a focus at this moment. So, what we have to do is really to adapt our management to the age and also the individual disease that the patient is suffering from. Yes, I totally agree with you. Do you want to add something?
[00:28:07] Prof Can Ficicioglu: Yeah, I think this case is really very interesting and it shows us the whole picture. Almost 40-year-old patient, we kind of see the general course. The most striking is that the psychiatric manifestations, I think it is really important to emphasize that this disease can cause some psychological issues. It is important to monitor it very closely. And that part is, I think, quite striking to me. And each individual is also different. I think we talked about different organ involvement and so forth. Not everyone gets the same degree of severity in all organ systems. Some patients have different, I think, involvements. For example, in this case, heart is perfectly normal. It seems to be lungs are kind of normal as well, right? But the frequent infections, I think, quite striking too. So, he had multiple infections.
[00:29:02] Dr Nathalie Guffon: Yeah, exactly. And I think also it is very important to have multidisciplinary team for the follow up of this patient and to check very, very attentively each organ that may be involved in the disease.
[00:29:26] Dr Christina Lampe: But it's also a very typical case, Nathalie a very typical case, from the disease progression I guess, so with the earliest signs and symptoms that are with hearing loss and recurrent infections. So the development of the disease progression is very typical I guess. So it's a very good illustration of alpha- mannosidosis.
[00:29:50] Dr Nathalie Guffon: Yeah, I think it's an illustration of this boy has a chance to be diagnosed very early and to be followed, so we have all the picture of the progression of an attenuated form of the disease do it is not so attenuated. Now we will continue and Christina will speak about patient- reported outcome and quality of life in alpha-mannosidosis.
[00:30:18] Dr Christina Lampe: Thank you, Nathalie. Yeah, we saw also in your case that you presented the burden of the disease and the question is always how can we measure this disease burden and how can we understand the disease burden not only on the patient but also on the carers. Next slide, please. So, if we see the broad spectrum of clinical manifestations in our alpha-mannosidosis patients, we see that they have a high burden on not only patients but also the caregivers. The individuals with alpha- mannosidosis usually have complications or difficulties with ability to work or study and impaired mobility, which is one main complication of the disease, but they also have difficulties with self- care, sleep quality. They have a big impact on their psychological life and also pain is an important factor. If we see the caregiver's point of view, we see that social life is affected with financial burden, impact on relationships, ability to work also for caregivers and also depression, anxiety and stress is one part of the burden of caregivers. So, what are patient- related outcomes? What is the impact of patient- reported outcomes for our patients? And actually, they provide the patient's view about symptoms, severity, function, psychological problems, treatment satisfaction and so health- related quality of life. And they are directly obtained from a patient or caregiver, so they are without any interpretation by a clinician, which is extremely important. But due to the diverse nature of this rare disease, it makes it really important to track an individual's natural history and the extent to which their health and social care needs are changing. Also the loss of autonomy that are experienced by our patients can negatively impact their quality of life, but nevertheless, it is extremely difficult to collect patient- related outcomes routinely because there's a lack of patient- related outcome measures that are validated for alpha-mannosidosis and also for children and adolescents, so it is not that easy. There's one study that was performed in UK in nine individuals with alpha-mannosidosis and it showed that those patients with the least mobility had the lowest EQ5D5L utility values, indicating a lower health- related quality of life than those with more mobility, which means actually that the reduced mobility had a direct impact on their ability to undertake self- activities. And this can be seen also here in this scheme that the patients with mobility or low mobility have also complications with self-care and usual activities, but also anxiety, depression, pain and discomfort are playing a role for our patients. So how can we monitor now this patient- reported outcomes and the Delphi recommendations and Can has already mentioned it. It is important to monitor regularly school and work performance, disease burden, quality of life, motor skills, cognitive skills, difficulties associated with hearing loss and social competence. It is not that easy to find good measurements as already said but possibility is to ask direct questions to the patients and carers about school, work, social interactions, daily activities and overall well- being. Measurements that can be used and are already used in alpha-mannosidosis patients is the EQ5D5L questionnaire or HAQ and these responses may be collected by a proxy if needed and this should be performed in pediatric and adult patients every year. Concerning the caregivers quality of life and well- being there it is recommended to ask questions about physical and psychological health, the impact of caregiving on daily activities and social activities and this should be performed in adult and pediatric patients every year as well. So and to show that sometimes the burden of the disease and also the burden of the regular monitoring of the disease is an issue in our patients I would like to present two female twins with a mild cognitive impairment. They were quite late diagnosed due to an alpha-mannosidosis affected younger sister so they were 18 years of age when they were diagnosed living with their parents and they started treatment at this age first six months in hospital and then they moved to home treatment. If we look to the decision why we started treatment in these patients actually they had a mild cognitive involvement so they attended specialized schools for handicapped people. They had a speech delay and psychomotor developmental delay when they were younger and an hearing loss at the age of two and a half years and they began using hearing aids at the age of four years. They were suffering recurrent infections but no psychosis by now although they showed a severe fear of animals including in comics. Non- clinical characteristics that suggest the patients are appropriate for treatment were that the seven years old sister with alpha-mannosidosis had been undergoing treatment for one year with very good results. So the clinical observations included fewer infections very similar to Natalie's case, improvements in endurance and agility and fatigue and no tolerability issues were reported in the younger sister. How did we manage and monitor these patients? The challenge with managing and monitoring these two twins were that the mother was not willing to perform many follow-up assessments due to the fact that the younger sister is treated in a different center and she did not want to spend a lot of time with the three affected children in hospitals and one sister of these twins suffered from psoriasis and recently experienced an acute episode and had even more time in hospital for visits. So how could we overcome these challenges? And actually, we started to perform, well, we asked the family to perform some assessments close to home. The core assessments were reduced to a minimum, so six-minute walk test, pulmonary function, medical history, blood tests, and hearing tests. This were performed in the multidisciplinary care in our hospital. We measured the health-related quality of life. We re-evaluated the patients every six months. And for the sister with the recent acute episode of psoriasis, we started the treatment with premedication to avoid any infusion-related reactions. So our final or clinical observations in these two girls was that they were less fatigued and more active. This was reported by the patient, but also the mother. They had an improvement in concentration, and they had no tolerability issues, as I already mentioned. And this is actually in line with the study on health- related quality of life in alpha-mannosidosis that found trends of improvement in EQ5D5L, and ΗΑQ scores, as well as an improved pain and disability following up to 48 months on treatment. So I think it was, from my point of view, a good decision to start these two on treatment.
[00:40:48] Dr Nathalie Guffon: Yes, exactly. I think I have to do the same. So now, thank you so much for this presentation. I think we all agree that it is very important to report patient and caregiver outcome and to measure quality of life. But in this population, we may have some challenges, and how can we overcome them? Do you have some recommendation to give?
[00:41:24] Dr Christina Lampe: I think my slides showed that it is extremely difficult to find a really fitting patient-related outcome questionnaire or quality of life questionnaire for our patients. First of all, because we don't have a clear patient-related outcome for this disease in particular. Second is we have different age groups. We have different disease severity. So it is quite difficult, but nevertheless, it is important at least to collect what we hear from patients. So about school, about pain, about depression, although we have no good instrument for that, at least to collect all this information and to see in the follow-up if there's some changes.
[00:42:19] Dr Nathalie Guffon: Yes, I agree with you. Do you think, Can, that we may have the possibility to work and to try altogether to have an international specific quality of life questionnaire for our patients, or it's not possible?
[00:42:49] Prof Can Ficicioglu: I think it is very important. We struggle to develop and validate disease-specific PROs, unfortunately, for many different diseases, but it is really important to choose one, and I think we need to do something because patient-reported outcomes are very important, and we use patient-reported outcomes in clinical trials as certain endpoints and not primary, but it definitely helps in rare disease drug development. So patient-reported outcomes are important. I think it's very important to work as a group internationally and develop something for maybe storage diseases, because there's overlap with some disorders, and important, I think, to focus on what domains are mostly affected, and then what, and important to develop something based on those domains.
[00:43:51] Dr Nathalie Guffon: Yeah, yeah. So we have to work and to find a solution also for cognitively- affected patients. It's another challenge. So, sorry, but we have to move to the question and answer session now. Just before, I have to give the information that every webinar in these seriers is accompanied by an infographic that is available to view alongside the on- demand video.
[00:44:22] Dr Nathalie Guffon: Next please. So now we can start. Please ask your questions if you have some. If not, maybe we can continue to discuss about the payroll or quality of life. For the moment there is no. See there is one question. Are there there any patient-reported outcome or quality of life tools or questionnaire that are tailored to alpha-mannosidosis?
[00:44:54] Dr Christina Lampe: I will start. I think unfortunately not. But this is our problem in such a rare disease. It is extremely difficult to validate questionnaires and then also to different pediatric ages and also adult patients. But I think that the EQ5D5L is a good measurement. At least it gives an impression and also the shock is a good tool to measure patient related outcome or quality of life in our patients.
[00:45:35] Prof Can Ficicioglu: I think at this point all physicians should choose one whatever is best in their you know country and easily accessible. But I think it is important to establish a work group to come up with something. It will not be perfect but at least it could be more disease specific something. But the question, the answer is unfortunately we do not have specific from alpha-mannosidosis. No.
[00:46:09] Dr Nathalie Guffon: No we have not. The check is more functional questionnaire that quality of life. I think it's more functional and for quality of life or for anxiety or something like that. Yes we have the 5Q but if possible I think it will be better if you may have some help to try to do a more specific questionnaire for our patient. Because we each ask probably the same question to our patient because we want to see what happens in each area. But we report what the patient say but it's not completely self- reported because more or less we have some idea or maybe. So it's not completely self- reported. So it will be fine I think to be able to work but it's got many money to work on a specific tools for this patient. But we don't have now. So for the moment there is no. How can we capture quality of life data when self- reporting is difficult? So Can do you want to start?
[00:47:39] Prof Can Ficicioglu: I think you know self-reporting is difficult I think but the majority of these patients come with caregivers. I mean in pediatric ages I think we depend on mothers and fathers. So I think if you really want high quality data important to ask the same question maybe the same person, the same caregiver. Sometimes we do differences in different caregivers but most of the time I think we collect it through you know family members mostly you know mothers and fathers.
[00:48:16] Dr Nathalie Guffon: Yes it's very important for this disease or for patients who It's very important to discuss with them of the patient. When should anticipatory care planning to the long term be discussed with patient and family at what stage of disease progression?
[00:48:45] Dr Nathalie Guffon: I think it's probably like other progressive disease. In my experience I think I will discuss this, in patient, in the very late stage of the disease and with some maybe severely cognitively impaired or bedridden, or with some very end disease stages. But it is a very slow progression of the disease so I think will be too difficult to anticipate too much.
[00:49:26] Dr Christina Lampe: I totally agree. It also makes quite a lot of concern to caregivers if you discuss the end of the disease or the progression. And you never know, I mean some patients are getting very old, other patients have more complicatioins. So I think all these, problems or discussions about progression of the disease must be discussed very carefully because we never know. Each patient is really individual and different
[00:50:04] Prof Can Ficicioglu: and especially these patients are living much longer. Now it is really important to also focus on the adult transition and that it becomes extremely important to have neurocognitive testing in these patients to see what their ability is and how much they can do for themselves or at what point, you know, when they turn to 18 and over and then who will make the medical decision making and others. The neurocognitive testing is really important.
[00:50:38] Dr Nathalie Guffon: Are any practical support resources available for individuals and their family. I think it depends on each country. So, do you want to, Christina? Do you want to start for Germany?
[00:50:51] Dr Christina Lampe: Well, yeah, it's actually quite difficult. I think worldwide there are patient organisations that are extremely helpful and supportive for families and patients because they can connect to other affected families, they get information about treatments and so on. But I think this is something very general and extremely important. The other hand, in Germany- and I know also in other countries in Europe- it could be better, so all the support systems could be better. There's, for example, a lack of psychological support in many European countries, but nevertheless, there are social workers, there are psychologists, there are homes for handicapped people, schools for handicapped children. So there are some structures. But I think at least in a big study that we SurveyMonkey, that we performed two years ago for metabolic diseases, we learned that there's quite a lack of support that would be needed. But how is it in the US?
[00:52:03] Prof Can Ficicioglu: I think when the disease is ultra-rare, it is extremely difficult to establish those resources. Sometimes we use the resources provided by MPS Society here in the United states. We use those resources for these patients as well. There's a very small group in the US, but I think there is an international group and the patients sometimes take part in it. These are family support groups. How is it in France? Is it different?
[00:52:37] Dr Nathalie Guffon: It is more or less the same as in Germany. We have two different parent associations, so some support for this. We have also a school for disability people and also on some management for walking or something like that. So most difficult is with psychologists for psychomotor home management or ergo therapies or something like this, because because there is a financial issue for the family because it's not covered by the social security, so it may be difficult and not the same for each family and the family in poor situation. It's more difficult for them.
[00:53:26] Prof Can Ficicioglu: One thing I would like to add, Christina mentioned that that family with twins and another seven-year-old struggles to go to multiple appointments. In our center, we try to do multidisciplinary clinics, so we bring physicians to those clinics and patients see multiple physicians on the same day instead of scheduling multiple appointments and go to see each on different days. So it kind of helps if there are resources available.
[00:54:00] Dr Christina Lampe: We do that, but we also have to take into consideration that a lot of appointments with a lot of waiting time in between is quite exhausting for patients and they are sometimes not able to manage more than three or four appointments a day. Although, and in addition, they don't live close by the center, so they also have to travel to the center. They have a lot of assessments that are tiring and then they have to go home a long distance again. So we try to do that as best, but in particular, MRI or something, assessments that take longer, the family is a little bit distant from that because they have to stay maybe in hospital for a night and they don't want. But I agree. I mean, the more we collect and do these things in one day, the better it is.
[00:55:03] Dr Nathalie Guffon: Yeah, it's just the same for me. I try to do all the appointments in one day, but it's the same. When we have too many exams we have to perform it in two days. So we generally, we perform it two following days and the parents stay near the hospital. We have a home for parents and or caregiver and patients, not in the clinic but in the same place. But it is too difficult if we want to perform all the appointments in one day, it's too much. But it's good for hearing, physiotherapists, orthopedics, cardiologists, if we want to perform punitive tests or MRI or some functional evaluation, it's not possible. We need at least two days, two different days. So there is another question. Ataxia and hearing loss always together, appears at the same time? No.
[00:56:09] Dr Nathalie Guffon: Clearly no. The first symptom, maybe we are not clear, but the first symptom is hearing loss. And there is very often in a child with no language, hearing loss, or speech delay, we can find some mild motor disturbance, but it's very sometimes very very mild. It may be only some clumsiness or some balance or coordination problems, but not seen in in daily life. It needs some time for them to perform some exercise and ataxia is more in adult and it's a late stage of the disease. I think we have to distinguish ataxia, mild motor and balance or coordination problems. I think.
[00:57:12] Dr Nathalie Guffon: Any dietary advice for patients? Managing intake of carbohydrates.
[00:57:21] Prof Can Ficicioglu: No, I think there is no dietary management.
[00:57:28] Dr Nathalie Guffon: There is no dietary management for the disease. Sometimes it may be necessary to give some advice for patients who have many diarrhea or for patients who are overweight. There is some patients who eat too much with alpha-mannosidosis, like for some lysosomal, but we have to give them some advice, but there is no dietary management for the disease, like for PKU or something like that. I think we don't have more questions, so I have to close this webinar. So I remind you to complete the feedback survey because we need to have your opinion.
[00:58:28] Dr Nathalie Guffon: I also remind you that the webinar will be available to view on demand and I would like to thank the audience for attending and participating and the speakers for their presentation and the discussion. So, goodbye.