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[00:00:04] Dr. Caroline Sevin: Good morning, my name is Caroline Sevin, I am a paediatric neurologist working in near Paris, and I am the head of the reference center for leukodystrophies, and particularly involved in metachromatic leukodystrophy and also other leukodystrophies, and I'm also involved in my research part in trying to find a new therapeutic option for this disease. So in this webinar I will particularly speak about the early signs of MLD, metachromatic leukodystrophy. Just on these slides it is indicated that you should not take any screenshots, and the format of the webinar I will speak during around 20 minutes, and you will have the opportunity to ask a question through the chat, and I will answer the question at the end of the chat. Metachromatic leukodystrophy is a lysosomal storage disorder. It is a relative frequent disease among rare disorders and it is an autososomal disease that is due to the deficiency of the arylsulfatase A enzyme This enzyme catalyzes the degradations of sulfatase, which are myelin components, which are big lipids, particularly important and in a high level in the oligodendrocytes, oligodendrocytes being the cells that produces the myelin. And this accumulation of sulfatase leads to the myelination in the cental and peripheral nervous system which you can observe we just put the laser, we didn't do it, okay. You can see on these slides, and particularly on this brain MRI,the leukodystrophy, Just a few words on the pathophysiology of this disease. As explained, there is an accumulation of sulfatides mainly in the myelin forming cells, which are oligodendrocytes, and that leads to a degradation of the myelin. But these sulfatides are also accumulated in other cell types, like neurons, and also astrocytes, and microglia. And the combination of all these features leads to the neurodegeneration and also neuroinflammation, in addition to demyelination. There are several clinical phenotypes of the disease. The disease can occur from around one and a half year of life, that is early onset forms, and until adult holds. And we can globally classify this disease in two forms. The early onset forms, with an onset between one and six years. In these early onset forms, there is a motor impairment followed by a cognitive impairment, leading to very, very rapid degradation, and complete loss of motor and cognitive function. Then vegetative states, and premature death. And for these early onset forms, once the children are already symptomatic, there is no curative therapy.
[00:04:07] Dr. Caroline Sevin: When the children present very early on set of the disease ex vivo gene therapy, and we will say a few words about this new treatment, is able to significantly modify the disease. The late onset forms have onset after six years and they are more heterogeneous in terms of age at onset, in terms of evolution, in terms of severity. They are more progressive and for this disease hematopoietic stem cell transplantation, allogenic hematopoietic stem cell transplant, may be an option. The diagnosis of the disease is based first on clinical symptoms and when you have these clinical symptoms- and we will see the early onset symptoms- you can confirm the diagnosis first doing a brain MRI which shows leukodystrophy. But MRI can be normal at the beginning of the disease. You have also signs of peripheral nerve involvement that you can measure through the nerve conduction velocities and the biochemical diagnosis is based on the low arylsulfatase A activity and increased sulfatiduria. Of course exams should be performed to confirm the diagnosis. Of course you will do the molecular testing to llok at the mutations in the ARSA gene. The mutation will look to perform the genetic screening which is very important for this disease. What we can say is there is globally a low correlation between the clinical phenotype, the level of ARSA activity, the mutations and the brain MRI relations. Except for the early onset forms particularly the late infantile form which occurs between 1 and 4 years. Therefore, in this disease most of the level of ARSA activity is very low. Whereas, for the later onset forms there may be residual activity. When you look at the brain you can see these hyper T2 lesions that you can see here which are diffused, symmetric and confluent, most of them occuring in the posterior part of the brain and then expanding to the whole brain but it can start everywhere in the brain. In the evolution of the disease there is an important atrophy of the brain. And you can see in this picture the typical aspect of radial stripes with a trigoid aspect reflecting most storage of material in the white matter and maybe presence of preserved myelin. As I said before, we should be very careful because even if you suspect the diagnosis at the moment, at the early phase of the disease, MRI can be considered as normal. So it should not exclude the diagnosis. If you have a normal brain MRI, you should do the biochemical tests. This is a representation of the evolution of the disease. In the patients there is first what we call a pre- symptomatic phase, with a normal development, motor and cognitive development, and then there is sort of stagnation of the acquisitions and that we call the early symptomatic phase of the disease and this phase is followed with rapid degradation, particularly in the early onset forms, very, very rapid degradation and then a sort of plateau. But at this moment the children are severely affected with loss of most of the motor and cognitive function. What we can see is most often, when the diagnosis is performed, we are already at the symptomatic phase, with a rapid degradation, and at this moment we can think that it will be difficult to find a treatment able to stop the disease at this time. And that's the reason why, because of the new treatment- and we will speak about that- it is very, very important now either to be able to detect the patient before the onset of the disease or at least at the very early phase of the disease. Because what we can do now, we can try to prevent the disease, we can try to attenuate the evolution of the disease, but up to now we cannot repair and if we have this child at this moment, there is already a destruction of the myelin in the brain and today it's not possible to be able to cure that of course. So what is MLD today? MLD is a rare disease, but it's one of the most common leukodystrophies, so it's not a so rare disease. It's a disease with a dramatic evolution, with three phases, progression, normal progression, stagnation, regression, and it is a disease that is diagnosed too late, and in terms of therapeutics, in the early onset forms, once the symptoms are present, there is no therapeutic option. For the late onset forms, which are more progressive, which progress more slowly, hematopoietic stem cell transplantation may be an option, but only if performed very early, and even if performed very early, we know that this treatment may only slow down the disease or modify the natural history of the disease, but cannot cure the disease. In patients with early onset forms, ex vivo gene therapy, which is this new treatment that we will speak in the next slides, may prevent or significantly attenuate the disease if performed before the onset of symptoms, or in the early juvenile form, performed before and or at the very, very, very beginning of the symptoms. So even if this treatment exists, it must be performed very, very early, and thus it is crucial to detect now, today, it is crucial to detect MLD, either pre- symptomatically, or as soon as the first symptoms occur. I will just say a few words about ex vivo gene therapy, because maybe you are not familiar with this kind of treatment. What is based on this treatment is an autologous transplant of genetically corrected cells. It means that you take the hematopoietic stem cells of the patient, which are deficient, in the laboratory, you correct these cells with a viral vector, which is an antiviral vector, and you will re- administer the cells to the patient through intravenous injection. And before this injection, of course, you have to do a myeloablation, just to empty the bone marrow, and so that the new cells which have been transplanted may go into the bone marrow and and do their job. In fact, their job is to do all the blue cells, and a part of these blue cells, from the white blood cells, will go into the brain and will be able to produce the deficient enzyme and secrete this enzyme that will be endocytosed and will be recaptured by adjacent cells. And through this mechanism, you can correct cells in the brain, including your neurons, including oligodendrocytes, and so on. And the second mechanism of this treatment is that you do a hematopoietic stem cell transplant. It means that you make a reset of the immune system, and as I said at the beginning of this talk, that MLD is also an inflammatory disease. Changing the immune system may also have an effect on the disease itself. And that was the principle of this disease, and there have been some clinical trials in the past years that were performed in the pre- symptomatic late infantile patients and in pre- symptomatic and early symptomatic early juvenile patients. And what the research shows is that this treatment has a significant effect, not only on survival, of course, but also in the capacity to prevent motor and cognitive function. You can see in this slide first that the treatment is able to restore a normal activity in the cerebrospinal fluid. You can see on this graph. You can also prevent the motor disabilities. This is based on the condition of the motor score and the normal range is 100, but you can see that in the patients that are treated, who are treated with the treatment, you are able to maintain this normal motor function in comparison with the gray box, which corresponds to the non- treated patients who completely lost their motor functions. And it is the same when you look at the cognitive function. Here you are the normal curve, which is in gray, and you can see that the treated patients, either late infantile or early juvenile, are able to follow the normal evolution in terms of cognitive function, whereas the untreated patients are very low level in cognitive functions. So this treatment is now available. There is an authorization from the European Union and this treatment is now available in some European countries, including France, and now it means that now you can treat early pre- symptomatic patients or, in certain countries, early symptomatic, early juvenile patients. And that's the reason why now it is very, very important to detect this disease very early. When you have no treatment, it's not so important, but when you have a treatment, it's very, very crucial. On this slide, you can see globally the natural history based on the paper by Kelver and all, and you can see that in the early- onset forms, the first symptom is most often a motor symptom, whereas in the late onset forms you have most often cognitive symptoms as the first symptom of the disease. That's the case for the late infantile and also the adult forms of the disease. In terms of evolution, you can see on this panel, this is a motor score, which is named GMFC MLD score, ranging from 0 to 6, 0 being a normal motor function and 6 being loss of any motor function, including loss of head control. And you can see that these are the different types, different forms of MLD. You can see that when you have the late infantile form, there is a very, very, very rapid degradation of the motor function. When you have an adult form on the opposite, it is more progressive for adult forms and late juvenile, and the early juvenile are globally the same curve of degradation than the late infantile form, but the beginning of the symptoms occurs later. So that the global representation of this disease, in the early- onset forms, motor symptoms are most often the first symptoms even after there is cognitive degradation. And in the late- onset forms, there is mainly cognitive signs as first symptoms for the motor degradation. And I would just say a few words of a recent study that we have performed recently, because, of course, as you know, if we had the possibility to screen the babies at birth to see if they have the disease or not, you would not have to diagnose the disease very early, because newborn screening will allow that. But at this moment, we don't have this newborn screening, and it's very important to try to have the first, first, first symptoms of this disease. So our study was focused on the very, very, very first symptoms and it was a retrospective study on 80 patients. And what we observed, so there were 64 late infantile patients, 12 early juvenile patients, and five late juvenile patients. So it's a French study. In terms of repartition, we confirmed that the most, most, most frequent form is the late infantile that occur in around 80% of the patients. The first thing that we looked at was if this. diagnosis in the index case allowed to diagnose the disease in younger siblings. And we have 30 siblings that were screened among our patients, 55% of the index case had a younger brother or sister that we could screen. And that allowed us to screen nine babies, nine younger brothers or sisters who were affected by the disease. And these patients were able to have an early treatment and more recently, three of these patients were able to have the Gene Therapy, ex vivo Gene Therapy with very very good results. So it's very important to, it's an emergency to screen the younger brother or sister if they are, because this younger brother or sister may have a treatment today, whereas unfortunately when you make the diagnosis in a symptomatic late infantile patient, unfortunately for this patient only supportive care is available, there is no cure. So we asked the parents which was the first symptoms for which they were alerted. What we can observe is globally the same kind of symptoms that in the study from a carer and all. It means that for the late infantile form, it was many motor symptoms, for the late juvenile it was many cognitive symptoms, and for the early juvenile form it was a mix of motor and cognitive symptoms as the first symptoms. In late infantile patients, I mean in young patients, what did the parents say? The first symptom was gait disturbance, motor delay, not only stagnation but motor delay, stiffness, only 15% of the parents were anxious about regression, and also orthopedic deformities, particularly in the feet, and strabismus. I say a few words on this strabismus because it was noticed by around 10% of the parents, and until this new study that was published recently by our colleagues from Amsterdam and Tübingen, strabismus is not a very specific symptom, but they published that it may be an early symptom of the disease, so it doesn't mean that each patient with a strabismus should have a metachromatic leukodystrophy, but we should be alerted if, for example, there is an acute occurrence of strabismus. So this is a new early symptom that may help us. For the late- onset forms, what did the parents say? They were aware of school difficulties, attention deficiency, behavioural problems, psychomotor problems. You see that these are not specific symptoms, but what is important is that these symptoms occur whereas there were no previous symptoms. I mean, you have a normal child that starts his first year of school, and he was perfect before, and he has some new difficulties that weren't present before, and that's a very, very, very important red flag. It's not only true for MLD, it's also true for other degenerative diseases. So you see that all these symptoms are not very specific, but the age at onset and the association of these symptoms should be a red flag. The second thing that we looked at was how long was the journey of the parents from the first time they noticed symptoms to the diagnosis. The first thing is that, as you know here, as you see here, most of the family should see two or three or four practitioners before the diagnosis is performed. It's very incredible because it's a very, very long trip to see a physician who will suspect this disease. What were the first physicians that were seen by the parents? For the early onset form, as predicted, it's the pediatrician, and then the pediatric neurologist. For the late onset forms, it's either the psychiatrist, because I say that behavioural problem or school difficulties are the first symptoms, but it can also be a neurologist or pediatric neurologist. When the child was seen by the physician, by the doctor, what were the first clinical signs that was observed or that were observed most often, once again, in the early onset forms, these were motor symptoms, pyramidal syndrome, peripheral neuropathy, cerebellar syndrome, either isolated or associated. You see that, for example, in the late infantile form, the physician noticed, in more than 60% of cases, pyramidal syndrome, in around 40% of cases, signs of peripheral neuropathy and, in around 20% of cases, cerebellar syndrome. In the late onset forms, as expected, the more present clinical symptoms were ataxia, attention deficiency, behaviour problems and learning disorders. So it's important to note that if you have a combination of symptoms, of neurologic symptoms- for example association of pyramidal syndrome with peripheral neuropathy, it is a red flag for MLD. I'm sorry, because the slide is French, I made a mistake, but this is globally the results of the study and what we can see- and it's very, very terrible but it's the same conclusions that 10 years ago- is that between the first symptoms and the diagnosis there is a delay of 12 months, one year to make the diagnosis once the parents have noticed something, and it's a very, very, very long delay and, as you see, also the diagnosis is made. The mean age at diagnosis for the infantile forms is more than 30 months and it's very strange because in fact, we also observe that 90% of the patients affected with late infantile MLD never walked normally. It means that if you are a pediatrician, you know that we learn that a child must walk at 18 months and the diagnosis is made at 31 months, whereas 90% of the patients never walk normally and that's the problem for this disease is the age at onset, which is the age of the acquisition of the walking and sometimes the parents say, oh, my child doesn't walk and the pediatrician says: oh, it's normal, he's still not 18 months, so you should wait, and so on. Or the parents say: my child doesn't walk normally and the physician answers: it's not a problem, he walks only for one or two months. Okay, he has a gait imbalance, but it will be okay in a few months. So there is this delay and if we cannot improve that, we will not be able to treat efficiently the patients. Oh, sorry, that's wrong. So, that's, I wanted to just make a short summary on this slide, which are the red flags in the caregiver's language. What we can hear from the parents, there are some sentences, and I think that if you are a pediatrician or a pediatric neurologist if you hear this sentence it should be a red flag. For example, he has done, he or she, of course, my child has done everything normally so far, but now he can start to walk alone. This is an important flag, with the signification of the stagnation. Or he has a poor balance, he stumbles often, this can be a sign of peripheral neuropathy or cerebellar symptoms. Or he walks on tiptoes, very, very frequent, and it may be a sign of spasticity or peripheral neuropathy. And he walks on tiptoes, it's a very, very frequent sign, and most often, the physicians say, okay, you will see the physiotherapist or the orthopedist, and so on, and it's a loss of time. Another situation, everything was fine, but recently my child has some problems with concentration. It can be a symptom. Or his behavior has recently changed can be a cognitive symptom. Or since he starts school, he has difficulty with fine motor skills, and the teacher talks about dyspraxia, what do you think about that, and so on and so forth. If it is something new, it should be a red flag. And I have added the strabism, because even if it's not specific, it could be associated with It could be an important thing. And in terms of clinical signs, of course, the red flags are a stagnation or regression of pyramidal or cerebellar signs. The recent onset of attention deficiency or behavioral problems. And in summary, what we can say is that today new treatments are available for MLD and particularly ex vivo gene therapy. That I didn't talk about, but there are also clinical trials using enzyme replacements, intrathecal injection of enzyme replacement treatments that maybe should be available in a few years. So these treatments are present or will arrive. But however the treatment, the treatment must be performed very, very early. Ideally at the pre- symptomatic stage, but also for some of them at the early symptomatic stage. Thus, of course, familial screening is mandatory. You should absolutely and urgently detect the younger brother and sister. We hope that newborn screening will be available in France or in other countries. For caregivers and teachers, but also physicians, we should be aware of these early symptoms of MLD because the diagnosis is urgent and the diagnosis is finally relatively easy to perform. And in one or two weeks, if you stimulate, if you call the lab, if you say to the lab, I think it's a metachromatic leukodystrophy. We should have the result very, very quickly. You may have the results in one or two weeks. Stagnation regression, this sequence of normal progression, stagnation regression is very, very evocative of neurodegenerative disease and particularly metachromatic leukodystrophy. And finally, we are currently at, this is an initiative, which name is MLD Initiative, that was initiated by our colleagues from Amsterdam. This is an international data collection registry. And this will be very, very important to collect all the data and particularly this early onset clinical data to decipher this early MLG and be able to act as quick as possible with this emerging treatment. And that's what I wanted to say. And I thank you for hearing me. And I am, of course, I can answer your question if you have some. And I will just leave the screen and try to go to the chat. That's here, OK. So for the moment, we have one question, which is, do you request the contrast MRI brain for MLD diagnosis? No, we don't. There is no contrast, no gadolinium enhancement in the brain. Sometimes, but it's not often, but sometimes you may see some enhancement in the peripheral nerves, in the brain nerves, or in the spinal cord. But it's not important for the diagnosis, I would say. Maybe it could be important for differential diagnosis. And for the differential diagnosis of MLD. Of course if you have a boy becaue it is an X- linked disease, adrenoleukodystrophy, if you have a boy with white matter abnormalities and a clinical presentation of attention deficiency or behavioral problem, you should also think to adrenoleukodystrophy. I am not speaking about young boys, but boys around four to six years. If you have a boy 5 to 6 years with behavioral problem or cognitive problems and white matter abnormalities, you may have to do a gadolinium injection because of the differential diagnosis of adrenoleukodystrophy. But for MLD, it's not requested. I think that we don't have other questions. Do you have any other questions? No, so I don't know if we should stop the meeting here. I'm asking to the organizers. Sorry. Sorry, because I have OK, there is another question. Just in the resource- limited settings, what is the best initial test? I would say, but it's not easy to perform in all places. But I would say that if you have one test to do, it's the sulfatiduria. Why? Because if you do only the activity, there are some people who have low activity without disease. These people are named pseudo- deficient. They may have low activity but no disease. So it's important to perform sulfatiduria to confirm the diagnosis. So if you may have only one exam, I would prefer sulfatiduria. If it's not possible to have sulfatiduria, the first exam to do is, of course, ARSA activity. And if you don't have the possibility to do ARSA activity, you can also do the mutation. But the problem with the mutations, if you found two mutations, maybe it can be an MLD. But you will have to confirm with biochemical testing. And it will take time, first to have the results of the mutation and second to confirm with biochemical tests. So I think that sulfatiduria would be a good option as the first exam, if not possible, as activity. And in the best condition, both. And then, biogenetics. OK. In child, if child with behavioral problem, should we go for MLD testing? If you have a child with behavioral problems, if the child was perfectly normal before and starts to have behavioral problem, you should look at MLD and also other neurodegenerative disease. But for these behavioral problems, as I said at the beginning, these children most often have late onset forms, early juvenile or late juvenile forms of the disease. And when you have these behavioral problems in MLD in this child, most often you have already brain lesions at MRI. But however, it means that if the MRI is normal, it's likely not probable that the child has MLD. However, if you can do the test, you should do. But as you should do other testing for other neurodegenerative diseases. As are the early signs similar in other diseases, such as mucopolysaccharidoses, are there a combination of symptoms that signal a red flag? In mucopolysaccharidosis, most often the cognitive symptoms are speech delay or things like that are the first symptoms, I would say, in children. In early onset forms of metachromatic leukodystrophy, most of them the motor symptoms are the first symptoms so you can say that any neurodegenerative disease will have this kind of sequence with a normal development, stagnation, or regression. It's true. It's perfectly true. But what is important for the late, mainly the late infantile MLD, which is once again a more frequent form, is that first symptoms are most often motor symptoms. There is this stagnation period. You have most often, when you do the clinical examination, the association between cerebellar, pyramidal, and peripheral symptoms. so for example if you have a child with a motor delay or walking problems, and you see that he has a pyramidal syndrome and that you cannot have the deep tendon reflexes, for example, which means he has an association of pyramidal syndrome and peripheral neuropathy, it's very, very evocative. But also, of course, it can be another disease, it can be a disease, but you should test the child for metachromatic leukodystrophy, and it's important because there is a treatment.
[00:41:21] Do you routinely request psychometric testing for children with learning difficulties or behavior difficulties or behavioral difficulties in the pediatric or pediatric neurology settings? Yes. Yes. Of course. Of course. We most often do the test and repeat the test. I have just something to say that I didn't say seeing this question. It has nothing to do with the question, but I'm thinking about that. When you are a pediatrician, most often you see a patient, for example, the family comes because the child has some fever or respiratory problem this is the rule of the consultation. At the end of the consultation, the parents say, oh, I should say, doctor, that I'm a bit anxious because my child, he has 15 or 16 months, and that's very strange because he did all very, very early, and now I don't understand he's not able to walk. At this moment, you are at the end of the consultation, you are still 10 or 15 patients to see after. I think it's not a good situation to see the patients, and I think that the best thing would be to say, okay, we will speak about that in one week, when you will have the fever. I will see you again and see your child for this question. And at this moment, you take all the consultation, making the development of the child, asking the parents for the different steps of the development, with a perfect neurological examination and so on. And at this moment, you may see some symptoms or some signs that you would not have seen one year earlier. So just to finish with this question, yes, we always perform this psychometric testing, of course. Okay, I think that there is no further questions, so I thank you very much once again for your attention, and I am, of course, available if you want to have additional questions, and I think that you can send me an email without any problem. Thank you very much. Bye-bye. Thank you.