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[00:00:07] Nicole Wolf: Good afternoon. Welcome to the session on metachromatic leukodystrophy. My name is Nicole Wolf. I'm a child neurologist working at the Amsterdam Leukodystrophy Centre. And I will take you with me through the early science in metachromatic leukodystrophy in children. So I hope you will have an interesting 20 minutes as leukodystrophy, metachromatic leukodystrophy is a fascinating subject and I'm also still learning new things about it. So I try to move my slides. There are no disclosures. My involvement with the pharmacy in metachromatic leukodystrophy is advisory board for Takeda and also taking part in a clinical trial with Takeda. I think it's important to remember please do not take screenshots or reproduce slides and submit your questions at the end or throughout the presentation via the questions panel and I will do my best to answer your questions. I already warn you because I will not show videos. Parents usually don't give approval to show videos through webinars which is for us also a new situation. Two years ago I didn't give any webinars. So we still are looking for videos on patients with approval to show it on the internet. Okay so the learning objectives of this webinar are explaining the hereditary causes, the impact of MLD on central nervous system and peripheral nervous system and motor function and focus on early onset clinical manifestations. And in the end you should understand the most important early signs of MLD that you should have in your head when to think of metachromatic leukodystrophy. So what is metachromatic leukodystrophy? It was first described more than 100 years ago by Alzheimer. It's a lysosomal storage disorder with autosomal recessive inheritance and its laboratory hallmark is low to absent activity of the enzyme arylsulfatase A or ASA and this absent enzyme activity leads to accumulation of sulfatides especially in membranes. And because myelin in the central and peripheral nervous system consists of so many stacked membranes I think it's quite understandable that symptoms of metachromatic leukodystrophy should involve myelin, peripheral myelin as well as central myelin. And arylsulfatase A actually cleaves this little sulfatide group from the sulfatides, this little sulfur group from the sulfatides and that is actually sulfatides, galactosylceramides are important parts of myelin membranes. Diagnosis is made usually with clinical presentation and especially the MRI. I will show you some MRIs, typical and also unusual MRIs for MLD and when you think of MLD you confirm it with a measuring of the ASA activity in leukocytes and our cell mutation analysis. You also usually look for sulfatide excretion in urine because quite a high percentage, one to two percent of the population have ASA pseudo- deficiency which means a relatively low activity of the enzyme. This is not associated with disease and those people have a normal sulfatide excretion in urine. So a low ASA activity should actually be confirmed best by both but at least by one of those two examinations. Other lab abnormalities you may encounter and which may lead you to the wrong path, we will talk about this in a minute, is a high CSF protein and also metabolic acidosis in the young children. The name metachromatic leukodystrophy comes from metachromasia with certain stainings. Metachromatic cells are staining dark violet and autochromatic cells with the same staining look actually light brown. I think you see the difference between metachromasia and autochromasia here in that picture quite well. That's by the way a patient who had allogenic bone marrow transplantation for his metachromatic leukodystrophy. So you do see both normal cells, metabolically competent cells with normal ASA activity and also still some diseased cells with the metachromasia. There are some variants of metachromatic leukodystrophy. One is multiple sulfatase deficiency, there's another genetic defect. You also have low activity of arylsulfatase A and also other sulfatases. You also have peripheral storage in this disease, but also the symptoms and signs of metachromatic leukodystrophy. And the other disease which can mimic metachromatic leukodystrophy is prosaposin B deficiency or PSAP, the affected gene. And here you have clinically a patient with metachromatic leukodystrophy and the MRI also looks like MLD, but you have a normal ASA activity in vitro at least because that's an activator protein which is not actually assessed by the usual in vitro testing of arylsulfatase A. So keep that in mind when you are convinced that a child has metachromatic leukodystrophy, but you find a normal arylsulfatase A. The clinical presentation is actually divided in three forms. Onset before age of 30 months is called late infantile presentation. Onset from 30 months onwards to 16 years juvenile form and then above 16 years adult form. And there is some correlation between presentation and residual arylsulfatase A activity. If there is no activity you have the late infantile presentation and with the higher rest activity you have the adult presentation, but it's very, very difficult to correctly quantify those low ASA activities. So there is not a perfect, certainly not a perfect relationship between residual ASA activity and presentation, but on the broad view you can say that at least the absent activities have an early presentation. And broadly speaking early onset patients present most often with motor symptoms and have a rapid progression and late onset patients mainly present with cognitive symptoms and have a very slow insidious progression. In the Netherlands, and you are from all over the world, but in the Netherlands we see actually only a quarter of patients are presenting with the late infantile variant. Most of our patients are juvenile patients. In the rest of the world it's a bit different. About half of the patients have the late infantile variant. And we see in the Netherlands about four to five patients per year which actually confirms the expected incidence of one in 40, 000 births. So it's a very rare disease. There is some genotype- phenotype relationship, but also this is difficult. The genotype- phenotype relationship is mainly for three common mutations which make about a third of all variants and there is one mutation, a splice site mutation, which in homozygous form leads to late infantile disease and there is one frequesnt missense mutation which leads to later onset disease. And you also see that there are a lot of private mutations which makes a good genotype- phenotype relation still difficult. Now about symptoms, what are the symptoms to take into account? We often call the late infantile and the early juvenile variant which manifests up to the age of six years, early onset MLD, and in those forms motor symptoms are prominent. The late infantile patients usually present with a slowing of developmental progress, so they leave their developmental trajectory because their progress actually stagnates. Then they have a regression of motor function. If they have learned to walk without support, they lose that, they develop tremor and other fine motor problems, and another early symptom is strabismus. Patients who present a little bit later, so the early juvenile patients present with increasing clumsiness after a normal development, frequent falls, often also already concentration problems and problems with school performance and loss of continence. Usually they come to us with motor problems but when you do the history you actually also get to hear that there are concentration problems for example. The late juvenile patients sometimes have a long history of problematic interaction with peers and that's of course something very difficult to pinpoint because it's not rare and in most cases not associated with the disease SMAD. They show a slow decline of school performance that can go for years, they might actually drop regarding school levels, they are clumsy and it's a very insidious progression and they can have no motor symptoms at diagnosis. And I also just would like to mention shortly the adult patients they can present with depression, psychosis, slow cognitive decline, gallstones and their motor function even if there is already a quite clear dementia can be completely unaffected. Why is early diagnosis important? There are new treatment options, hematopoietic stem cell transplantation has been used for two or three decades already and there is also now the ex vivo gene therapy registered. Also there are still not rules for reimbursement in Europe but both treatments are only effective if applied before the onset in the late infantile patients or very early in the disease course for the early juvenile patients. So this is really important to remember so that's why we want to diagnose those children so early. It's also important for participation in treatment trials because patients who have progressed already a lot are usually not eligible to participate in treatment trials. And of course it's also essential for genetic counselling, both for prenatal or preimplantation diagnosis and also for the pre- symptomatic diagnosis of a sibling who then would be eligible for treatment. So that's I think also a very important point to remember if you have made diagnosis of MLD in a child please also test the sibs even if they are slightly older. So what can be early clinical signs? I mentioned them already a little bit on the previous slides but also to remind you of what you could mistake MLD for. Patients with late infantile form can present with peripheral neuropathy and that may be severe and areflexia for example and you might misdiagnose them as chronic inflammatory demyelinating polyneuropathy or CIDP. And of course remember that I mentioned the high CSF protein that's something you usually use to diagnose CIDP. So if you have a patient with a demyelinating neuropathy and an elevated CSF protein I think many of us would think of this but in a young child please think of metachromatic leukodystrophy as well and do the proper testing because polyneuropathy as itself would not as long as there is no central nervous system involvement we could even treat those patients. Slowing of development can be misdiagnosed as a simple delayed development and again you would do the normal testing for delayed development but look carefully at your patient. Was the development slow from the beginning or did the child develop first normally and then slowed its development? So did the child leave its developmental trajectory? And those patients are really at high suspicion for neurodegenerative disorders not only metachromatic leukodystrophy. I saw a patient today with infantile neuronal ceroid lipofuscinosis who also had a slowing of development. So those storage diseases can present like that and that can be very subtle in the beginning to see. Strabismus, especially paralytic strabismus can be an early warning sign. That's also strabismus frequent in children, perhaps not that frequent in young children but think about it. In the juvenile form, we have many children who have been diagnosed as having attention deficit type activity disorder or autism because of school and behavioral problems. And I think one of the most important points here to remember is look please carefully at new onset problems. Because a child who has been doing fine until the age of 7 or 8 or even 10 years old doesn't all of a sudden develop autism. Autism is something which is very early on visible. So don't make that diagnosis and it has happened in our patients. Mood problems, slow decline in school performance can be misdiagnosed as just being puberty or due to life events. I think you all know patients with life events and in the end they did have a serious even neurological disorder and I have those patients also in my clinics. And I agree that this is very, very difficult. Certainly the juvenile patients are very difficult to diagnose, but again, look at something is something new, is a child who was always very good at school, dropping in levels and in performance, this is a warning sign. The MRI is another thing. I think many of you know the typical MRI of metachromatic leukodystrophy and that actually mirrors very nicely the finding at autopsy where we see a relatively preserved subcortical myelin with this a bit irregular, you could almost say a tigroid pattern of the white matter here in that brain slice of a MLD patient. And you see exactly this, you see the preserved subcortical myelin with the affected area of hyper intense white matter when you compare it with the normal MRI and here those dots or stripes depending on the plane, which we call a tigroid pattern. So this is something you all know for metachromatic leukodystrophy and many patients have those typical changes at diagnosis and you also see how patients may differ, for example the late infantile patients have a parietal occipital predominance of the MRI changes, you see that very well compared with the frontal white matter. Juvenile patients actually have in most cases an affection of the whole white matter without this clear gradient and in late juvenile patients or adult patients you have a frontal predominance instead of a parietal occipital predominance and you often have at diagnosis already quite severe atrophy. So those are the typical changes and there are also patients, even children with early changes and those are very difficult sometimes to pinpoint and even more difficult to connect them with metachromatic leukodystrophy, but you might be in the position to make an MRI for example in this patient with peripheral polyneuropathy and I think you see he was two years so his MRI should look approximately like this one and you see that he has not a normal signal of the myelin, certainly when you compare it with corpus callosum, the splenium and the genu. So the myelin signal is too high, it looks you could say delayed myelination, it doesn't look so much like MLD but it's not completely normal. So MRI changes in MLD may be very nonspecific. This is also a child with presymptomatic metachromatic leukodystrophy and that as well, both of those children were diagnosed because of a diagnosis in a symptomatic SIP, but you might come across those MRI changes because you make an MRI due to a headache for example or due to a fall and I would like to point out some changes. You see here those changes in the genu. The genu of the corpus callosum looks a bit swollen because of the storage and you also see a slightly hyper- intense signal here in the genu. And the same holds true for this patient. Here the splenium is even more affected than the genome but the corpus callosum is certainly abnormal and also the white matter here shows a mildly abnormal signal which is not the full picture, full blown picture of metachromatic leukodystrophy but which is nevertheless abnormal. The corpus callosum involvement is a good giveaway for metachromatic leukodystrophy. There's also gallbladder involvement in metachromatic leukodystrophy. I personally haven't seen a child presenting with the gallbladder but adults, I know two adults with gallbladder colics and polyps as their first symptom and at diagnosis most patients, most children do have gallbladder involvement so you might even have a child with gallbladder polyps. In that case please think of metachromatic leukodystrophy. So to summarise, metachromatic leukodystrophy is difficult to diagnose in early stages. It's really difficult because the symptoms are so mild and the early symptoms are relatively common also to other disorders. So most symptomatic diagnoses are made relatively late and unfortunately usually too late for treatment. So the patients we are able to treat at the moment are mostly siblings of affected patients. The early warning signs are important and those are slowing of development, early peripheral neuropathy. In all young children with peripheral neuropathy, especially if you confirm demyelinating polyneuropathy, think of metachromatic leukodystrophy, paralytic strabismus, a new onset of ADHD or clumsiness. So thank you and it's a teamwork, metachromatic leukodystrophy, the Amsterdam team consists of lots of people of different specialties and we have a very nice collaboration also with the Tübingen team and you will hear in the next weeks more from them and about their experience in metachromatic leukodystrophy. So thank you for your attention. Questions? So I have to open the chat I think. So the question here is what percentage of tested siblings typically go on to have MLD? I would say what percentage of tested siblings are confirmed with metachromatic leukodystrophy? Well it's a one in four tested siblings on average. So I think, I hope that that answers your question. Is there hope for routine newborn screening for MLD in the near future? Thank you. I think that's an important question because I think that just because those early symptoms are so vague, we really are dependent on a newborn screening. There are some pilots going on, a pilot in Italy, a pilot in the US. It's possible. It's difficult to predict the precise form of metachromatic leukodystrophy. So would you have an infantile patient, a juvenile patient or even an adult patient which has some implications for treatment decisions? That makes it more difficult than for example phenylketonuria to screen for. But yes we hope that we will have access to newborn screening in the next years. Are there more questions? What about neonatal screening if treatment is only efficient in pre- symptomatic patients? Well yes I think I answered that already. Neonatal screening is really the thing to go for. But we are not there yet. So we need to pay attention to the early symptoms. Is loss of hearing a symptom? Well not really. I know it from the X- linked adrenoleukodystrophy patients that they may complain of loss of hearing or loss of vision. I haven't heard that from my metachromatic leukodystrophy patients. So, should MLD be tested for those with ADHD or autism at age 7? What other key signs should trigger testing? Well, if you had a child at the age of 7 who was normal under that age and then developed symptoms of ADHD or autism, you should always think of a neurodegenerative disease, not only of metachromatic leukodystrophy, so X-linked adrenoleukodystrophy in a boy of 7 is also an important differential diagnosis. So personally, I would start with MRI in those patients because at that age, the MRI would give you away what other key signs should trigger testing, demyelinating polyneuropathy, loss of motor function, so increased clumsiness, increased force, onset of pyramidal symptom, deterioration in school performance, yes, so those are things of tests, signs suggesting a neurodegenerative disease. Aside from the MRI of the brain, are there other changes in the retina that may suggest MCL but I think you mean MLD? Well, in the young children, in some of them, you might see a cherry red spot because there's also storage in the retina, but that's rare and that's not the typical finding, certainly not early on in the disease. What is the suggestion to a pediatrician in the Netherlands when suspecting a patient with MLD? Whom should he contact? Well, there is an expert centre, a national and international expert centre for leukodystrophies and that's in Amsterdam where I'm working and so please contact us. So what is the value of sulfatide determination in the urine samples of suspected cases? Well, that's a good question and it's a high value of sulfatide testing. Actually, we made a diagnosis some time ago because the urine was screened for sulfatides and this was actually quite nice because it wasn't a thought of MLD right away, so the sulfatide elevation actually made the diagnosis and the other thing is that you needed to confirm your low arylsulfatase A activity, certainly if you don't have access to genetic testing. So what about CIDP in young children? Do they have it as an isolated symptom in MLD? When to think about MLD if we find polyneuropathy? Well, CIDP in young children can be metachromatic leukodystrophy. I think all of us know patients who have been diagnosed as CIDP as first diagnosis and in whom the diagnosis of MLD was only made when they also developed central nervous systems like asbesticity. So yes, please do think about MLD if you find polyneuropathy. I also know a young boy of 15 who was investigated during two or three years for neuropathy and who had an exome sequencing for neuropathy and he had MLD actually. So yes, think about it. There's another question with which other special centres exist in Europe. There are other centres experienced in metachromatic leukodystrophy. The main centres are Tübingen in Germany, Milan in Italy, Paris in France and all those centres do also quite some research on MLD and there is a European reference network for rare neurological disorders and leukodystrophies is one of the diagnosis and you can look up on the website of the ERN rare neurological disorders which centres in Europe actually deal with patients with leukodystrophy including metachromatic leukodystrophy. Okay, so there are no further questions I see. Thank you very much for taking part in this webinar and thank you very much for all your questions. See you around.