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[00:00:09] Dr Alberto Zambon: So, good morning to everybody and thank you for joining this webinar titled Avoiding Missing the Early Onset Clinical Manifestations of MLD in Everyday Practice. My name is Alberto Zambon, I'm a Pediatric Neurologist working at San Raffaele Hospital in Milan, Italy. Please before proceeding with the presentation, please do not take any screenshots and if you've got questions you can submit them through the panel and I will try to answer at the end of the presentation.
[00:00:38] Dr Alberto Zambon: So, the learning objective of this seminar is reviewing the main pediatric manifestations of MLD and understand why it is difficult to diagnose MLD, so Metachromatic Leukodystrophy, in an early phase and why it is important to diagnose the disease early, so exploring the importance of an early referral, not only for the patients but also for the families and siblings. But first up, though, I want to give you a little bit of background about Metachromatic Leukodystrophy. So, this is a progressive lysosomal storage disorder. It's an autosomal recessive disorder and it affects 1 in 100, 000, 160, 000 children worldwide. So, the enzyme which is involved, the gene involved and cause for an enzyme which is called a arylsulfatase A and the lack of the enzyme cause the accumulation of sulfatides. So, sulfatides are substances that when accumulates have a toxic effect on many tissues but most importantly for a neurologist to the peripheral and central nervous system. The clinical manifestations of MLD are a spectrum and range from a very severe early onset form with onset before 30 months of age, which is called late infantile. Then there is another early onset form called early juvenile between 30 months and seven years and there is a late juvenile form before the age of 17 years and then an adult form. Of course, we will focus on the first three manifestations today. The disease spectrum depends on genotype and on ARSA activity. Of course, this is not the only factor, but it's the main factor contributing to phenotype. Another very important point is that this is not a congenital disorder. So, children normally are normal at birth and then develop normally in the early months of life, but then they start stagnating the acquisition of motor and cognitive milestones and then they exhibit a rapid progression of motor and cognitive skills and bulbar function, etc. The severity, of course, depends on the type of the disease, but this is a very important concept because here is when we need to make the diagnosis. But as I will show you, it's not so straightforward and it's not so simple. So what are the main pediatric presentation of metachromatic leukodystrophy? Of course, they depend on age. So they differ from age. First, we will see the presentation of late infantile form. So again, I remind you, this is the form with onset before the 30 months of age.
[00:03:25] Dr Alberto Zambon: And of course, the symptoms are quite specific and they start from six months of age onwards. So more typically around the first year of life with hypotonia, we can observe muscle weakness. We can observe abnormal deep tendon reflexes. We can observe abnormal cranial nerves, and we will see that in a moment. Most importantly, a delayed or lack of achievement of motor milestones and also cognitive milestones, ataxia, feet deformity, retro-curved knees. And then later on in the course of the disease, of course, hyperlordosis, spasticity, Babinski sign, which might not be evident in the beginning. When we reviewed a large cohort of patients, natural history cohort of patients, what we saw is that actually half of the patients with a late infantile form never acquired the ability to walk. So not only the achievement of walking is delayed, but some of these children might be even more severe within the most severe end of the spectrum and probably never gain the ability to walk unassisted. So when we look at walking, what we see is unsteadiness, frequent falls, toe walking, musculoskeletal abnormalities such as feet intra-rotation or retro-curved knees. Of course, these are subtle symptoms and not easy to detect. And although it's a rare representation, we should be aware that a new onset of strabismus or nystagmus, as pointed out by our study and also by study of other European colleagues, could be a presenting symptom of MLD. Here I can show you some videos displaying MLD patients at different stage. So of course when they are young it's not easy. Maybe they are able to sit without support, and this occurs in the vast majority of patients, but maybe they do not move around much. They have very mild difficulties and only around the first year of age we see that maybe they cannot walk independently and they show poor balance. And of course in the acquisition, the time of the acquisition of walking, that is not easy to recognize and many, many conditions and also physiological conditions can cause a delay in walking. So it's not easy. But we should look at reflexes, so clinical examination, ataxia, and see if there's a foot deformity with new onset, hyperlordosis, retrocurve, knee- again it's quite typical in older children what we see is ataxia. So ataxia means lack of balance. The children will look for support. They walk with a broad base. So we should not overlook a patient with ataxia and of course this is a chronic condition which might go in the differential with acute ataxia. But it's very important to recognize and not to underestimate. When we look at the early juvenile and late juvenile patients- so slightly older patients- what we see is a slightly different presentation. So of course we can have gross motor impairment such as abnormal gait, ataxia. Again, fatigability could be some kind of spasticity, particularly evident when the child runs or a foot drop, but also, which is quite typical, a fine motor impairment. So maybe slight tremor, slight dysmetria in the index to nose test. But most importantly, in the cognitive domain, what we see is a worsening of school performance: apraxia, destructibility, slowness in processing speed, regressive behaviors, difficulties in controlling impulses. Another very important red flag is the onset of urinary incontinence, and these are the kind of questions you should ask to parents: has anything changed in the behavior or school performance of your child? Of course this is very difficult to recognize, this is not specific but should not be overlooked because there are many different reasons for beyond, behind the regression in behavior. But this should not be overlooked and I think it's very interesting also to note that also seizures, strabismus, could be a symptom of onset and also some extra neurological involvement such as a gallbladder abnormality, and this was confirmed again in a cohort of natural history patients. So we have a different combination of cross fine and cognitive impairment in patients with early juvenile, while in the late juvenile- so slightly older patients- what we see is a predominant cognitive and behavioral phenotype.
[00:07:58] Dr Alberto Zambon: So again, it's probably even more difficult to detect, although the children are slightly older. So I think the difference between pre and after the onset of symptoms is quite. It's more clear, it's more evident than early juvenile maybe. And again, as I told you, gallbladder, so the sulfatide accumulates not only in the peripheral and central nervous system but also in other tissues. Among these the gallbladder is very important. And also in the first stages of the disease, what we can see? If we perform an ultrasound of the abdomen we can see sludge, wall thickening, polyposis, papillomatosis, cholecystitis. So there are a number of findings which can support the differential diagnosis within a neurodegenerative disorder if we find a gallbladder involvement that points to metachromatic leukodystrophy. So we saw the symptoms but it's not difficult to detect them. And of course it's not easy to think about MLD because it's a rare disorder and it's not the only disorder causing such symptoms. And the differential diagnosis is difficult because the MLD is characterized by an involvement of peripheral and central nervous system. So what we see is a combination of signs and symptoms of peripheral nervous system involvement or central nervous system involvement. As an example, we can see reduced tendon reflex instead of brisk tendon reflex which we would expect with a neurodegenerative central disorder and, of course, as I told you, like in the older population, be aware of the behavioral regressions or the child starts to behave in a different way, urinary incontinence, again very important, red flag, attention deficit, etc. And look at the skeletal abnormalities etc. And, most importantly, refer to a tertiary center. So what are the most important diagnostic tests? Of course, we understand that MLD is affecting the central nervous system, so what we think in the first place is brain MRI. And what you see in this slide is the characteristic tigroid pattern of the MRI, but this actually is evident at the later stages of the disease. So the key message I want to convey today is that, of course, you need to request an MRI quickly, but be aware, and the doctor and the neuroradiologist should be aware that, especially in the youngest patients, so before the second year of age where myelination is not complete, what we can find is normal exam or very subtle abnormalities in the exam. So it's not that easy to detect changes when the children are very, very young. And this was also acknowledged by, again, European collaborators and experts in MLD. So there are some radiological signs that we should look at, but, again, this should be assessed by an expert in the field. So it's important to refer the children to an expert center as soon as possible, and we will see later in the presentation why. Another aspect, it's a very peculiar combination of central and peripheral nervous system involvement. This is not the common feature of neurodegenerative disorder. So when you have both, you have a hint to the diagnosis. Of course, this is not the only one. What we can do is perform an EMG. What I would suggest is perform the EMG during the sedation for the MRI so you can perform both exam together. And what we know in the natural history of the disorder is that, especially in the most severe end of the spectrum, most of the patient will develop peripheral neuropathy. So if you look at the graph, especially panel B, C, and D, so the gray area is the normal values for age, and, of course, you see that the blue areas, the blue dots and the orange dots and the green dots represent patients. And what we see is that in the late infantile, so the blue one, invariably, all patients experience peripheral neuropathy at a certain point. But, of course, these are exam performed on symptomatic patients.
[00:12:01] Dr Alberto Zambon: While in early juvenile and late juvenile, it's more variable, so it's not obvious that we will find peripheral neuropathy in a patient with MLD. And it's important to know, also, that this sulfatide starts to accumulate early in life. So probably, if we look at early stages, we will find some, I will show you in a moment, some evidence of peripheral nervous system involvement even in the earliest stages of the disease before the disease manifests clinically. Again, as a curiosity, there are some reports of MLD patients presenting as an acute polyradiconeuropathy, so Guillain-Barre syndrome, or resembling CMT. So this goes in the differential. So if we perform a lumbar puncture, what we can see is increased CSF protein. And so we should think about something else if the clinical picture doesn't fit. Of course, these are clinical reports, but should be considered in the differential diagnosis. Again, be cautious. When we see, so these dots represent single patients. This is a Z-score, which means that the Z-score below, which falls in this red square, mean abnormal values. Zero is exactly a value in the mean of the population, and this is lower limit of normal. So what we, sorry, these ones. So what we see is that if we perform an EMG before the first year of life, we could detect abnormal values, but also normal values. So be aware that if you assess a patient quite early in his life, not always the exam is pathological. So it's very important, but be aware of possible flaws. There are other investigations which might help the diagnosis, which is brainstem evoked potential. Again, you need experts to assess this kind of exam, which is a non-invasive exam, evaluating this conduction speed within the brainstem. So it gives you an idea of the myelin damage within the central nervous system. But again, in the first years of life, myelination is developing, so especially in the first two years. So all the reference values changes. So in order to interpret if an exam is pathological or not, you need an expert. And maybe the exam is normal even in symptomatic patients. So what you should do, or what the tertiary center should do, is start and submit biochemical testing, which means detecting the activity of the arsenic enzyme on different cells, like reluctance or cultured fibroblasts. So it could be a blood test. And you can measure sulfatides also in the urines, and this helps you differentiate with pseudo-deficiency. But what is important, I think nowadays, is to request genetic testing as soon as possible. Of course, the combination of biochemical and genetic testing give you the diagnosis, but we should not waste time. So normally, probably the ARSA enzyme is included in many panels, but you should, or maybe the tertiary center should liaise with the genetic department to speed up the genetic testing. Why? Why it's important to prefer early MLD patients and what delay in diagnosis, what's the impact of delayed diagnosis on patients, but not only in patients? we will see in a moment. So first, we have treatment. Early diagnosis means early access to treatment. So in early juvenile, late juvenile, and adult onset forms, we can perform a hematopoietic stem cell transplantations. But a few years ago, a gene therapy was developed, and now it's approved in the EU. So there are five referral centers in Europe. I will show you them in a moment.
[00:15:54] Dr Alberto Zambon: And a key concept, of course, it's more complicated than that, but a key take- home message is that the earlier the treatment, the higher the probability of a better outcome. But what is the indication for gene therapy? So gene therapy could be administered to patients when they are asymptomatic, meaning without clinical manifestations. But of course, we are talking about detecting early the disease for treatment. So of course, if a patient, in particular, a late infantile patient is already symptomatic, we will not be able to treat him. But if a patient has an early juvenile form, then he can access the disease if he meets specific criteria, which you can find. If a late infantile patient is diagnosed because of the presence of symptoms, as I said, maybe it's too late for him to be treated, at least with gene therapy, but there might be some trials going on. However, as I said, early diagnosis is crucial for counselling of the families. So not only for the patients and for the planning of the care of the patients, so palliative care and build- up of the MDT, of the multidisciplinary team, and again, counselling of families, but also it's not uncommon. So this is an autosomal recessive disorder. I will say a good proportion of patients might be consanguineous, the parents of the patients. So the risk of a second child being symptomatic or early symptomatic and affected is quite high. So if you diagnose late the first child and you have an affected children, an affected sibling, and you do not diagnose MLD, within a few months, maybe you have two affected children and none of them could access the treatment. While if you do an early diagnosis of the first child, maybe the second child could access the treatment, which is efficacious, particularly if the treatment is given early. And these are the treatment centres in Europe. So here in Italy, where I work, but also in the Netherlands, in France, in Germany, and in the UK, you should refer to this treatment early. What are the take- home messages of this presentation? So I didn't go into much details of the neurological aspects because I think this is beyond the scope of the presentation but I think it's, be aware that nowadays there are treatments so early recognition is important and early signs of the MLD varies across the spectrum. So if you have a child who's younger than 30 months, be aware of delayed milestones, abnormal gait, again, ataxia, retor-curved knees, foot deformities, squint, Babinski's kind, of course, it's not significant if the child is too young, but do not wait and see, let's say. And also squint could be a significant and important hint for diagnosis. When we look at early juvenile patients, so between 30 months and six years, again, the clinical picture is slightly different. What we see is abnormal gross motor function could be a presenting sign, so abnormal walking, maybe introversion of the foot or the child start to fall down, maybe display early signs of spasticity, but sometimes the signs are very subtle. So fine motor, maybe the writing changes, the way he draws changes, maybe in his cognitive and behavior performances changes at school, but the child might be quite young, so it's very important to talk also with the teacher and to understand from parents if anything changed.
[00:19:32] Dr Alberto Zambon: And I admit that sometimes it's not easy because there are many other factors in the life of a child could justify a change in his behavior. So it's not impossible. I mean, it's easy to overlook symptoms of onset of MLD, especially if we consider that this is a rare condition. but you should not overlook them. And in late juvenile patients, so in this age window between seven and 16 years, again, predominantly it's a cognitive phenotype. So especially in the latest group, the diagnostic delay can be of several years. So in my experience, we've seen patients maybe diagnosed 14 years after because the rate of decline of the cognitive and behavioral abnormalitites is not that steep as opposed to the late infantile and early juvenile forms. So patient could be diagnosed with psychiatric disorders or ASD- like or any other kind of disorders and spend many, many years without the diagnosis. Again, can be subtle and easily overlooked. I think as a pediatrician, which I acknowledge is the main audience of this talk, it's not easy. And of course, you should not send every children you see to a referral. But if you see this red flag with the treatment in mind, you should not wait and see. And this is the other key message, which goes beyond MLD. So we have got other treatments nowadays for neurological disorder, also for neurogenetic and inherited neurological disorders. You might be aware of the new treatments like for a spinal muscle atrophy, for example, but I think others are in the pipeline. And generally speaking, I mean, this is common sense, but also it's based on scientific evidence. So the earlier you treat the patient, again, the better is the consequences for the patient himself, because of the lack of accumulation of further damage to whichever structure is involved in the disease.
[00:21:36] Dr Alberto Zambon: So the wait and see strategy, which is quite common, I think, when you see a patient, you say, let's see in the next three months, especially if the child is one year old, for example, so maybe it's not really delayed according to the WHO criteria. So you might think, yes, maybe I wait three months and see, do some physiotherapy, et cetera. But nowadays we should be aware, again, that there are treatments and the early access to treatment can change the prognosis, especially like for SMA, but also MLD, neurodegenerative. So we should be prone and active in the referral to tertiary center. And why it's crucial to refer to an expert center? As I said, experts in the field are aware of the limitation of diagnostic tool. If you send the children to perform an MRI to a secondary or first center, maybe the radiologist reading the MRI when the child is 15 months, 18 months, 12 months old, cannot detect that very subtle changes, and maybe they do not perform like advanced techniques such as MR spectroscopy, which may help in the diagnosis. So this is why it's important. Also the machine itself might be not good enough to detect these subtle changes. And again, as you said, as you have seen in the presentation also peripheral nervous system involvement could be there, but it's not easy to diagnose and to test children, especially before the second birthday. So it's quite tricky. From a technical point of view, you need an expert in the assessment itself, but also in the interpretation of results.
[00:23:15] Dr Alberto Zambon: But also early referrals to an expert centers mean that the expert center knows the pathways to achieve rapid diagnosis in terms of genetics. They can speed up things, they can reinforce this with the genetic laboratory or the biochemical laboratory, so to have a diagnosis quite early. So this is very important. And I repeat this, but this is the take-home message of the whole presentation. It's early diagnosis means early access to treatment for early juvenile and late in juvenile patients, early family counseling, and we should not underestimate this aspect. It's very, very important to avoid families going on for years, especially in the later forms or for months in the first ones with DABS and then all the psychological aspects related to a misdiagnosis or a later diagnosis, especially considering that maybe there's a younger child, affected child who is pre-symptomatic and it could benefit greatly from new treatments. So I think I finished a little bit earlier than expected, but I thank you for the attention and thank you for joining this webinar. I think it's very important that the people working and seeing all these children are aware at least of the red flags. And I'm aware that as a pediatric neurology, I might overemphasize some aspects, which for me is everyday practice, but it's not so straightforward for people seeing a lot of children, not to over-diagnose or over-test people. But you have seen there are some specific findings that you should look at.
[00:24:54] Dr Alberto Zambon: I acknowledge also the team, which is a very complex and beautiful team which I work with in Milan. And if you've got any questions, I will try to answer. Remember, you can post the question in the window and I will try to give you the best answer. Thank you for joining this webinar.
[00:25:17] Dr Alberto Zambon: So, I see one question is, are seizures a key sign or rarely seen, EJ only, or do you see it in late juvenile? So I think seizures, of course, they are not uncommon, let's say, they are quite common in the later stages of the disease. I think as a presenting sign is a quite rare presentation, especially in late juvenile. So there are some early juvenile reports, but of course, when neurodegeneration occurs and the white matter involvement is more important, of course, we have a higher probability of observing seizures, but I would say as a presenting symptom is quite rare, although it could be the presenting symptom. Okay, the second question is, you mentioned that 50% never walk, should this be the main red flag or are these only the severe cases? So thank you for this question, it's very important to clarify. So when I talked about 50% of patients never gaining the ability to walk, what I refer to is the group of late infantile patients, meaning those patients with onset before 30 months of age. So within that severe end of the spectrum, probably there are patients who are even more severe, and of course these have implications for treatment, but this is not the place to discuss this, but what I mean is that these patients do not achieve, but some of the late infantile patients achieve independent walking and may even achieve independent walking within the time expected for normal children. So again, it's tricky, if the child is delayed, again, sometimes we talk about delayed motor, is it delayed or is it not delayed? But of course we need to put this in the context of the clinical assessment, so when we see a child in clinics, in a pediatric neurology clinic, because of delayed walking, we perform a neurological examination, that is why I refer to a specialist, because we can look at signs and symptoms, check for hypotonia, check for feet deformities, tendon retractions, altered deep tendon reflexes, so this is why it's very important to put the delayed motor myosines in the context of a clinical examination. Is trouble in swallowing in late infantile onset likely? What percentages of cases, this is the third question. So trouble in swallowing, which we could call dysphagia, is a common feature of both late infantile and early juvenile forms. What we see is that in the beginning probably is not the presenting symptom, might be, but I would assume this is quite rare, but what we see especially in the late infantile but also in the early juvenile phase is that we have a stagnation, as I showed you in one of the first slides, and then we have a rapid regression, also in the early juvenile. When the rapid regression occurs, what we see is basically in parallel lack of motor control. Of course, otobulbar function is in a way a motor function, so onset of dysphagia, lack of trunk control, loss of trunk control, and then loss of language and cognitive skills. So these go, I would say, in parallel, generally speaking. So in the first months after the symptom appear, especially in the late infantile, this is very, very rapid deterioration. But also in the early juvenile, when they start to deteriorate, say when they lose independent walking, the time from loss of independent walking to loss of trunk control is quite early. And yes, so swallowing impairment is, I would say, the rule in these severe etraparetic cases.
[00:29:23] Dr Alberto Zambon: Okay, so this is the question number four is, is it common for the MRI to not show any abnormalities in the early stages of the disease development? Any signs before second years in past cases? When are signs more common? So, yes, so what I meant is that when you perform an MRI, so basically this is a leukodystrophy, so the main, let's say, tissue involved is the myelin, and what we see, of course, is an alteration in specific sequences at the MRI, and what we call white matter abnormality, okay? In the first three years of life, there are many physiological changes in the images we take because of the myelination process, so the normal myelination process. So myelin is completed, I would say, around the second year of age. Again, I'm simplifying, but as a rule of thumb, if you consider the second birthday as a cutoff, before myelin is not completed. So if some pathology is occurring in the myelin, what we see with the image is not an overt abnormality, so it might be very subtle periventrical posterior abnormalities or in the corpus callosum. So this is why if you perform an MRI in a late infantile patient, say, when he's or she's 13, 15 months old, you might not see any abnormality. In the nearly juvenile children, of course, the onset is later, so you would not expect to see symptoms before 30 months, so when you see symptoms, they are older, and normally what you see is an abnormal MRI. So I would say in early juvenile patient, especially if they are symptomatic, you will see some kind of abnormality that might be subtle, so not the overt characteristic tigroin pattern, but it's more common to see abnormal pattern. And when are signs more common? Again, I would say the older they are, the more abnormal is the MRI, and also I think it's of interest in older cases, like in late juvenile cases, so those patients who present with psychiatric disorders, sometimes what we see is an abnormal MRI, say, in siblings who are perfectly asymptomatic. So again, as many neurological conditions, it's not that easy to navigate throughout MLD, but I would say the older, the more probable is that the MRI is not abnormal, I would say would be quite unique or particularly if the MRI is normal in an early juvenile or late juvenile patient, in the late infantile before two years, it's not uncommon, and you need to look at specific signs. So question five, is there an algorithm for the diagnosis?
[00:32:24] Dr Alberto Zambon: So I think it's in one of the slides, I think a very good reference I use for neurological conditions is gene reviews, I'm not sure it's an open access, I'm not sure if I know how to share, but I think it's an open access, it's very good, normally they state what are the exam, what are the limitations, what should be done, so it's an open access tool that should and can be used for any metabolic i would say, neurogenerative condition. It's very well done. So the question number six is a patient has been diagnosed late juvenile and he has positive sibling that is asymptomatic, will the sibling be eligible for gene therapy? So I am not sure if, so I will try to give a double answer. So the question is a late juvenile but I am not sure if who posed the question referred to a late infantile, so I will try to give an answer for both cases. So for late juvenile patients att he moment there are clinical trials assessing some of the older patients, assessing the efficacy of treatment. For a late infantile, so the most severe end of the spectrum, if the sibling is asymptomatic, it can be eligible for gene therapy. So normally if gene therapy is provided before 12 months, this should be the best scenario, even before, but I'm not sure if the person who posed the answer meant the late infantile, I assume, because of the kind of question, but I tried to answer both. So there are no more questions, and again, thank you very much for joining, and thank you very much to those who will listen to the webinar in a second moment, and please join the next webinar organized by EIP, and thank you again.