00:37:13
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[00:00:03] Dr Simon Jones: Hello everyone and welcome to the next. In a series of webinars about metachromatic leukodystrophy- and I know recently you had an excellent webinar from Nicole Wolf giving you a good background on MLD- the focus of today really is to try and look at the way this disorder presents in children and specifically the early diagnosis of this condition in children, and so we'll be looking at very specific aspects really with the aim of trying to achieve an early diagnosis, early and accurate diagnosis. As before, we would ask you please not to take screenshots or to use the slides again without specific permission and, although it would be much nicer if we could have an interactive discussion face- to- face, with the way of things in the world at the moment, we will do the presentation as it is and then, if you can ask some questions via text, I'll try and answer those at the end, if that's all right. Thank you okay. So a quick revision slide here really, and I think you should all be familiar with this: the overall spectrum of the disease of metachromatic leukodystrophy or MLD, and we have here children with a very severe form of the disease, with no residual enzyme activity, who accumulate substrate rapidly, and these children, and perhaps about half of the children we see with MLD present between the ages of about two years and two and a half years, and these children have no residual activity and a rapidly progressive disease, as you can see from the survival figures, and very, very few, if any, are alive at 10 years. There's then a slightly more slowly progressive form which tends to have its neurological onset a little bit later, between 30 months and six years, and these children almost certainly will have a small amount of residual RSA activity and they'll accumulate substrate in the brain slightly more slowly and have a slightly more indolent initial disease progression. And so there, once they really get into the neurological progression, they can progress actually quite rapidly, but the early features are subtle and nonspecific and that can be challenging when it comes to diagnosis. There's, of course, much later onset forms of the condition, the so- called late juvenile, which presents a little bit later on in childhood, late childhood- and then the adult form, which overall are much less common but of course still exist. And as time goes on, as these subtypes go on, they become somewhat more heterogeneous, and the late infantile patients are the most homogeneous group, although of course each individual child is different. So if we think about how these children present, it's not like this. This is a really old picture, as you will see, of a child with late infantile MLD, towards the end of life. A child is profoundly dystonic, profoundly disabled and is wasted and emaciated, and so we don't get kids like this to make a diagnosis. This child has all the features that we would see of MLD and we don't see children quite as unwell looking as this anymore with our intensive feeding regimens. But actually it illustrates quite how challenging these kids are to feed in the later phases of the condition and with the GI disease and the severe dysmotility that some of these children can have coupled with their very challenging dystonia, actually feeding these children, even with modern enteral feeds and gastrostomy and continuous feeding regimens, can be really challenging. Likewise, we don't see scans like this. I apologise for the greenness. It's an old scan of a very late stage child with really quite cystic white matter and very damaged brain. This presentation is all about early signs and how to pick these kids up really early, and so we wanted to go through a couple of cases, illustrating the differences in some of the different subtypes of MLD and with the focus really thinking about what would we do in this particular situation? When does it become obvious and clear? So I'll take a very recent case here. Really, the second child of non- consanguineous parents with no specific family history of anything notable. The child's early milestones were entirely normal. He walked at 14 months. He's a male child and he presented to local primary care practitioners at 20 months with parents' concern about the in- toeing, so the toes going in, and concerns from the parents about possible flat feet. Now they were seen by primary care because, of course, this was during Covid and pandemic restrictions. They were seen, or not seen I should add, on the telephone call and because of parental concerns about flat feet were referred to feet specialists or podiatry to see if the child would benefit from specific shoes. Of course the child could not be examined because they were seen virtually. As things moved on, a few months later, the in- toeing had not improved and the parents were more concerned. They came back to raise more concerns with their primary health care team. The child was falling more often, so becoming more unsteady on his feet and once again they saw the podiatrist on a video call, not face- to- face, and because things were getting worse rather than better, the podiatrist asked the physiotherapist to see, or the physical therapist, and once again because of pandemic restrictions they were seen on a video call, so at least they were seen rather than just heard. The physiotherapist, quite reasonably, was concerned. They looked at the child and they could see how they were standing and the story about the child becoming worse and worse did raise concerns and so they arranged to see the child face- to- face within a few weeks of that video call because there was concern and only once the child was actually seen, this young man was seen face- to- face by a physiotherapist, they were able to realise that the child had a slightly wide- based gait and stance and that there was some stiffness. This wasn't just a typical sort of hypermobility type situation or an unusual foot posture situation, there was actual raised muscle tone and so they were rapidly referred to paediatrics because things were getting worse with time, not better. This didn't sound like a simple static motor condition of childhood which is seen very frequently and by the time they were seen by the general paediatrician, the local acute paediatrician, there were real concerns about neurological regression and once again on examination this child had an increased tone actually of all the lower limbs and the local paediatrician was confused because they were expecting to find clonus and increased reflexes but in actual fact they couldn't demonstrate that. The child was still speaking but had no new words over the last two to three months and so there was concern that there was a plateau in the learning of new words but that actually from a motor point of view, things had got worse. Really quite worryingly, the family reported that he was coughing with thin liquids and so they did very reasonably at this point organise an urgent MRI scan. You can see and I'm not a neuroradiologist but we can all see the very dramatic white matter abnormalities here, slightly asymmetrical, slightly more prominent posteriorly but present anteriorly and on different slices you see widespread occipital parietal periventricular white matter abnormalities and so the concern was raised about an aggressive or progressive disorder and so what's the differential? So the differential of leukodystrophies as I'm sure you're aware is broad with hundreds of different genetic conditions and of course many acquired conditions also. There's a couple of things that I think are very important to rule out really early and I'm as a metabolic paediatrician somewhat skewed and biased of course but I think adrenoleukodystrophy or X- linked adrenoleukodystrophy and metachromatic leukodystrophy are perhaps the two most important and most urgent neurometabolic disorders that present as a leukodystrophy that require diagnosing rapidly. And I've said here CCALD in the slide. That's childhood cerebral adrenoleukodystrophy. For those of you who know X- linked adrenoleukodystrophy, there are several different phenotypes that can be present even in the same family. But in a young boy of this age, it's really important to rule out the very rapidly progressive childhood cerebral form of this disease, as some of those boys can be treated. And that's why it's so important to try and diagnose that condition early and urgently, because early symptomatic boys can sometimes be transplanted, whereas the more progressed boys, from the point of view of neurology and the white matter changes on MRI scan, those boys are not suitable for transplant. So it's really important to get in there early. And the same, to some extent, has held true for MLD as well. There are treatments and possibilities of treatments available. And so getting in there early with regards to a diagnosis is so key. And so the two key pod tests, from my perspective as a metabolic paediatrician, would be to think about the very long chain fatty acids and the lysosomal enzyme screen liaising with your local metabolic lab to make sure that these tests are sent rapidly and are treated as urgent by the lab, given the setup of the case. X- linked adrenoleukodystrophy likely here because or a possibility here because this is a boy and that's an excellent condition. But in a girl, you'd probably send both tests also, as other disorders can be diagnosed by the very long chain fatty acids. Important that the lab, your lysosomal lab, know what the presentation is, give them clear clinical details as that helps them understand what tests need to be organised. And the rapidity of those tests and how to interpret them. Here in Manchester, we will do a 20 enzyme white cell enzyme screen on five mils of EDTA blood and can always, in that screen, measure your arylsulfatase A. And in this trial, it was very dramatically low, giving us a diagnosis here of late infantile metachromatic leukodystrophy. But before I go on to the present day of the child, thinking again about diagnosis, as I'm sure Nicole said in her previous presentation, a number of cases are diagnosed by exome screening or by leukodystrophy genetic or genomic panels. And while that is a completely reasonable way to make a diagnosis of this disease, you want to make sure that that's diagnosed rapidly. Some of those panels can take some months to get an answer back, that's not appropriate with screening for MLD, where the biochemistry is usually very rapid. If you do have access to your rapid panel, then that should give you a clear diagnosis quickly. Although, of course, you may get variants of unknown significance and therefore you'll have to go to blood enzyme testing anyway. So when this child was seen here in our centre, I saw this young man recently, he was only walking with support from his parents and both hands held. He had significant lower limb, increased tone with spasticity and actually absent reflexes. And when seen by the local paediatrician, they were confused that he didn't have increased reflexes. They were thinking of a spastic diplegia type presentation, and they were expecting to see increased reflexes with the increased tone. But of course, this young man had MLD and therefore, as well as having the central leukodystrophy with lower limb increased tone, he also had peripheral neuropathy. And so his reflexes, when assessed at this point, were absent. And so a somewhat initially confusing picture. He had relatively preserved upper limb function and his speech remained actually within normal limits for his age. But importantly, he hadn't progressed. And so this child was picked up relatively early, but nowhere near as early as he could have been picked up. And in large part, that was because of the challenges that we've all had with the COVID pandemic. And one would imagine if he was seen earlier, either by the physiotherapists or the doctors, that the abnormal neurology would have been obvious at an earlier point, and that would have prompted a more rapid and earlier investigation. OK, so this is late-infantile MLD, and we see a much more rapid progression in that disease, but with a few signs emerging for some months before a phase of more rapid progression. I'm now going to talk about another case. This is a case of an older child. This child is seven years old when they came to see me and she had really very normal early development, although parents were a bit worried about whether she was flat-footed early on. The first concern for this child, for these parents, was that at the age of four they were worried a bit about her speech being a bit less clear and she was a little bit troubling when they started school in that she wasn't interacting quite as well as they would have hoped with other children. Over the course of the next year, by the time she was five, they certainly felt that she had less good motor skills than other children her age, although she was still gaining skills. So at this point we've got a very non-specific presentation and this child was seen by community health care workers, primary care, physiotherapy and community paediatrics and they felt that she had a bit of a combination of dyslexia, dyspraxia, perhaps a developmental coordination disorder and that seems really quite reasonable. At this point there was no real sense of things getting worse. By the time she was about five and a half, six years, however, she really was struggling at school and that was both from a cognitive perspective but also from a behavioural point of view and keeping her in school, her interactions with her teachers and her peers was getting worse. And so things were getting more and more difficult and parents and her local team were spending a lot of time trying to get the right support in for school. However, they did notice as well as this that her coordination was getting worse and this resulted in her gait actually starting to change. Around the age of six and this indeed was also accompanied by when you spoke to the parents and asked them a detailed history of some unusual upper limb movements, especially when the child was trying to walk or concentrating on things which almost certainly were episodes of dystonia. At this point it was becoming clear that there may be a progressive disorder and there may be a new problem and this may not all be simple dyspraxia and dyslexia and the child was referred back to the paediatric team. While they were waiting to be seen, however, by the neurodisability team the child had an acute viral illness, nothing dramatic, not encephalitis but she did not do as well. She deteriorated really and was really quite sleepy for a few days and was really unable to walk. Whilst this was felt perhaps just secondary to an acute illness, as the fever went and the child started to recover from this apparent acute viral illness, it became clear that she wasn't actually returning back to her normal level of mobility and wasn't ambulating in the same way that she was before, even after four weeks later. And so it was somewhat felt that actually perhaps this really was a significant underlying problem and an MRI scan was again acutely organised and actually the MRI scan was much more subtle than the previous child. We probably do have some increased ventricle size here and there probably is, in retrospect, a little bit of grey matter loss and atrophy that actually wasn't really picked up when this scan was first reported. But we do see again both at the anterior horns and the posterior horns of these lateral ventricles a bit of white matter abnormality. And this prompted, of course, a detailed set of examinations and assessment by neuropediatric neurology in our own hospital and a set of tests which included the lysosomal enzyme screen and this showed metachromatic leukodystrophy with a deficient, although not quite as deficient, arylsulfatase A. The child at this point was only managing half days in school. She was really struggling to walk by herself and had both increased tone in her lower limbs and absent reflexes. There was some obvious tremor and dystonic posturing in her upper limbs and pes cavus. So this diagnosis is now clear and genetics confirm this. And because of the age at presentation of this child, she has early juvenile, the early juvenile subtype of metachromatic leukodystrophy. And whilst we see a relatively rapid progression in the later phases of this disorder and within really two or three months of me seeing her initially, she was unable to walk at all. We have some years of known specific mild signs that cause parents and community healthcare workers some concern, but nothing specific that prompted significant investigations that would have led to this diagnosis. I want to ask parents of children with MLD how long they were worried before the diagnosis and what symptoms they were worried about. We see a slightly different pattern here and this is a survey of caregivers and parents of children with MLD and if we look here in the late infantile column, what were the initial symptoms that parents were worried about? Well, concerns that the development was to some extent stagnating or not continuing as they would have expected, slight changes in their gait and their ability to walk and run but these children are still walking and running, and then in some, perhaps a third, tremor. This is contrasting really with the more common symptoms seen in the juvenile onset patients where, yes, there is abnormalities in gait, difficulty walking and running, but really importantly and very frequently in the majority of patients, you're getting this sort of change in personality and behaviour which can occur for, to some extent, two or three or even four years prior to the hard neurology. And that's a very non-specific feature, it's a sign, it's hard to quantify, but again very common in what parents will say and perhaps very different to what parents of a child with cerebral palsy will talk about, for example. So what we see here that as well as the age difference in onset between late infantile patients and juvenile onset patients, we also see subtle differences in the way these children present, and that, unsurprisingly, when the same sets of parents were asked about what sort of disorders they were told about from the start, and what misdiagnoses did they receive on their way to hearing about metachromatic leukodystrophy, unsurprisingly many of them were told that their child might have developmental delay, many were given diagnoses of dyspraxia, developmental coordination type disorder, or learning difficulties. Again, because of all the challenges of school, ADHD and other sort of child psychiatric conditions were felt to be common, but also because we've got evidence of peripheral neuropathy, some of these children were felt to have other rare neurological disorders once the actual neurological features had been identified. And we can see that, despite the fact that some of these children, that there's a progression over months and years for all subtypes, some of these children do have episodic progression or periods of more rapid progression, sometimes perhaps sparked off or triggered by an acute infection, and so there can be concerns about transverse myelitis, Guillain-Barre, or a more acute acquired neurological disorder. So early on, there's lots of capacity for misdiagnosing these very commonly seen conditions in childhood, and you can entirely understand why there is a significant time lag in the diagnosis of many children when it comes to metachromatic leukodystrophy. So to try and summarise my cases here today, I think we have to have a high index of suspicion, especially if we're finding a new onset of neurological signs in a young child. So if there's anything hard that's actually, that you can find on examination, then that's really important and you should investigate. Clearly, if you're in doubt, investigate. Do you send a whole series of metabolic tests off on every child with developmental delay or learning impairment? Of course not, and that's not what we all do, and we understand that. But if there's concern about progression, then children do need a much more detailed and comprehensive assessment. As you've seen here, I think there's really no replacement for simple clinical examination. And whilst we get caught up often on panels of tests to do and how early we should do them and screening tests, actually, it's the clinical examination, the clinical neurological clinical examination, which often, if we're very clear about how we do that, often the most enlightening and helpful thing that will discriminate this child between other children who may have simple dyspraxia. So the scans, especially in the late infantile cases, are usually very classical, but are not always. And I've certainly seen early and late juvenile children, juvenile onset children, have abnormal scans very early on in the course of the disease. So they may or may not be typical. When the scans are classical, then the diagnosis is made almost by the radiologist. However, we would always want to quickly move to formal diagnostic testing. And usually that's quickest by enzyme testing in blood, but not always. And when we're screening children who've got leukodystrophy, I guess my plea would be that we should focus on the most important, rapidly progressive and modifiable causes, not necessarily the causes that are most common or the most academically interesting. And we all get tendencies to go down roads and sometimes the radiologist can be excited by the particular features on scan and say, oh, I wonder if it's this particular gene or that particular gene that's just been described. And again, really important to always think of, you know, could this be an adrenoleukodystrophy, X- linked adrenal leukodystrophy, which is rapidly progressive? Could this be metachromatic leukodystrophy, which is rapidly progressive? As the importance of early diagnosis in both of those two diseases is, you know, really cannot be stressed enough. And so I'd like to stop there. And I think we've got some time for questions. So the first question I have here would be, is CIDP the most common misdiagnosis with MLD in young children? CIDP, of course, chronic inflammatory demyelinating polyneuropathy. And so the children, I don't think that that would be the first and most common misdiagnosis. Actually, in lots of these children that I've seen, the peripheral neuropathy is identified actually after the fact. So we make a diagnosis of MLD because there's a decrease in motor skills. An MRI scan shows leukodystrophy and the focus is very much on the central disease. And so early on, there's usually a concern about dyspraxia type presentations. And then we move into the, you know, the big leukodystrophy panels, lists of hundreds of genes type concerns. So I would, although we have seen CIDP as a early differential, actually, that's not absolutely typical and perhaps more common in the early and late juvenile cases than the late infantiles. And the next question here is, at what age should ADHD or Attention Deficit Hyperactivity Disorder be considered as a possible sign of MLD? And of course, whilst I spend my life looking after children with rare diseases, I do indeed have to admit that ADHD is profoundly more common than MLD. And I've seen a number of children with neurodegenerative disorders identified early on as ADHD. And obviously here, the big differential would be for those early juvenile children at the ages of four or five, starting school often when ADHD is suspected as well, who are struggling early on. And I guess in MLD children, it wouldn't just be the standard ADHD signs. Yes, the child may well be struggling in school. They may well have poor attention, but there's also some motor concerns as well. And so like with many neurometabolic presentations, we would ask you to think about the neurometabolic causes when some of the very generic presentations have a little bit extra. So if it's not just an attention problem, but there's some motor concerns as well. It's not just a delay in development, but there's perhaps some actual neurological signs as well that these sorts of ADHD plus or development delay plus would perhaps make it much more likely for you to be picking up an underlying neurometabolic disease. But also, I think it is no substitute for review of patients. And whilst these kids start off in a very nonspecific way, and it's really hard to expect anyone to pick them up early on, what they do is they progress. And so problems don't get better with time. They get worse with time and new problems emerge. And so that's the key, really. And only by really good history taking and an actual sensible and simple clinical examination are you able to pick these sorts of things up. So the next question is about how to proceed with laboratory testing for query MLD cases. Excuse me. Excuse me. And this depends kind of where you are. And historically, almost all of these patients would be diagnosed initially by a enzyme level. Our software is a enzyme level in leukocytes and different labs will do that in different places. There's no development of a dry blood spot assay to make some of that diagnosis perhaps easier. Urinary sulfatide is elevated. So that's the accumulating substrate in MLD that in the absence of arylsulfatase A, the body cannot break down. And the sulfatide can be measurable in the urine. And that's available in some countries in Europe, much faster and easier than than in others. And so certainly here in the UK, it's probably easiest and fastest to get an enzyme level. But in other countries and other settings, the diagnostic pathway may be different. You can. There are very few other things that will give you an abnormal urinary sulfatide. But, you know, you shouldn't rely on that by itself. And you would want to measure the enzyme level. And of course, you also want to sequence the gene and look to see whether there are mutations in the gene. And in some cases, we know that if you can get a rapid leukodystrophy panel, perhaps within two weeks, then that will be a fast and accurate way of diagnosing most cases of MLD. But in general, we would suggest don't use any one of those tests by itself. And in most cases, we would like to get all of those tests to feel very confident and secure in the diagnosis. And so I think speak to your local laboratory. About what's likely to be fastest to get a diagnosis for MLD and ALD. And the next question I've had is about division and visual impairment. And do we see it in MLD patients and when we might see it in MLD patients? Yes, we certainly can see visual impairment in MLD patients. However, it's usually quite a significantly later sign. So it's not usually an early sign of the condition. And it would not certainly aware of any patients presenting like that. So it's not like buttons disease, for example, where you will get early seizures and you may well get early visual impairment in MLD. You tend not to get early seizures at all. This is more of a white matter disease. And the visual impairment is a late sign and is often cortical in nature. The next question is about speech and whether this is always normal for age. And it isn't always normal for age. In the infantile patients, they may have developed because that's most commonly presented by the age of two. They may only have developed sort of one to two word sentences before they start to deteriorate. But it's primarily early motor presentation. So I wouldn't say that speech is always normal, but it's not the main part of development which would progress in the very early stages. There's another question here about treatment options. In this form, this is somewhat challenging to start talking about. But the key element is, of course, that early diagnosis is critical for treatment. And the earlier the diagnosis can be made with the smallest number or the fewest number of neurological signs, then the more likely there are to be options for treatment. But I can't get into that in this webinar, which is, I think, about to finish and is an entire topic by itself. OK. Thank you very much for listening, everyone. And I hope you find this useful. And I will end the webinar here. I think the presentation will be available as a video link.
[00:37:04] Dr. Simon Jones: Thank you very much.