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[00:00:09] Dr Federica Deodato: So good afternoon everybody. Welcome to this new webinar dedicated to metachromatic leukodystrophy and, in particular, to the importance of family screening. My name is Federica Deodato. I'm a pediatric neurologist. I've been working in the unit of metabolic disease of the Hospitale Pediatrico Bambino Gesù of Rome. Just before starting this session, please few notes for you. I kindly ask you to do not take any screenshots, not reproduce any slides, and at the end of this session that will last 20- 25 minutes, I will try to answer as many questions as possible. Please be free to send your question at any time and at the end I will answer and remind that this webinar will be recorded, so will be available online at the end. So briefly, an introduction about MLD that you probably know because of previous webinar is a rare autosomal recessive lysosomal sphingolipid storage disorder. It is caused by the deficiency of arylsulfatase A enzyme due to the mutation of the ARSA gene, more rarely due to the deficiency of the activator. It is a disease characterized by variable symptoms, such as onset and disease course, but eventually all patients experience a severe neurocognitive impairment with progressive vegetative states and finally death. It is the pathophysiology is related to the lack of the enzyme which is responsible of the degradation of sulfatides, which are one of the major components of myelin membrane. So the lack of this enzyme determine and neutralize the autosomal accumulation of this toxic compound for many neuronal cells, leading to a destruction of myelin, triggering a neuroinflammation and both of central nervous system and peripheral nervous leading to a severe neurodegenerative disorder. Based on the age of onset symptoms related to the residual enzyme activity, we can distinguish different phenotypes. When we have a complete loss of enzyme due to new mutation, we will have the, the most early onset former, which is also the most severe and also the most common form, called the late infantile, with an onset before 30 months and with a rapid progression of the disease. On the opposite, when the we have a higher residual enzyme activity, we will have the so- called adult form, with an onset beyond 16 years of age and with characterized with a slower rate of progression. In the middle we have the so- called juvenile forms that we can also distinguish in the early juvenile or late juvenile. The onset is comprised between 30 months to 6 years in the first case, or between 6 to 16 years of age and of course the progression is different in these two different kind of phenotypes. Let's see the symptoms at onset. Of course it is a neurodegenerative disorder, so we have a combination of motor and cognitive problems. But if we look at the late infantile forms, it is characterized by gross motor impairment since the beginning, meaning an impairment of walking ability. More than 70% of patients never walk independently. They progressively lost the ability to stand, then fine motor function be compromised, then problem with eating, swallowing and the speech problem. Instead, in the juvenile form we can have both problems, cognitive and motor, but it is typically the onset with cognitive impairment. So typically these patients have problems at school in terms of behavioral problem, of learning, problem with speech problem, and only later usually appear the decline in gross motor function. So as you can see, of course we are speaking about very unspecific symptoms and so for, as in many other rare disease, it is not uncommon a diagnostic delay, which has- it has been estimated with a median 1. 2 years and 3. 7 years respectively in the late infantile and juvenile forms, and frequently the patient with late infantile still remained with a diagnosis of unspecific developmental delay before receiving the correct diagnosis of metachromatic dystrophy, while for juvenile patient is very common the diagnosis, the wrong diagnosis, of attention deficit disorder or something similar because of the cognitive and learning problem at school. Of course, it is a leukodystrophy, so, of course, when we perform a brain MRI in the presence of severe symptoms, we can see the typical pattern of involvement of white matter and, of course, an expert neuroradiologist is able to recognize the typical pattern. But what I want to underline here to you is that in the early onset form, in particular, the late infantile, the most severe, at the onset of symptoms, at the beginning, the brain MRI may be normal. On the other hand, it has been reported an isolated cranial nerve enhancement in when we still not have white matter involvement. As I told you at the beginning, it is not only a central nervous system disease, but there is an involvement also of peripheral nervous system because of the accumulation of sulfatides also in the peripheral nerve. And it is important to remind that in the early phenotype, we can have the onset of peripheral neuropathy before the onset of symptoms related to central nervous system. So we will have clumsiness or muscle weakness with areflexia that is important to reveal before the onset of symptoms of central nervous system. In the late onset form, the onset of peripheral neuropathy is later, and usually it's combined with pyramidal signs due to CNS involvement. This is a disease which was considered until now a so- called untreatable disorder. So therapy was based on palliative and supportive care. The challenge in treating this kind of disease is due to mainly two reasons. One is the difficulty to cross the blood- brain barrier, and so to reach central nervous system with the drugs. And the other important thing is the timing of treatment, because in this disease, like in some other similar neurodegenerative disorder, at a certain point, there is an irreversible damage so we can't treat this patient when an irreversible damage is triggered. As in many other lysosomal storage disorders, the hematopoietic stem cell transplantation has been performed in some patients worldwide, because based on the concept of cross- correction, so the enzyme is secreted by donor cells and then taken up by the recipient bodies. But in the case of MLD, beyond the risk of mortality and morbidity related to the procedure itself, there is a limited efficacy in modifying the course of this disease, especially in the early onset form. In particular, in the late infantile, it is not recommended anymore because it has been demonstrated that bone marrow transplantation is not able to halt the disease because it's too fast. Some benefit may be obtained in the later phenotype, even if performed early. So new therapeutic strategies have been evaluated in the recent years. One is based on the use of direct intrathecal administration of enzyme replacement therapy by using a device implanted in the children. And the first clinical trial was a Phase I- II study, evaluating the ascending dose of replacement therapy in children with late infantile form. The preliminary result was not so brilliant, absolutely, but some benefit has been obtained with the higher dose. So a new clinical trial is now ongoing by using a higher dose every week instead of every other week, but we will see the result in the future. But the most impressive result has been obtained with a gene therapy trial. This is a gene therapy based on autologous stem cell collected from the bone marrow of the patient and then transduced ex vivo with a lentiviral vector encoding the human ARSA gene. This was applied in pre- symptomatic early onset, meaning late infantile and early juvenile, and early symptomatic early juvenile. this publication of a few weeks ago. The result was very good, both in terms of cognitive function and in motor function, and the results maintained well for years. So, now is actively recruiting a new trial, enrolling also late juvenile patients. So, the results of these trials were so amazing that this gene therapy has been approved in all the European member states. It's the first gene therapy approved for a neurodegenerative disorder in children, but it is important to remind the limited indication, so it is indicated only in late infantile or juvenile with no clinical manifestations, so pre- symptomatic, or in the early juvenile with early manifestations, so the patient needs to be maintained in working ability and no cognitive decline. So, a very limited therapeutic window for the reason I told you before of irreversibility of damage. And this slide is only to remind that this is very exciting to have a gene therapy approved and reversed in so many states. So, let me present some history, some clinical example, showing the importance of family screening. This is a girl born with no problem. She was normal during the first year, normal psychomotor development, normal working ability. When she was 18 months, the parents observed for the first time after an episode of fever strabismus. They bring the patient to an ophthalmologist and only astigmatism was diagnosed. But in the following months, they started to observe an impairment of gross motor function. She was not like the other children, and also they observed a kyphosis of the spine. So, they bring the patient to an orthopedist, and an X- ray was performed showing no skeletal abnormalities. In the meantime, the baby continued to worsen, and she underwent a first neurological evaluation when she was 30 months old. It was evident a wide based gait, clumsiness, difficulty in jumping, and of course she underwent several examinations, including a brain MRI, which was normal. So, she received the diagnosis of developmental delay, and it was indicated physical therapy. But she continued to worsen again, and she was evaluated for the first time by us when she was 36 months. She was frankly ataxic. She had pyramidal signs. She had also a speech problem. The reflexes was slowly. She also had drooling, expression of dysphagia for liquids. And so, we decided to perform a second brain MRI after six months. And in this case, it was evident white matter involvement with a typical tigroid pattern. But it was also evident a contrast enhancement of the third and five cranial nerve. For the hyperreflexia, we performed also nerve conduction velocity, demonstrating motor and sensitive peripheral neuropathy. So, the diagnosis in this case was done by evaluating the activity in leukocytes and then confirmed with the gene mutation. And as you can see, the diagnostic delay in this case was 11, 19 months, sorry. Of course, we evaluated the therapeutical options for this girl, but we excluded bone marrow transplantation for the reason I told you before. We evaluated possible clinical trial because at that time, gene therapy was starting, but she was excluded because she was already symptomatic. And so, we enrolled her in the trial of in particular enzyme replacement therapy. She's still ongoing and we will evaluate in the future the outcome. But when we explain the autosomal recessive nature of this disease to the parents, they told us that there was a younger sister for the parents. She was normal. She was 10 months old at the time. She was effectively normal when we evaluated, but we confirmed the diagnosis also in this younger girl. And so, the diagnosis was made when she was 11 months and she was absolutely normal, pre- symptomatic. And so, she was enrolled in the gene therapy. So the results were absolutely amazing. She is now more than seven years old. She has a completely normal motor and cognitive development, so nothing more to say absolutely brilliant. So this case. I think that clearly underlies the importance of pre- symptomatic diagnosis that we can do in presence of an affected sib. So when we have an autosomal recessive treatable disorder we need absolutely to perform family screening. Of course you know that newborn screening is a program aiming to detect pre-symptomatic patients who have the possibility to be treated before the onset of symptoms. But you also know that newborn screening is complicated. It's much more than a lab test. So recently the European metabolic network is working hardly to create to develop an agreement for the definition of testing in all Europe to decide which kind of disease to add in the program. Until now newborn screening for MLD is not a standard practice. But surely it would be absolutely useful. It's because it's critical to permit an early diagnosis of patients and to treat them before the onset of symptoms. But the problem specifically related to MLD with newborn screening is the high rate of false positive results because of the so-called pseudo-deficiency, with low enzymes but no disease. So it's a problem in a newborn screening approach, but technically new. Several approaches are under development, and probably the most effective would be based on the so-called two-tier screening strategy, which means a contemporary measure of sulfatides in blood and enzyme activity and then sequencing the gene. So to conclude, we can absolutely say that MLD is a fatal, severe inherited neurometabolic disease. Symptoms at onset, unfortunately, like in many other cases, is unspecific, and so the diagnostic delay is frequent. Remind that brain MRI may be normal at the onset of symptoms in the late infantile form. On the other hand, the peripheral neuropathy may precede brain demyelination so evaluate the reflexes but remind that now we have a very effective treatment, absolutely able to change the natural history, but only if performed before irreversible pathogenetic damage. And so remind that pre- symptomatic diagnosis, until now is possible only by family screening, but we hope in the future by newborn screening.
[00:19:55] Dr Federica Deodato: I think I've finished and I will try to answer to your question, if you have some question. So I'll try to read your question. How often are MRI normal, even with the patient that has MLD? Yes, I can't say exactly how many times, I don't know, I don't have a statistical evaluation. But this regards only the late infantile. It's absolutely unusual to have normal MRI in the juvenile or adult cases. So it's only for late infantile but it's not uncommon. If we have at the beginning, when the children have developmental delay, only brain MRI may be normal. But, as I told you, especially if there is an involvement of cranial nerve, evaluate the use of gadolinium to reveal the contrast enhancement of the cranial nerve. This is very important when we evaluate a patient with developmental delay, because of course any of us perform at first a brain MRI but if it is normal and the patient continues to work, so to show regression different from normal psychomotor development, psychomotor delay, repeat and consider the diagnosis. So, let's see, what are the split between MLD being caused by a gene deficiency against the activator deficiency? Yes. I reported that there is the possibility of the disease due to activator deficiency, but it's very, very limited, so rare and rare. I don't remember now exactly, unfortunately, the statistical, but I think less than 5%. And of course, this kind of gene therapy, of course, is indicated only in case of MLD due to ARSA mutation, of course, not due to activator deficiency. So, how do you differentiate from CP in early stage? Well, good question, of course. I know that for a pediatrician, it's not easy to understand at the beginning if the children who show developmental delay will be a neurodegeneration or not. So, my advice is that if a baby is not walking properly at 12 months or 12, 13, to evaluate in few weeks. So, to try to evaluate the patient rapidly, not after 6 months because it's too late, after a few weeks, because in the late infantile, surely some other signs appear. Let's see if other questions, do onset type and timing, early, late, juvenile, let me, it's a long sentence, it's, do onset type stay the same with family or can they present a different? Oh, okay, yeah. Yes, there is, we can have different phenotypes in the same family and also different kind of response to treatment. For example, I had a family with two girls, one was diagnosed very late and so she is in natural history, the other one with early juvenile was treated with bone marrow transplantation at that time, several years ago, and they were clearly different, but I'm not able to say if the difference is related to a different phenotype in the same family or a different response to, related to bone marrow transplantation because anyway, bone marrow transplantation did not resolve the disease. I can say that it's slowly, but I'm not able to say if it is different because some other, some other factors influence the phenotypes in the same family with the same genotype. What about hearing issue? Is this seen in MLD? I think no hearing is not usually a problem in MLD. It is not a characteristic of this kind of neurodegenerative disorder, no, my answer is no. Let's see another question, ex vivo gene therapy, when will it be available across Europe? I think I told you clearly, it is available, it is, it was approved, so please review in the webinar recorded the slides, I show you two slides, and you can see that this therapy has been absolutely approved in all Europe member states and in some in Italy, England, Germany, and I'm not sure if Spain, I'm sorry, it is also reimbursed. So it's a real therapy, a real therapy with the limited indication that I told you. So I think that no, no many other questions, so thank you for your attention, I hope you enjoyed it and see you, bye bye.