00:43:13
Trancription
[00:00:05] Professor Maria Gizewska: Hello, everybody. My name is Maria Giżewska, and I am a pediatrician, metabolic pediatrician, from Pomeranian Medical University in Szczecin, Poland. Thank you very much for joining me today for the webinar organized by Excellence in Pediatrics Institute. And the title of our today's webinar is Spotting the Signs of Inborn Errors of Metabolism in Neonates and Infants. But before we start, let me give you some webinar training notes for attendees. So please do not take any screenshots. Photos are shown with the permission of parents and can't be reproduced or shared without the express permission of the author. And our webinar will have 30-minute format, followed by question and answer via text. And please submit your questions at any point via the questions panel that you will receive. And questions can only be submitted via text and not verbally. And as many questions as possible will be answered at the end of the webinar. What are the learning objectives for our today meeting?
[00:01:19] Professor Maria Gizewska: First of all is to answer the question, how to undertake a comprehensive medical history of a child suspected for inborn errors of metabolism. Later on, we will talk about how to identify the early signs of inborn errors of metabolism in neonates and infants, and how to avoid common misdiagnosis and confusion with other conditions. So let's start. At the beginning, I would like to give you a bit of history. The term inborn errors of metabolism has been introduced for the very first time by Sir Archibald Garrod, a physician from London. Garrod was the first who found that there are probably some diseases which may be related to abnormal course of the biochemical reaction taking place every second in our bodies. Moreover, he was the first who linked these disorders to the phenomena of inheritance. So since Garrod's time, we know that inborn errors of metabolism is a group of genetic disorders with a clinical significant block in the metabolic pathway. What about the incidence of inborn errors of metabolism? Well, all of them are rare, rare diseases, which mean that they have the incidence lower than 1, 000 to 2, 000 live birth. Some of them are also ultra- rare, which means that they are really extremely rare. And in fact, there are some conditions that have been described only among several families in the whole world. But even if they are individually rare, they are collectively numerous. And there are really hundreds of inborn errors of metabolism that we can detect among our patients. And please remember that even the rarest inborn errors of metabolism may appear among your patients. The incidence is different regarding different diseases and regarding different countries. We have specific ethnic groups where particular diseases are more common. So we always have to remember and ask parents, where do they come from, and ask the question if they are not related, if there is no consanguinity between them, because that may focus our thinking to genetic diseases, including inborn errors of metabolism. Why we have to talk about these disorders, especially in respect to newborns and young infants? Well, this is because 2/3 of all inborn errors of metabolism manifest themselves already in the neonatal period. What is very difficult about this group of diseases is that clinical symptoms are often non- specific and may suggest common complications typical for newborns. And there is no doubt that many of these diseases are not diagnosed, and the wrong diagnosis of neonatal sepsis or other common complications in the neonatal period are established, like the respiratory distress syndrome, birth trauma, ileus, and other possible complications. So in other words, the clinical presentation of all of these complications during the neonatal period, including inborn errors of metabolism, may be very similar. So please remember that symptoms of sepsis in a full- term neonate without any risk factors strongly suggest inborn errors of metabolism. And here are some important information, some general information about this particular age group of metabolic patients. So we have to remember that neonate has a limited repertoire of responses to a severe illness, regardless of whether the disease has an infectious, genetic, traumatic, or other background. Metabolic disorders should be considered, along with other diagnoses like infection or CNS pathology, in all neonates with unexplained, overwhelming, or progressive disease, particularly after normal pregnancy and delivery. We have to suspect that any neonatal death may be due to an inborn errors of metabolism, particularly those who have been attributed to sepsis. Therefore, many of these patients have to be, the autopsy findings of many of these patients, have to be carefully monitored. Well, how to come closer to the final diagnosis or reasonable suspicion of inborn errors of metabolism? Well, some very important information may come to us also when we will start to look into this particular patient's history, also including the pregnancy. Many inborn errors of metabolism may show the fetal hydrops. And this will be non- immune fetal hydrops. And here you have the whole list of inborn errors of metabolism, which may go together, which may present with the fetal hydrops during the pregnancy. But there are also some possible disturbances during pregnancy, which may be shown by the mothers. So mothers who are carrying the baby affected by LCHAD deficiency or other inborn errors of metabolism, especially fatty acid oxidation defects, due to negative influence of the metabolites produced by the affected fetus, may show severe liver insufficiency, and many other hematological complications in the form of HELLP syndrome or acute fatty liver of pregnancy. So here you have the best example of such a situation. This is a picture of a six- month- old child who was born from the mother whose pregnancy was complicated by severe acute fatty liver of pregnancy at the 32nd week of gestation. This child was born in our center at the time when the tandem MS screening was not available yet. And being treated by the neonatologist as totally healthy, she was discharged home. And she appeared in our institution at the age of six months in the course of severe liver failure as the result of first presentation of LCHAD. So especially in the places where tandem MS is not available, until beta oxidation defects are excluded, a child of a mother with hepatic complications during pregnancy should be treated as potentially affected. Now I would like to focus your attention on a very special group of metabolic diseases, which are those which go with metabolic intoxication. These disorders are related to a significant enzymatic block, which simply block the proper course of biochemical reaction. And this is the result of acute or progressive intoxication from the accumulation of toxic compounds proximal to the metabolic block. The list of inborn errors of metabolism which can go together with intoxication presentation is pretty long. The main that we're supposed to remember about are inborn errors of metabolism with amino acid catabolism, organic acidurias like propionic, methylmalonic, or isovaleric aciduria, very severe diseases related to congenital urea cycle defects, and we will talk about them later on, and sugar intolerance like galactosemia or hereditary fructose intolerance in older children where the fructose is introduced to their diet. So these four categories are the main representatives of inborn errors of metabolism with intoxication syndrome. So when we should suspect that our patient may be the one affected by inborn errors of metabolism with metabolic intoxication? First of all, we have to take a very detailed family history. There is never enough time that we can dedicate to a quiet discussion with our parents and trying to collect as many information and as many data as it is possible. However, all complications are possible. In most of the cases, we will find that this child is a child of young and healthy parents. Most of these cases are sporadic, so they may appear for the very first time in the family, but sometimes there is a history of parental consanguinity and maybe the families come from the specific ethnic groups. So sometimes we may already have information that this family is already affected by some strange disease. Therefore, we always have to ask if there were no unexplained and sudden deaths among newborns or young infants in this family. Sometimes mom may tell you that this family already lost some children or one child before with the diagnosis of birth trauma, neonatal sepsis, or unexplained sudden infant death syndrome. These are sometimes really crucial information that are essential for us to establish a reasonable suspicion for inborn errors of metabolism. But now let's come to this particular patient. And however, inborn errors of metabolism, of course, may occur among premature babies. It is quite common that they are born from uneventful pregnancy as a full- term baby. Uneventful pregnancy, uneventful delivery, and quite high, sometimes even the highest score in the Apgar scale. So in the very first hours or days of life, these children look absolutely normal. They look and they behave like absolutely healthy children. And then after several hours in some diseases or several days or sometimes even several weeks, something wrong is going on with this child. Why not immediately? Because child simply needs some more time to accumulate these toxic compounds which are not properly metabolized due to enzymatic block. And it depends on the quality and on the kind of this toxin. More toxic they are, the shorter will be this symptom- free interval. And the best example for this are urea cycle diseases, disorders, when due to the accumulation of ammonia, which is very severe toxin, the first clinical presentation may be presented already several hours after the delivery. This unexplained and sudden acute deterioration is due to postnatal accumulation of toxic metabolites, which are prenatally removed by diffusion across the placenta and metabolized by the mother. But of course, metabolites accumulate even in babies who do not receive oral pills. And this is because the catabolism is a part of normal adaptation to postnatal life. So now, if we come to more deeper into this patient's history, once again, I would like to remind you that neonate has a limited range of responses to severe illness. Therefore, acute symptoms of inborn errors of metabolites with metabolic intoxication in neonatal period may suggest the most common complication in the neonatal period, including neonatal sepsis. But to make the whole story even more complicated, we have to realize that there are some inborn errors of metabolism which, due to different mechanisms, may predispose a child to develop this common complication. Like, for example, in organic acidurias, galactosemia, or urea cycle diseases, there is a higher risk for the child to be affected by sepsis. So in such a case, we will have two situations, sepsis and inborn errors of metabolites. Children with organic acidurias, due to bone marrow suppression and thrombocytopenia, may develop intraventricular hemorrhage. So they may have a hematological presentation. And the same may be with children suffering from different kinds of hyperammonemia. Coming again back to the patient's history, I would strongly suggest you to listen to the mom, to the mother, because mom is the person who spends the most time with the baby. And she may be a person who will notice the initial symptoms that can be sometimes ignored by the others. And there is a possible correlation of inborn errors of metabolics first symptoms with protein or lactose content of the food given to the baby. Because this is simply the source of this metabolites and substance that a child, affected child, is unable to metabolize. OK, now let's come to the clinical presentation of this disease in our patient. So the most common presentation is neurological deterioration. This is because the brain of the neonate is especially sensitive to toxic influence of this accumulated metabolites. And the first symptoms presented by these children are really non- specific. They may show poor sucking and feeding. They may vomit. And we may wrongly think that this is maybe formula intolerance or pyloric stenosis. They may have different, quite a big variety of abnormalities of tone with hypertonia or axial hypotony. There are rarely typical seizures, but they are, of course, possible in, for example, non-ketotic hyperglycemia or urea cycle disease. Children, especially those with organic acidurias, may show very spectacular involuntary movements in the form of boxing or pedaling. And if we won't act aggressively at this moment, we simply may lost the patients already after several hours of this presentation. Many of these children may show neurovegetative symptoms like respiratory abnormalities, bradycardia, and vasomotor instability or hypothermia. We shouldn't forget about hepatic presentation, which is also possible with the whole symptoms related to liver failure syndrome, which are especially typical for galactosemia or tyrosinemia type 1. Especially children, neonates affected by galactosemia can show in the very first days of their lives liver failure presentation with jaundice, hemorrhagic syndrome, ascites and edema, elevated transaminase, and hypoglycemia. So in all children, newborns with severe pathological jaundice, inborn errors of metabolism should be considered. There are also some more specific symptoms, like, for example, abnormal odor. And you have some strange odors which may be produced by these children. So we shouldn't forget to use our nose as a diagnostic equipment. There may be cataracts, kidneys enlargement typical for galactosemia, and many other more specific symptoms presented by these children. Here you have a picture of one of our patients born many, many years ago, who came to us with severe symptoms of metabolic intoxication in the course of isovaleric aciduria. We were able to establish this diagnosis after a really pretty short period of time. And right now, this patient is almost 20 years old and is doing really great. And I remember him as a neonate in really critical condition due to acute intoxication in the course of isovaleric aciduria. OK, so now we have a child. We have the reasonable suspicion of inborn errors of metabolics and how to diagnose these children, how to came more closely to the final diagnosis. So right now, we are very happy having population screening available with the use of Tandem MS. This is a fantastic procedure, really a revolution in early diagnosis of inborn errors of metabolics, which, thanks to the involvement of a pretty complicated procedure, Tandem mass spectrometry, allows us to diagnose really more than 20 or even more conditions which are asymptomatic in the very first days of life and can be detected very early and very early screened and very early treated. However, of course, Tandem MS does not cover all possible inborn errors of metabolism. And for the rest of the diseases, we should direct child to the procedures related to selective screening. But let's say that we are in the part of the world where TandemMS is not available or we do not have the results of the test performing in our center. So how to establish this, as I said before, reasonable suspicion of inborn errors of metabolics? You have the whole list of investigation that should be done at the time of a septic screen. So when we are dealing with a really sick newborn, of course, we have to think about the sepsis or infection, however we would call this, because it is really quite possible. But please look, you have the whole list of really pretty simple, pretty simple investigations which, if abnormal, together with the family history, together with the very detailed examination of the newborn, can help us to establish the suspicion of inborn errors of metabolics. These children may have the abnormalities in blood cell count, in pH and blood gases. They may have electrolytes imbalance, glucose problems, including hypo- and hyperglycemia. They may have abnormalities in the simple liver function test. And they may have also increased concentration of lactic acid and ammonia. And I would like to focus our attention especially on the ammonia. This is an investigation which should be performed always in all newborns suspected for severe sepsis or with some other difficult- to- explain symptoms, because ammonia is really a terrible toxin to the brain of the neonate and should be detected as soon as possible. Many hyperammonemic children are those affected by inborn errors of metabolism, especially those which have increasing concentration of ammonia. But there is also the whole list of other causes related to development of hyperammonemia. Please remember that if there are technical problems with taking the blood for ammonia analysis, that may also cause some problems with interpretation, because due to hemolysis, the results might be false positive. The other very important source of information is urine. And we really have to look close to the findings in the general examination of the urine. However, of course, we can perform numbers of other tests which will help us to establish the diagnosis. But for example, such a finding as ketonuria in the newborn, together with severe metabolic acidosis and together with a severe condition of the child, strongly suggests organic aciduria, especially if, for example, additionally child spread abnormal odor around his body. There may be some other findings in the urine of this child related to the possible development of Fanconi–De Toni-Debre syndrome, which is related to the kidney damage by this improper metabolites. But after the evaluation of this, or at the same time when we will be evaluating this basic laboratory test, we have to store some biological materials for further specific metabolic investigation. And this includes blood, urine, and cerebrospinal fluid. Even if in the future we will not use them for more sophisticated investigation, these materials for sure should be stored for further investigation or immediately sent to the lab when the suspicion of inborn errors of metabolites is really in our mind. Here you have some example of additional investigations which should be performed in these children. Many, many other investigations may bring us more information which will direct us more in the direction of inborn errors of metabolics. But unfortunately, sometimes, however we are fighting very, very hard, the child is dying. And we do not have the diagnosis. At that moment, it is really a mistake to close the case. Because we should be able to come to the final diagnosis and to give the proper information to this family. The family has a right to know what was the reason of this child's death. Because that may significantly influence their future plans regarding the family planning and reproduction. So here you have the whole list of specimens that should be taken in the event of death when inborn errors of metabolics was or still is suspected. So at the end, I would like to summarize by saying that in a severely sick child, especially a neonate, it is a mistake to place inborn errors of metabolics at the end of differential diagnosis. Inborn errors of metabolics should be considered in all children from the Department of Neonatology Pediatrics, especially if patients present symptoms of encephalopathy, liver failure, or cardiomyopathy. We have to do everything to diagnose these patients. And we have to remember that they really may occur among our patients. And what is absolutely crucial is to understand and remember that many of inborn errors of metabolites are treatable conditions. So we have to do everything to avoid missing patients with potentially treatable conditions. So I would like to finish my webinar at this moment. And don't be afraid if I was speaking too fast or if you were unable to make a sufficient amount of notes, because everything has been registered. And you have the website where you can find. And via this website, you can also contact me and ask for my comments or answer to your questions. So please do not hesitate to contact me in case of any doubts. I will be more than happy to contact you and answer your questions. And now you have a question and answers panel. So I will wait, and I will look if we already have some questions. And if there are any questions, please write them, and I will try to answer. So let me check the questions panel. So the first question that appears is how many disorders are included in MS/MS panel for population newborn screening? Well, thank you for this question. It is really an important one. So tandem MS, tandem mass spectrometry, as I already said, is really a revolution in early diagnosis of inborn errors of metabolism among children and in early diagnosis of really growing numbers of diseases. In different countries, the list of the conditions that are included in the MPS panel performed with MS/MS is really very different and it is very country- specific issue. The country which developed the system right now on the highest probably level is United States. In United States, in November 2016, there was a core condition list that is supposed to be included in all states published and in this list there are about, as far as I remember, 25 conditions, inborn errors of metabolics, that are supposed to be checked in all newborns born in North America. And besides inborn errors of metabolics, there are also numbers of hemoglobinopathies, endocrine disorders and other disorders which are screened in the program called newborn screening. And there are 25 core conditions related to inborn errors of metabolism, mainly organic acid disorders, amino acid disorders and fatty acid oxidation defects. But based on this core conditions list, there is another list published, so- called secondary conditions, which are able to be diagnosed based on, during the procedures of differential diagnosis based on the results of this core conditions examination. So altogether, in most of the states in United States, the children are screened for more than 40 inborn errors of metabolism. In the United Kingdom, for example, there are so far 9 diseases included in newborn screening, including 6 inborn errors of metabolism and it is phenylketonuria, maple syrup urine disease, organ isovaleric aciduria, glutaric aciduria and homocystinuria. In Poland, we are very proud about the way how we screen our newborns and thanks to the huge involvement of our colleagues from Institute of Mother and Child in Warsaw, we screen right now for 24 disorders, including 21 inborn errors of metabolism. And beside inborn errors of metabolism, we also screen for congenital hypothyroidism, congenital adrenal hyperplasia and cystic fibrosis. So as I said at the beginning, this is absolutely country-specific issue, but we have to remember that however, in most of Western and developed countries, this list is really very long. There are still countries where screening is not available totally or where the children are screened exclusively for phenylketonuria or congenital hypothyroidism. So newborn screening introduced for the very first time by Robert Guthrie at the beginning of 60s is still unfortunately not universal. So this was about this question and let me move into the next one and the next one is how to avoid misdiagnosis between neonatal sepsis and inborn errors of metabolism. Well, this is more or less a kind of summary of my webinar. So first of all, we really have to remember about these diseases. This is first thing. They really may occur in our centers, and it doesn't matter where do we come from. This is one thing. The other thing is we really should have enough time to speak to the parents and ask them some of these particular questions that I already listed to you during the webinar. And we have to speak to the mom and ask her, what were the first symptoms presented by her child? If she will find that there were this symptom-free period, and now there is unexplained sudden deterioration, the suspicion for inborn errors of metabolism is really quite possible. Plus, if there are negative inflammatory indexes, typical for sepsis, or if it was a newborn born at term with no contact with any infection diseases, with no risk factor for development of sepsis, where all the bacteriological investigations are negative, we have to remember about sepsis. But in the same time, we have to think about the possibility of inborn errors of metabolism. Because again, it is a mistake to place these conditions at the end of the list for differential diagnosis. Because if we will wait to exclude all other conditions, and if we will think about inborn errors of metabolism at the end, we may simply lose this patient. It may be simply too long. One moment, let me see the other. What are the main patterns of inheritance in inborn errors of metabolism? Well, there are all possible patterns. All types of inheritance are possible in inborn errors of metabolism. Of course, autosomal recessive is the most common. However, again, all types of inheritance are possible, including mitochondria, which are pretty sometimes difficult to explain to the parents. And our knowledge about this particular disease, as well as about the type of inheritance, is really crucial for us to give a proper genetic counseling to affected family. Why it is like this? Because we have to explain to the patients, to the parents exactly what is the risk that they may have another child affected from the next pregnancy. We have to explain them that they are, let's say, playing from the beginning in each pregnancy. So for example, in autosomal recessive type of inheritance, of course, there is risk of at least 25% to have another child affected by the same condition. And if we are talking about very severe condition, we really have to give this information to the parents, because they may really be very surprised that the next child is born with the same condition. OK, let me see if I have any more questions There is a question from Greece. And it is that, in Greece, most private obstetric clinics recommend full metabolic disorders test immediately before the newborn exits the clinic. Do you agree with this recommendation as routine screening? I don't know what is the list of the diseases included in newborn screening tests in Greece. But if the test is performed according to proper technology, it means, I don't know, the second day of life it is done with MS/MS it is always a good idea to take it before the newborn be discharged. But the question is at what time the children are discharged because if they are discharged very early let's say at the end of, i hope, I suppose it is not the case in Greece, but in some countries, children may be discharged home before the end of second day of life. And it depends on technology if it will be enough duration of the time, enough for these metabolites to accumulate. So if this procedure, and I am quite sure that this is a case in Greece, is performed under strict technology procedures, it is good idea to have. And this is the idea about so- called expanded newborn screening, to take this test before the child is discharged home. OK. And let me, the question is, which are the first exams that the general pediatrician can ask so as to pose an early diagnosis of an inborn error of metabolism before deterioration? So first of all, if you are in the centers where tandem MS is available, and if you have any doubts about the condition, what we are doing is we are calling immediately to our colleagues in Warsaw, telling them, hey, listen, we have a child at the age of four days, and this child is suspicious for us. Can you tell us what are the results of this child MS/MS screening? So if they will tell us, well, on MS/MS everything is OK, at least we have the first information that this test is proper. However, I have to underline this at this moment, if still a suspicion of inborn errors of metabolism is actual, we are obliged to perform MS/MS for the second time. Because you never know. Maybe the first one was, let's say, false negative. So if there is still a suspicion for inborn errors of metabolism, then this test may be repeated. And it is quite common that we repeat tandem MS, we perform GC-MS, but at the same time, as I told you before, I perform a routine test looking for pH, looking for ammonia level, for glucose. These are really simple tests, which together with the clinical history of this child may let us come to the final diagnosis. OK, I am not sure if we're, ah, there is more or less the same question about which are minimum tests to be carried out in newborn to screen for inborn errors of metabolism. Minimal tests, for sure, I will perform blood gases, ammonia, lactic acid, detailed investigation of urine. And at the same time, never forget to collect blood on the dry filter paper, and full blood, as well as the urine for GC-MS, gas chromatography, mass spectrometry, which is really a very good investigation, which together with tandem MS helps us to create the final diagnosis. OK, I suppose we are almost out of time. And I don't see any more questions. So really, thank you very much for joining me. And I would like to remind you that if you have any more questions, if you would like to discuss any issues with me, do not hesitate to contact me via website. And all this webinar was recorded, It was Maria Gierzewska speaking from Szczecin, Poland. Thank you very much.