In this webinar, Prof. Soumeya Bekri & Abdellah Tebani, PharmD, PhD from the Metabolic Biochemistry Department at Rouen University Hospital, France have covered a topic on inherited metabolic disorders and how omics technologies help. They also talked about the clinical actionability of omics-based biomarkers in the inborn errors of the metabolism field and beyond.
Soumeya Bekri is the head of the Metabolic Biochemistry Department. They are dealing with the diagnosis and follow-up of inherited metabolic disease, and she’ll explain, in a simple way, the tools they use to do the diagnosis and the follow-up for their patients. She’ll also give an overview of the metabolic landscape and a few examples, from their experience in diagnosing some patients.
Abdellah Tebani works along Soumeya in the laboratory of metabolic diseases. On a daily basis, they try to diagnose and follow-up their patients that have these conditions. So, the idea of the presentation is to provide some very simple basics of what these diseases are, how they occur, how they diagnose them, and to which extent these are important to follow.
The topic presented is about Inherited Metabolic Diseases using some tools called Omics. As you can imagine, a human being is just an assembly of different small parts called molecules. These molecules come together to form very small structures, to form at the end a human being. Therefore, the way a human being works is defined by how these small parts interact between each other through the lifespan.
The metabolic syndrome is not an inherited metabolic disease. It’s a metabolic impairment, but it’s an acquired a metabolic impairment, not inherited. To answer the question as well it depends on what stage the diagnosis is made, and what age and what stage, and the environment, the diet that’s taken by the patient, but yes, in some cases it’s reversible.
One thing about this. If you look at the slide I showed about environment, biology, and clinic, I think metabolic syndrome fits very well in that picture because it depends on the three layers. You have the three layers and one of the challenges to embody the precision medicine perspective is metabolic syndrome as well because it takes the biological layer, the environmental layer, and the clinical layer.
It’s important to understand in any disease is how these different parts work together through the lifespan. In very simple terms, how does metabolism work because these diseases deal with metabolism.
Metabolism is when you eat food, it breaks down into small pieces, which are broken down through the metabolism. Thus, it’s just the conversion of food, the big part into tiny parts so that the human body can assimilate them, and the final point of this assimilation is to produce energy, so that people grow, speak, feel, see, etc.
To understand, the diseases, people need to understand how metabolism works to produce energy to live. The break-down of the metabolism into a unique unit, it’s very simple. According to Abdellah, they take a very small part that is converted into another small molecule called B, so, they take part A and are converted to B using a tool that’s inside people’s bodies called enzyme.
Enzyme 1 converts the small molecule A to B; then, another tool Enzyme 2, converts product B into product C. As can be seen in the image, there’s a highway that’s drawn from A to C thanks to the 2 machines, Enzymes 1 and 2 which are proteins. These proteins come from the gene which is in the DNA, therefore, metabolism is defined through the DNA.
This is the very smallest part of the metabolism. If you take a lot of pathways, as shown by Abdellah, something complicated will be obtained.
The whole metabolism is just an interaction between the small parts to form the whole of it. This is called a metabolic network.
As explained before by Abdellah, to convert the molecule A to B, Enzyme 1 is needed and if it’s broken, out of charge, it doesn’t work at all, and there will be a lack of conversation. Therefore, you will get a lot of A that it’s stored and a lack of C because it’s not converted from A to C. So, in your body, you’ll get a lot of A and a very low concentration of C.
As your body requires C to survive, to talk, and to produce energy, and there’s a lack of C, you will lack a lot of functions. On the other side, your body needs to get rid of A if it’s normal, but if there’s a problem with the Enzyme, you will get a lot of A and, if this is toxic, then your body is in trouble. This is the first part to understand what a metabolic disease is.
According to Tebani, this machine is coded in your DNA, with your gene 1 that codes for Enzyme 1, and gene 2 that codes for Enzyme 2. If there’s an alteration in your DNA, in your genome, you’ll get an issue with Enzyme 1 and make it inherited because you transfer it through generation. For this reason, it’s called Inherited Metabolic Diseases.
If you take the whole metabolism, almost 1000 diseases have been described so far that cause a metabolic disease because one of these, 13000 machinery is altered.
Inherited metabolic diseases can appear at any stage of your life span. They can appear in the following:
According to Abdellah, these are not paediatric diseases, but they span the whole life.
When we understand inherited metabolic disease at the basic level, we can act through different therapies. – explains Abdellah.
If you take the basic line pathway, you have A that is converted to B and then to C due to Enzyme 1 and 2. Following the example given by Abdellah, the machine has a problem with Enzyme 2 and, if you have a problem with this, you have an increase of B and a decrease of C. What makes the disease is that you have a lot of Bs, but also because you have a low concentration of C.
The treatment of these diseases is either to restore B, get rid of the increase of B so that you have no more toxic effects by activating another pathway, like opening a door so that it goes through, or to give the patient the molecule that’s lacking, in this case, C. The patient can receive C directly or take another drug that can produce C, thus, there will be an increase in the concentration of C, and then the patient will no longer suffer from the disease because he or she receives the lacking molecule.
Tebani gives an example of a broken car as you can just replace it using a spare piece, this is the same thing with the machine. When there’s a problem, which is Enzyme 2, it can be just replaced through injection. The patient is injected with the new Enzyme called Enzyme Replacement Therapy.
Therefore, there are 3 main ways or weapons to treat a metabolic disease:
You have a molecule A that is converted to B through an Enzyme or protein produced by a gene.
The first thing to do to diagnose the disease is to prove that you have an increase of A or a decrease of B; this is done using a technology called Metabolomics. For this reason, Tebani takes samples from the patients, either urine or blood, and he should see if there’s an increase in Metabolite 1 or a decrease in Metabolite 2.
The second thing to do is to prove that Enzyme 1 doesn’t work or doesn’t work enough anymore, so Proteomics is used.
In simple terms:
There are 3 tools: metabolomics, proteomics, and genomics, to diagnose inherited metabolic disease. However, they’re not seen very easily. According to Abdellah, they need to put the patient in his or her environment, so he or she evolves in a social environmental ecosystem.
To precisely diagnose the disease and go through a serious follow-up of the disease, they need to know:
Afterwards, they need a precise picture of what the patient feels physically on a clinical side. For this reason, they have three parts to be able to precisely diagnose an inherited metabolic disease. They also need to prove the biological problem and shape the ecosystem in which the patient evolves.
Soumeya Bekri states that they have all the possibilities for the onset of an inherited metabolic disease from the prenatal state to the elderly state. During the prenatal stage, there’s a possibility of having an inherited metabolic disease during the pregnancy and its main sign is Hydrops Fetalis, which is an edema of the fetus.
According to Bekri, they know some really common ideologies like immune aetiology, but if they read about the common etiologies, there are a lot of hydrops fatalities without any diagnosis and they know that inherited metabolic diseases can come with this presentation. Nevertheless, with conventional biochemical investigation, they aren’t able to do all the diagnosis because they’re sequentially doing some analysis and they have a hypothesis; they think about a disease, then they will try to explore it, and if it’s not they will have another hypothesis and so on.
Moreover, they ended up having a lot of cases without any causes known and they could not handle the patient. Bekri also shares that 5 or 6 years ago, in their lab, they decided to perform a new generation sequencing analysis including all the known genes able to cause such a condition, such as prenatal presentation of inherited metabolic diseases. This way they can analyze 42 pathologies in one shot and have a data-driven hypothesis because they’re looking for a global analysis and they end up targeting one pathology.
At the first-line investigation, they do a genetic analysis. Then, they end up with a pathology they can confirm using the three tools: proteomics and metabolomic study.
Abdellah and Dr Bekri had a female pregnant patient of 35 years old at the prenatal ultrasound examination at 31 weeks of gestation.
The examination showed a kidney abnormality because the kidney was very big. They performed different genetic, viral, and metabolic aetiology and there weren’t any clues for this condition. They also performed the NGS analysis with the hydrops fetalis genes and ended up identifying an alteration of a gene known to cause the kidney disease.
In the end, the pregnancy went well and they had an uneventful birth. They were able to provide an early management of the renal function for the baby and he’s doing well with normal psychomotor development. In addition to this, they could also do genetic counselling afterwards.
Another example given by Dr Bekri is related to the prenatal. The majority of inherited metabolic diseases had a neonatal presentation.
She mentions that they often have some days or hours without any symptoms. This case is of a little girl who presented a 12-hour-of-life, anorexia, poor consciousness, hypotonia, and abnormal movements. All these critical signs helped them think about the metabolic impairment, thus, they did some metabolic analysis and ended up demonstrating some abnormal amino acids and concentrations with a metabolite elevation and some decrease in other metabolites. This allowed them to determine the protein, the Enzyme that wasn’t working.
In this case, it was a disease known very well called the Maple Syrup Urine Disease and, even though it’s a very serious disease, the good news was that they were able to manage it using the appropriate diet. Moreover, the prognosis would have changed completely if they had been able to do the diagnosis in the very early stages of the disease, then she would have had an almost normal life. They were also able to perform genetic counselling as well.
In order to provide an example of a late presentation, Bekri mentions that in the medical community, inherited metabolic diseases are always linked to pediatrics and people are not aware that they can have a late presentation of the disease.
In this case, they had a 45-year-old woman with a serious liver abnormality which ended up in fibrosis. When they assessed the lipids in her blood, there was an increased level.
For the diagnosis they first did metabolic analyses, they assessed the acid Enzyme activity which was at a decreased level, and then they confirmed the diagnosis by using genetic analysis, which showed that the patient had Cholesterol Ester Storage Disease. This disease is treatable by Enzyme Replacement Therapy, and they can also perform genetic counselling.
Abdellah Tebani mentions that nowadays they have new lenses to look at diseases at unprecedented depth and resolution. The new tools, basically, next-generation sequencing, mass spectrometry, and other tools, allow us to dig into a more detailed visualization of the problems at the metabolic level.
Therefore, when the problems are seen at this depth, they can be better understood and better treated, and patients can also be better counselled. The next generation of healthcare in this disease and in healthcare in general, will be heavily based on these different omics technologies.
All you hear in the media about artificial intelligence and this big data thing, this will help us a lot to provide better health care to the patients because, at the end, what we all seek is more precise information, more precise treatment, and healthier life when we do understand things at a higher resolution.
The way they do the diagnosis nowadays is by relying heavily on omics technologies that allow them to see things they weren’t able to see before.
Moreover, Tebani concludes the presentation with the following:
I just want to thank all the people working with us to handle these diseases; these are only a few and, of course, we can’ t thank more patients because they are the heroes of all these stories.
The presentation for inherited metabolic disease, the main transmission, is equal for men and women. We can have the same clinical signs in men and women except for the diseases that are transmitted through chromosome X. For chromosome X we have, for example, Fabry disease which it’s a rare disease, and the gene is on chromosome X.
Women are more protected since we have two eggs, in this case, we can some difference in the presentation between males and females. For the male, since we have only one X in the male patients, if the only copy of the gene is altered, the disease will be present and will disappear and all the symptoms will be present.
In the female, it depends, because it’s quite complicated, but we can have a more moderated presentation or, sometimes, in some diseases we can have no presentation at all. The difference is that in the majority, 99% of the inherited metabolic diseases, we have the same presentation for males and females. I hope that I answered the question. The example that we have here is female, but just by chance.
In the majority of Europe, at least, we have in all our countries a program of newborn screening. I think that you’re aware that for each newborn in Europe, at least, it’s not the case in some other countries such as Africa or other countries, the poor countries. But in Europe and Occidental countries, we have this newborn screening and in this national program, systematic screening helps detect, diagnose, and screen for inherited metabolic diseases that are treatable if the diagnosis is done very early.
That’s why we decided to start from the beginning of 1917. It’s a systematic screening to detect these diseases and to provide the appropriate diet, generally, it’s diet, sometimes the treatment just to have this metabolic block bypassed using another metabolic pathway. Just to give you an example, I think you heard about Phenylketonuria or PKU, it’s the disease part of all the newborn screening in Europe, and worldwide as well. With the inherited metabolic disease we can have at least examples in the three major pathways: sugar, lipid, and proteins. All the Enzymatic reactions can be targeted or blocked. We have all the huge networks that Abdellah showed you, which can be broken into steps.
With different omics tools we use them on routine basis, but those that are really being used in the clinic, are mainly Next Generation Sequencers, which is Igenomix, heavily used in diagnosis of genetic diseases, and metabolomics because we look at metabolites, and proteomics as well, it’s getting more and more involved. The prices are getting very low now and most of the labs can afford these genetic diseases at affordable prices.
There is a lot of science that can help us to think about an inherited metabolic disease. For paediatricians, it’s straightforward, they are used to and the main problem is the shortage of energy; if you do have not enough energy, you have some organs that cannot be well. The first one is the brain, the first sign, for the children at least, is coma or neurological decompensation, epilepsy, and so on. In the paediatric stages, we don’t have concerns because paediatricians are aware and, if they see that the metabolic disease can be suspected, they do what they have to do very quickly, and we can do the diagnosis and take care of the child.
We insist on the fact that the symptoms can appear at any time, for adult patients we can have some delay in the diagnosis because the medical doctors dealing with adult patients are not usually used to this kind of disease, then, sometimes we have patients that have varied symptoms since several years, and the diagnosis is very, very late. That’s why I think that we have to continue to talk about these diseases and raise awareness.
One of the symptoms we usually see in these kinds of diseases is for example, it’s not always the case, but to give you an example which is obvious, some kids, when you give them a specific diet or food, in some cases when you give some meat to a kid, and it has some reaction about that, we can’t think about some specific metabolic disease because we can have the link about high protein diet that could cause some commas.
In some cases, we can think about this way, but as you may have said, one of the challenges of getting this metabolic disease is because they’re called rare diseases, they are not that rare because if taken as a group of diseases they are more often than we could imagine, one of the challenges we’ve all faced, and I think this kind of meeting try to fill in the gaps, is to raise awareness of this so-called rare diseases because they’re not rare as I’ve said. Sometimes, just because you know that this could be a metabolic disease, they just light a ball in your head, and you can go through the right pathway. Sometimes, it’s just a matter of hours or days, and you can save a lifetime of a kid. It’s not straightforward, but just thinking about it is a way to go.
Yes. It’s roughly as you see.
It depends on the way the disease is transmitted. This question is similar to the previous one because even if we have a monogenic disease, with the same gene, we can have the same alteration with the same context, the sibling we can have. Last week, we had a case in our lab with a moderate presentation and in the family, we have the same variant, the same alteration in the gene, a very severe presentation, and that’s why we think that other factors, genetic factors are our environmental factors or whatever we’re not able to have all the exact answers right now for all the diseases. But for sure, we have this heterogeneity in the phenotype and clinical phenotype, and we’re not able to say that this disease will behave exactly in the same way for all the siblings in this family, for example. Even if we sometimes have some gene alterations that are severe and others are moderate, or we have this individual specificity, that’s why the omics tools enable us to have a huge amount of data that can represent this heterogeneity that can enable us to approach this complexity.
The way we present the disease so far, we did it just for the sake of simplification of the talk, this linear vision of this disease, if you have A or B, if it’s linear, if another sibling has the same thing, biology is not at all a linear phenomenon and we in our research, in the lab, we are using omics tools and other tools to prove that unfolding this disease complexity is, for sure, not linear. That’s why, in the beginning, we said that calling these diseases monogenetic diseases is not true because, as we said, we got the same gene alteration with a different clinical presentation. This obviously and eloquently shows that biology is not at all linear.
For mitochondrial diseases, the question is quite different, and the transmission might be different. Mitochondria is an organelle, it’s a small part of the cells, and in the mitochondria, we have a mall DNA that is different from the DNA in the nucleus. This small DNA is encoded for only 13 proteins. All the other proteins that are needed for mitochondrial functions are encoded by the nuclear DNA.
The point is that the mitochondria are inherited only from the mother, so it’s maternal. If a woman has a mitochondrial disease due to the alteration of the mitochondrial DNA, she may have children with this disease, male and female children, however, the male with this kind of mitochondrial disease will not be able to transmit this disease to children. It’s easier to predict and to cancel if we have a mitochondrial disease with a nuclear origin because it’s straightforward, we can have a variant in the fetus, for example, for a prenatal diagnosis or not, and we can cancel based on this.
If the variant is on the mitochondrial DNA, it’s more difficult to be sure whether the maternal mitochondria are not inherited in the fetus or not. I don’t know if it’s clear because it’s kind of complicated. Mitochondrial disease is not a straightforward transmission, so it needs some schemes just to show how things work.
The metabolic syndrome is not an inherited metabolic disease. It’s a metabolic impairment, but it’s an acquired a metabolic impairment, not inherited. To answer the question as well it depends on what stage the diagnosis is made, and what age and what stage, and all the environment, the diet that’s taken by the patient, but yes, in some cases it’s reversible.
One thing about this. If you look at the slide I showed about environment, biology, and clinic, I think metabolic syndrome fits very well in that picture because it depends on the three layers. You have the three layers and one of the challenges to embody the precision medicine perspective is metabolic syndrome as well because it takes the biological layer, the environmental layer, and the clinical layer.
