Short Summary: The science of glycosylation, its impact on health, and potential treatments for congenital disorders of glycosylation (CDGs).
About the guest: Dr. Eva Morava is a pediatric geneticist originally from Hungary, who has specialized in inborn errors of metabolism, particularly CDGs. She has a background in pediatrics and genetics from training in Hungary and the U.S., and currently leads the genetics and genomics department at Mount Sinai.
Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and to everyone on YouTube. Partial versions are available elsewhere.
Episode Summary: Dr. Eva Morava discusses the critical role of glycosylation in biology, where sugars are not just used for energy but in modifying proteins to perform their functions. She explains how defects in this process lead to CDGs, a group of rare genetic disorders. The conversation covers the mechanics of glycosylation, clinical presentations of CDGs, current research on treatments including dietary interventions and gene therapy, and the broader implications of glycosylation in health, such as in liver disease and cancer.
Key Takeaways:
Glycosylation Basics: Sugars are attached to proteins (glycosylation) to modify their structure and function, influencing everything from clotting to immune response.
CDGs: These disorders are caused by genetic defects in the glycosylation process, leading to a wide array of symptoms because many proteins require glycosylation to function correctly.
Clinical Variability: CDGs can range from severe, multi-systemic presentations to relatively mild cases, affecting life expectancy and quality of life variably.
Therapeutic Approaches: Current research includes drug repurposing for enzyme activity enhancement, dietary interventions with special sugars like mannose, and gene therapy, with some trials underway.
Liver Connection: A significant portion of glycosylation occurs in the liver; thus, liver diseases like non-alcoholic fatty liver disease can impact glycosylation.
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Episode transcript below.
Full AI-generated transcript below. Beware of typos & mistranslations!
Eva Morava 2:54
me wonderful. I'm delighted to share with you the mysteries of CDG. And do you want
Nick Jikomes 2:59
to just start off by telling everyone a little bit about who you are and who you are and what your background is, what you
Eva Morava 3:06
study? Yes, I have very adventurous past. I'm a Hungarian who trained in Hungary as a pediatrician and then trained as a geneticist in New Orleans at Wayne University. That's where I fell in love with inborn errors of metabolism. And when I first heard about this rare disease, congenital disorders of glycosidation, I worked most of my career in Europe, mostly in the Netherlands and Belgium, and 10 years ago, I was re recruited to come back to the US and work as a clinical medical biochemical geneticist, first at Tulane, where I trained, and at Mayo Clinic, and just very recently at Aman Sinai, at the Department of Genetics and Genomics sciences, I'm responsible for the training of The residents here, categorical and a combined residencies in genetics, including medicine and genetics and pediatrics and genetics, and I also lead the metabolic team here and see patients and do Research.
Nick Jikomes 4:38
So what is glycosylation? What is the actual biology going on there under normal, normal circumstances? What is it?
Eva Morava 4:48
Glycosylation is a process of activating sugars, and after they are activated, to assemble them to Gly. And chains. These glycan chains are made step by step in the endoplasmic reticulum and later in the Golgi. In the endoplasmic reticulum, usually a protein accepts the glycan chain, which is synthesized and later further processed in the Golgi. But lipid molecules are also able to carry a glycan chain, so there are different types of glycosylation, and the very basic division is N linked glycosylation, bowling glycosylation, combined glycosylation defects and lipid and other glycosylation disorders. So
Nick Jikomes 5:50
this is a way of modifying proteins with sugars. So in other words, this is a way that our cells use sugars, other than just using them for energy. They can actually sort of stick them onto proteins, and that has consequences for what the proteins do.
Eva Morava 6:03
You hit the nail on the head. They are thinking about sugars as energy source, but we have to build structures from sugars, and without them, the most of our proteins, most of our functional proteins, won't be able to get their secondary and tertiary structure, and they want won't be able to function correctly. So if we
Nick Jikomes 6:24
think about this just in a step by step, in basic terms, we've got genes in the genome in the nucleus of the cell. Those genes are transcribed into RNAs, that's the process of transcription, and then those RNAs are translated into proteins and folded into proteins. But it doesn't necessarily end there. Basically one of the things that can happen after that a post translational modification, is this phenomenon of glycosylation, basically a chain of sugar molecules is essentially stapled onto the protein, and that helps it do stuff.
Eva Morava 6:56
Yes, I think you described it quite well. I think that the structure without the sugar antenna would be very different. And for example, in a case of an enzyme or a transport protein, if that glycan is not attached to the protein, that maybe the active site remains open, or just the configuration of the protein would be so different that won't be able to carry something like iron or copper?
Nick Jikomes 7:24
Yeah. So it has potentially a very strong effect on what the proteins can do and how they work, whether or not they work as intended. And I think you said that. Did you say that most proteins have some kind of glycosylation? It's a very common thing.
Eva Morava 7:40
Most functional proteins do. I can give you examples for such proteins. Secretary, proteins in measurable in your blood, are very good examples. And actually a good example is coagulation factors. Almost all coagulation factors are glycosylated, and if you miss the glycan, then you don't have normal clotting. So you have a surgery and you would bleed, or you have an accident, and you won't stop bleeding. Also, anti coagulation factors are glycosylated, so even more complicated, in a problem with glycosidation, you can bleed and also get a stroke or a thrombotic episode, because the clot, whenever it forms, it cannot dissolve. But other good examples are hormone regulatory proteins, if you think about proteins which are which are essential for your survival. FSH, LH, for example, in your brain, which is essential to get you into puberty or or thyroid stimulating hormone, which is essential that your thyroid gets enough stimulation to to keep you imbalance for your energy regulation. Other examples could be transferring, which is transferring your iron in your blood, but it seems like I only talked about Secretary proteins. You should know that immune proteins are also highly glycosylated, so immunoglobulins, you won't be able to fight bacteria if you don't have glycosylation, because that's the actual chain which recognizes the or surrounds the bacteria for further killing action. And then all your proteins in in the brain, which are, for example, on your cell surface to signal to other cells, very often glycosidated proteins. Receptors are almost always glycosylated, so your. Acetylcholine receptor in your muscle. If you don't have the antenna, it cannot receive the acetylcholine message and cannot contract. So it's quite complex. If you don't have glycolation, you are involved every little piece of your body, every inch is affected by a glycosidation problem. Wow.
Nick Jikomes 10:25
So lots of different proteins are glycosylated. This affects all sorts of stuff in biology. I would imagine, you know, so, so if glycosylated proteins are involved in everything from the immune system to metabolism to development to, you know, muscle and neurons, I would imagine that if there's a problem with glycosylation, that lots of lots of different things could go wrong.
Eva Morava 10:48
Well, I told you that there are different glycosidation sorts, right and glycosidation The most common pathway. Which is affected by human disease. And you can actually, you cannot really mention an organ which is not affected if you have a congenital disorder of glycosidation, so all organs get some functional defect in in most of the common and glycolation disorders, and there are just a few exceptions where only a few organs or just the brain is affected. I have to add to this, though, that I mentioned all glycosylation disorders, and these are more tissue specific disorders, so it's not so easy to diagnose them, because you don't have a blood marker to because n glycosylation mostly happens in the liver, so you secrete out the proteins, and then you can measure them in the blood. But in all glycosylation disorders, or lipid linked glycosylation disorders, you need very specific tests, because the liver is not so much affected, and not giving us easy markers to diagnose the disease. So
Nick Jikomes 12:20
given that glycosylation is the addition of sugars, chains of sugars to proteins and things, does dietary carbohydrate intake affect glycosylation?
Eva Morava 12:35
You made a big jump going towards potential therapies. It's very important thought. And there are a few disorders, maybe I should mention there are actually 200 disorders known due to glycosidation defects. So that's really a high number of type of disorders under one biochemical umbrella. So from these disorders, unfortunately, only maybe six or seven are treatable by dietary modifications, and these could be adding very special, rare sugars to the diet or adding certain elements like manganese or magnesium, which are very important for the normal function of glycosylation the Golgi, but in some degree, in the Er as well. So
Nick Jikomes 13:40
after proteins get made, they're often being glycosylated within organelles like the endoplasmic reticulum or the Golgi apparatus. When this is happening like I want to understand a little bit more about the mechanics of glycosylation for the actual process itself. Is it an enzymatic process? Are there dedicated enzymes that are attaching or doing this to proteins? How does it actually happen? How does it get stuck? How did the sugars get stuck to a protein?
Eva Morava 14:08
Yes, you're right again. And if you ask me, how I teach this to my students, I usually say it's like the ER is a conveyor belt, and lipids like dolly cool are the actual seeds where glycolation starts and an enzyme comes and grabs a sugar, and then the next Step is another enzyme comes and add another sugar. And there are many, many steps just along the ER, there are like 20 something steps which happen enzymatically, and then you go to the Golgi. And there are very specific transporters, which are also and some like proteins, they bring in special sugars to the ER but there are also the conveyor belt is working in the Goji as well, so you have enzymatic steps following each other. Now you asked me, maybe, is that the only way you can just you can get a congenital disorder of glycosylation? Actually, there are several proteins which are responsible for Golgi integrity, trafficking, regulator proteins, for example, which are not per se enzymes and have more global problem or Global function, leading to glycosylation problems. You could say maybe these are secondary glycosylation disorders. But at the end, these regulators affect the enzymes in the step by step or a step wise process. So from my perspective, these are also true glycosylation disorders.
Nick Jikomes 16:22
So I would imagine that a congenital disorder of glycosylation means that there's just some problem with this process somewhere, somewhere in the assembly line. There's probably multiple places where things can go wrong. But because this is such a basic and widespread cell biological process, there's many, many many proteins, as you said, that get glycosylated. And so this, this, this has, you know, it's a widespread thing. It's not just an isolated thing. I would imagine that when you have a problem in the glycosylation assembly line, so to speak, it's probably the disease probably manifests in a very general way. It's not like one part of the body is affected. It's probably a whole body. Issue is that the way these disorders work,
Eva Morava 17:04
where n glycosylation disorders, this is true for most n linked glycosylation disorders. It is probably surprising for you that in all linked glycosylation disorders, sometimes only one organ or a few organs get affected. For example, there is glycosylation or monocylation disorder called muscle, eye brain disease. And in is a very severe disease. And patients can be born without eyes or very tiny eyes. Their brain can be zoom out form that they don't have gyrate so they is the gyration of their brain. So the brain is just like smooth, smooth, exactly. And you can imagine you cannot really learn much if you're born with the brain like that, and then the muscle is affected and and weak, and gets weaker with time. So we still don't really understand why other organs are not affected. We understand why the organs or systems affected. Why do they get affected? Because the monocylation is very important, for example, for a muscle protein called dystroglycan. So I understand why, then the muscle weakness happens, but why other organs do not suffer? Why it's not expressed in all the organs? That's that's an exciting question for the future geneticist, and you
Nick Jikomes 18:44
said before you said something about special sugars being involved in the glycosylation process. Are when a protein, say, is glycosylated these these sugar motifs that are stuck out of the protein, are they made out of like special sugars, or are they composed of things like glucose, that we think of as sugars? Normally?
Eva Morava 19:05
Yes, that's a very important question. And if you think about biochemistry, I think that it's clear that glucose should be used for something else and some glucose molecule. How should I say so, for example, anocetic glucosamine, that's the sugar which is built into the sugar chain. But glucose itself, it doesn't, it has regulatory role, but it it's we are not spilling our glucose to to build it in structures, but there are a couple of very special sugars. One, one is, for example, the monos, which is very important in the sugar chain, especially in the brain. And that's a sugar maybe you heard. About, because when somebody has a UTI, then this is prescribed to to help urinary tract health, and also available in cranberry and other sugars. But it's very, very tiny amount. What? What's in the diet? So actually, the body keeps these sugars inside and not spill them. So actually, you reuse them for your glycosylation. You don't burn it. Pee it out you, yeah, it's rebuild it. So,
Nick Jikomes 20:38
so there's, obviously, there's different sugars in the in the world, basically, it sounds like what you're saying is from like, a bioenergetic and efficiency standpoint. You know, glucose is an energy substrate for ourselves, so we want to use the glucose for energy purposes, to make ATP. So we're generally not going to use that to build, build these sugar residues that are going to be part of the glycosylation process. We use other types of sugars. Are all of those things dietary in origin, but we just ingest them in smaller amounts. Or are we sort of making new sugars from other sugars or something?
Eva Morava 21:09
Yes, you can actually make these new sugars. So for example, monos, monos, phosphate can be made from fructose. So you're able to make them, but they are also in the diet, but there's such a small amount, and usually you just keep them inside. And then when protein gets old, the sugar residues, they get cut off, and then you get back all your substrates, right? And you break down your protein, and you start to build a new one, and then you make a new antenna. So you're very you know, there's a
Nick Jikomes 21:53
recycling process when, when a protein, a protein gets made, maybe it gets glycosylated. It does its thing for a while. At some point it gets old. It's broken in some way. The cell rips off the sugars, probably breaks them down and reuses them, and sort of the whole process can happen again with recycled components. Yeah,
Eva Morava 22:10
very frugal, right? This is just use, reuse everything. And the other rare sugars, maybe, maybe an important sugar is colactus, which is really in the diet, right? That's what was it called, galactose. Oh, galactose, okay, yeah, galactose. And I'm Hungarian, I'm glad. I wish
Nick Jikomes 22:34
I actually visited Hungary last year. Was, it was a really cool place.
Eva Morava 22:38
Yes, it is Bucha, especially so galactose is is the monosaccharide from lactose, which is in our diet, and we think it has a very important role. When you are born, you get a lot of Mother milk, and actually that's how you fill up your colatos reservoirs, and patients with significant galactose restriction could develop some problems just by the dietary restriction. That's how important that sugar is for your biochemical health. Interesting,
Nick Jikomes 23:18
so so that sugar is found uniquely, or mostly in milk, and if you were to restrict it too much that that could lead to glycosylation issues, basically,
Eva Morava 23:27
yeah, secondary, yeah. But actually it's also in tomato and in some vegetables. So it's really funny. Probably people don't know that it's also in in vegetables, but yeah,
Nick Jikomes 23:41
and because these sugars are are minor sugars, we don't consume them in large quantities like we do with glucose. And because these recycling mechanisms exist, you kind of just need a little bit in your body. It sounds like your cells can sort of hold on to them, store them, and recycle them for long periods of time. That's correct. And so, so you've used the analogy of an antenna multiple times. A lot of times, these glycosylation residues are acting as something like an antenna, helping helping a protein. You know, sense something in the environment.
Eva Morava 24:10
Yes, maybe antenna is not so good idea, although in the brain, I I'm thinking about, you know, for example, lipid linked glycosylation. They stick out from the cell surface, right? And signaling is important. But also you could say arms, you know, because when immunoglobulins have their sugar chain residues, they actually find the bacteria and come around the bacteria and sort of grab it, and the killer cells come in and they kill the bacteria. So coagulation, if you think about it, like a coagulation factor, has the sugar chain attached to it, then and. Other coagulation factor comes and these sugar chains, they they help to assemble the different factors and make the clot. So protrusions or, yeah, yeah,
Nick Jikomes 25:13
yeah, they're attached to proteins. They stick out usually, and they're doing something functional. I mean, oftentimes when we talk about biology, we think of sugars as being for energy. We think of proteins as being for doing stuff, but, but what you're saying is actually certain sugars can get attached to proteins and be part of the doing stuff, the action, the action. Yeah. And so what are some of the more what are some of the more common? My understanding is these things are all pretty rare. But among them, what are the more common congenital disorders of glycosylation, and how do they clinically present?
Eva Morava 25:49
So the most common type is called PMM to CBG, and you have to know that they name these disorders based on their gene. So the defective gene name, and then we add CDG, so PMM two is from phospho mono mutase. Then the gene for that enzyme is PMM two. This is a disease which was described by Professor yakin, who is a famous, famous Belgian pediatrician. He's still alive, and he still sometimes sees patients in Leuven Belgium. The story is really, really fun to hear how he discovered this, because this, this was 45 years ago, he encountered two patients who had a b star, number of blood abnormalities. The patient had bleeding abnormalities, but then more than one clotting factor was wrong, and also problems with dissolving the clot had hormonal problems. But not just the thyroids were wrong, but there was also the prolactin, which is important for lactation, but also sex hormones were abnormal, and then their transport proteins as well. And so it was just a bizarre picture. Nobody saw anything like that. And then twins both had the same presentation with some developmental delays. And so he was just thinking about what's common in all these proteins. And he just said, well, they are all glycosylated proteins, so this should be a new genetic defect of disorder of glycosylation. And so it was more than 20 years that the gene was found. And he was right, but it's just showing that some clinicians are brilliant in discovering disorders before we have the way to to prove and but that does also or it gives an answer to to your question. So most patients with this disorder have all these really bizarre clinical picture with bleedings and thrombosis, early on, liver problems and and and endocrine problems, low blood sugar and not going into puberty and not growing. And that's only just just a few symptoms I mentioned, because obviously other organs can be affected. The heart, yeah, the kidney.
Nick Jikomes 28:47
The clinical presentation is multifaceted, and that's what makes it bizarre. They've got multiple issues with blood clotting and, or developmental problems and, or multiple hormones that are not acting appropriately. So, so it's not like there's just one process that's defective, or one protein you can point to, which is probably what made it so mysterious. But it also speaks to the fact that this is a general process. If you've got a glycosylation issue, it's going to affect lots of different
Eva Morava 29:10
stuff. Yes, you're completely correct. And
Nick Jikomes 29:15
so how how common is this? Is this extremely rare? Is it like? How rare is it? So
Eva Morava 29:21
this disorder I mentioned, PMM two, CDG, it's about one in 20,000 so actually it's, of course, it's a rare disease, but this is a frequency we would do newborn screening for if we had an FDA approved therapy, but unfortunately, we don't, not yet.
Nick Jikomes 29:44
And so what, what are people working on in terms of possible therapies? Is there anything that looks particularly hopeful? Are there are, I would imagine that there's, you know, potentially some drug therapies people are working on. But also, earlier you mentioned the possibility of dietary intervention. You know, this is a biological process that involves sugars, using sugars. Is there a way that it can be affected in some way by diet?
Eva Morava 30:09
I would like to bring up another disorder. It's less common, but just maybe easier to understand the treatment dilemma. So one step before this enzyme defect is another defect where it's called phospho mono isomerase, and that's the first phosphorylation of or phosphorylated monos, which is in this machinery of activating monos, the rare sugar which is essential for the glycans in the ER so in that case, because phosphorylation of a sugar at the sixth position of the sugar molecule is possible by another enzyme. You can treat it with giving a very high dose of monose in the diet, and then that monose will trigger the hexokinase, which is normally phosphorylating glucose, to phosphorylate the monose, but you have to give a really high dose, so it's almost a diabetic dose of monos you're giving to the diet. Well,
Nick Jikomes 31:30
normally, normally, there's so much glucose and so little mannose that this enzyme sort of will never just see it and process it. But if you just really crank up the mannose relative to the glucose, it will actually work
Eva Morava 31:41
on it. Yes, exactly. And I just wanted to tell you, what's the name for this. This is, like a fun name for this enzyme. This is a moon lighting enzyme, because it comes in and helped out. Yeah, it has a Yeah. So that is possible in this MPI, CDG, phosphomony, isomerase defect, but the step after which is actually the most common, CDG, PMM, two. CDG, unfortunately, that is coming phosphor to the first place. So the monose molecule at the first position, and there is no other natural enzyme which could take over that task. So it's a very difficult challenge, because options for treatment would be either you provide this phosphorylated monos to the body, but then it's an active phosphorylated molecule, it would wouldn't make it to the cell, wouldn't make it to the right compartment, but also wouldn't so unstable, but also would hurt membranes. Other option is to change somehow, the configuration of the sick enzyme. So use a chaperone, or use small molecules, which would just change the configuration that the enzyme could be more active. Or you could also think about genetic treatments, like gene therapy, right? So there are options, but none of them are trivial and easy to accomplish, because it's a very specific compartment of the cell and how hard to direct the therapy there at the inside.
Nick Jikomes 33:37
Yeah, yeah. And you know, when patients have a congenital disorder of glycosylation. I mean, in general, what are, what are, what are the outcomes? Is this something that affects lifespan? Can they live somewhat normal lives? Are they, or are they like very much impaired
Eva Morava 33:58
initial disorder was a very severe disorder described by Professor yakin. The twins discovered them. Are 40 something year old. They're still alive and they're in wheelchair, but they're able to stand up and make a few steps. They have some speech. They are very happy and very social individuals, but they do need a lot of care. This is the severe end of the spectrum, and since I'm seeing many CDG patients as it became my focus and I really enjoy meeting the families and taking care of the kids. I met exceptional, mild cases, diagnosed cases where the diagnosis was made at 18 years based on delayed puberty. And no other symptoms. I have little ones who are developing pretty much close to normal. So far so good. We don't know if that stays that way, but I think that the phenotype is quite variable and and there are many, oh, and the oldest patient is 76 I know of. And that's also good news for you know, outcome, prediction
Nick Jikomes 35:29
and so what? What are so in the field, your work, or just anyone in the field, what are people working on today as it relates to developing therapies,
Eva Morava 35:40
um, drug, repurposing is very strong in the CDG field, because chaperones or small molecules could really benefit enzyme activity, and not just In PMM two CDG, but in many other disorders, this is a viable option. Besides that, there are several cdgs Where there is gene therapy already on mice or fish model level, and there are two or three gene therapies, which are in clinical trial for CDG.
Nick Jikomes 36:25
And I would imagine, you know, if, say, you know a CDG exists because there's some sort of enzymatic defect, a mutation in a gene that's involved in the glycosylation process, you would want something like a gene therapy in order to fix that, and you'd want to probably fix it early so, so right, there's probably a developmental aspect of this is important, because the the defect and glycosylation, you know, if it's, if it's there from the beginning, it's going to impact the entire trajectory of development. So in theory, you'd want to sort of correct the the you'd want to correct the issue early on in development, I would imagine,
Eva Morava 37:02
yes, I should interview you, because you're so good in glycosylation, you would get an A plus from me. So yes, you're right. This is a big challenge. Glycosylation is so important for fetal development and cell migration that even though the mother compensates some degree, but we do see malformations, especially brain malformations, cerebellar malformations in many cdgs. And so if you want to treat then the optimal treatment is to diagnose these fetuses early and then maybe treat them intra uterine, that would be the coolest thing.
Nick Jikomes 37:49
And so you said, this is about one in 20,000 people, or something like that. So when, when you have something that's this rare, it's common enough that there's probably quite a few people out there that have this in their lives, but it's less common than other things. How does that affect the ability to obtain funding for this research? Is that a challenge?
Eva Morava 38:17
Yes, it is a challenge. I think Rare Disorders just go back to the frequency. So you asked me the most common disorder? PMM, two CDG, one in 20,000 some disorders are extremely rare. One in several millions. So it's there are really unique cdgs as well. You can imagine even more difficult to get support, financial support for such a disorder. But from my perspective, glycosylation is so important in so many you know specialty, if you just think what I told you, from hematology to immunology, but even in cancer, because glycosylation is essential for metastasis. So if you use your CDG as a model to understand glycosylation, then you can, you know, deduct certain things which could help common diseases as well. So hopefully one day, people understand that, and we'll get FDA support. Yeah,
Nick Jikomes 39:29
I would imagine in your field, you know, even though you're focused to some extent, on the cdgs per se, you know, understanding glycosylation as a biological process has ramifications that go beyond cdgs, exactly, yeah, exactly, yeah, and then
Eva Morava 39:45
teach that to the NIH and all the authorities. Very timely,
Nick Jikomes 39:51
Yeah, I bet so, because this is such a basic aspect of biology, glycosylation is so common, there's so many different proteins. That that get glycosylated. What are there so, so if you don't have a CDG, if you're just an otherwise normal person, are there defects in glycosylation that can develop as a consequence of, say, just metabolic dysfunction or chronic disease? Can something go wrong with glycosylation in a normal person? Basically,
Eva Morava 40:19
yes. This is a significant problem if you have a liver disease. Now it's a pretty hot topics, Nash, I don't know if you know that non alcoholic liver disease got designation like that, and that's just one example. Actually, autoimmune liver disorders and other liver dysfunction also have a major effect on glycosidation, because that's where it's happening. And glycosidation 90 more than 90% of glyco and glycol station happens in the liver. So that's a good example where it's changed, and the other is cancer, because the glycolation changes, so metastasis can spread. In my patients, actually, cancer is very rare. They are missing glycolation. So, so the cancer, in case a cancer appears, it doesn't have that easy way to spread to other parts of the body.
Nick Jikomes 41:27
So if I'm hearing you correctly, a lot of glycosylation happens within the liver, and if one develops non alcoholic fatty liver disease, or fatty liver for from any cause, that probably then starts to compromise the liver ability to glycosylate things normally,
Eva Morava 41:43
and then that depends on how severe the liver disease is, but, and in a case of a severe, severe liver disease, glycosylation will get affected.
Nick Jikomes 41:55
What you know is, you know, this is a this is a basic cell biological process. It can manifest in these diseases, these cdgs, but glycosylation is important for everyone. The biochemistry gets pretty complicated, pretty fast. I mean, if you had to sort of summarize everything, what do you want people to take away from this conversation in terms of the importance of glycosylation and the need to study it,
Eva Morava 42:23
right? It's a big ask, so I'm a clinician, and I mostly focus on my patients, and I really focus on trying to understand how glycosidation affect their function and and to try to treat that. So that's my personal interest in this. But evaluating glycosidation, we learn so much about the function of the body that there is no student or trainee who wouldn't benefit understanding this more, because you can just take that information and use it as a diagnostic method or understanding what the biology or changing proteins in their function by altering glycosylation. So I think that that is really relevant for everyone. And another interesting, a little anecdote. PMM, two CDG, patients are genuinely cheerful and social. I'm not saying that there are no exceptions where a child has severe developmental delay and autistic or or learning problems. But if you one day meet the kiddos I'm taking care of, you would be surprised how they embrace life and that sun shiny attitude is actually contagious. So what I want to learn one day, what is the genetic or biochemical reason for an incomparable positive attitude in a severe multi system disease compared to other medical disorders, where the patients are so frustrated and unhappy and and, and, yeah, different,
Nick Jikomes 44:36
yeah, they're often cheerful. Or you might even say, I don't know, depression resistant?
Eva Morava 44:41
Yes, so there are exceptions, but majority of the patients are so lovely, it's hard to resist interesting,
Nick Jikomes 44:54
and I don't want to take too much more of your time, because I know you're busy and you got to get back to the clinic. I. Is there anything you want to reiterate from this conversation, or anything, any final thoughts you want to leave people with about these diseases or about the underlying biology?
Eva Morava 45:09
You want to come and train with me? I think you'd be a great train and genetics. Are you interested in further developing your career and be a geneticist? Well,
Nick Jikomes 45:21
actually, my original training was in genetics. That was in my bachelor's degree. It's been a while since I've I've been in that world, but we'll see what happens.
Eva Morava 45:31
Maybe I the only thing I want to say is that CDG research is heading towards developing good models that we can better understand what's happening in the human body, and we are starting to leave animal models like fish and mice behind, and one exciting perspective is the use of organoid systems, which we develop from patient derived cells. That's brain organoids, heart organoids, liver organoids and systems. And then, if you think about it, you have the whole epigenetic, genetic, everything environment in your little, you know, model system. And so if you find a treatment in that system that's very easily translatable to that individual, even it's ASO therapy or gene therapy or a small molecule. So I think that for glycosidation research, this is really a breakthrough, because most of the animal models do not survive the genetic if you, if you build these models, then the mice either doesn't show the phenotype or dyes that they were born. So there is a new era for us, and I think these organoid and patient self derived model systems are really cool to make the next step and understand this better and then to find therapies.
Nick Jikomes 47:18
All right. Well. Dr Eva Morava, thank you very much for your time. Thank you.
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