MBG INBORN ERR. PT 2 PDF

Okay, while we grab some of these lovely snacks the OMS students brought you, we'll just do some fun announcements. So yes, I will be here on Monday. That is always part of the plan, so, but what I am changing in terms of the plan, it is my goal to pre-record the following week's content so you have...

Okay, while we grab some of these lovely snacks the OMS students brought you, we'll just do some fun announcements. So yes, I will be here on Monday. That is always part of the plan, so, but what I am changing in terms of the plan, it is my goal to pre-record the following week's content so you have it over break. So if you so choose, you can literally go through all of the content for the semester. So wherever we stop on Monday, I will record all of what's left and the final lecture, I'll pre-record all of that and get that up there on Tuesday and so you will have it for the duration of break. What that means is when we come back, we essentially will have three days for honed in review and practice. Does that sound like a good change? Okay, so that is the new plan. All right, did we all get our snacks because that was really sweet of the OMS students to do. All right, so let's get back to a galactosemia as you enjoy some lovely sugars. So the goal for these conditions, if you look in your packet, you'll see that last slide, the question slide has a nice table. That's the goal. With most genetic style questions, you're given two pieces of information and you need to come up with the third. Sometimes you're given the name of the condition with symptoms and you've got to identify the specific gene. Sometimes you're given the gene and the symptoms and you need to identify the condition. Sometimes you're given the gene and you need to go from there. So I want us to be able to go from any of those pieces and tease out what would I expect to see? If I have this mutation, what mutation would I expect to see if I have this condition? And so tables and summaries that link the specific genes to the outcomes. And so this one is a great place to start because I'm not asking you to regurgitate a biochemical pathway. That's not what this semester's for. What I'm asking for you to be able to do is see that depending on where in a pathway you're altered, your phenotype can be more or less severe. With galactosemia, one of the problems that is created is you actually produce a toxic galactitol byproduct. This toxic product builds up and creates much of the more severe phenotypes. And so we expect that to be more closely associated with our type one mutations in GALT. GALT and gale have far less severe implications and we can use the pathway to see why. So if you look at GALT specifically affecting this uridyltransferase, that is a very different step than these others. And if you have too much of one product, you do end up with that toxic byproduct. And so being able to classify these against each other, if I were to say something like, which of the following genes would be associated with the most severe phenotype for an individual that cannot properly process galactose? So which one? GALT. Does that make sense? Okay. Why does this never wanna do that? All right. So just to simplify the metabolism piece, we can see the important role for our uridyltransferase in that pathway. So again, this is a four year information to put this into context of a bigger pathway. Many pathways have what we call rate limiting steps or crucial enzymatic steps where the function of that enzyme is very determinant for products. In galactosemia, we have not only an inability to utilize a fuel properly, but also the potential to build a toxic byproduct. Toxicity is a major concern in these inboard errors of metabolism as many of the things that we're trying to process cannot build up without causing a problem. And so we're gonna move past sugars to our amino acids. And so again, we have glucogenic and ketogenic amino acids, and it's all about how they're utilized and where they fall into our glucose metabolism pathways and where they feed into providing us with fuels. And so this is a, you'll notice, there's no lecture objectives on this. This is just giving you an orientation of where we're going because we're gonna talk about PKU. Phenylcatenuria. This is an autosomal recessive condition that is all about toxic byproduct, toxic buildup of a key amino acid. Phenylalanine. You need to be able to properly build and break down material. When you have too much of it present, you end up with the potential to throw off the whole system. You can have things crystallized. You can have things literally block ducts. Literally block openings to major structural components. You're just filling it with stuff. Those are bad things to have happen in terms of a systematic functionality. And so for toxic buildups of phenylalanine, you literally end up most predominantly impacting the brain microenvironment because they can build up in those cells. In that compartment. And so that damage of having that too much phenylalanine along actually begins in utero. If a woman with PKU is pregnant, she must pay attention to her phenylalanine intake because she will begin damage to the developing fetus if she does not. You essentially cannot properly process phenylalanine. Specifically because you lack or have mutations in phenylalanine hydroxylase. So it's a typically a loss of function mutation. And in some of these cases, if we have some retention, like just a little bit of activity, that's gonna result in a, I cannot talk today, I am so sorry. Happy Friday. If we still retain some function of the enzyme, we will have a less severe phenotype because some function will give us the ability to break down some. But we will not be able to deal with high levels of dietary phenylalanine. And so much of what happens with the inborn errors of metabolism is many of the actual interventions that we have are dietary. Dietary restrictions, preventions, changes in diet, but they have to be implemented as soon as possible. And so for phenylalanine, build up begins in utero and will continue throughout infancy unless changes are made. And you cannot reverse the damage once it's begun. Does this make sense? So next one is the maple syrup urine disease. This is also autosomal recessive. And this one is about processing other amino acids. And we have three specific mutations that we correlate most strongly with this condition, BCK-DHA, BCK-DHB, and DBT. And essentially this is all about branch chain keto acids. And so if we come back to our glucogenic and ketogenic amino acids, we are having difficulty dealing with our amino acids. And so we get what? If we can't break it down, we can't make changes to them, what's gonna happen? They're gonna build up and it's gonna cause toxicity. This can be a lethal level of buildup. This can be lethal in early infancy. And so specifically, leucine, isoleucine, and valine will be among those contributors. So I'm gonna go back again and just really highlight where those are. Here's leucine and that's our ketogenic. But then you'll notice that some things are exclusively ketogenic and other things are glucogenic and ketogenic. There's isoleucine over here. So use this when thinking about where that's coming into play. Ultimately, we are not able to break these down, which means we cannot use them. Amino acids are phenomenal carbon sources. We use them to build other things. When we break them down, that is happening because we are out of our preferred fuel. What's our preferred fuel? Glucose. But we also bring amino acids in in our diet. So we have to have the ability to deal with them, especially in excess. Too much of a good thing is a bad thing. Anything in excess can be toxic, including air and water. So what is the actual process where we see these branch chain breakdown? This is just a contextual. We will talk about this more in the painfully near future. No, we're not super excited for BioCalm. It should be, it's lovely. So much fun. Anyway, we're literally talking about this step right here. Does that make sense? So that is the expectation from these. Be able to link the gene to the toxic byproduct. And what that would mean for the whole system. So taking the big picture view, why are these inborn errors of metabolism correlated with systemic implications? Structural changes, cellular deficiencies, lethality. I don't know why I shouted the word lethality at you just now, but why? Why are these things, galactosema, fructosemia, breakdowns and the ability to utilize amino acids correlated with systemic implications? Structural changes, lethality. All of your cells need fuel. When you are that important to a biochemical or biological process and it is a universal importance, you will see systemic effects on the organism because all the cells need that. Now the very levels of expression imply the varying levels of importance to that tissue. But we must consider systemic implications for an inability to break down or utilize fuel. If you never take in phenylalanine, if you do not bring it into your diet, you have far fewer implications in PKU. That's literally the goal of therapeutic intervention, is get this out of the diet. So you can manage many of these with key dietary changes, but you're not gonna completely eliminate some of the structural or developmental things that occurred in utero. Does this make sense? Cannot reverse damage that has been done to the brain in these cases. All right, so that is inborn errors of metabolism or common metabolic disorders. Do not spend time on the pathways. Link the gene to the condition, to the changes observed. Which ones produce toxic byproducts? Not just lead to toxic buildup, but actually produce toxic byproducts. Which ones lead to toxic buildup? What is building up? Be able to link those unique features to the gene, to the condition. Make sense? Okay, so now we're on to essentially a, really what only amounts to a snapshot of the wide world of molecular biology implications and genetics of human disease.