MBG Inborn Errors of Metabolism - Part 1 PDF

okay so now we're going to spend some time with our inborn errors of metabolism which is a basically the common metabolic disorders and the biggest biochem block of this class so I use it as kind of an introduction to biochem by starting from the here's the gene here's the disorder oh yeah that's a...

okay so now we're going to spend some time with our inborn errors of metabolism which is a basically the common metabolic disorders and the biggest biochem block of this class so I use it as kind of an introduction to biochem by starting from the here's the gene here's the disorder oh yeah that's a biochemical pathway sound like fun all right we do have specific goals that's going to be about linking some clinical features to these at no point will you be expected to memorize one of these pathways please don't that's not the goal here we want to see why a change here causes the phenotype we see that's it know the gene know the condition know the phenotype what does it mean to be genetic versus inherited this isn't sort of a moment that I take and I picked the biochem one for it because you hear the term genetics and we kind of did this at the beginning of the semester but you hear the term genetics what do you think genes DNA change right something being genetic does not mean it's inherited many many instructors will use the term interchangeably or specifically mean genetics as solely inherited the problem is if you are a cancer geneticist you can't do that because most of those things that come in terms of cancer changes are somatic and not truly inherited to the next generation but what are the concerns for an individual who has cancer especially if they have an inherited predisposition to cancer what are they often concerned about risks to their offspring right risks to the next generation what is the chance that my mom gave me this I don't know why I picked on my mom just there but you know does that make sense so that's a different conversation when we're talking about a truly inherited piece of information and not just a cellularly inherited one and so for us it's important that we make that distinction there is a difference between a hereditary cancer disorder and a hereditary disorder with cancer and we're going to talk about that but from this perspective we are going to say that anything genetic is anything that involves the genes any change in a gene is genetic but to be inherited it must affect the germline it must be present in the germline this doesn't mean that the same exact change must be present from parents to offspring and a great example of that is Huntington's expansions we can get increased expansion with each generation does that make it any less an inherited disorder no that makes sense so using Huntington's as our example for inherited how could we see in a family with no prior history a sudden presence of it well it's based on those numbers of repeats right so you could have a situation where the first person presents with it due to random de novo additional mutation or simply because they are now at the generation where the expansion has gotten long does that make sense okay so when we talk about the common metabolic disorders or the inborn errors of metabolism I use both names interchangeably because the inborn errors is the one you're probably most familiar with but it is technically common metabolic disorders because the implication that we're trying to do with that new name is less on the inherited piece more on the commonalities of impacts on metabolism does that make sense sort of a better way to categorize the condition so in this case we are talking about literal changes that affect biochemical and metabolic pathways when you have one of these mutations a pathway will be impact impacted what are the thing about biochemical and metabolic pathways is staying the same can be also a problem because some of these things need to be flexible they need to be capable of shifting up and down and so you could be in a situation where you're not really a gain of function you're not really a loss of function but you are a loss of regulation makes sense but still we're gonna keep with that three go up go down so is it make sense yes okay the majority of these are going to be autosomal recessive tell me why go for it yeah you have one good copy you've got enough of the activity you're okay what might be some exceptions to that I love it when I ask a question we've looked down enzymes that requires like gene dosage of two yeah like any type an enzyme that requires a gene dosage of two specifically to carry out the full activity right if we're trying to build something and we're lacking a piece of the something we're gonna try to build that could easily be inherited in a dominant fashion because we just don't make enough of it to build the thing we're trying to build the other one is toxic buildup if what you have reduces the function to a point where we end up with toxicity we're going to see impacts of that oftentimes a little bit even in the headers I go does that make sense toxic buildup is bad so I absolutely love this last line on here I almost forgot to say you cannot just identify these in a clinic like you can get hints that you have is it requires specialized training to be able to differentiate all of these that's not the expectation for a lot of people so like I will not be expecting you to carry out that level of comparison does that make sense I just I love it because it really does require special training to do so much of what we do in medicine because it's so specific in the field of genetics all right how do we categorize something that is literally all of metabolism well onset signs and symptoms that are appearing first and most predominantly the organs and systems affected and whether the presentation is acute or chronic what does it mean for a presentation to be acute it's not adorable yeah I went there what does it mean rapid short-lived sometimes appearing out of what appears like nowhere right oftentimes they'll the symptom will recede and return what does it mean to be chronic often longer period of time for the development pervasive happens for a long time a chronic condition can often take a long time to develop but also a long time to resolve the best example that is the differences between acute and chronic lymphomas and leukemias is oftentimes something that is acute or rapid is much harder to treat than something that is chronic does it make sense so what is interesting about this is we have another spectrum literally everything which is going to be a spectrum from now on hopefully we like that in this one we can have no obvious dysmorphology to significant specific dysmorphology these are conditions or this classification of conditions can be very compartmentalized where we only affect one system or highly affected to all systems right lots of crossover loss of systems affected most of the time we are going to start from immediate infancy with normal outcomes when you're talking about something like a toxic buildup before you have symptoms what has to happen have to build up of the toxin right sometimes that can happen very quickly especially depending on diet but other times that can take longer so many of these are also just nonspecific like how do you tell the difference between low metabolism in one tissue versus lethargy how do you tell the difference between a dysmorphology caused by congenital abnormal congenital anomaly in metabolism versus a structural congenital anomaly the answer is testing but visually it's the same anomaly there are so many conditions that have cleft palate as a phenotype do you when you see a kluff I do you immediately want to investigate further yes but that symptom alone is not enough to tell you the cause does that make sense and so much of this is going to have wide tissue distribution we're going to have dermatological ophthalmologic cardiac liver hepatic musculoskeletal we are going to have a wide range of symptoms possible and the answer to all of it is going to be where is that pathway important and what is it doing in that cell type if it is not important or doing anything in that cell type that cell type is not going to be affected if it is critical to that cell type you're going to lose function or have excessive function in that cell type not all of your cells utilize their genome in the same way and so biochemically and metabolically they have unique differences a liver's job is different than a kidneys so our broad categories are going to be based on the metabolism affected so we have urea cycle organic acid emus fatty acid oxidation defects amino acid opathies carbohydrate disorders and the mitochondrial disorders these are our broad categories the underlined ones are ones we're going to talk about next semester the bold ones are the ones we're going to talk about this semester I may have mentioned this one quite a few times during office hours today as an example so our interests here today are maple syrup urine disease the phenylketoneuria galactosemia and ferctosemia so inborn areas of metabolism do have known structural anomalies because we impact development when you impact development you can impact literal structural development and of course when I use the word development I'm embryological or even that maturation within lifetime right secondary sexual development specific characteristics over time so looking at some specific disorders I want us to just have an idea of the wide range of effects we can have this is a mostly for your information slide there's a learning objective at the bottom I just want you to appreciate the wide range of changes we can have with specific disorders that's what this is so if you want to be like oh that's cool and put a giant X through it go right ahead but here's one of my favorite pieces of this because yes we have the lovely newborn screen and it does wonderful work and many of these conditions are present in the newborn screen because early intervention is critical to preventing toxic buildup or errors with this but these are things of metabolism and you have this wonderful sense that COVID for many of us mess with and that's the olfactory sense right and it turns out that many of these conditions actually produce biochemical products that you can pick up an odor the maple syrup urine disease is so named because of the odor fetal catch an area has a distinctive mousy odor at birth this is a toxic byproduct that we are stuck with we cannot break down phenylalanine in this condition and we have a corresponding sense to that why does this matter why why am I doing something as silly as to this because sometimes especially in a place where we're not doing the same newborn screening where we have a lot of outside of the hospitals sort of burst outside of the medical present these are still indicators that people use and it's a really fascinating thing to think about all right okay I know it's a scary slide I promise you by the end of next semester you'd be like oh that's I got that but for right now I just want us to have that introduction to the concept of what we call the absorptive state when we take in food we have specific behaviors that take place that are tissue specific from plasma the liver muscle and adipose that are different than when we are starving or fasting so these are again slides they're just giving you context they are a big deal next semester our first one is a fructose emia in the fed state we are bringing in material externally that we then have to process in fructose emia we essentially have what is called a hereditary fructose intolerance we cannot break down and utilize fructose when we cannot break down and utilize fructose we have a buildup of this the specific mutation of interest is aldob or aldolase B because we have the inability to break down fructose you would think we could easily just get rid of this and it should be fine but it turns out it actually can build up and lead to hepato splenomegaly and jaundice so we are actually impacting both the spleen and the liver the liver and spleen both become enlarged hepato splenomegaly and the best way to think about this is when you have something you can't really get rid of or you can't use and you can't get it out it's gonna build up somewhere and it's a really general idea there but anytime you have an inability to store something you see an absence but when you have an inability to utilize it or eliminate it you get a buildup and that buildup can literally affect the size of a cell when you have excessive triglycerides when you have excessive fats you literally make more adipocytes but you also have adipocytes that are larger and holding more material literally increasing the compartment and that's a similar thing that's happening here it's important again this underlying piece we are going to talk in the future about the connections between the pentose phosphate pathway and glucose 6-phosphate dehydrogenase and deficiencies in there our goal here today is to say here is a condition in which I cannot break down fructose meaning I cannot utilize it as a fuel so what is the best way to deal with this do you think don't consume fructose and so many of our connections here that that dehydrogenase there many of our connections here are going to be if I can't break this down I shouldn't have it in my system so we have lots of dietary interventions we can do for conditions like that and so I just want you to see here's a pathway we're going to talk about in the future but here's one of the crossovers our next one is a galactosemia also out of the zebra this one is all about galactose we're getting the connections here with the naming conventions now I if we cannot properly process galactose we actually get toxic build-ups and depending on which type of mutation we have we get very specific consequences so another system in which we have here's a condition but because enzymes are often multi complex things with multiple subunits which subunit is impacted can have vastly different outcomes and so in terms of a pathway which step of a pathway is impacted can have vastly different outcomes and I am finishing on time today so we will pick up with our next piece which has a lot of our beginning introductions to cancer genetics and involves our other hereditary pieces that are really interesting questions or concerns all right