so today's super high-yield video is one that I'm really really proud of this took a lot of time to create and I really was careful to include only what you need to know and like literally nothing more so today's video is on glycogen storage diseases so what do you need to know guys first we're gonna touch on the difference between glycogenolysis versus glyco genesis that is to say glycogen synthesis versus glycogen breakdown and then once we have an understanding of the biochemistry behind all of this stuff we'll talk about the specific diseases that they love to test you on on USMLE and comlex so let's get started with an overview of the biochemistry and talk about glycogenolysis versus glyco genesis so this is what you usually see in glycolysis right you start with glucose you have step one of glycolysis that that creates glucose 6-phosphate and then if you continued all the way down that pathway you'd eventually form ATP and we've already had a video that has discussed glycolysis versus gluconeogenesis and i would refer you to that video if you need a refresher in this topic but I'm just bringing this up because where glycogen synthesis and glycogen breakdown occurs is if you pivot off of this pathway so let's say that you create glucose 6-phosphate and you really don't need to be doing glycolysis anymore instead you want to store all of that excess glucose as glycogen so you want to do glycogen synthesis so what happens well you pivot so instead of taking that glucose 6-phosphate and carrying out the rest of that glycolysis pathway you turn and now we're gonna enter into the glycogen synthesis pathway and the first step is shown here phosphoglucomutase is the enzyme and it turns glucose 6-phosphate into glucose 1-phosphate now for the purposes of USMLE and comlex you don't need to know that enzyme I've just included it there for completeness sake now once you have glucose 1-phosphate I'm gonna kind of split the pathway into two now and on the right side we're gonna be talking about glycogen synthesis and on the left side we're gonna be talking about glycogen breakdown and this will all make more sense once I draw out the pathway here now the next step is converting that glucose 1-phosphate into something called UDP glucose so imagine you have this glucose molecule and then a UDP literally gets stuck right on top of it and that is catalyzed by the enzyme UDP glucose pyro phosphorylase and then taking UDP glucose and turning it into glycogen is catalyzed by the enzyme glycogen synthase so that is glycogen synthesis those three enzymes nothing else that's glycogen synthesis you're starting from glucose 6-phosphate in the glycolysis pathway kind of stealing it from the glycolysis pathway going to glucose 1-phosphate and then turning glucose 1-phosphate into glycogen those are all the enzymes and that's just what you need to know about glycogen synthesis now let's say you have glycogen now it's floating around and you want to mobilize your glycogen stores right maybe the glucose is low in the body the blood glucose is low all of a sudden glucagon is floating through yelling at the cells hey man release some glucose our glucose is low what do you do well you got to break down that glycogen go back to glucose 1-phosphate go back to glucose 6-phosphate take a left and get back to glucose so this is glycogenolysis also known as lysine glycogen right breaking glycogen down and when you break like a gin down you're eventually going to release glucose so how does that happen really simple guys one enzyme glycogen to glucose 1-phosphate is catalyzed by the enzyme glycogen phosphorylase now that is pretty much all you need to know as far as the biochemistry here there's a little bit more that we'll get into as we move through this video but this is the overview now we should talk about a few things first the rate-limiting enzyme in each of these steps in each of these pathways is extremely high yield and I bolted them here for you glycogen synthase is the rate-limiting enzyme in glycogen synthesis glycogen phosphorylase is the rate-limiting enzyme of glycogenolysis or glycogen breakdown this is really important because when glycogen is glycogen synthase is active glycogen phosphorylase is inactive and vice versa so one thing that you should know in addition to the fact that these are the rate limiting enzymes is what regulates each of these enzymes so glycogen synthesis excuse me glycogen synthase and glycogen synthesis as an entire pathway is turned on an act by insulin conversely glycogen phosphorylase is turned on and activated by glucagon now if glycogen phosphorylase is activated by glucagon that means glucagon is going to inhibit glycogen synthase so whatever activates phosphorylase will inhibit synthase whatever activates synthase will inhibit phosphorylase so these are opposing enzymes and they are the rate limiting enzymes which is a very high yield concept that you should memorize now what I would like to do is kind of pause for a second and just talk about the glycogen synthesis side of the pathway shown here now when you DP glucose is turned into glycogen how this works is that every time that glycogen synthase works it's adding new glycogen buns in an alpha 1-4 manner now if this this could go on to infinity and in what would happen is that you'd have this straight line of alpha one four linkages putting glycogen after glycogen after glycogen on this chain and eventually it would grow to infinity but that would be really bad because if you have a really really long chain compound it's toxic to organs in the body so what you need to do instead is stop the single linear growth of this compound and instead branch it so that's what a branching enzyme does a branching enzyme creates an alpha one six linkage or an alpha one six bond now let's pause for a second knowing visually where the bond is is not important for boards all that you need to know is that glycogen synthase is the rate-limiting enzyme of glycogen synthesis and it slowly adds alpha 1-4 bonds eventually those alpha 1-4 bonds will become too large and you need to use an alpha one six linkage and branch the chain using branching enzyme so the name kind of tells you what it does now if we go forward eventually in order to break this chain down and release glucose we're gonna have to break the alpha one six bond you're gonna have to do exactly what you see there so you want to go from position a to position B glycogen phosphorylase will turn glycogen into glucose 1-phosphate but then you need something called the debranching enzyme to cut that one six bond and release the glucose want the glucose one phosphate into glucose 6-phosphate so gloop so basically let's slow down debranching enzyme comes in after glycogen phosphorylase so glycogen phosphorylase creates the glucose 1-phosphate then debranching enzyme will cut that one six bond and turn glucose 1-phosphate into glucose 6-phosphate glucose 6-phosphate will take a left as you see in the pathway they're shown in green which again is a glycogenolysis and using the enzyme glucose-6-phosphatase glucose 6-phosphate turns into glucose and glucose can be released into the blood to serve its purpose so here is an overview of everything we've talked about so far at the top we started with glucose 6-phosphate and actually came down to glucose 1-phosphate glucose 1-phosphate was turned into UDP glucose which was then turned into glycogen every time you DP glucose was turned into glycogen you formed an alpha 1 4 linkage eventually that very linear compound would become too large and would become very toxic to organs in the body so we used branching enzyme to create an alpha 1 6 branch in the chain if the body wanted to go through glycogenolysis and release free glucose we would have to take that branched chain and first go through glycogen phosphorylase to create glucose 1-phosphate then the glucose 1-phosphate would use the debranching enzyme to cut that one 6 branched chain then we have glucose 6-phosphate using the enzyme glucose-6-phosphatase being turned into free glucose so this is the overview and I've now summarized everything I know that I kind of spoke a lot and it may seem a bit overwhelming but it's very important that you understand this biochemistry because everything that you see on this slide is how we're gonna understand where the diseases come into play and what goes wrong in glycogen storage diseases so let's talk about the first one if you don't have the enzyme glucose-6-phosphatase shown there in the top left of this slide you get something called von Gierke disease so because we don't have glucose-6-phosphatase we cannot form free glucose we're gonna have a buildup of glucose 6-phosphate so von york disease is a lack of glucose-6-phosphatase and I took the top of that slide that you just saw and because we don't have glucose-6-phosphatase we get a buildup of glucose 6-phosphate and as you might imagine this is really bad right we can't form free glucose and glucose 6-phosphate is just accumulating in the liver so the the symptoms of this disease should not surprise you you're gonna see hepatomegaly or big liver because glucose 6-phosphate is accumulating in the liver and you're gonna see hypoglycemia or low blood sugar because you cannot form that free glucose to raise the blood glucose now something that is another symptom that you really need to know are hyperlipidemia and hyper URIs emia now the reason that this occurs is because you're unable to get free glucose you need to get your energy with through the fat and protein breakdown so if you break down fats you'll have hyperlipidemia and if you break down proteins you'll have hyperuricemia so to summarize von york's disease is a von york disease is a lack of glucose-6-phosphatase which causes an elevation of glucose 6-phosphate accumulating in the liver causing big liver also known as hepatomegaly causing hypoglycemia because it can't be turned in free glucose and causing high levels of fat and uric acid in the blood because you have to go through the fat and protein catabolism pathways in order to get your energy so how do we remember all this stuff well instead of von Gierke disease i want you to think von geek disease and here's a fat geek at his computer again a character taken from South Park and he is fat he has no muscle and he has fatty liver because he's so overweight and does not take good care of himself so this is what we see in von Gierke disease also known now as von geek disease hyperlipidemia because he's fat hyperuricemia because we're breaking down muscle and causing uric acid to be released and fatty liver because he does not take care of himself that is von Goethe's ease due to a lack of glucose-6-phosphatase so that's what we talked about so far right the purple star was von Gierke disease now what happens if we don't have debranching enzyme well you get something called Corre disease so quarry disease is a lack of the debranching enzyme and the debranching enzyme is also known as alpha one six gluco sigh days now think about this for a second you're gonna get all of the same symptoms as von Gierke disease the only difference is that you're gonna have an abnormal glycogen structure because remember normally glycogen is branched and debranching enzyme cuts the 1-6 bond and releases it so that it can be used as glucose if you cannot cut that bond you're gonna have an abnormal glycogen structure but you're gonna have the same symptoms of von York disease because you still can't produce free glucose so you'll be hypoglycemic and you still have an abnormal accumulation of something in the liver causing hepatomegaly so quarry disease and von Guericke disease are very very similar the only difference is that in query disease you have an abnormal accumulation of this super branched glycogen structure that cannot be cut and d branched because we lack the debranching alpha 1/6 glucose iTaste enzyme so it's very similar to von york with an abnormal glycogen structure now how do we remember this when I think of quarry disease I think of coral disease and coral like a coral reef I think of this this is a coral reef and it is very very branched what else is very very branched guys well an abnormal glycogen that cannot be d branched so quarry disease I think of coral reef that is a super branched plant that lives in the sea and that is literally what glycogen looks like if it cannot be cut up and it just keeps branching keeps accumulating in the liver in its abnormally branched structure you get hypoglycemia hepatomegaly and abnormal glycogen accumulation in the liver how beautiful is that pneumonic so that is quarry disease now what happens if you don't have glycogen phosphorylase well if you don't have glycogen phosphorylase there are two diseases that can occur the one the first one is called McArdle's disease and the second one is called Herz disease these diseases are extremely similar and the way that we're going to understand the symptoms of each of these diseases is by understanding where the glycogen phosphorylase is absent so glycogen phosphorylase is an enzyme that can be in both the muscle and in the liver McArdle's disease it and I put the apostrophe there of course and after the wrong letter because I'm an idiot but if you don't have glycogen phosphorylase in the muscle you get McArdle's disease if you don't have glycogen phosphorylase in the liver aka the hepatic you get hers disease and it should be no surprise that my pneumonic there is m2m and HDH hepatic for hers muscle for McArdle's this is a lack of glycogen phosphorylase now the symptoms in these diseases are kind of similar but there's a little bit of difference depending on your understanding of what a muscle does versus what a liver does so let's just touch on this briefly in McArdle's disease you're gonna get muscle cramps and hypoglycemia on exertion as well as myoglobin Ariha think about it guys lack of glycogen phosphorylase in the muscle means that glycogen is stuck in the muscle it cannot get out as glucose 1-phosphate to be turned into glucose 6-phosphate to be turned into free glucose you're gonna have glycogen sitting in the muscle cell hanging out like a fat slob and when anything accumulates in a muscle cell what do you think happens well during exercise when the muscle needs to be able to break down that glycogen and kick it out and turn it into glucose so that it can use the energy it's not gonna happen so you're gonna get hypoglycemic when you exert yourself and you're also gonna get muscle cramps when you exert yourself because the muscle not only can't turn it into glucose to use for energy but it's just abdi abolish it in the muscle so what do you think happens if a bunch of stuff stays in a muscle cell of course it's gonna break down the muscle cell and that's why you get myoglobin area so think of that think of it as like dead muscle cells being pissed out in the urine that's McArdle's disease so muscle cramps hypoglycemia both on exertion myoglobin iriya because the muscle cell breaks down because all of that glycogen just sits in it now hers disease i told you is glycogen phosphorylase deficiency but in the liver or in the hepatic but that happens you're gonna get hepatomegaly because you're having glycogen sit in the liver unable to get out livers gonna get big you're gonna get fasting hypoglycemia and this is a really subtly high-yield point here that differentiates disease from McArdle's disease the liver is responsible for a baseline level of basically releasing free glucose to maintain sugar so in McArdle's disease where you only become hypoglycemic when you exert yourself because the muscles can't use their energy in hers disease you'll have fasting hypoglycemia because the liver can't really do its baseline job of maintaining blood glucose so hers disease in the hepatic McArdle's disease in the muscle that's a lack of glycogen phosphorylase and the inability to do glycogenolysis so we are making great progress now let's talk about something called anderson disease so anderson disease is if the branching enzyme doesn't work so the branching enzyme is basically just as a reminder of what takes those alpha one four linkages that the glycogen synthase is making and branches the glycogen to make it non toxic to the organs in the body so if we lack the branching enzyme that creates the alpha one six branched linkage you get anderson disease now i told you if you have a super long straight compound which would be the case if the branching enzyme didn't exist and all you did was keep making those alpha 1-4 bonds and forming that long long straight compound of glycogen you would get something called you would get cirrhosis because it's just completely fatal to your liver so this would turn into this you have this completely long a completely toxic long single-line compound that cannot fit in the liver it damages the liver it causes repeated fibrosis and inflammation in the liver which is cirrhosis and it's absolutely fatal so if you don't have the branching enzyme and can't create those alpha one six bonds you're gonna get anderson disease you're gonna get cirrhosis that's single long chain glycogen is going to accumulate in the liver so how do we remember this anderson disease I think of Anderson Cooper and he gets straight to the point so straight reminds me that this is one long straight line glycogen that is not branched Anderson disease Anderson Cooper he gets straight straight line to the point that's Anderson disease don't don't overwhelm yourself just memorize it Anderson disease straight to the point one straight compound because it can't be branched now this is everything we've talked about so far we did von Guericke Khoury McArdle's hers at Anderson there's one more disease that you need to know and I saved the path of Theology for the end because it's really simple and it didn't really fit in with the rest of the schematic it didn't really fit with the rest of the biochemistry so quarry disease I told you is when debranching enzyme isn't working or isn't there now debranching enzyme also exists in lysosomes so here's a lysosome shown there with debranching enzyme inside of it so a lysosome literally walks around and kind of scavenges not only glycogen but things that look like like a gin and it has a debranching enzyme in there to cut it up and make use of it the same way that you see there with Cori disease now if a lysosome lacks debranching enzyme you get something called pompe disease and pompe disease is a lack of the debranching enzyme but specifically in lysosomes and the really really high yield symptom here that this causes is cardiomegaly so the heart is a muscle and if you lack the ability to D branch glycogen in a muscle specifically through the lysosome then the branched glycogen will accumulate in muscle in lysosomes in the heart so I know that sounds crazy it's a lot of like sort of extra stuff to remember both let's slow down pompe disease is the same thing as Corre disease but if a lysosome lacks the debranching enzyme so it's lysosome specific so how do we remember this pompe disease think of the actual location pompei and think of Mount Vesuvius now Vesuvius filled up for so long with lava eventually exploding and that's literally what happens in Pompeii disease so in Pompeii disease you will have an accumulation of branch glycogen in the lysosomes because you lack lysosomal debranching enzyme which will accumulate in the heart causing hypertrophic cardiomyopathy or if you have pompe disease and die early so people with pompe disease this is a fatal condition because they incur hypertrophic cardiomyopathy because of that accumulation so that's exactly what happened in Mount Vesuvius right lava accumulated accumulated accumulated becoming hypertrophic eventually exploding the other way to remember this is that Pompeii affects the pump so pompe disease affects the pump the heart is the pump that's pompe disease so you know don't don't bog yourself down too much but just remember Pompeii affects the pump it's a lack of debranching enzyme but specific to the lysosome so that's pompe disease guys that's it this is the summary slide I know I absolutely flew through this lecture and I flew through the biochemistry but come back to this slide and look at what we have here enzymes are shown in red rate-limiting enzymes are bolded diseases are shown in purple glycogen synthesis is shown with the blue arrows glycogen glycogen that lysis and AKA glycogen breakdown is shown in the green arrows and where we're branched vs. d branched is shown with those orange boxes that is everything you need to know about collected in storage diseases