MBG Congenital Myopathies Transcript PDF

testing okay so we are hopefully recording nicely I apologize for the slight delay so a couple of things the beginning of Monday Monday's lecture is missing right now because I did not turn the mic down and it sounded like this it was bad so I hopefully fix that for today but I will rerecord all of...

testing okay so we are hopefully recording nicely I apologize for the slight delay so a couple of things the beginning of Monday Monday's lecture is missing right now because I did not turn the mic down and it sounded like this it was bad so I hopefully fix that for today but I will rerecord all of those questions as kind of like a walkthrough piece all together because we have the three from that and then we'll have these that we may not get to before break so I want to make sure you have that recording so you can go through those questions over break so also you may have seen my update my apologies for getting kind of behind in class but I figured that the best solution to that to avoid splitting content that goes together was to move the learning activity so as always for a normal lecture session we will be recorded and that recording will be available so Monday's class is no longer required attendance it's going to be a traditional highly encouraged but it will be recorded session it's the Monday after break that we're moving to the learning activity and I cannot record that session because of the content so it's a highly encouraged but you will not lose points for not being present on that day so it's just because I had to move it it's no longer a required session but highly encouraged and will not be recorded does that make sense so hopefully that adjusts the whole rest of the block and we have no days where content is split across seven days away because I don't want anyone to sort of lose content in that way does that make sense so I do apologize for getting behind and causing that need for that change but I don't think we hate it we're not too mad at not having a required day on Monday of that week okay bothering you I appreciate that but now we're back on congenital myopathies let's get started shall we okay again the goal here is to focus on how we can take an individual effect and categorize it so we can tell the difference even if all of the changes are within one system and so in this case we have five categories or subgroups for changes in the structural development of muscle groups so these are architectural anomalies okay we have some callbacks here from MPP that we have to pay attention to and I'm going to take a step back because we're resetting at three at 110 please note that in terms of these particular congenital abnormalities that we're going to talk about we do have a situation where not all genetic changes are going to be created equal and certain mutations even specific mutations within the same gene may have different inheritance patterns so this is probably one of our most complicated pieces and it's part of the reason why it was chosen for this purpose right that idea of complex inheritance where not all pathogenic variation is created equal and we can get those spectrum of consequences so as we may remember regarding our calcium signaling and our different types of muscle we are going to focus on this particular area as well and we are going to sort of start by that compare contrast our core myopathies versus our nemaline myopathies remember the change is in the physical architecture of the skeletal muscle we are changing the actual shape and viability of fibers so in core myopathies you have cores or mini cores so you will have areas of disruption in the fiber that look like open areas if you're looking at the pathology it looks like a core like you have an opening in that region that's at least that's how I think of it that core is actually due to an area lacking mitochondria so if you were to do a mitochondrial specific stain on a honest the histology of this particular type of fiber you would see areas of absence of mitochondria hence the core does this make sense where something should be there's not that thing when you have the lack of oxidative enzyme activity as a result of the lack of mitochondria activity you actually will see whether a large central core especially for a cell type or an area of the cell where we would have expected a very individualized mitochondria or mini cores and so these are two sub categories of this core this sub category of course so we have sub categorization of a sap of sub category we having fun yet so in this case multiple genes can do this right we are talking about losing enzymatic activity from a mitochondria there's lots of appearance in this particular result could involve multiple genes and so the one we are going to focus on is the one that's the most common which is our way our one particularly in our central core myopathy it is essentially going to affect calcium release what happens if you can't release calcium in a skeletal muscle can't contract okay in our neem aline myopathy on the other hand you're core versus rods and bundles and this particular rods and bundles actually can involve more than 14 different genes because you're talking about creating a slightly different architecture to the fiber depending on which gene you're talking about it could be dominant recessive autosomal *** linked depends on the gene so we will focus on act one and nebulin act one is going to account for more of our severe cases and it actually is seen to be pathogenically altered in about 50% of the cases slightly more than 50% so that's a pretty strong indicator of those severe cases nebulin or nebb is going to be your typical correlation and it's 50% of all cases so do we understand that make sense so this right here your call back to MPP this is what we're talking about RYR moving on to our centronuclear and congenital fiber type which we're not really going to talk about but our centronuclear we have that larger than normal centralized nuclei so a very distinct pattern for something like a dappy stain this is going to correlate with muscle weakness and a kind of more of a wasting presentation and again variable inheritance patterns each of these conditions have multiple genetic causes and multiple inheritance patterns as a result we have more than nine genes associated with this but our main causes are mtm1 dnm2 and ttn we are not focusing on the inheritance of congenital type so I just want you to be aware that this is a more atrophy based alteration we're going to have effects on muscle function and this is typically because we can have that change in the overall diameter of the fiber we do see multiple genes here as well and multiple inheritance patterns so just reminding us the connection here we're talking about the T tubule this time and still playing in that same realm of calcium release and understanding polarization so just to remind us a little bit more about T tubules because you've slept since then yes it's been a while we are talking specifically in our terms with the lipid phosphatase the membrane bound lipid phosphatase that's the mtm1 and the gtpase the dynamin 2 both of these help you form the T tubule so what would you expect to see if you have alterations in both of these probably in absence of T tubules right make sense so the last one that we're going to talk about is the Titan because of the role in the actual fibers themselves and I just want to remind you of that but now we have our myosin storage myopathy what does that sound like so you may be more familiar with it from its other name the higher high-aligned body myopathy or maybe not it's fine other way that's why I'm introducing you to it this is essentially going to be all about the myosin heavy chain and so if you have a storage myopathy or a condition that affects storage you are going to affect the ability to hold on to maintain or store key things in this case we are talking about affecting myosin heavy chain 7 and its ability to be held within the cell itself and so with this issue we also see and this is one of our first ones where we have a more crossover system we are going to see significant cardiovascular impacts from the inability to store this myosin does that make sense the names of these conditions very nicely aligned with the phenotypes and observations that we have NEMA line we're creating lines bundles of fibers core myopathy we're creating cores due to lack of mitochondrial activity make sense if you're looking for ways to categorize and so the gene of interest here is of course myh7 if I was going to talk about how did just to differentiate these from like a generic case certain pieces of information would have to be there we biopsy muscle to make these determinations there's genetic testing for panels that can be done to evaluate which of these particular conditions is present genetic testing is a little bit easier and less invasive than a muscle biopsy but you would do the test that is indicated by the clinical presentation so in a clinical presentation of a myosin storage myopathy we should see congenital cardiovascular effects as well and that should lean us toward that again there are many many many of these with many many many genes affected and incredibly unique inheritance patterns so why do we talk about them what is our takeaway from this clinical discussion just because you know what gene is affected and you have symptoms doesn't mean you're always going to have the most clear-cut inheritance pattern you are going to have to investigate the specific pathogenic variation for some of these conditions in order to be able to identify risks to the next generation there is a difference between the risk from an autosomal dominance condition and an autosomal recessive one make sense okay so because I like to make things a little bit easier I made a nice summary for you I have two nice summaries for you this first one really takes our clinical features and ties it to the genes that we have that are of interest all of the ones in bold are of interest to it and there's that that TTN from that one for the Titan the eye involvement cardiac congenital hypotonia there's our our way on one respiratory involvement severe respiratory involvement and facial dysmorphia and so giving you your quick gene reference over here these three were ones that I thought you would be relatively familiar with but definitely tie to other things you've done in MPP all of them have one thing in common marked muscle weakness muscular hypotonia we also have the potential for what is called wasting or atrophy all of them that is what brings them into this category that makes sense so inheritance yeah only the ones that are bolded are the ones that we're actually doing I just wanted you to see all of those in there to get a better picture so if it's not on another slide pretend like it's not there don't do that like look at it and see it but you don't have to to try to memorize it the biggest takeaway from this section is you cannot fully identify risk without sequencing pathogenic variations are highly specific in this group so to make it a little bit easier I've given you the summary again with the corresponding inheritance pattern of the specific variation on the far right to you so if we're looking at our YR1 first this is going to be inherited in an autosomal dominant manner when it is specific missense mutations in order for it to be autosomal recessive we tend to have nonsense and biallelic effects so we need to have see this mutation in two copies before the disorder is manifested for our neem line myopathies our a CTA one is different than our nib what did we say about this gene compared to this gene a CTA one was more severe and so its inheritance pattern makes sense doesn't it what's its inheritance pattern dominant why does that make sense that it would be correlated with severity and be a dominant condition because if you have even one copy altered you're seeing an effect there's a half low insufficiency to it that makes sense is it going to hold true for everything no but it makes sense in something structural now for nib most of the mutations are actually going to be splice variants missense and nonsense so our sorry frame shifts and nonsense the splice variance can involve loss of key domains which is pretty cool for our central nuclear myopathies the DMN2 and the MTM one these two have very different patterns of course we're x-linked because we are on the I've really thought I'd maybe get like a whole classroom responsive what does it mean to be excellent on the X chromosome yes X chromosome means inherited differently what's the key about the X chromosome that we always have to pay attention to in terms of inheritance in a human pedigree affected father to daughters affected mother to sons next one our myosin storage myopathy lots of missense in order to get this diagnosis you must also have cardiovascular implications I didn't want to leave it as all just inherited you can have somatic or mitosis related early mitosis related changes as well and we had talked about some of the signaling mechanisms and specifically mTOR and so I wanted to come back to the brain as that sensitive instrument where changes are going to impact it often first and worst right such a sensitive compartment so we are going to talk about mTOR signaling and the brain specifically mTOR is going to control cell growth autophagy or autophagy as I learned and apoptosis in the cells of the brain so critical components of development for the structures in the disorders that have effects in mTOR signaling specifically pathogenic mutation in mTOR that develops after initial fertilization but during development we actually see dysplasia hyperplasia brain overgrowth and an increase in things like epilepsy and appearance of autism spectrum disorders this makes sense this impact is completely related to variation of the mTOR signaling pathway the thing that's interesting about this is this signaling involves both gain of function and loss of function options with similar outcomes and so if you're looking at the images above you can see that you have different development of the brain where we have regions of increased brain growth so taking us full circle in neuro we have the anomalies that are present that can be inherited that can be present since birth the congenital anomalies and some of these things can develop somatically not just during initial development but also later makes sense okay so now we're going to spend