in this very high-yield video we're going to be talking about the trinucleotide repeats this is brought to you by dirty medicine the for diseases that each have trinucleotide repeats that you need to know for USMLE and comlex are depicted on this slide the reason that trinucleotide repeats are so high-yield is because the way that they occur that is through the genetic problem of having a trinucleotide expansion is a pretty genetically rare event and because of that examiners latch onto these for diseases and love to test you about the different symptoms findings genetic modes of inheritance and above all else the actual trinucleotide repeat so all of the different components of these four diseases are extremely high yield and tend to show up on complex and USMLE all the time with that said we're going to go through these diseases one at a time carefully summarizing for genetic inheritance the China Cleo tide repeat the symptoms and associated findings and then for each of these four diseases I'll give you a really awesome mnemonic to help you tie that all together and of course memorize the trinucleotide repeat that's unique to each of these four diseases so let's go through these one at a time beginning with Huntington's disease so in Huntington's disease the trinucleotide repeat is si AG and this is an autosomal dominant inherited disease the symptoms of Huntington's are aggression psychosis Coria and dementia now the findings that you should probably be familiar with are the different changes in neurotransmitters and different neurologic regions of the brain so you've got increased levels of dopamine decrease levels of acetylcholine decreased levels of gaba and decreasing size of the caudate so the way that you can tie this all together is by using a really simple mnemonic that I've come up with years ago and that mnemonic is that you can't aim great when you hunt for an animal so the reason that this is the mnemonic for Huntington's disease is because the mnemonic we're using the hunt part of Huntington's and because hunters go out and try to aim their guns and shoot animals we're saying that you can't aim great when you hunt for an animal so what does this tell us well can't aim great CAG is the repeat so the trinucleotide repeat is the first three words of this demonic can't aim great when you hunt for an animal well hunt is just telling us that we're talking about Huntington's disease for is telling us that this is actually conferred through a problem with chromosome four and the a n in n animal tells you that Huntington's disease features something called genetic anticipation genetic anticipation is actually really high yield to understand basically what it means is that let's say that you're the first generation in your family to get Huntington's you might get it around age 60 the next generation will get it younger than you so they might get it around age 45 and then the next generation if this gets passed down we'll get it even younger than that they might get it around age 35 and that's what genetic anticipation is basically in subsequent generations the person's affected by the disease get it earlier in life that's genetic anticipation but again just to summarize everything that I've talked about Huntington's disease were talking about hunting so the mnemonic is that you can't aim great when you hunt for an animal can't aim great for CAG trinucleotide repeat hunt reminds us that we're talking about Huntington's disease four tells us this is a problem on chromosome 4 and in animal a n is an anticipation because this disease features genetic anticipation so subsequent generations get the disease earlier and earlier than the generations that were affected before them the other thing that I really like about this mnemonic is that if you think about the symptoms of Huntington's disease if you get them and you were actually trying to go out and hunt you wouldn't be able to aim great you can't aim great because think about it you have Coria so if you have Coria you're not gonna be able to hold a sniper rifle up to your face and shoot an animal you're just not going to be able to do it if you have psychosis or dementia probably not going to be able to aim great right so understanding the symptoms of Huntington's also tie in to my awesome demonic so that's Huntington's disease where you can't aim great when you hun for an animal that's all you need to know about Huntington's disease let's now talk about fragile X syndrome so fragile X syndrome the trinucleotide repeat is C G G and this is an x-linked dominant disease which is pretty easy to remember because in the name of the disease you see the giant letter X so this is X linked dominant the symptoms include macro or catism and intellectual disability long face and large ears and here's a cartoon depiction of what that tends to look like what will really give away fragile X syndrome on us Emily or comlex is the macro organism so I've bolded that for you here and because that's the key symptom that you should focus on of course in addition to the long face and long ears we need to have a mnemonic that reminds us about large testicles so the way that I remember this is with congenitally giant gonads for CGG the trinucleotide repeat in fragile x syndrome is CGG congenitally giant gonads that will tell you that the predominant symptom and fragile X syndrome will be macro organism but also don't forget the long face and the long years and that's it that's it fragile X pretty simple that's all I need you to know let's talk next about Friedreich's ataxia so Friedreich's ataxia is probably the most complex and difficult to understand but I'm gonna simplify this for you the trinucleotide repeat in Friedreich's ataxia is GAA gah and the inheritance pattern is autosomal recessive so this is the only one of these four diseases that is autosomal recessive so for that reason it should stick out a little bit in your brain the symptoms include a taxi ax and what is sometimes referred to as a staggering gait hammertoes PES cavus which is an increased arch in the foot and scoliosis it's also really important and high-yield to understand that the most common cause of death in patients with Friedreich's ataxia is hypertrophic cardiomyopathy so HCM or hypertrophic cardiomyopathy is heavily associated with Friedreich's ataxia now Friedreich's ataxia is the one of these four diseases where I think it's really important the pathophysiology of what happens that leads to all of these symptoms in the nervous system so Friedreich's ataxia again is an autosomal recessive Li inherited disease that causes the Tri nuclear tri nucleotide repeat GAA or gaw to lead to a defect in the frataxin gene normally the frataxin gene is responsible for shuffling iron into cells so when a normal functioning four taxon gene is doing its job under physiologic conditions the perfect amount of iron comes into cells but when you get Friedreich's ataxia and you knock out the frataxin gene you can no longer put the right amount of iron into cells and instead an overabundance of iron gets shuffled into the cells and when you have cells that are just flooded with iron different intracellular components are going to be damaged and in the case of Friedreich's ataxia the one part of the cell that takes the most damage is the mitochondria so if you zoomed in on a microscope under the cell you would see damaged mitochondria and if mitochondria cannot produce energy and pronounced it cannot produce ATP for the cell to function you're going to get dysfunction and this defunk dysfunction occurs predominantly in the central nervous system and the peripheral nervous system and it's that pathophysiology that manifests itself as the neurologic findings such as inability to walk having an abnormal gait and then the structural findings of course of hammertoes PES cavus scoliosis etc so this is all really important to know and you need to know that the path of is kind of behind the scenes here is an abnormal iron accumulation due to a defect in the frataxin gene now just in case the test writers want to get fancy and show you some pictures I want you to see what hammertoes and PES cavus looks like because if you see these pictures you should think Friedreich's ataxia or you should think autosomal recessive or gah trinucleotide repeats so you have to be able to associate all of these symptoms with one another hammertoes kind of look like exactly what the name describes your toes are just popped up like little hammers and PES cavus is an increased arch of the foot so those are the the physical findings of Friedreich's a taxi and now I know what you're thinking dirty how am I going to remember all this crap well here's what we're gonna do so first the disease is called Friedreich's ataxia right a taxi it means that you can't walk or that you stagger and fall down and we also need to remember that the trinucleotide repeat is gah gah gah so how are we gonna tie this together well this makes me think of Lady Gaga Gaga Lady Gaga okay and if your music fans or maybe you saw her concert in October of 2018 Lady Gaga jumped up onto a fan and then the fan tried to stand up and he fell off the stage with Lady gaga so I remember that Lady Gaga was ataxic and fell go on youtube and watch the video of her falling it's it's kind of funny everyone was fine so you're allowed to laugh at it but Lady Gaga gaga for GAA was ataxic and fell the word ataxic reminds me that we're talking about Friedreich's ataxia so this is my pneumonic to remember GAA for Friedreich's ataxia lady gaga so we're done three of four and let's wrap up with myotonic dystrophy type one in my atonic dystrophy type one the trinucleotide repeat is C T G and the inheritance here is autosomal dominant the main symptom of myotonic dystrophy type one is that you get problems with the distal extremity musculature specifically when the muscle contracts it has a difficult time releasing that contraction sometimes this is written as distal extremity weakness other times it's written as like you know distal muscle hyper contractility there's different ways that they can write this out but but just remember distal extremity weakness usually in the forearms and the hand the associated findings include cataracts testicular atrophy and hypo gamma globulin emia and I'll tie the mnemonic into helping you remember these associated findings because they are really high-yield now on exams on USMLE and comlex what the test writer is probably going to do is try to clue you in to the distal extremity weakness and how they're gonna do that is they're gonna describe one of three scenarios they're gonna say that the person can't release their grip when they're opening a door so they can't release the doorknob that they can't release their grip when they are turning a screwdriver and that they can't release their grip when they're engaging in a handshake with somebody so all of these collectively for myotonic dystrophy type 1 you can't stop the contraction in the hand and the forearm and it's for that reason that my mnemonic is can't terminate grip so CTG is the trinucleotide repeat and it's really handy that the mnemonic here is they can't terminate their grip so if you start to grip something and turn handshake doorknob screwdriver it doesn't matter can't terminate grip CTG is the trinucleotide repeat for myotonic dystrophy type 1 and conveniently all of the associated findings are also CTG cataracts testicular atrophy and gamma globulin emia which is short for hypo gamma globulin anemia so that's myotonic dystrophy type 1 and now we've gone through each of the four trinucleotide repeats and now let's do a summary chart so again here's your summary what you need to take out of this video are the trinucleotide repeats for each of these four diseases the modes of inheritance and the main symptom so Huntington's disease can't aim great when you hunt for an animal fragile X syndrome congenitally giant don't add CGG Friedreich's ataxia well whose ataxic lady gaga gah gah gah for gaga and then myotonic dystrophy type 1 remember problems with distal extremity weakness and therefore they can't terminate their grip or CTG so those are the trinucleotide repeats I know that I went rather quickly but it's an easy topic to know if you use the dirty medicine mnemonics good luck