DIP Episode 428 - X-Linked Dominant Disorders (for Step 1-3)

All right, welcome. I need to find this is episode 428 of the Divine Intervention Podcast. In today's podcast I'm going to be talking about X-Link dominant disorders. X-Link dominant disorders. This does pretty high you to understand, pretty high you to know. There are few X-Link dominant disorders that are really pretty important for the USMLA exams. This is a continuation of episode 424 where I talked about some high-yield rules for remembering modes of inheritance. You should probably go back and listen to that podcast before jumping into this one. But if you also just want to understand the X-Link dominant disorders, this podcast is for you. So basically what is X-Link dominant inheritance? X-Link dominant inheritance is not as common as X-Link recessive. Many of us are familiar with X-Link recessive. And we talked about in the episode 424 that many immunodeficiency diseases have X-Link recessive inheritance because many genes for the immune system reside on the X chromosome. Now, in terms of X-Link dominant inheritance, the problem is when you have an affected X chromosome, you demonstrate symptoms. There will be a phenotype. There will be a phenotype. So the dominant gene is carried on the X chromosome. So if you have the bad gene on your X chromosome and you have an X chromosome, whichever human being has, then the person is going to be affected. So just having one bad X chromosome is sufficient to cause problems.

If you remember in the X-Link recessive case, if you have one good X chromosome or one bad X chromosome, you won't have any problems. If you have two bad X chromosomes, you will have problems in the X-Link recessive case. If you have one bad X chromosome, one good X chromosome, in the X-Link dominant case, you have symptoms. As long as you have one bad X chromosome, you will have problems in an X-Link dominant disorder. And just a few general rules, and then I'll try to discuss different permutations. But remember, if a father has an X-Link dominant trait, then all his daughters will have that problem. If a father has an X-Link dominant trait, all his daughters will have that problem. But his sons will not. Why? Because the sons, they get their Y chromosome from their dad. So they're not going to get that bad X chromosome, they're not going to get in trouble. But all the daughters must get one X chromosome from dad. So all his daughters will be affected. Now, if a mom is affected with an X-Link dominant disorder, there is a 50-50 chance that her sons will have issues. There's a 50-50 chance that the son will have issues. Let me explain. Because mom very likely has one good X chromosome and one bad X chromosome. By me saying good and bad X chromosomes, I just mean an X chromosome containing the defective gene. I don't mean the entire X chromosome is messed up. But basically, if mom has one good X and one bad X, well, her son has to get his X chromosome from her.

He has a 50-50 shot of getting either of those X chromosomes. So the chance is 50%. So 50% of the sons of an affected mom will be affected. So if you see a son with an X-Link dominant disorder, he got the bad X chromosome from mom. That's a very simple role that you can establish. Now, let's maybe look at again some permutations of this thing. Because the theme is every now and then our friends at the MVM is, and this podcast applies to step 1 to step 3. And complex level 1 to 3. They love doing things where they will give you probability questions and how to figure them out. Many of these things make sense if you just reason through them. But basically, let's look at the situation where mom is a carrier. So let's look at the situation where mom has one good X chromosome and one bad X chromosome. Obviously, mom is going to have problems because he's an X-Link dominant disorder. Now, if you look at her sons and her daughters, there is a 50-50 chance that they will have problems. So there's a 50% probability that her son's daughters will have problems. There's a 50% probability that they will not have problems. So think about it. The son gets his Y chromosome from mom. I mean, Y chromosome from dad, X chromosome from mom. He can get either or with a 50-50 probability. Either or either the good X chromosome of the bad X chromosome from mom. So he has a 50% chance. Same thing with the daughter.

If your daughter, you're going to get one X chromosome from your dad, one X chromosome from your mom. If your dad is fine, but your mom is affected, there's a 50-50 chance that one of the X chromosomes you get from mom will be defective. So you have a 50% chance of being affected if your daughter, 50% chance of not being affected if your daughter. But let's assume that dad is a career. Let's look at another limitation. Again, notice I've said some of these things already. What repetition always helps. If you notice, if dad is the career of the disease, obviously again, he's going to have the problem because his ex-ling dominant. But if you look at dad's daughters, all of them are going to have the problem. Because dad gives X chromosomes to his daughters. So if dad is giving X chromosomes to his daughters, then, and dad has the problem. Remember, it may have only one X chromosome. So the X chromosome is problematic. It has an issue. So 100% of his daughters will have the problem. 100% of his daughters. But none of his sons will have any issue. None of them whatsoever. None of them whatsoever will have the problem. Because again, he does not give them his X chromosome. He gives them his wife. But let's assume that both parents are careers. That is a career. Mommy is a career. Again, you can already see that that issue makes perfect sense, which will happen. If that is a career, Mommy is a career. Then 100% of their kids will have their daughters. Let's look at the daughters.

100% of the daughters will have the problem. 100% of the daughters. Why? Because again, if that is a career. And the daughter for sure is getting the X chromosome from dad. So for sure, get a bad chromosome. So she is going to be affected. 100% of the daughters are going to be affected. Well, the sons of 50% of them will be affected and 50 will be unaffected. Why? Because again, as a son, you're getting a Y chromosome from dad. So that bad X chromosome that has you and don't get it. So you then have to battle with the X chromosome you're getting from mom. You can get the good one from mom or the bad one from mom with a 50-50 probability. So the chance of a son being affected is 50%. The chance of the son being unaffected is also 50%. So that's pretty high yield to know. And again, if you notice, I like to try to break things down. So that you're memorizing things because again, when you memorize, you're not really helping yourself. The thing is memorization is necessary in medicine. For really any medical board exam, you need to memorize. But your memorization is way more powerful and is way more high yield when you understand. You don't have to memorize as many things if you can work it out in your mind. You then end up memorizing the things that matter. Because you see many people, they memorize things that should be worked out in their brains. In fact, I'll probably mention this in another podcast or at the end of this podcast, if we have the time.

But try to not memorize things that you can work out in your mind. It's much better to understand. And the thing is, the way you assembly exams are written, the step one exam, the step two CK exam, the step three exams. These days, most of them are written with working things out in mind. Where, oh, you're not going to get the answer by just memorizing some mindless detail. A lot of questions these days. You'll really have to work things out in your mind. And that's a focus I use in many of my review courses. In fact, for those that are taking step one, I have a course in January. It's from the fifth to the seventh and from the ninth to the tenth of January. It's going to be in the late afternoon, early evening. If you're interested, just shoot me an email. It's a 25 hour review and I'll give you some more information. And for those that also want to attend my step two and step three courses, I, one is currently ongoing right now, but I hopefully plan to have one in December. If you're interested in the one in December, just shoot me an email. And I can try to give you some more information as I have more finality my thoughts on, on dates. And then I also offer other courses like an NV Me test taking strategies class and a biostatistics bootcamp. My upcoming biostatistics bootcamp definitely for people taking step one to step three, come next one to three. It's going to be taking place on the 20th of November. Again, I feel like it's something you'd find to be really helpful.

And again, it applies to step one to three, come next one to three. If you want to truly understand bio stats and be able to manipulate data to arrive at the correct answers on your exam, then I will strongly encourage you to attend those, attend the bio stats review. So again, if you're interested in review course for step one or review course for step two or three, or come next one to three, I do have something for you. Now, let's go ahead and continue. So to wrap up here today, I'm going to talk about some important ex-link dominant disorders that you need to know for your exam. I think probably the big, the first one I'll mention is, you know, what if they give you a question about a child? The tell you that this child has cranial tabies, has multiple fractures, and they tell you that the child is that knows what a vitamin D deficiency. Well, then the child is given vitamin D and the not responding to it, right? You'll notice that, you know, they get weeks and months of vitamin D therapy and they are not improving. Well, if you see that, I really hope you're saying, oh, divine. It sounds like this person has vitamin D resistant rickets. In fact, this is what is known as ex-link typeophosphatemia. Ex-link typeophosphatemia. So what's the deal there? What's the pathophase? Well, the big problem is you have mutation in a gene known as fex, pH ex, pH ex, right? Just think of phenix. Phenix is a big city in the state of Arizona, pH ex.

So you have that pH ex mutation and when you have that pH ex mutation, the thing that's going to happen, the thing that's going to happen is that you're going to have very high levels of FGF23. So is the high levels of FGF23 that really cause a lot of your problems? Maybe like, okay, divine. What's the point of this FGF23 issues? Well, if you have high levels of FGF23, it does two things. One, it prevents you from reabsorbing phosphate in your kidneys. So you're going to be losing a lot of phosphate in your kidneys. So you're going to have hypophosphatemia. And two, it also prevents the one alpha hydroxylation of carcydial. Remember, carcydial is also known as 25 hydroxy vitamin D. It's converted by one alpha hydroxylase in the kidneys to 125 dihydroxy vitamin D. So if you're preventing one alpha hydroxylation, you will not make active vitamin D. So you'll notice this person has very low levels of phosphate and they have very low levels of carcytrial, very low levels of 125 dihydroxy vitamin D. Again, that's pretty high yield, you know. That's what I'm going to say about that. Now, for a second, Viniette, what if they give you a question about a patient? They tell you that she's a four-year-old female. And her mom has noticed that she has these rank, hand-ranking behavior. And she also has, she has also been losing her, kind of not progressing from a motor perspective.

In fact, they tell you the question that she has been regressing, she has been regressing from a motor perspective. When you see something like that, and they tell you that she has had some seizures and whatnot, when you see something like that, what should be thinking about? I hope you're thinking about red syndrome. Red syndrome, R-E-W-T. Can red syndrome happen in males? It can. But most of those males, they either don't make it to term or they die very early in life. So red syndrome on your exam is going to be in a female. Now, about 95% of cases of red syndrome are actually, they are actually from sporadic mutations. They're actually a rise from sporadic mutations. And what about very single, low single digit percentages of red syndrome? Actually, they are a rise in an X-link dominant fashion. Okay? They do a rise in an X-link dominant fashion. So the thing is, what is the pathophysiology behind red syndrome? Well, the pathophysies, you have a defect in a gene known as MEC P2, the MEC P2 gene. Okay? You have a mutation in the MEC P2 gene. And again, it's on the X chromosome, the MEC P2 gene. Okay? The MEC P2 gene, the MEC P2 gene. That's probably about as much as you need to know for red syndrome. And really, the only thing you need to do for these kids is trade the asymptoms. If they have seizures, give them an anti-convulsive, but that's pretty much it. That's probably about as much as you need to know.

But again, remember, it's going to be in a lady in a female where, you know, after about six months of age or there about, she starts losing motorboules stones, they have speech impediments, they'll have 100 gene behaviors. They can have like a small head. Those are all pretty classic signs and symptoms of red syndrome. So make sure you know red syndrome. Okay? Now, what if they give you a question about a boy? They tell you that, you know, he has hip puberty and his parents are noticing that he has very large testicles. And they tell you that he has a long face, he has very large ears. They tell you that on physical exam, he has to, this must, when you see stuff like this, what should you be thinking about? Or really, what you're saying, oh, divine. This sounds a lot like fragile X syndrome. This sounds a lot like fragile X syndrome. So fragile X syndrome is another high-odd ex-lindominant disorder to know about. And it's actually kind of unique because it's a try nucleothelrypid disorder, right? The CGG try nucleothelrypids, the CGG try nucleothelrypids. And remember, in fragile X syndrome, the gene that's messed up is the FMR1 gene, the FMR1 gene, the FMR1 gene. The thing is, when you have that FMR1 gene problem, you're going to methylate and silence certain genes that are important. And when you lose those gene products, you then begin to run into problems. Those gene products, if I'm not mistaken, are very important in the brain.

So you're going to run into problems, but remember the classic findings, microarchitectism, bake testicles, large ears, long face. These kids can have a gird, we can have strabism, they can have ambleopia, they can have many different problems. So that's something you want to keep in mind on exams with fragile X syndrome. And again, remember, it's CGG try nucleothelrypids, CGG try nucleothelrypids. And many of those kids that have fragile X syndrome in general, they tend to have a normal life expectancy. They tend to have pretty significant intellectual disability. And remember, ADHD is very common in kids with fragile X. The most common, I'll say probably one of the more common psychiatric disorders in people that have fragile X syndrome is ADHD. And then, the final condition I'm going to go to, what if they give you a question about multiple family members? They tell you that they have hearing problems, like sensory neuro hearing loss, they have problems with vision, they can even tell you that they have a cone-shaped lens or something like that. They tell you that they have a proteinuria and things of that nature. If you kind of put everything together, this is outboard syndrome. Outboard syndrome is another high-yield, excellent dominant disorder to know for you exams. Outboard syndrome was the battlefield, it's a type 4 collagen defect. Many times it's the COL4 E5 gene that is messed up. It's kind of high-yield to know that gene actually. The COL4 E5 gene doesn't work.

If it doesn't work, you're going to have problems. Many times these people have like nephritic syndrome. And usually when they have those nephritic syndrome, when you take a biopsy of the kidneys, look at it on the electron microscopy, those people have this basket weave pattern. That's a classically described pattern that is shown in electron microscopy. It's very high-yield to know by the way. So if they have this nephritic syndrome, they can have proteinuria. In fact, these kids tend to get yeast inhibitors. That's a very good indication for yeast inhibitor therapy in these kids. So it's just very high-yield to know about outboard syndrome. Remember, it's a type 4 collagen defect. Remember the findings. Here in issues, eye issues, nephritic syndrome. It's going to run in the family. And again, it's excellent dominant inheritance. So I said the gene that's messed up is COL4 E5. But it can also be any COL4 G, like COL4 E3, COL4 E4. But really think more about COL4 E5 or your exam. Again, this podcast, I think I'm going to go ahead and pause here. But I think I've said pretty much most of the high-yield things I want to say about ex-lendominated disorders. So thank you for listening to me today. I do offer one on one tutoring for step one to three, complex one to three. I just don't tutor to OMM. I offer review courses for step one. I have one in January. I offer review courses for step two and step three. And a complex level two and three.

And obviously my step one course in January also applies to complex level one. Or if you're a 30-year medical student, you have a very poor foundation from step one. And you don't, you want to repair that foundation. Then the step one course will be perfect for you. Gunn is going to be taking place very early in January. Just shoot me an email and I'll give you some more information. I also made a few podcasts ago on the step one class. And then I also help with mock interviews and errors applications. So if that's something you're interested in, please just shoot me an email. And I'll give you some more information. And then I have a website. I have these podcasts on the major podcasts apps, Apple, Google, Spotify, at least the most recent 150 podcasts. I also have a You Tube channel, Divine Intervention, US Mally Podcasts and videos. That's where I post the videos that I make. And then I have another website called Divine Intervention Lifelessens.com. Divine Intervention Lifelessens.com. That's where I post the life lessons that I make. Many people say, oh wow, Divine, I love the life lessons you put at the end of your podcasts. So I said, oh, make a separate website, Divine Intervention Lifelessens.com. In fact, it has a podcast that you can find on Apple Podcasts. Just look for the Divine Intervention Life Lessons Podcasts. But basically I use the Bible to put out like two podcasts every week on a common problem that's faced by humanity.

And I just cause it from a biblical perspective. Now, the quick thing I just want to say at the end here, I will encourage you, do not memorize what you can mentally work out. It's very important. Do not memorize what you can mentally work out. You should only memorize things that are very hard to mentally work out or require extreme amounts of time that you don't have on an exam to mentally work out. That's like a very good algorithm for dealing with what should I memorize and what should I really try to understand. So thank you for listening to me today. I'll see you in the next podcast. Have a wonderful rest of your day. God bless you. Bye for now.

In X-linked dominant, having one bad X chromosome (heterozygous) causes symptoms; in X-linked recessive, two bad X chromosomes are required for symptoms.

All daughters will be affected because they must receive the defective X chromosome from their father. His sons will not be affected as they receive the Y chromosome.

A mutation in the MECP2 gene, located on the X chromosome.

Osteogenesis Imperfecta (OI).

Macroorchidism, large ears, and long face.

$1\alpha$-hydroxylase activity (due to high FGF23).

Rett syndrome.

FMR1.

Low levels of $1,25(\text{OH})_2\text{D}$ (active vitamin D).

Type IV collagen defect (often COL4 E5 gene).

50% chance of son/daughter being affected, as they have a 50/50 chance of receiving the bad X chromosome from her.

Rett syndrome.

FMR1.

Low levels of $1,25(\text{OH})_2\text{D}$ (active vitamin D).

Type IV collagen defect (often COL4 E5 gene).

50% chance of son/daughter being affected, as they have a 50/50 chance of receiving the bad X chromosome from her.