Welcome back. In this module, I'm going to talk about two additional very interesting syndromes called Prader-Willi and Angelman syndrome. And let me begin with Prader-Willi syndrome. What the phenotype is. Prader-Willi syndrome, the most distinctive aspect of Prader-Willi syndrome is that individuals with Prader-Willi have what's called hyperphagia. Uncontrolled eating. When babies with Prader-Willi syndrome are born, actually ironically, they have a feeding problem. They're not able to eat, and they need to be fed through a feeding tube. But as they get older and into childhood, they have an uncontrollable appetite. The problem is that people with Prader-Willi Syndrome just never feel sated. They never feel full. They're always ravenous. And so they can't control their eating. The problem with overeating in Prader-Willi Syndrome is compounded with another feature of the syndrome. They have very low muscle tone. They don't have a lot of muscle mass because of that. And so they're not very physically active. Not because they're lazy of course, but because they have low muscle tone. And the combination of low muscle tone and uncontrolled eating actually leads, if, if, people with Prader-Willi Syndrome are not effectively treated to morbid obesity, and here's a picture of a young man, he's 19 years old with Prader-Willi Syndrome who's morbidly obese. The in order to maintain a normal weight, this individual would be limited, because of the low muscle tone would probably be limited to about 1,200 to 1,500 calories a day. That's not very many calories. I think, I know I would have a very difficult time eating only 1,500 calories a day. But compound that with never feeling full. On the course web page, I've placed a little YouTube video of a young man with Prader–Willi syndrome, who talks about his, the challenges that Prader–Willi syndrome present him. He's always feeling very hungry, but at the same time if he gives into that he's going to end up morbidly obese and certainly that will reduce his lifespan significantly. Prader-Willi syndrome can be treated. It's very challenging to treat, but it's treated by usually by growth hormone to try to build more muscle mass so that individuals will burn more calories, and also to try to regulate diet. With young children,. Parents with Prader-Willi Syndrome might have to lock the cabinets, or the, put a lock on the refrigerator. Because again, people with Prader-Willi Syndrome have really an uncontrollable, un, uncontrollable appetite. They always feel very very hungry, and that's tough. They also suffer. A mild to moderate level of intellectual disability. Prader-Willi Syndrome is another example of a copy-number variant. We know that in many cases, in fact, 75% of people with Prader-Willi Syndrome, they're missing about 3 million or three megabases of DNA. On the long arm of chromosome 15. This region right in here. So, it's like William Syndrome that we talked about earlier although William Syndrome of course is chromosome here we're talking about chromosome 15. Angelman Syndrome is a much different. It has a much different presentation. In children with Angelman Syndrome, they have a, they have a difficulty in, in cordering, coordinating their motor movements. And because of that, they have a balance disorder. They might have a, find it very difficult to walk. They have what's called ataxia, which is a, a movement disorder. If they do walk, they have kind of an odd gait which is, which, or an atypical, I shouldn't say odd, an atypical gait for us. Which is illustrated here with the arms kind of placed in this distinctive pattern to try to help with their balance. They have great difficulty in developing language and in fact some children with Angelman Syndrome would not develop much language at all. Behaviorally they are, and you can see with the picture of these children here with Angelman Syndrome, they're dispositionally very very happy. And you can see that I think almost all of these have a smile on their face. There are treatments to treat Angelman syndrome that, they try to focus on helping them develop language. Some drugs to try to help. With the movement disorder and also of course using a stretching exercise and balance exercise to help with their movement. Angelman Syndrome we, also an example of a copy number variant. In this case, oh, remarkably, the same region of chromosome. 15 as is deleted in Prader-Willi syndrome. Individuals with Angelman's syndrome are deleted approximately 3 million bases of d n a on this region of chromosome 15. Exactly the same region as Prader-Willi syndrome. But Angelman syndrome doesn't look anything like Prader-Willi syndrome. They're completely different syndromes. How is it that you can get two different clinical syndromes from deleting the same region on the same chromosome? [BLANK_AUDIO]. Well a clue to the answer comes from looking at those chromosome 15s. So here is a kind of schematic of the normal pair of chromosome 15s, and here I've highlighted. The 15, the region of 15 that's deleted, the 3 million basis in Angelman and Prader-Willi Syndrome. And let's just say the blue chromosome is the chromosome this inherit, this individual inherited from his or her father, and the red from his or her mother. So that's a normal pair of chromosome 15s. In Prader-Willi syndrome, if you look at the chromosomes of individuals with Prader-Willi syndrome, if they're deleted this region, and 75% of the time they are deleted this region, it's always the father's chromosome 15. Where the, where that region was deleted. If you look at the father, he's not deleted this region, so again it's something that occurred to novel. It's a new mutation, it occurred during the father's meiotic process. But it's always the father's chromosome 15 that's deleted. In, in Angelman syndrome, if the region is deleted, it's always the mother's chromosome 15 that has the region deleted. Well that's really interesting, why should it matter, whether it's the father's chromosome 15, or the mother's chromosome 15. It turns out, and I, I mentioned this, I I alluded to it kind of very indirectly when we, we got into Mendel's laws. And, and we talked about when Mendel discovered his laws, he reasoned that it didn't matter, whether or not the Leo came from the mother and the father, or the father. And in general, that's true. Whether or not you inherit a Leo from your mother and the father, the function of the Leo may not. It doesn't matter. But there are actually reasons of our genomes, where whether or not you inherited a gene from the mother or the father of that region, that depend, it makes a very big difference on the expression of that allele. Genomic imprinting is a phenomena. Where the gene expression depends upon the sex of the parent who transmitted the gene. About 1% of our genomes are imprinted in this way. That is, you and only in that 1%, you might only express the gene if you inherit the gene from the father. Your mother's gene is silent. Alternatively there are other regions of our genome that you would only express the gene if you inherit the mother's copy. The father's copy is silent. If we look at this region of chromosome 15. In, Prader-Willi, in Angelman Syndrome, and here are all the genes in that 3 million bases of DNA. This region right here, There's about seven or eight genes I guess in this region. In this region here, these genes are only, expressed, if you inherit those genes, from your father. People with Prader-Willi Syndrome didn't get that region from their father. They don't have these genes, they end up with Prader-Willi Syndrome. Alternatively, there are other genes here that are only expressed in the same region but they're different genes, they're only expressed if you inherit them from your mother. So people with Angelman Syndrome have a father's chromosome 15, but they don't have the mother's. So they don't have these genes expressed at all, right? Because they don't, they don't have the mother's genes here. That ends up as Angelman Syndrome. So there's certain regions of our genome where the gene is only expressed if you inherit from your father. In other regions where it's expressed if, only if you inherit from the mother. So if you're missing the father's genes or the mother's genes in those regions, then you're not going to have it at all. That's likely to have a behavioral effect. And you might know one example of this, there are various examples of this that occur. But the mating between. You usually write lions and tigers, they actually don't meet each other in the wild. But in captivity, they do meet each other. And they can actually produce viable offspring. But the viable offspring differ pheno-typically. And I'm sorry, the pictures don't really illustrate it that well. But they differ phenotypically, depending upon whether the father was a lion and the mother a tiger versus the father a tiger and the mother a lion. A liger is when, results when the father is a lion and the mother is a tiger. Ligers are extremely big. A tigon is, when the father is a tiger and the mother is a lion, and they're actually quite small. It's hard to see that because of the different scale. So, again, the father's contribution and the mother's contribution can be different. Last kind of amazing thing here I want to highlight before ending this module. Is right 70, about 75% of the time, I said that Prader-Willi syndrome is due to missing those three million bases of DNA from the father's chromosome 15 and similarly 75% of the time, Angelman syndrome is due to missing those three million bases of DNA from the mother's chromosome 15. But, but what about the other 25% of the time? Well, I'm not going to count for all of the 25%, but I'm going to count for a big chunk of it. About 20% of the time, you get people with Prader-Willi syndrome, not because they're missing a portion of Chromosome 15 from the father. But because they don't even have a chromosome 15 from the father, they have two mother's chromosome 15s. And a little bit less of the time, about 10% of the time, you get individuals with Angelman Syndrome, not because they're missing the chromosome 15 region on the mother's, on the mother's chromosome 15, but they don't have a mother's chromosome 15 at all, they have two father's chromosome 15. This is what's called uniparental disomy. In this case of Prader-Willi syndrome, there's two mother's 15s. And in this case, of Angelman's syndrome, two father's 15s. How did that happen? That's pretty remarkable. That's something that Mendel led us to expect would happen. Well, what must have happened early on is there must have been a, a father's chromosome 15 as well. Two mother's chromosome 15, and a father's chromosome 15. So there must have been aneuploidy, a whole extra chromosome in the cell. But they, somehow the cell was able to throw off one of the chromosome 15s and so this case threw up the father's 15, and you end up with two mother's chromosome 15s. And in this case, earlier in embryo development must've been able to throw off the mother's 15, and resulted in two father's, 15s. So sometimes I guess. Early in embryo development, if we have an abnormal number of chromosomes, we must be able to detect that, and in some cases, get rid of one of them. But in the cases of Prader-Willi and Angelman syndrome with the Chromosome 15, sometimes can still end up with the syndrome because you end with right no father's 15 or no mother's Chromosome 15. Next time, the last module in this unit will, will kind of pull together the, what I've been trying to illustrate here with Prader-Willi syndrome and Angelman syndrome, the X chromosome. The whole notion of the regulation of gene expression. [BLANK_AUDIO]
