Schaaf-Yang Syndrome: What Do We Know? [2018 CONFERENCE VIDEO]

This blog is based on a presentation at the FPWR 2018 conference. You can watch the complete presentation by clicking on the embedded video. In case you don't have time to watch the full video, we've included a full transcript below. You can also watch the full set of conference videos on YouTube.


Video Transcript

Christian Schaaf:

Thank you to the Foundation of Prader-Willi research for hosting us and for allowing us to be part of the conference; for the support that you have given us and the families in regards of the research that we do but also helping us raise awareness and move the field forward. My name is Christian Schaaf and most of you know me. There are some new faces and several of you I've met for the first time today. Then there's new faces that we yet have to meet. I'm very excited to be here. For me this is one of the highlights of the year to come and meet you, to meet your children, to get to know more about you and your children, and to learn from you. I hope that we can give a little back to you and help educate you and answer some of the questions that you have so both this session and other sessions that we are part of. They're really for you and we need to make them whatever you need them to be. I have a slide deck and I've prepared information but if you feel that I'm moving too fast or I'm telling you things that you all know already please let me know and we can modify this. We can keep this interactive and we can make it whatever you need it to be.

As I mentioned, there some familiar faces. Several of us have met last year at the foundation for Prader-Willi research meeting which was in August in Indianapolis in 2017. Then there's new faces. There are some families who couldn't make it last year. There are some families whose children were only diagnosed over the last year. My presentation today recapitulates some of the basic concepts of Schaaf-Yang syndrome. I think even though it may be a repetition, some repetition is good because oftentimes, the first time we hear something it doesn't sink in all the way and we may not retain all the information. There may still be open questions and I have some repetition, but then I also have some updates about what has happened, what we've found out over the past year, and where we're going from here. This is kind of the basic introductory session and then we have more specialized sessions on Schaaf-Yang syndrome.

Johanna Reed from Seattle Children's will present information about sleep apnea, which is a big issue for a lot of kids with Schaaf-Yang syndrome and some of the data that she has analyzed is preliminary data on the Schaaf-Yang children and also potential for future research studies. Then we have Leandra Berry, who's a clinical and research psychologist at the Autism Center of Texas Children's Hospital. She was one of the key psychologists in our deep phenotyping study where we brought ten children with Schaaf-Yang to Houston, Texas to do a very thorough two-day examination and investigation of their cognitive abilities, their autism related phenotypes, and also their behavioral profile. We just got an email yesterday and the manuscript, the paper that we've written for medical journal about that part of the Schaaf-Yang study, has been accepted; which is great news. It will be coming out soon and she will present the data that will be part of that manuscript. This is our picture from last year in Indianapolis and we should consider getting together and take a group picture again this year. I have this picture in my office and it reminds me of all of you every day. I keep using Hannah's quote of us being a tribe. I use it for all different kinds of purposes and I don't give you any copyright but I always mentioned your name. I think this is the major feeling that we have when we come together; that we get together with this group with people who we thought we would have nothing in common with them. They are actually a family that we didn't know existed. The better we get to know them the better the kids get to know each other. The more we realize how much we have in common, it feels like some kind of home where we can talk about things very openly and we don't feel like being judged by others because the other people in this room have been going through the same. They've been traveling the same road and they've experienced a lot of the same issue. They have the same hopes and expectations for the future, so having common goals is also part of that feeling. The definition of the tribe is that we have a common goal and that is to help our children develop to the very best of their potential and ultimately find treatments for them.

For those who don't know the Schaaf-Yang syndrome history, I want to show you the picture of Donnie. Donnie was the very first patient with Schaaf-Yang syndrome who came to see me from Arizona and obviously at the time I didn't know that that's what he had. He came as a teenager with autism spectrum disorder mostly, but upon taking the history it became evident quite quickly that there was much more to it than just autism spectrum disorder. He also has mild intellectual disability and there was this history of contractures, history of feeding difficulties, low muscle tone, undescended testicle, and the physicians thought that he had Prader-Willi syndrome. When he received the testing in the newborn intensive care unit, the testing came back negative for Prader-Willi and the family was left without answers for—I want to say 16 years or so, until we did exome sequencing and found out that he has a mutation in the MAGEL2 gene. That was one of the first questions I remember when the family came to see me; I always asked the family what are your expectations for today's visit and what are the questions that you want me to answer? The mom said, “I want to know if he has Prader-Willi syndrome or not because I've been confused for 16 years”. She was on the right track; she kind of hit the nail on the head because we then found out that indeed, he has a condition that is very closely related to Prader Willi syndrome. We then identified three more individuals and published our first report in 2013 and following that initial report, Theresa Strong from the Foundation of Prader-Willi syndrome research invited me to come to one of these family meetings and present. All I had was four patients at the time and we really didn't know where this would go; whether we would be at five patients after three years or ten patients. As of today, I mentioned this before, it depends on how we count. We have 120 very definitive cases of Schaaf-Yang syndrome, following the strictest kind of definition that we use and there’s many more patients in our database who have other types of mutations in the MAGEL2 gene. They have symptoms that are very much related to Schaaf-Yang syndrome but those are individuals that we're still studying to find out whether we feel 100% certain that that's what they have. Initially we called it Prader-Willi light syndrome and we got a lot of criticism about that at the time. People felt that you can’t call it that because the key manifestation of Prader-Willi syndrome is the overeating and the hyperphagia which then leads to obesity. These patients typically do not have obesity, so other physicians in the field felt that we can't call it Prader-Willi syndrome. For a while called it MAGEL2 related disorder and then the institution that names genetic syndromes (which comes out of Johns Hopkins University in Baltimore) decided to name it Schaaf-Yang syndrome after the first and the last author of that initial report. That’s the policy that they often have. They take the initial report the first time a new disease gene is discovered, and they take the first author in the last author of that paper and that's what it's called. We have worked together for many years and at some point she wants to come along and get to meet you. I always provide them with updates but she's more of a diagnostic molecular geneticist. She doesn't really have patient contact and so she's not quite as familiar with the things that are most important to you, but she's certainly been critical in identifying the first set of patients. Then last year we had the first Schaaf-Yang syndrome family meeting, which I think was a major milestone because it was the first time we actually physically got together and got to know each other. I hope there'll be many more occasions over the next year's and decades.

Here I have a section- genetics 101 and it's like genetics 201 and 301 because the genetics of module two are quite complicated. These are repetitions of last year, but because it's so complicated. I think it doesn't hurt for anyone to go over this again. In our body, we have many cells and most of the cells have a nucleus. In the nucleus we carry the genetic information and the genetic information is packed on chromosomes. The chromosomes typically come in pairs of which we get one copy from mom and one copy from dad. For most of the genes in our body, we have two copies. One comes from dad and so on. If you think of your genome as a library, the chromosomes would be the shelves in the library and then on the shelves you have the books. You could say the books, those are the genes and each book has a certain set of information. That's true for the genes as well. Most of the genes, they have one piece of information that is necessary to be encoded or to encode to translate into a protein. From the genetic information, proteins are made and then the proteins fulfill the function in the cells and within the body. Sean McDade, who is the father of a child with Schaaf-Yang syndrome; he did these beautiful illustrations of the MAGEL2 gene, which is the critical gene for Schaaf-Yang syndrome on chromosome 15. It is in a region that is known to be the critical region for Prader-Willi syndrome. In most cases of Prader-Willi syndrome there's a chunk of chromosome material that's missing. It's just like on the shelf that's that represents chromosome 15. In your library there's a set of books that's taken out of the shelf and that's missing. What’s important is that the missing information is on the chromosome 15. That comes from the dad. There is something special and kind of unique about this region on chromosome 15. That is the only information that's on dad's chromosome. The chromosome that came from dad is the part that is active and that is used by the body. That's the part that's translated into proteins, etc. The equivalent section on chromosome 15 that comes from mom is silenced. We call it imprinted, so it's almost like there's this shelf that we got from mom, but there's a certain section on the shelf that has a door in front of it and it's locked. We can't go there and use it and that will become very relevant and translates into the situation that is important to Prader-Willi syndrome and Schaaf-Yang syndrome. If you miss the same exact section on mom's chromosome, you do not get Prader-Willi syndrome. Also, you can get Prader-Willi syndrome if you have two copies of chromosome 15 that both come from mom because you then have two copies of chromosome 15. What you're missing is the dad’s contribution and so you can also get Prader-Willi syndrome that way. Typically, there's a piece missing in this section or you get two copies from mom, but that's not the situation in Schaaf-Yang syndrome.

In Schaaf-Yang syndrome it's a smaller change within that region. We zoomed into the Prader-Willi syndrome region and within that region there are multiple genes. MAGEL2 is only one of those genes within the region and in Schaaf-Yang syndrome you're not actually missing this piece, but you have a point mutation in this area. Several of your kids may have had Prader-Willi testing when they were little and the test comes back normal; just like for Donnie that I mentioned. It comes back normal because the test looks at whether you have this piece of chromosome material from the dad. All your kids with Schaaf-Yang syndrome, they have this piece of chromosome material. They have a misspelling within that region but that's not what the Prader-Willi syndrome test looks for. That's why the Prader-Willi syndrome test will come back normal. Here is the difference between Prader-Willi syndrome on the left and Schaaf-Yang syndrome on the right. In Prader-Willi syndrome in almost all of the cases it's about a missing piece of chromosome material or a situation where the child got two copies of chromosome 15 from mom and no copy of chromosome 15 from dad. In Schaaf-Yang syndrome it's a what we call a single base substitution, so in most of the cases it's only one letter or only a few letters in the genetic code of the major two gene that have been changed. In going back to the analogy of the library, it's not like they're missing books or such on the shelf, but in one book that is the book for MAGEL2. There is a misspelling and you have to do a different test because if you just walk through the library and count the number of books everything will be fine. You have to open the book of the MAGEL2 gene and read the text and check for misspellings and typographical errors within the MAGEL2 gene. That's why also you need different kinds of diagnostic tests to diagnose Schaaf-Yang syndrome. You need sequencing tests like a chromosome test or chromosome microarray tests. Prader-Willi syndrome methylation test will not find this. You need to spell out the genetic code and that can either be done by a single gene sequencing for MAGEL2. We have a few patients now who've been diagnosed that way, where the physician in the newborn intensive care unit recognizes the condition and say, “this looks like Schaaf-Yang syndrome and let's do the testing just for that gene”. It can be diagnosed that way or whole exome sequencing. The vast majority of your children have been diagnosed by whole exome sequencing because the physicians felt there is something, but we don't know what exactly it is. Oftentimes we feel like we're not smart enough to say it's this or that, so we just do the big test and sequence (like several thousands of genes at the same time) and they will still find the mutation that way.

Participant question, inaudible.


The question was whether the single gene testing is less expensive than the whole exome sequencing test. Yes, it's much less expensive so in a lot of situations, especially in an outpatient setting in the United States or in most situations abroad, insurance companies will not pay for whole exome sequencing as of today. They will or may pay for the single gene test. Just to give you an idea, in whole exome sequencing I think the insurance company is charged about ten thousand dollars. The single gene test—they probably charge about one thousand dollars. So, yes, it’s a significant difference. Most of the cases that have been diagnosed by direct sequencing of the MAGEL2 gene were in Houston; not just by me, but also colleagues. My wife always says I talk too much, so I guess I've also talked sufficiently about Schaaf-Yang syndrome to my colleagues over the last five years and I've infiltrated this group with the idea that this exists and that they should be looking for it. I have several colleagues who have diagnosed kids directly, not just in the NICU but also in the genetics clinic; older kids who came and gave the history, and the physician felt that this sounds very much like Schaaf-Yang syndrome.

Participant question, inaudible.


Kim brings up a very good point. Raising awareness is really important when it comes to identifying more patients with Schaaf-Yang syndrome; which is not only good for us and the group but it's also good obviously for the families primarily who may be seeking answers for their children. Some of them have been seeking answers for years and years so the things that we can do: each and every one of you could bring copies of our publications about Schaaf-Yang syndrome to you physicians and say, “This is what Emma has and this publication just came out. You know, this may help you take better care of Emma and understand what she has. We would be most grateful if you shared this information with your colleagues”. Especially at the University Medical Center's; physicians always look for interesting cases to be presented at grand rounds or other kinds of seminar series. So, if you feel okay with having your child on display at a medical conference. You could let them know, “here's this information. Why don't you think about presenting Trinity at the next grand rounds at our Children's Hospital? We would be happy to give you all the information that we have”. Sometimes, I as a medical student felt that the best lectures were those where patients were brought to the lecturer and the families were interviewed as part of the lecture. I actually still do that at the medical school where I'm at now in Germany because the students will remember this so much better and so much longer than any information that they just read in a textbook (and they forget five minutes later).


From an insurance standpoint, I know you guys aren't thinking with the growth hormone getting approved and stuff like that (which our main development team has helped us). I know you said that they couldn't call it a Prader-Willi like syndrome. However, insurance does that part because then they're like okay, Prader-Willi syndrome—here we know that that's an approved treatment, so here's your script. Out doctor says, “Schaaf-Yang syndrome, MAGEL2, genetic mutation, Prader-Willi like syndrome- yes”. For some reason that made a huge difference in what services our kids were approved for.


It’s a very good point that Hannah brings up, especially when it gets to approving more expensive treatments such as growth hormone. You may run into walls and have challenges with the diagnosis of Schaaf-Yang syndrome that does not have an ICD code that you know. Most people obviously have never heard about Schaaf-Yang syndrome and Prader-Willi-like syndrome. Theresa from the foundation mentioned that the plan for the new ICD-10 codes is actually to have Prader-Willi syndrome as an ICD-10 code and then have a sub code that is Prader-Willi-like syndrome. That would be a good way to have that listed as an ICD code in the medical records of your child because it may open up possibilities that allow your child to get resources and therapies that otherwise you would have to fight for very hard.


This group meets under the Prader-Willi umbrella. There was the assumption that underneath this foundation we don’t need to consult will all these people.


Someone will say, “let me see your computer” and I will pull up the foundation for Prader-Willi and then I'll do the drop down to Schaaf-Yang.

I’ll pull that up and it gives them a good baseline for baseline treatment, I guess. Then they’ve gone in and watched your video and that’s given them more information.


Do we have a packet that you were talking about? Is there something that can be put together than can be distributed to the NICUs, the other hospitals? I’m usually bringing things together.


We don’t really have that. Usually when families reached out to us- Megan who I should introduced her right at the beginning—Megan is my research coordinator at Baylor and is here with us today. She is your best resource and she's my American outpost at this time. She puts together some information and some links. We also have some information on our labs website but this is actually something that you as a group of families could do as you talk about outreach and activities; things that could be achieved to create a flyer or package of information that is an introduction to Schaaf-Yang syndrome; that summarizes some of the main points using the some of the graphics that Shawn created; and a little write-up. We have a one-page summary that we created at the time. This is actually a good idea. I know you'll have an extra session about what you as a group of families will do and what you can do. For example, newborn babies with Down syndrome. The local Down Syndrome Foundation has a welcome package for those families and that's not just information. It usually has a teddy bear or something like that comes with it. It’s a nice warm welcome into that community I guess that's also something that could be thought about.

After the mutation has been found in the MAGEL2, if you want to be a 100% sure that it is the cause of your child syndrome (to get the ultimate proof) you would also need to show that the mutation is on the father's copy of chromosome 15 (the copy that was inherited from the dad). Then there is a special test that can be done to prove that and that test as far as I know right now is only offered by one lab and that's at Baylor College of Medicine in Houston. In many cases for your children, the testing with a whole exome sequencing test included something where it shows whether it comes from dad or from mom. In some families that’s the case; that dad carries the MAGEL2 mutation. Then you don't actually have to do this additional test because you know that it has to come from dad. In other situations, the mutation will be shown as part of the initial exome sequencing. If it was done as a trio exome test, where the mom and the dad were also sequenced, the test will also give information if it was de novo (which means that none of the two parents carried the mutation and you could say that if the mutation de novo not coming from either mom or dad). It's a typical mutation and the child manifests the clinical features of Schaaf-Yang syndrome. A lot of physicians would say, “well that's enough information and we don't need to do this additional test to show that this is a new mutation on the father's copy of chromosome 15”. This is just for completeness I want to show this. There’s some familial cases of Schaaf-Yang syndrome including some really big pedigrees and families where this has affected multiple people over several generations. What you see in these pedigrees is that they're people who carry the mutation. They are unaffected. They do not have Schaaf-Yang syndrome and that is because they have the mutation on their maternal chromosome 15. They have the mutation on the chromosome 15 that they got from their mom and because that's the MAGEL2 gene, that's not huge. What's imprinted and locked away they don't manifest the features. Men who carry this mutation—once they pass it on to their children, it doesn't matter whether those children are girls or boys. It has nothing to do with the sex of the affected individual. All that matters is: from which parent do you get it? These men carry the mutation and they have a 50% chance of passing it on to their children. They can have multiple affected children, which means that if you have a child with Schaaf-Yang syndrome and you as a father or your husband has not been tested and he carries the MAGEL2 mutation, it would be good to have him tested because that will change the whole situation. I’ll get into the chance of recurrence in one of the subsequent slides.

We see these situations: either the mutation is de novo (neither mom or dad carry the mutation) and that's a majority of cases or it is inherited through dad (where dad carries the mutation and he has a 50% chance of passing it on to his children). Then we also have this situation (and this seems surprising) where both mom and dad were tested, and they were found not to have the mutation but they still have two affected individuals. This situation is known not only for Schaaf-Yang syndrome but for multiple genetic disorders. This mechanism is called germline mosaicism, which means that when we test the dad we get a blood sample from him. We test if he carries the mutation in his white blood cells and we don't find it. How could he still have two affected individuals? Most likely that's when we think the mutation happened at some point in his sperm. In some of the premature forms of the sperm—if that's one of those premature forms the mutation occurred then all the subsequent sperm that originate from that original cell will have the mutation. We call it a mosaicism. It’s like a mosaic in the testicle. Most parts of the testicle or most sperm do not have the mutation but there could be a subset with hundreds or thousands of sperm that have the mutation. It is rare. Megan, do we have two families with that kind of setup? I think we have two families right now. Generally, in genetics once both parents have been tested and have tested negative, then we quote a recurrence risk of less than 2%. In medicine, we never say zero. Nothing is black or white in medicine. We always try to be a little vague because that is nature. Nature is not always predictable. We empirically based our studying not just Schaaf-Yang syndrome but many genetic conditions. When a disorder is inherited the way that Schaaf-Yang is inherited (and both parents test negative) the chances of having more than one affected child after the first affected child, there’s likely a subsequent pregnancy (another affected child is small, but it's not zero). We typically say less than 2%. It can't really be tested for theoretically. You could test a sperm sample and do single-cell testing for the mutation but that's not clinically offered. Even after you have tested the sperm you can't use them for in vitro fertilization so the ones that you've tested would be gone. In a situation like this and I would say that's about a quarter of all families; where dad is found to carry the MAGEL2 mutation. Then we know that for every pregnancy there's a 50% chance because the dad has two copies (one from mom one and from dad) and when he passes them on it's a 50/50 chance which one goes into the sperm. Whenever he passes on the mutation, the child will be affected with Schaaf-Yang syndrome. This is something that can be tested for and this is also something that could be tested for prenatally (or even as part of a pre-implantation genetic diagnosis through in vitro fertilization). As I mentioned, the numbers keep changing. When I put this slide together we had 115 definitive cases of Schaaf-Yang syndrome to date. This is the MAGEL2 gene and we’ve plotted it. Sean McDade helped visualize this, so we've plotted the mutations along the MAGEL2 gene and the size of the circle corresponds to the number of cases. You see that the majority of cases (more than half of all cases) cluster in this middle region of the MAGEL2 gene. There's one particular area where a lot of mutations occur. You see, we have 61 cases so more than half of all cases have the same exact mutation. It’s a so-called mutational hotspot and it has to do with the sequence at that site because it's repetitive with multiple C's. When the genetic code is read and transcribed and the machinery that reads the genetic code gets confused is almost like I got confused. I didn't notice when I put like seven or eight C's there so if you ask me to transcribe that kind of thing it’s drop a C or add a C and not notice that. The majority of Schaaf-Yang patients have an extra C in that train of C's. Then, of course, there's also some patients who lack one C and that has a quite traumatic consequence. There are five patients that have been reported to date. That's the most severe form of Schaaf-Yang syndrome. Those are individuals who have extremely low muscle tone. They have very bad contractures and stiff joints to the point that their well-being is so compromised that they often die prenatally or shortly postnatally. I'm not aware of a living individual past the first year of life with this type of mutation.

Let's talk about the clinical features of Schaaf-Yang syndrome and I'll try to be brief because this is something that I think most of you are familiar with. This is something that we have in our publications and I should highlight that there is a publication coming out on Monday which is the work of John McCarthy. He is my former research coordinator who spent the summer with me in and hauled the whole group to get more clinical information. This has been written up and accepted and will be published on Monday summarizing the clinical findings of 78 patients with Schaaf-Yang syndrome. I want to thank everyone in this room who contributed to that study. It starts before birth. The babies have decreased fetal movements. Because of the decreased movements and because they may not swallow as much of the amniotic fluid, they may have swallowing difficulties even in utero. It leads to a situation where more water accumulates in the amniotic cavity. Some of you may have experienced what's called polyhydramnios. The doctor who does the ultrasound says there's a lot of amniotic fluid around the baby. When they are born oftentimes Schaaf-Yang syndrome is recognized shortly after birth because the babies have low muscle tone and they have feeding difficulties. Many of the boys have undescended testicles and it leads to this combination of features that makes a lot of physicians think of Prader-Willi syndrome. I should also add that a good number of children (and we'll have that in the publication that comes out on Monday) have breathing difficulties and they may not be able to breathe sufficiently by themselves. They may need supplemental oxygen. Some of them need to be intubated. Some of the kids have been intubated for several months, to the point that they need to tracheostomy in order to go home. Then as the kids get older their developmental milestones are delayed. On average there's a lot of variability in the development of children but on average we expect children to be able to sit by themselves at six months of age, to take their first steps independently at 12 to 14 months of age, and to speak their first words other than “mama” or dada” also around 2 to 15 months of age. Among all the kids that we have gotten information the average time to sit independently for kids with Schaaf-Yang syndrome is 18 months, but there's a broad range. Some kids sit at eight months and some kids sit at sixty months (which is five years). Walking at fifty months of age is the average age for the kids to walk independently (between their fourth and their fifth birthday). The first words on average is at three years of age but again a broad range. We even have some teenaged kids with Schaaf-Yang syndrome who are still nonverbal. In the publication that comes out on Monday, we'll have that information; like how old is the oldest child with Schaaf-Yang syndrome? Who doesn't speak yet? We decided to pay $3,000 for the publication so that it's open access and so that everybody can access it. You don't have to pay when you want to look at it once it comes out. Megan can put it in the Facebook group. It’s the 78 cases of Schaaf-Yang syndrome and it's coming out in the American Journal of medical genetics. This the most up-to-date data that we have which is also included in the publication.

Almost all of the kids have developmental delay and have cognitive challenges with intellectual disability when they grow up. Developmental delay and intellectual disability are basically present in all of your children. With all of the children that we've studied today, autism spectrum disorder is also a very common phenotype. More than 75% of all the kids who had tested for autism tested positive and got the diagnosis. Leandra Berry, the psychologist who's coming in today will present on the cognitive abilities, autism, and the behavior in much more depth tomorrow. She can also tell you about the spectrum of IQs that we found, etc. There are some physical features related to Schaaf-Yang syndrome. One of the first features that can be noticed (even in the newborn unit) are the contractures, which most typically affect the hands but when more severe can also affect other joints such as the knees or elbows. Then you see some of your kids and some of the other kids with Schaaf-Yang syndrome on this panel with some kind of combination of features on the face and the skull that makes them look in some ways. If you brought a new child to my clinic I would not feel comfortable making the diagnosis based on visual inspection. I know that some of you have mentioned that on Facebook; that when pictures are shared, people say, “he looks just like my child or I got confused because I thought how did this picture of my child come up on Facebook?”; until they notice that it's someone else's child. Additional common features: sleep apnea. Johanna Reed will talk about how we differentiate between obstructive and central sleep apnea or combined sleep apnea. Sleep apnea in general is a common feature in Prader-Willi syndrome and even more common in Schaaf-Yang syndrome. A lot of the kids have some kind of respiratory problem at some point and more than half of them needed to be intubated typically right after birth. About 1 out of 5 children required tracheostomy, which means that they've been on a ventilator for a long time and it was a necessary step to be taken for them to go home. Feeding problems are seen in almost all of the children with Schaaf-Yang syndrome. They have difficulty swallowing and in part that's due to the hypotonia, the low muscle tone, but in part it's also a problem of coordinating the muscles to get the food down. 3/4 of all children have a history of tube feeding. The endocrine system is affected in Schaaf-Yang syndrome. There is a publication on this based on our FPWR funded study. The first author of that study was also John McCarthy. I had talked about the results and that has been published. That's not open access, but if you need a copy of that paper please send an email to Megan and she can forward the paper to you.

What we found in the kids that we studied is that there's a high percentage of kids who have growth hormone deficiency; which is in line with Prader-Willi syndrome and is one of the rationales why growth hormone supplementation or treatment may be a viable option. It seems that a subset of kids develops glucose intolerance and if that continues it leads to diabetes. We have several teenagers who actually already require treatment for diabetes, including some who need insulin treatment. Then there are other abnormal hormones related to food intake and satiety that we studied. Ghrelin is one of those that's not something that's clinically important but that's important to the field to understand the pathways that regulate feeding behavior. We did studies on the bone and skeletal system and found that a lot of your children have decreased bone mineral density. That is something that I recommend for every child once they're 5 years old; to get a DEXA scan. That's the age when normal values are established for children. This is a fairly easy test. They only need to lie on a table for a few seconds and it's like an x-ray that's taken. If they don't lie still you can hold them down so that they just take the x-ray of the hips and the spine. It determines the bone mineral density and some of these kids have values of bone mineral density that are well in the range of what you would consider osteoporosis. Because some of them are not quite as steady when they walk and they have low bone mineral density, they are at an increased risk of fracturing bones. This is something that you may want to know about. If there is low bone mineral density there are some things you can do: optimizing their calcium intake, their vitamin D intake, and there may also be treatments specifically for osteoporosis coming up for Schaaf-Yang syndrome and Prader-Willi syndrome. There's a whole group that studies the bone system as it relates to the MAGEL2 gene and there's some nice new data that suggests that there may be treatments available at some point. It’s a DEXA scan or bone mineral density scan. It's like what a lot of women do after menopause. They do that at some point. I think that it may have a positive effect on bone mineral density, but I would have to ask my endocrinology friends. Bone marrow density also get’s better the more mobile the kids are. The more weight-bearing exercise you do, the more they walk. The kind impact on the bones when you walk—you increase your bone mineral density. Being mobile is a good thing in that regard.


I know a lot of kids that aren’t flexible and not fully formed and don’t start weight-bearing early.


That's something that we haven't looked into systematically. I know that some kids have that, but I couldn't give you a percentage of how many have that. Scoliosis is a feature that's present in a good number of kids which most likely relates to the low muscle tone. I see that in a lot of the kids with the more severe hypotonia. They also tend to have the scoliosis more severely and this is something that relates to the MAGEL2 gene, even when you take the MAGEL2 gene out of the mice. The mice also have a high prevalence of scoliosis.

These are studies that Rachel did several years ago I think. Does the type of mutation correlate with severity? That's a question that we are only beginning to investigate in the publication that comes out on Monday. You will see a first piece of information in that direction to really show correlation of the genetic mutation. With the severity we need more patients to really prove that that is the case. What I can tell you is that when you compare the kids with the c.1996dupC mutation, the mutation that's the most common mutation when we compare these to all other kids. This group of kids has a somewhat more severe phenotype than the others. This does not mean that each child with this mutation is more severe than any of the others, but they as a group compared to all the others as a group are more severe. That relates especially to some clinical manifestations such as the breathing problems, the intubation, and the respiratory problems. I think it also relates to the feeding problems. More detailed information is in the paper that's coming out on Monday. I have listed it here on the slide. These kids compared to all others have more respiratory distress. They have more feeding problems. They're more likely to require two feeds and a g-tube surgery and they're also more likely to have contractures. I mentioned to you before that these individuals with this particular mutation—there’s a fairly small number. They have the most severe form and they all passed away shortly after birth.

This is something that has come up recently. I told you that initially we called it Prader-Willi like syndrome then it was named Schaaf-Yang syndrome. Over the last two years there were groups that had patients who have been medical mystery cases for many years and now with the exome sequencing technology they were found to also have mutations in the MAGEL2 gene. Those patients and their clinical presentation had been named differently before they knew what the cause of their disease was. In 2017, there was a child that was reported with what was considered Opitz C syndrome. The key presentations in that case where craniofacial abnormalities, intellectual disability, cardiac defects, and patients with this condition also have a high mortality rate. They had multiple patients with this condition but when they sequenced them in one of the patients they found a major mutation. This a report that says Opitz C syndrome can be caused by MAGEL2 mutation and then this year another study came out from a group in Canada. They had collected patients with arthrogryposis, which means the contractures, intellectual disability and hypopituitarism. It’s in a decreased function throughout all the functions of the pituitary gland, which results in multiple hormonal and endocrine abnormalities in the in the affected individual (including growth hormone deficiency). This is a group of geneticists and endocrinologists who had collected a group of patients with those manifestations and now they sequenced them. They found three patients with MAGEL2 mutations. I'm mentioning this because it may be confusing to you and it's confusing to all of us. It kind of gets back to the question of what do you call it? Do you call it Schaaf-Yang syndrome? Do Chitayat-Hall syndrome? Do you call it Opitz C syndrome? Are these different disorders? Are those all the same disorder but just named differently? Realistically, it doesn't matter right?

I believe that you know manifestations of the same condition. They are all caused by the same type of mutation in the same gene which is the MAGEL2 gene. We know from our kids that some of them are milder in regards of their cognitive deficits, others are more severe. Some kids have an autism diagnosis, others don't. Some kids have very mild contractures, others have very severe contractures. Some kids have needed a tracheostomy, others haven't. There is a significant variability within this group and I think this is just a reflection of the overall variability. It doesn't matter what you call it. I think as long as these families get an answer, get help, and get the treatment that's needed and some of them find their way to us. There was a mother I think who posted a comment on Facebook this week and that said our child was initially considered Opitz C syndrome. Now we know it's Schaaf-Yang syndrome. I think that's all that matters; that they find the community that's the right community for them. We need to wrap up. These are the new studies that are coming out in the next couple of weeks and months and things that we're working on. We will get together again when have more time to interact. If you have any questions you can always email us. We are always there for you and I look forward to our interactions and the talks of Johanna Reed and Leandra Berry over the next two days. Thank you.


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Topics: Research Blog

Susan Hedstrom


Susan Hedstrom is the Executive Director for the Foundation for Prader-Willi Research. Passionate about finding treatments for PWS, Susan joined FPWR in 2009 shortly after her son, Jayden, was diagnosed with Prader-Willi Syndrome. Rather than accepting PWS as it has been defined, Susan has chosen to work with a team of pro-active and tireless individuals to accelerate PWS research in order to change the future of PWS. Inspired by her first FPWR conference and the team of researchers that were working to find answers for the syndrome, she joined the FPWR team in 2010 and led the development of the One SMALL Step walk program. Under Susan’s leadership, over $15 million has been raised for PWS related research.