Rare Genetic Obesities


This session was dedicated to increasing understanding of rare genetic obesities. It includes information on what we can learn from children and adults with hypothalamic obesity due to rare genetic disorders (specifically relating to hunger, satiety and weight regulation), and discussion on experience of rare genetic obesity within the COMs network. Key speakers: Professor Erica L.T. van den Akker, Professor Liesbeth van Rossum, Professor Karine Clément


Transcripts are auto generated, if you spot an error, please email enquiries@easo.org

Okay everybody, welcome to the latest edition of the the ASOCOMS Network webinar series. Today we are talking about rare genetic obesities. So welcome, thank you for joining and please remember that the video recording and any relevant materials and slides will be shared with you after the session.

Please also remember to mute if you are not speaking but you can ask questions orally or in the chat when the time comes. We'll have a Q&A session after the presentations. So there's not much more for me to say because this is a recurring webinar, we all know each other quite well I think now, so I'm going to hand over to my great colleague Katie Mitchell who is going to introduce the esteemed faculty for you.

So thank you very much for joining and enjoy an excellent webinar, thanks. Thank you Ewan and just to make sure I'm keeping Shireen's good books, can I just mention the hashtag ASOCOMS, so if anybody's talking about the sessions please use that that has the hashtag, I've put the details in the chat and just connect with ASOBC when you're doing that as well please. So we have three fantastic speakers today, we're going to start with Erica and Lisbeth.

Now I have a very detailed bio from both which I'm going to put in the chat but I'll just keep my introduction brief so that we can get on with the final interesting section of the webinar with their talk. So Erica is a paediatric endocrinologist and associate professor, she's head of the division and lecturer based in Rotterdam, she's the co-founder of the obesity clinic CGG together with Lisbeth which is an EASO centre of management and a national referral centre specialising in children and adults with obesity and Lisbeth is an endocrinologist and professor in the field of obesity also based in the Netherlands. She obtained an MD and PhD and performed an obesity research fellowship over in Baltimore in the USA.

She's contributed to the national prevention agreement and in 2020 and 2021 was appointed as top 10 most influential women in the healthcare in the Netherlands which is fantastic. So I will pass the floor to both of you and like I said I'll drop the more detailed bios in the chat so people can read those at their convenience. Thank you very much.

Yes thank you very much Katie for giving us the opportunity to present here today and I will do no further introduction of ourselves because I cannot do better than Judith but we will, Lisbeth and I have founded and are coordinating this centre together so we will also do this presentation really together and so I will start today if that's okay. Lisbeth? Yes hi nice to see you all. I will start to share the slides so Irka will start off with the presentation and I will do a show some slides next.

Great. Yes here we are. So this was the introduction and we'll go to the next slide which will show our disclosures.

These are my disclosures. These are the ones of Lisbeth and just before we start a little bit about our centre. We are located in Rotterdam, the Netherlands and our centre focuses on, it has a broad focus on children and adults with obesity and we aim to do diagnostics of underlying causes.

That will be especially the subject of today but also focus in care and research on personalized and innovative treatments, research and education. It's important to say because today is focusing on part of what we do, the genetic obesity part and we do that. We are a national centre of expertise together with the Department of Clinical Genetics in Amsterdam, Mieke van Houst and we are the centre of expertise on genetic obesity.

Next please. Lisbeth. Yes so this will be what we will be discussing today.

We will talk shortly about some weight regulation then discuss the clinical phenotype of rare genetic obesity disorders, talk about the prevalence and then who should we test for genetic obesity. First of all, there are many causes of obesity as you quite well know and as all being obesity experts. Category 1 to 4 is very prevalent.

Lifestyle induced obesity, mental factors contributing to obesity, medication induced obesity and endocrine factors or diseases. They are all very prevalent and very often it's a combination with lifestyle and category 2, 3 and 4. But category 5, hypothalamic and 6, monogenic and syndromic obesity or 6 is together genetic obesity is more rare and that's the focus of today, category 6, so the genetic obesity. So what's important here? We first have to start with some regulation.

How is our weight and our appetite being regulated before talking about the genetics because these are the factors which are being disturbed in genetic obesity. So when looking at our appetite for example, we have many systems influencing it. So of course our cognitive function, our ratio, we can say well I want to eat healthy, that's very important, it's an important factor, but many other food decisions are based on for example the homeostatic and hedonic system and sometimes also on the brainstem reflex.

So when we also look to the weight regulation, we know that if you have a certain amount of fat mass, this fat mass is an active organ that produces the very important fat hormone, the adipocrine, leptin and this signals to the brain, to the hypothalamus and tells basically the brain how much fat is in the body. It's like a weight skill for fat mass and normally if you have a normal healthy weight, this signal is being received by the leptin receptor and automatically due to the hypothalamus, there's a reduced food intake, so a decrease of feelings of hunger and your metabolism is being increased. So normally you have a perfect balance in the amount of fat mass and how your brain is being stimulated or inhibited, but if there's obesity, we know there's more leptin and this leptin is because there's more fat mass, but we know that in the hypothalamus there's also pro-inflammation there, like it's in the visceral fat and the whole signal of too much leptin is not being sensed very well.

So sort of leptin resistance, about discussion whether it's really resistance, but there is a compensatory higher level of leptin, but the whole negative feedback system on reducing the food intake is being disturbed and that we know that it is progressive and this whole system, this disturbance can cause further weight gain. So as you all very well know, obesity is a chronic relaxing disease. So when we go to the system and we look at the homeostatic system, this is part of the homeostatic system, so the amount of fat in your body, the leptin, but also your intestines are very important endocrine organs regulating your body weight and your appetite.

For example, if you start eating or you see some food, you start making more ghrelin, the hunger hormone, and after about 20 minutes you start producing all kinds of intestinal hormones like GLP-1, PYY, CCK, and they all signal to the hypothalamus and decrease hunger. So they increase the feelings of fullness, they increase satiety. But still, sometimes if you have this homeostatic system working perfectly well and you feel very full, you can still eat through it and that's mostly the case when you look, for example, like something really delicious like a dessert.

And if you eat a dessert, it creates a feeling of comfort and this is mainly due to the hedonic system, like being related to dopamine, serotonin, and endocannabinoid factors, of course, and it just gives you feelings of comfort. And in these times we mostly eat on our hedonic system and not so much on our homeostatic system. So this is when we look around us, we all see the delicious things, our body starts to respond with our hedonic system and we take the chocolate, although we know the chocolate is not the optimal food for us.

So the hedonic system is also very important. Now basically in obesity you have not only disturbance of your leptin system but also disturbed hormonal communication between fat, other organs, intestines, and the brain, and you tend to further gain weight. So now we will start off with a case, Erika will show, which is with a defect in one of these systems.

Please, Erika. Yes, we would, because you are all involved in centers of obesity management, we thought we'd make this more tangible by presenting this clinical case. And before I start, in the end my question will be, what is the diagnosis, the underlying cause in this case of the obesity? So this boy was born in a Dutch family, a Dutch farmer's family, and his birth was uneventful.

He had a normal weight and height at birth. Next slide, please. But very soon, in the first months after birth, parents noticed that this child was crying all the time, an excessively crying infant, and they noticed that the only time he was not crying is when he was being fed, bottle fed.

So it looked like he had no satiety. He had a normal development, he was otherwise healthy, but, and we look back in the photograph book, his mother says, he's everywhere, he's always eating, he's always asking for food. That's hunger.

His weight soon moved completely out of range. His height was relatively tall, and at the community centers, the healthcare professionals said, this is not going well, he's eating way too much. And his parents said, you're right, but how can we change this? He's asking for food all the time.

Next slide, please. And there's one more sign that's important in this case, is that he was different than the rest of his family. Here he is with his sister, and this was about the age that they put locks on all the doors in the kitchen, because else this boy would start stealing food out of it.

Next slide, please. And the last sign and symptom I want to share with you is that at night, as soon as he got old enough, he climbed out of bed and ate even frozen chicken from the fridge or apples with plastic on it, still on it, the plastic wrappers. So the question is, what diagnosis did you make of this patient? Next slide, please.

I will show you. It was, in this case, it was a defect in a gene which is involved in functioning of the leptin melanocortin pathway, which is located in the hypothalamus. So here an MC4R gene defect, which means that the hypothalamus was not sensing satiety, and he was always hungry, and his weight increased immensely.

Next slide, please. We feel it is really important to diagnose these patients. Why? First of all, because they need tailored supportive care.

It just works different in these patients than in other patients. But the other thing is that there is, there are real new pharmacotherapeutic possibilities, and we will mention more about that later on in the presentation of today, what kind of pharmacotherapy is possible, because I will focus on how to diagnose these patients. Next slide, please.

Well, there are two main or several main clinical characteristics that are hallmarks of this disease in children. First of all, the early onset severe obesity in the early years of life, and second of all, the phenotype of hyperphagia. Next slide, please.

The first sign, early onset severe obesity, here you can see in the right slide, that especially in specific diagnosis of rare genetic obesity disorders in the leptin melanocortin pathway, the weight is already way increased in the first, immediately after birth, it starts increasing, and it is immense in the first years of life. So the weight trajectory and the graph is really important. Next slide, please.

The other sign is the hyperphagia. And I want to mention here that hyperphagia is really something different than occasional overeating, than the hedonic overeating, than binge eating. This is really the most upper level of having hunger that we know about.

So how do we diagnose hyperphagia? Sorry, one slide back still, because how do you ask for that in your outpatient clinic? How do you diagnose this? There is not a validated tool for this yet. So what we do currently is use questionnaires on eating behavior. For example, the external eating behavior score is one that is usually very high in these patients.

And the other thing is that there are five questions that you can ask to patients to have an indication on this. The first is on satiation, which means what happens during a meal. It makes you stop eating.

Does somebody have satiety, which is after the meal? Does somebody know when it's full? Does somebody feel fullness? And for how long? The third is the hunger. How immense is the hunger that people feel? So on a score of one to 10, these people often experience a score of 10 in hunger. The fourth is binge eating.

And the fifth is nocturnal eating. So these are all signs that you saw in this boy. Next slide, please.

It's also important to mention that this can be a little bit different in adults. And Lisbeth will go on the subject of adults in a minute. But I want to say that the early onset severe obesity, while in children, it's usually below the age of five, in adults, it is much more, maybe even below the age of 10.

Or the onset can be a little bit later. And the same is for hyperphagia. It is less well discriminative from other eating disorders.

So that's important to keep in mind for adults. And the next thing to take into account in your clinic is to record a good family history. So genetic obesity can either be autosomal dominant, or it can be recessive.

And then in the last case, the patient is really different from the other family members. And last but not least, we have patients who are very therapy resistant. And then it's also a sign to think of genetic obesity.

Next slide, please. So this is not a slide to read. It's just that I want you to know where to find the information once you want to look it up again, because we are talking about rare diseases.

But in our clinics, we do find quite a lot of underlying causes when you look in the right group. So for example, as we have described that in much detail, how we do the diagnostic pathway in patients with, for example, early onset severe obesity in children. And then we do a very detailed screening, which includes questionnaires and lab tests and genetic testing.

But if you do it like that, your yield can be really high. So we found an underlying cause in almost one in five patients in this group, of which 13% had a genetic, really a hardcore genetic defect. So it might be nice to compare how you screen these patients to how we do it.

And this article also shows a nice table of what kind of genetic defects we found and what their phenotype was. Next slide, please. So how rare is it actually? Well, most of these diagnoses are rare to ultra rare.

But we still, even if they are rare, they are still underdiagnosed. How do we know that? Well, we know that because you can estimate the prevalence based on genetic databases and on literature reports, you can estimate how much individuals you would expect that are present in Europe, for example. And we did it, for example, for the leptin receptor deficient patients.

And we found that there should be around a thousand individuals in Europe at minimum. And if we screen literature, only 86 are reported until now. So we know that there are still a lot of patients around there not being diagnosed or not reported, of course.

Next slide, please. And again, so the question is, in which group will you screen? And I've been talking about which is the high risk group. We are talking about children with early onset severe obesity.

For example, before the age of four, that is a really large group worldwide. I was amazed to see these figures in this article, that between six and seven percent of the children worldwide already have an early onset severe obesity. And so if you look at papers that screens in this phenotype on their obesity clinic, which is, of course, a different group than in the first article, I recognize that there's a bias in this because these are the patients visiting your clinic.

But then you can have a yield of between five and 13 percent of a genetic diagnosis. So it's worthwhile looking for it. Next, please.

And it's not only in the children that we should look for it. We should also look in adults, for example, people with therapy resistance or in a group of bariatric surgery. We found that the percentages are quite substantial and worthwhile.

Next slide, please. I'm almost. Yeah.

Microphone. Yeah, thanks. So if you're by this time you're thinking, yeah, what kind of gene genetic testing should we do? Well, there are, of course, already many gene panels now available.

This is just an example of the one that we use. We use a gene panel. You can find it on the website that has been developed by Amica van Huis in Amsterdam.

And but there's something that you should take into account. These gene panels, you always only find part of the defects, especially the monogenic defects, especially the non-syndromic defects and the ones that that that have a single variant. But they do not find syndromes, for example, which are caused by a uniparental disomy or or by methylation problems.

So for that, you always need to think of do we need to do specific additional tests like an array or a VESS or a methylation studies? Next slide, please. And these slides are not for reading now. Again, you can look them up again when you want to look it back.

But I just want to mention, show here that to diagnose these specific syndromes or defects, there are features that are overlapping, like, for example, the early onset obesity or the hyperphagia. But there are also specific features that you can look for. For example, the MC4 patients are relatively tall, but some syndromes like Alstom syndromes, they have short stature.

So you can and and other endocrine abnormalities like hypogonadism are sometimes present in specific defects. Next slide, please. And especially in syndromes, you can often see that there is intellectual disability.

Or cognitive impairment. So that should make you think of could there be a syndromic form of genetic obesity here? Next slide. And this is the summary of that, which you can keep in mind and you can try to remember by head.

So the genetic obesity, you can divide them into two major groups. One is the non-syndromal, like the case I showed you, which are relatively otherwise actually completely healthy children. They accept for their severe early onset of obesity and hyperphagia.

Sometimes endocrine disorders. The other group is more often has many more features like their eating behavior can really be abnormal or other congenital disorders. Or short stature.

Next slide, please. And therefore, as a pediatrician, I cannot stress enough the importance of the growth chart in this. Because on the left, you see this chart typically of a monogenic form, non-syndromal genetic obesity and the weight already excessively increasing from birth onwards.

And on the right, the syndromal form, which sometimes takes a little while, can even have feeding problems at start and then start to increase immensely with a short stature at the same time. So that should really be a red light for the syndromic form. And the same is interesting for their eating behavior.

It is nice to be curious about what happens exactly with their eating behavior. The non-syndromal form is really the hardcore hyperphagia. While in the syndromal form, it's much more often more complex in their behavior.

They can be aggressive behavior, depressive signs or autistic features. So it's more often complex. Next slide, please.

And now, we'll switch to another case. And with this in mind, it should not be difficult for you to diagnose the next case. Liesbeth.

Yes, thank you, Erika. Yes, this is a case of a male. He came to our adult outpatient clinic of our obesity center, CTG in Rotterdam.

He was 30 years old and he had a history of weight gain around 11 years old. He had hyperphagia and his type of hyperphagia was related to abnormal eating. So when he was really young, he was eating like his mother told, he's eating crafts, which were meant to give to birds.

And he was eating all those kind of things. When he was adult, he had a more classical hyperphagia. So he didn't feel any satiety or satiation.

So he was always hungry. Also very typical, he had a delayed speech development and also autism spectrum disorder, which is more prevalent indeed in syndromal or genetic obesity. Also, he suffered from a psychosis during puberty and was treated with antipsychotic medication.

And he very much increased in weight. So at the time he was 15, he was living with obesity. So as an adult, his BMI was 33.

He was doing a lot on his lifestyle, trying to live healthy. He had some lab abnormalities. Also very typical was a mild hypergonadism, which can of course be due to any obesity, but also specifically in syndromic obesity, you sometimes see even more lower testosterone.

So what we did, first of all, we of course did genetic testing and he had a 16P dilation syndrome, which is one of the relatively more prevalent syndromes. And then what do you do? Well, he was not eligible for any study. Karine Clement will show some clinical studies.

We were also collaborating with Gary in Rotterdam on the set melanotype. He was not eligible. What we do have, we have obesity treatments in the Netherlands and of course, lifestyle treatments and also pharmacotherapy are the basis next to bariatric surgery.

But bariatric surgery is in monogenic obesity, not the preferred therapy, because there's some limited literature showing now that the response may be less than average. And pharmacotherapy, you can stop and start and stop if it's not effective. So what we did in this patient is sort of specialized combined lifestyle intervention, specifically for patients with autism.

And he lost substantial weight. And then when he plateaued the weight, we added liver glutide, three milligram. So what's the result? You can see it.

He actually, he started already to lose weight with this specific combined lifestyle program, really 27 kilograms, and then an additional eight and a half kilograms with liver glutide addition. And he actually normalized his BMI. And he's still on treatment on pharmacotherapy and very much struggling with lifestyle still.

We did another case series, also of two, in total, two 16P deletion syndrome and also two MC4 receptor mutation patients. And as you can see here in patients one and two, there are 16P deletion patients. You see that with GLP-1 treatment, that weight is decreasing.

And in these cases, it was a decrease for a substantial time. So here 40 weeks, here even there was another GLP-1 analog, more than 10 years. But also the MC4 receptor heterozygous we had in our patient clinic, also for a substantial time, they had a weight loss, which was more than 15 kilograms.

Well, to be honest, it's not in every patient it's successful. Sometimes we have patients it's not successful. Here we compared a very small group, this very preliminary data.

But just to give you an idea of our clinical experience, that when you compare with respect to weight loss, the non-genetic and the monogenic, for example, and the syndromic, that you see that on average, the weight loss is not so very different. Please realize the numbers are very low. And also this is a combination of liver gluotide, but also the naltrexone bupropion.

So you see that it's around four months that the weight loss is around 5%, which is already great because these people with monogenic obesity or syndromic obesity are very progressive in their weight gain usually. So stabilizing weight is already very good, but decreasing weight is even better. And most important is for these patients, what we hear from them is decreasing their hyperphagia.

They are getting back their lives. We had both stories we heard from our patients with treating with liver gluotide, that their homeostatic system, their satiety was improved, but also naltrexone bupropion. And during the ECO, also Mila Welling will show a beautiful case who had an MC4 receptor mutation, already had gastric bypass, had already lifestyle interventions and liver gluotide and still no weight loss.

But then treating with naltrexone bupropion, she lost 38 kilograms, so about 20% weight loss. And again, this is not for every patient. You see that some here, you see a lot of variation, some increased weight even and some decreased weight.

I think the advantage of pharmacotherapies is that you can stop it again. If it's not effective, just stop it. And if it's effective, then you can continue.

So we are sort of, it's trial and error and trying and I'm happy to share also with you the experience and I'm very looking forward to your experience too here. So I think this is a completely new field. And so this is not the targeted therapy.

And Carine will speak about the targeted therapy, which is also a beautiful new way for these patients. So to conclude, who should we test genetically? Well, it should be considered in individuals with an early onset obesity and hyperphagia. And in addition, also an alarm symptoms is if there is a family history of either severe obesity and or a striking weight difference with family members.

So a person who's the only one in the family that's very suspicious or one parent is obese and the siblings are of normal weight and the patient is living with obesity. So there are many other alarm symptoms Erika already discussed. So it's good to keep in mind that, for example, autism, developmental delay also is maybe pointing more to a syndromic obesity.

Tolstoy or more to monogenic obesity. So there are specific alarm symptoms to know where to look for. So to end, why is it important? Well, genetic obesity classically presents with early obesity and hyperphagia and it's very heterogeneous group.

You can divide it in non-syndromic and syndromic obesity. And for these patients, it's really a severe situation, very disabling. We always say it's rare.

Maybe some phenotypes and genotypes are extremely rare, but some are also underdiagnosed. And actually, if we know that many patients are underdiagnosed, we should be aware, especially when you're working in a specialized obesity center, they are there. So diagnosis is important also for the stigma.

They eat a lot because they're hyperphagic, for example, but also for personalized treatments and clinical trials. So to end, I would like to thank the whole researcher team and also the clinical team of the Obesity Center CGG. Thank you for your attention.

Let me see whether there are any questions. Thank you very much, both. Yeah, there's one in the chat there, Elizabeth, from Arina.

I don't know whether you or Erica would prefer to answer. The first question was, how do you define severe obesity? Oh, yes, I can do that. So in adults, everybody knows the different cutoff levels, like above BMI, above 25 is overweight, above 30 is obesity, above 35 is obesity grade two, and above 40 is obesity grade three.

And you have those age and sex specific cutoffs for children as well. So severe obesity means BMI in the category of obesity grade three. Yes, it may be good to just a question about this.

It was a BMI of only 33. The thing for me to test him was the speech developmental delay, the autism. Also, if sometimes are very subtle dysmorphic features, and a combination with a relatively early onset, and maybe it's good to be aware that the syndromic or there's a difference in making the diagnosis when people are adults when they present or when the children when they present, because when they're children, it seems to be you need to be more strict in the age of onset should be very young.

But now looking at the generation, if people 50 or 60, but they report to be living with obesity when they were seven, or 10. It's it would require unique in those times they did. Obesity was not so prevalent as now.

And then if you have a combination with other alarm symptoms, then it can still make you do the genetic testing. So it's a combination of early onset obesity, hyperphagia, only one in the family, and other alarm symptoms, which are listed and also in the article of the diagnostic workup we wrote, you can look at back in the table. So I think that's an important thing that the diagnosis, the age of the generation effect is important.

And for syndromic obesity, it's more around. And also, some of our patients, they developed obesity around puberty and monogenic, we found often more seven or lower of age. And in this specific patients, also when people compensate a lot, if they are exercising every day, and they're trying to limit their food intake, despite their hyperphagia, but they're still having a BMI of 33, including alarm symptoms, that that is making us testing it.

So BMI itself is not a good cutoff. There can be very well a lifestyle induced obesity and having an BMI of 40, 45, for example. And I see also the optimal patient profile for the use of MySIMBA.

Yeah, we use it specifically when patients, for example, are having the craving. So they had dinner, but they're still craving afterwards. I think that this profile is sometimes very well responding for the naltrexone bupropion, the MySIMBA.

Okay, lovely. Thank you. Are there any further questions at the moment, or would we prefer to move on? There will be time at the end as well.

But if anybody does have any questions, you can either raise your hand or pop them in the chat. I see more questions, but I think because of time, let's first do Carine, and then we can come back to that at the end. Okay.

Lovely. So I'll just do a quick introduction of Carine. And then as before, I'll put the bio in the chat so you can read that at your own time.

But Carine is MD, PhD, medical doctor and a professor in nutrition based in Paris. Her and her group have contributed to more than 400 highly cited publications. And she has received several national and international prizes and contributed to several scientific advisory boards and international consortia.

So Carine, the floor is yours. Yeah, thank you, Katie. Okay, so I share my screen.

Okay, can you see it? Is that okay? Yes, very well. Perfect. Thank you.

So hi everyone. So thanks to EA for this very kind invitation. So I think our presentation, well, we make complementary presentation, I will focus on the role of pharmacotherapy in genetic obesity.

So here are my disclosures. And so as we heard in the first part of the session, we spoke about all these key medical questions regarding the diagnosis of rare form of severe obesity. And we had discussion together with Erica and Elisabeth about obesity management in this patient with basically monogenic form of obesity or syndromic of obesity.

And you understood that there are major issues, which are of course, control of hyperphagia and or weight gain. And something very important was said about the importance of the control of hyperphagia, because that's a major factor factors and patients are suffering of this severe hyperphagia. And we understood also that obesity management in this patient is as multifaceted aspects with, of course, the role of taking care of dysfunction, behavior, comorbidities, and there is also an important role of caregivers.

I will come back telling you some words about biatric surgery, but my focus today is really to speak about the new approach and basically new pharmaceutical therapy. And now there has been great progress in this field. So I will start again by a clinical case.

And this is a young person. Her first name is Sarah, and I met her when she was 13. And as you can see on this part here, so you recognize what Erica has told you is a very rapid increase in body mass index from birth.

And what you have here, the first two body mass index curve are patient with leptin receptor deficiency. And with the squares here, this is the chart from Sarah, and you immediately recognize the very rapid increase in body mass index and, of course, weight. And it's like a patient with leptin receptor variance.

And here you have one patient with melanocortin 4 receptor, but in that case he has a homozygous mutation for MC4R. And here that's patient with heterozygous variance in the melanocortin 4 receptor. And then when you look at also Sarah's skin and you look at the family here, so that's a big family with actually nine children, and you look at her skin, she's quite pale.

And also, I don't know if you see it really well, she has red hair. And basically from birth, she was diagnosed as having a cortisol insufficiency and basically ACTH deficiency. Then as we discussed, and you can recognize in the chart, she has early onset morbid obesity and red hair and pale skin.

So, of course, she has a deficiency in the pro-pure melanocortin, so POMC deficiency. And when she reached 20, her weight was 160 kilos and her body mass index was above 50. And she started developing complications with sleep apnea asthma, and it was even difficult for her to walk, so she had a handicap.

And she started asking for bariatric surgery. And I was a little bit in difficulty here because in our center, we had the experience of bariatric surgery in patients with the leptin receptor variance and others, and the results was not very good. So basically the experience we had was that this patient can actually lose weight, but a minimal amount of weight, and it's frequently followed by weight regain.

But then about the same time when she asked about bariatric surgery, we knew about development of new molecules and especially new melanocortin for receptor agonists. And in the previous talks, you of course heard about the importance of this leptin receptor melanocortin pathway, and basically to some extent, the use of melanocortin for receptor agonists is kind of a chemical bypass of the system because, of course, you stimulate MC4R, which is so important in the decrease in food intake and increase in energy expenditure. And we knew also from previous studies that if you use the natural agonist, basically MSH for MC4R, and especially in POMC deficient mice, you can see a diminution in weight.

And so then in mice with POMC deficiency, this agonist is basically efficient in reducing weight. And there has been a conjunction of time and of good time for this patient and also another one in Germany, and especially in Berlin, where basically a German patient was also shown to have POMC deficiency. So we had two patients and together with Peter Kuhnen, and it was at the initiation of Peter Kuhnen, the idea was to test the hypothesis of the use of new MC4 agonists called set melanotide, that was to start to test that in those two patients.

And actually, so the patient one, as I told you, was from Germany, and the patient two is the profile of this French patient I just showed you, and they started receiving set melanotide. And it was amazing to see that rapidly after the initiation of treatment, and basically that's a daily subcutaneous injection of set melanotide, you have a very rapid diminution of the hunger score. And you use from 0.5 or 1 milligram set melanotide, and very rapidly, this patient described a major improvement of their hyperactivity.

And this is also associated with, of course, a diminution of weight, and you can see in both patients the profile with improvement of weight after 100 weeks here for the German patient and 50 weeks for the French patient. So then in the first period, after a bit more than four years, her weight was, as you can see here, 84, 89 kilos. And just to remember, she's a maximum reach weight was 160 kilos.

So basically, these two patients have now been treated for seven years with set melanotide, and as you can see here, and this is not published yet, the effect is persisting. So there is the hunger score, they really have a benefit on hyperphagia, and the weight has stabilized now, and basically for the French patient, she basically lost half of her weight, because her weight is now 80 kilos. And of course, she has major improvements in her quality of life, and it's quite clear, she completely changed life.

And in addition to that, they had, of course, improvement of their metabolic condition. So then one of the questions also, which is very important, is that in the first period, with the generation of new melanocortin for receptor agonists, there was adverse effect, and especially adverse effects regarding blood pressure and heart rate. So it was absolutely key to, of course, look at the change of blood pressure and heart rate in this patient.

But with the use of this molecule, set melanotide, as you can see here, they did not increase their blood pressure. Basically, they have improvement of their blood pressure and a diminution of heart rate. So there was no cardiovascular adverse event in those cases.

The main adverse effect is about pigmentation, and the reason for that is that set melanotide is not only an agonist for the melanocortin for receptor, but is also an agonist for the melanocortin-1 receptor, which is on the skin, and basically is involved in pigmentation. And you can see that that's something quite important, because of course, we have a follow-up of the skin with increased tanning, and also we can see a change in hair color. So then it seems that we can say now, to some extent, that we are kind of going towards a precision approach in monogenic form of obesity.

And we've seen in the previous talk that, indeed, if you have variants in, of course, leptin, leptin receptor, and genes downstream the leptin receptor, you develop a severe monogenic form of obesity, so early onset obesity and hyperphagia. And it's also true for other genes that can be involved in the regulation of the melanocortin pathway. So what we have learned here? So we knew already, of course, for some years, is that when these children, you can see here, are deficient for leptin, you can use leptin as a drug, which improve, indeed, weight and induce weight loss in leptin deficient children.

And that's a fantastic work from Faruqi in Cambridge. And so it's true in children, and it's true also in adults. And again, that's a very famous paper, where if you use leptin in adults, and you can see here, this was published some years ago, where after 18 months leptin injection, you have major modification of weight.

Here it's weight loss, so you can see more than 76, 47 here, 60 kilos after 18 months leptin. And in this case also, it was clearly described hormonal improvement. But of course, leptin cannot be used when people have a mutation, of course, in leptin receptor and also downstream the leptin receptor.

And then this is, again, some historic description where we showed this more than 20 years ago now, we described the first family with the leptin receptor deficiency. And again, you can see here the rapid increase in weight and hyperphagia, together with the hypogonadism, delayed puberty, and in that case, in those cases, growth retardation. So then the question immediately came, which immediately came was, can we use MC for agonist in this patient with the leptin receptor deficiency? So then in the first three cases, we describe, as you can see here, just to remind you, on the upper part here, you have POMC deficient patient.

Then here on the right panel, you have the use in offset melanocytes in DBDB mouse, which are animals genetically deficient in the leptin receptor. And here in the three panels here, you can see the treatment inpatient with leptin receptor variants. And again, on the dashed line, you see the reduction in the hunger score.

So this is efficient for hunger and the diminution in weight again. And you see here is that when you interrupt the drug, and you can see that in green for a patient with leptin receptor variant, or here for the patient with POMC deficient variants, when you have an interruption of the offset melanotype, the patient starts having again hyperphagia and the weight rebound. So all that was kind of the background for a phase three trials.

Of course, in this case of rare monogenic form of obesity. So with colleagues in Europe, you can see here the names. The idea was then to do a phase three trial where you can see the design here.

So the first phase was to titrate the set melanotypes, so having an effect on both reduction of hunger and weight loss, then an upper level phase, then a withdrawal sequence, and then again, the drug again is an upper level treatment phase, and this was for a year. And the primary endpoint in that case was the proportion of patients who actually achieved more than 10% weight loss. So, and we had the opportunity because of this, especially European consortium, we had the opportunity to test 10 patients with POMC deficiency and 11 patients with leptin receptor deficiency.

So as you can see on the table, they were quite young. So between 18 to 24 years old as a mean, it was quite balanced for gender, ethnicity, and you can see here a body mass index. So again, we are speaking of severe to morbid form of obesity, and you can see with the scale, the hunger score were high, eight for a top of 10.

So when we look at the weight loss, again, we observe what we've seen before in more limited cases. You can see the decrease in body weight in POMC deficient patient as well as in patient with leptin receptor variant. I'll bet it was less, to some extent, less impressive for LEPAR, but what clearly the patient said is it was this major improvement in the hunger score.

And again, you can see here for POMC deficient patients, a reduction of the hunger score, and it was even more for a patient with leptin receptor variant. And what you can see here is you see it's increasing again for some time, and this corresponds to the withdrawal sequence, where again, you stop the drug, basically you have a new feeling of hunger. So just as a little summary for this placebo sequence, clearly it has been associated for both LEPAR and POMC deficiencies in increased weight as well as increased hunger score.

So then the question is about adverse effects. So I told you already about cardiovascular effect, and it was, as I said, very important to show that there was no effect on increased blood pressure or increased heart rate, but what are the common adverse effects is mostly injection cytoreaction, skin hyperpigmentation, and I spoke about that, that's most nearly, so more than 80 percent of the patients. Some adverse effects, especially at the treatment initiation regarding nausea and vomiting, as well as disturbance in sexual arousal.

And what you can see here, which is also very important and that we can see in every patient, most of the adverse effects can be seen at the initiation of the treatment. So after three, four weeks, they are going better, but the first three, four weeks for some patients, not all can be difficult, especially with a gastrointestinal effect. So then in summary for this set melanotype trial, so as I told you, we had about more than 20 patients, either POMC or LEPAR mutation.

Of course, they achieve the, as you mean, the primary outcome. We had more weight loss in POMC deficient patients than in LEPAR, but they had major improvement. The hunger score diminished a lot, no cardiovascular effect, increased fragmentation with adverse effects improving this time.

And what was also very important, and we had the opportunity to test some quality of life using some quality of life questionnaires, and clearly there was an improvement of quality of life outcomes in this patient. So now what are the perspectives? So we heard about a syndromic form of obesity and especially also Bardet-Biedl syndromes. And we learn from fundamental studies that actually some of the genes can be regulator of the melanocortin system.

So to some extent, patients with Bardet-Biedl can be candidates to test melanocortin for agonist molecules. And then there has been overvariance in genes regulating the leptin-melanocortin pathway. And it will be important to identify which of these patients can be responsive to this type of drugs.

And just to show you a first study that has been published some time ago, where in Bardet-Biedl, there was indeed an effect with about a bit more than 15% weight loss in patients with Bardet-Biedl. And it appears that indeed in the case of Bardet-Biedl syndrome, some patients can be responsive to the drugs and others are less responsive to the drug. So this raises us to what we've heard also before.

So we've heard that we can diagnose this form of genetic of obesity and probably it's also under-diagnosed. And just to share our experience, what we are doing in our country in France is that we have a network basically for severe obesity management with 37 centers on the French national territory. And we have a network of groups, and it's called FORCE, where we try to harmonize prostheses and also perform a clinical investigation.

And thanks to these networks, we were able to disseminate a web tool for diagnosis of genetic obesity. So basically, medical doctors in these centers or also in other centers can use this web tool and enter the clinical phenotype of the patient, and we can orient the diagnosis and also orient where the genetic aspect can be screened. And I think it's very important here, it's in the national level, but probably in the future it will be absolutely key to probably develop that at the international level because now we have the possibility to target this patient and at least to test this new molecule.

Okay, I'm going to stop here and of course thanking the different colleagues and especially in the clinical networks I talked about, different colleagues in Europe involved in treating this patient with genetic form of obesity. And my very close colleague, Christine Poitou and Beatrice Duber, Christine is working on this special center for obesity management and especially, you know, patient with genetic form of obesity and Beatrice for the pediatric form in those cases. So I'm going to stop here, I'd be happy to take questions on this topic.

Thank you. Lovely, thank you very much Corrine. Do we have any questions at all from anybody? We had one from you and before, which was obviously about the level of under-diagnosis and how you as speakers reach obviously the healthcare professionals as well.

There's a bit of a theme coming through with these webinars at the moment about, you know, getting to the people that need this really. So I don't know if you have any thoughts on that. I guess, yeah, I agree with regarding under-diagnosis when, you know, we speak with these colleagues, it's really specialists, basically, who know, they know about these syndromes and so on.

And I agree with what has been said before, what Erika has said before, I think it's really under-diagnosed. And if we, for example, for some years ago, we did a screening for leptin receptor variants in a large cohort. It was something, it was more than 500 subjects at first and we realized that patients with leptin receptor mutation, it was nearly 5% of the group.

And then, yeah, so if we focus on a population with really rapid increase in weight from birth plus, as we've heard, hyperphagia, we are going to find not only variants in genes, in common genes, I would say, in the LEPR, POMC, PCSK1, MC4, but probably also in regulatory genes and there are many others. Katie, may I add to that answer? Because as I saw the question, it is also the question, how do we get them to our centers? And if that is one of the questions, we also noticed that it's very important to, first of all, put it into the guidelines and your clinical consensus statements, et cetera. And second of all, a lot of healthcare professionals working in obesity still need to be educated and trained on this specific, on the diagnostic of this.

And I'm sure, again, that's the same in our country, Lisbeth and I and many other people already give a lot of trainings specifically on this. And then you notice that people start to refer. Yeah, I agree.

I agree with you. And we had actually last year an initiative in France where we, and it was coordinated by Christine Poitou, where we had a specific genetic report on obesity management, especially in those genetic form of obesity. And yeah, so and then it was, so this report was disseminated by the health authorities in France.

And yes, we realized that education in physician is so important because this syndrome was looked at being ultra, ultra rare. And many people who are not specialists just don't know about the syndrome. And now we have the opportunity to have specific treatment.

So this needs to stimulate the genetic diagnosis. Yes. If I may add to that, I completely agree with Corinne and also Erica to more train the healthcare professionals.

I think also with, yeah, so we made also with the WUMKA for the European GPs, a webinar about all kinds of underlying causes because genetic obesity is one of it, but you also have endocrine causes, medication causes, hypothalamic causes, but genetic is fully in there. But another point is also to educate the broad audience. And that helps me notice here in the Netherlands, for example, that we wrote together a book, Fat, the Secret Organ.

It's in 11 languages in the meantime right now. And two of the chapters are stories of patients with genetic obesity, because we described the whole appetite regulation system, because also in other forms, it was important for the broad audience. And also the story of Erica's patient is in there with the MC4 receptor defect and the leptin.

And the funny thing is that people start to recognize their own stories or tell to their neighbors about it. They go to the GP, the GP don't know about it. But then we have those webinars also for the national GPs or other medical specialists, and they get informed.

And also the guidelines, of course, are very, very important in this field. But then if people are weaponed themselves with knowledge, they start to read about it and to ask for it. And that also helps.

So health care professionals on the one hand, but broad communication. So it would also be beneficial in all your countries, I think, talk about it. And also television influencers show that there's more types of obesity than people start recognizing themselves.

Lots to be done. So we have another question in the chat from Irina. I don't know which speaker would like to take that.

But she's asking about in a pediatric endocrine clinic, they're faced with infants with weight issues. Do you weight to screen? So do I understand the question right? That in the pediatric clinic, if you have patients under treatment for endocrine disorders, whether you want to look into obesity disorders? Yes. So it says in pediatric endocrine clinic, we may be faced with infants with weight issues.

Do you weight to genetic screen the infants that present with increased weight until after 12 to 18 months as some of them might sort of grow out of it, especially at 12 weeks range? OK. Yeah. So the timing of when will you start doing the diagnostics? Well, of course, it depends, especially on the clinical picture and how specific it is.

If the weight increase is immense and nothing helps and everybody already tries to do lifestyle, et cetera, and it doesn't help, then we already can do it under the age of one. Yes, certainly, because the earlier you diagnose, the better you can treat. So that's important.

But on the other hand, I can also know patients that in the first year of life have a terrible weight curve and then you first need to support them and coach them, et cetera. And then suddenly when they start walking, it gets better. You also have those, of course, they're in there.

Yeah. I mean, Lisbeth touched on the sort of the stigma around this. How is that? How is it when you have a patient that comes in with a sort of an infant that young? How do they often respond to such a sort of diagnosis if you do test them? Well, I heard I hear a lot of in the adults that also other colleagues are reacting.

Well, you maybe shouldn't test because they sort of have feel free to eat a lot because they have a disease. But in adults, at least I see the other way around. They they I mean, obesity by itself, of course, is a disease, but the monogenic obesity is even more considered by the by their their environment as a disease.

And they get more support. And that already helps them to to to feel better mentally, to to be supported in your lifestyle and not be exposed to too much food all the time. And and so I see the expectations are different of colleagues.

And it's not that if you test it, that people feel free. Oh, now I can eat everything I want. No, we they now they understand the body and they know why they have to to work so much more and to put so much more effort in losing weight than any other person.

So I'm not sure whether it's the same for the pediatric endocrinologist in the green. I often have patients who start crying when they hear the diagnosis. They it has been a terrible time before that.

And now finally, they understand what's happening with them. And so I find that very emotional often. And then still as you cannot say, oh, I have this disease.

I don't need to do anything anymore. No, we always say you need to work 10 times as hard as anybody else. And and and if that and then but now there is more specific support and pharmacotherapy.

So that's very important for them. Yeah, if I may. Yeah, I agree with you.

I mean, for most of the patient with the diagnosis, in my experience, it was a relief. And really, I'm mostly seeing adults. And so but really having and just have in mind some people were actually we made a diagnosis like above the age of 40.

And it was it was really a relief to know that there is something in their biology that and then it's even more, as you said, both of you, Elizabeth and Erika, if we have now new treatment opportunities, it's not I mean, we know that with this new treatment of opportunities, it doesn't solve obviously all the problems and and in the management, we still need to to have, of course, lifestyle action, psychological aspects, we spoke about stigma. I mean, these children, they are suffering during at school and for stigmatization, and even in the medical sector, it's difficult for them. So it's a really multifaceted approach to treat this patient.

Yes, and I totally agree, because what we also have to realize that even in a person with genetic obesity, also other factors can contribute to obesity. So like the case I showed with the 16P deletion syndrome, while there was a psychosis, he was way more weight gaining when he was using antipsychotic medication. He had autism and he was not so so comfortable in social environment and doing exercise.

There's so many other causes in top of their genetic vulnerability. And that's also what we always do. So now we're saying that we look at the patient with obesity with all the aspects and actually also made a tool we nationally we use in our digital to the obesity care tool to detect all these kinds of causes.

Is it lifestyle, is it medication, hormonal, or are there alarm symptoms to think of genetic obesity? And often it's a package, it's a combination. And also this combination can help against the stigma that also the antipsychotic medication also counteracts the weight loss, for example. So I absolutely agree with what Corinne just said.

I imagine the patient getting that information helps them to understand it. And then the understanding helps the acceptance and then the case of making a clinical pathway going forward. One thing that I wonder is if you have patients that come into clinic who themselves believe there is something in their genetics and maybe the testing proves that that isn't how they sort of respond to that news.

Now, we know it's completely multifactorial, but I'd just be interested if you have any cases where the results were expected to be positive and maybe they weren't and how that sort of panned out. Yeah, maybe I can start. I is about the genetic screening.

So what do we do? Which panel of genes? Which cost? Are the patient is going to be reimbursed? So this raised many questions. So what I can tell is in our center, for example, we were for many years, we were kind of stuck to some genes, mostly the main genes in the, you know, leptin receptor, PCSK1 and MC4. But then now with the new technological development and the possibility to screen more genes, so it's changing.

So maybe, I mean, some of the patients. So one aspect of the discussion is, OK, we haven't, we did not find, you know, variant in those genes, but it can be others. And especially if the clinical history is there and as it was said also before, the history of obesity in the families is also very important.

Maybe we can think of going further for the genetic screening. And then at the end of the day, maybe we are not going to find a variance, but we can explain it could be genetic. But with our current knowledge for now, we don't know.

But I guess what has been said before with the different now option for pharmacological therapies, it could be important maybe in the future to have kind of a panel of drugs to test. And we need to find, you know, that's really what is precision is about in this field. Yes.

And maybe also the expectations in advance. I recognize this. This is very often the situation that you have a high suspicion, but you don't find the exact gene mutation.

But still, if a very suspicious patient with very high, all the alarm symptoms, early onset obesity, autism, hyperphagia, only one in the family, very typical case. I still call it a clinical picture of genetic obesity. And sometimes it even works to ask for reimbursement to get pharmacotherapy reimbursed for this rare clinical picture.

Like we do it also for lipodystrophy, for example. We often don't have the gene, but you still have the clinical phenotype of lipodystrophy. And in the same time, I think if you have sometimes you're in the gray area, then it's difficult.

And we also know it's not always monogenic. It's sometimes a combination of, we know, very polygenic obesity. Some forms, if you have strong combination of polygenic obesity, it can be the same picture as monogenetic obesity.

There are new insights, new developments around that. And also the epigenetics can be present. So sometimes with our techniques, we don't find it, but doesn't necessarily mean it's not a genetic obesity.

It can still be a genetic obesity. So making a clinical diagnose and sometimes three years later, we do have the diagnosis. So expectation management, that's what I learned from those trajectories, not to create any disappointment, but do only proper diagnostics if you have a true suspicion.

Further comments from the speakers or any further questions before we close this afternoon? I can't see anything in the chat at the moment. Excuse me. Shall I take that? I'll take the silence as a no.

So I'd just like to thank again, Corinne, Elizabeth and Erica, fantastic presentations. The session has been recorded, which I will share on the SharePoint and via the email that you registered with later in the week. And the speakers have also given me some publications that would probably be of interest to share.

So I'll pop those on the email as well. Yes, I think we'll just say thank you very much. And the next webinar is on the 31st of May, and we will be looking at regulation of energy balance and body weight.

And Dr. Giles Yeo is one of the confirmed speakers for that. So I'm sure that'll be very interesting. And yeah, good evening to all.

And thank you very much for your time. Yeah, thank you.