Podcast Episode Transcript

A Rare Disease Day panel discussion on Congenital Hyperinsulinism

Elaine Quinn

The thing about rare diseases? – they’re not so rare! In the United States, a rare disease is defined as a condition that affects fewer than 200,000 people. And because the number of people affected by any one rare condition is so low, the resources or support allocated to find answers for those conditions, is often limited. The frustrating thing about this is that while close to 7000 rare diseases have been identified, there are many more conditions emerging that are yet unknown or undiagnosed. It is estimated that about 350 million people worldwide are affected by a rare disease which tells us that rare diseases are actually not as uncommon as people may think.

Well rare disease day is upon us and to celebrate this important day we have invited a panel of inspiring guests to share their perspectives on rare diseases and to raise awareness about one particular condition known as congenital hyperinsulinism. I’m delighted to welcome Julie Raskin, Co-Founder and Executive Director of CHI – Congenital Hyperinsulinism International and mom to Ben who was born with hyperinsulinism. Sheila Bose is also a parent of 3 children born with the condition and as VP of CHI’s board of directors, Sheila works closely with Julie.

We also have Dr Sarah Flanagan, Associate Professor of genomic medicine at the University of Exeter Medical School bringing the genomic research perspective. And from the clinical side we have Dr Diva de Leon-Crutchlow, Chief of Endocrinology and Diabetes, and Director of the Congenital Hyperinsulinism Center at Children’s Hospital of Philadelphia or CHOP and last but not least, Dr Paul Thornton, Medical Director of the Endocrine and Diabetes program at Cook Children’s Medical Center in Texas.

It is wonderful to have you all here today in celebration of Rare Disease Day. So, Dr. De Leon – what do we know about congenital hyperinsulinism and how rare a condition is it?

Diva De Leon

Congenital Hyperinsulinism is a rare condition, and although we don’t know the exact incidence of the condition it is estimated it to affect about one in 20,000 newborn babies in the European and North American population. So quite a rare condition here in the United States that would mean you know, approximately a hundred babies born with the condition every year. In Hyperinsulinism, the regulation of the secretion of insulin by the pancreas is affected by different mechanisms. There are different genetic defects that affect the regulation of the secretion of insulin. And it’s this problem with the regulation of secretion of insulin that results in hypoglycaemia or low blood sugar, which is the main manifestation of the condition. And because blood sugar is very important for brain functioning, when the levels of blood sugar are too low, the brain suffers from lack of fuel for metabolisms so that leads to brain damage and that’s the major fear of the families affected, with children affected by hyperinsulinism – it’s the fear of brain damage from the low blood sugar levels.

Elaine Quinn

Yeah, that must be pretty terrifying or parents. So, it sounds like identifying the signs early is critical in order to prevent brain damage – Dr. Thornton, can you tell us how this condition is manifesting itself? What are the kinds of signs and symptoms you’re looking out for?

Paul Thornton

The signs of hypoglycaemia in a newborn baby are actually very difficult to detect. And they’re sometimes very similar to signs that would happen to babies for other problems so it’s very important that paediatricians and moms are aware of the symptoms of hypoglycaemia that can cause trouble. And so, babies who are unable to suck and latch on and breastfeed and swallow because they’re so sleepy and tired would be a very worrisome sign. Obviously, if a baby has a seizure that’s a very worrisome sign and if a baby stops breathing for reasons that are not otherwise clear then all of these circumstances require doctors and nurses to check blood sugars and make sure that this is not secondary to a low blood sugar condition.

Elaine Quinn

Now CHI or Congenital Hyperinsulinism International is a leading non-profit organization that is committed to improving the lives of children and adults living with congenital hyperinsulinism. Julie, maybe you can talk about the fantastic work you are doing at CHI and why your work is so important to families affected by congenital hyperinsulinism.

Julie Raskin

Sure, I would love to. So, the experience of having a rare disease in the family, whether it’s a child, whether it’s a parent whether it’s a spouse or a friend – it can be very, very devastating because there is often not a treatment for a rare disease and in the case of hyperinsulinism, there are many who are born with it, who don’t have a treatment that’s been approved by the FDA. So, thankfully there are incredible researchers and physicians who focus on this condition and through their knowledge and through their research and experience are able to create the very best ways to really control this condition, but it’s still a very, very rocky road. The parents of babies born with it describe it as being on a roller coaster all the time because blood sugars are low, they’re hard to get up and the fear is so strong that if the blood sugars remain low are and there’s prolonged low blood sugar that that can cause brain damage. In some cases, it can even cause death. So congenital hyperinsulinism was founded in 2005 and our mission is to improve the lives of those living with the condition through research, through support, and through raising awareness, to prevent preventable brain damage and death.

Elaine Quinn

That’s wonderful and it must be a huge support to all of the families connected to CHI. Sheila, you are also very involved in CHI and I know you also have personal experience with congenital hyperinsulinism in your family. How has the CHI community been a support to your family and to other families impacted by this condition?

Sheila Bose

So, I think I found Julie and this community after my second child was born and unfortunately passed. And I reached out and I first emailed CHOP because when my child was in the NICU they were consulting with CHOP, and so I reached out and I got an email from Dr de Leon who put me in touch with Julie. A month later, we were in a mall and a food court talking about how we could you know how I could get involved and what I could do to raise awareness. I think knowing about a rare disease and being able to talk about it is really important, sharing our story sharing our journey. And so, it’s been a long journey, but it’s been a good one.

Elaine Quinn

Thanks Sheila – and that really is such an immense challenge for families faced with a rare disease – trying to get that diagnosis and getting it early. And it’s remarkable how you and Julie and others who have been faced with the most difficult of situations can become such advocates for others facing similar challenges.  So, Dr. De Leon, in talking about how important an early diagnosis is – if a new baby presents to you with signs that are so ambiguous, but you suspected hyperinsulinism how do you diagnose the condition?

Diva De Leon

So the diagnosis of the condition – Typically the process starts shortly after birth, if the low blood sugar or the hypoglycaemia is recognized before the baby is discharged after birth, which is the ideal situation, and what CHI and us in the medical community are really promoting – you know, the early recognition of the condition. The diagnosis starts with the detection of low blood sugar and the suspicion that the low blood sugar is the result of hyperinsulinism, which is the most common cause of persistent hypoglycaemia in newborns. So, it accounts for more than three quarter of the cases that present with a low blood sugar in the neonatal period. So, the diagnosis is based on measuring hormone levels and other metabolic fuels at the time that the blood sugar is low, so there has to be some understanding of that process of diagnosis, for the diagnosis to be made appropriately. So, part of our campaign to improve the early diagnosis include the promotion of how you make the diagnosis, because it’s important to recognize the low blood sugar but also it’s very important to know how to make the diagnosis of hyperinsulinism. So, once the diagnosis is made, then the next step is to get a better understanding of what the cause of the hyperinsulinism is and that’s where genetic testing comes in to play.

Elaine Quinn

And so, what do we know about there being a genetic link with congenital hyperinsulinism? Dr. Flanagan, maybe you can talk to us a little bit about what your work is uncovering in this area?

Sarah Flanagan

So, we know that changes in around 20 different genes can cause congenital hyperinsulinism, but when we screen these in children, we only find the disease-causing variant in around 50%. Many groups around the world, including my own, are really trying hard to identify new genetic causes of disease in the remaining 50% of individuals who remained without a diagnosis. It’s really important that we understand the underlying cause of disease, as this will help to guide management of these children and will also inform on the likelihood of future children within families being similarly affected.

Elaine Quinn

And there are different levels of severity when it comes to hyperinsulinism as well, aren’t there? Is genomic research helping us to understand why this might be?

Sarah Flanagan

Yes, so if we can understand the actual cause of the hyperinsulinism in the children, then we can start to understand the disease mechanism. And we know that the different genetic changes result in slightly different variations of different types of hyperinsulinism. So, some children have hyperinsulinism in isolation, so that’s the only clinical feature. Whereas other children will have it as part of the syndrome where others, systems around the body are also affected.

Dr. Diva De Leon

Unfortunately, this ability to do the genetic testing is not available everywhere, and sometimes even if it’s available, the lack of understanding or knowledge of how to take that step to make a genetic diagnosis is not available in the hospital where this baby may be cared for. So, part of what the CHI community do; and when I refer to the CHI community I refer to the family, but also to be physicians because I do think that this is a community that embraces the physicians as well as the family. So, part of what we try to provide is a network of knowledge that reaches beyond the families to the physicians that encounter these babies. So, through this network we share our knowledge to help the diagnosis of babies that are being cared for in countries or in hospitals, where that knowledge may not exist. Because that’s incredibly important to make sure that the baby is diagnosed early but that also the precise diagnosis is established based on genetic testing. And that really dictates the next steps on the treatment which you know to this point, we had had very limited options for treatment, but there is a tremendous progress going on to develop new medications to treat the condition. And you know, our goal is that, in the near future, we really can apply precision medicine to every single baby born with hyperinsulinism. We do some of that right now, when we identify that the genetic testing results suggest that a baby has the focal form of the disease. That’s exactly what precision medicine is about. We identify those babies. Those babies need a specialized imaging and those babies can be cured by hyperinsulinism. But because in about half of the babies, we still don’t know the specific genetic cause and because medical treatments for the condition are limited to two or three options, we still cannot really apply precision medicine to all the cases but that’s the goal and the dream and I think it’s going to be possible, because of the research that is going on.

Elaine Quinn

And with advances in research, AND technology and medicine happening at such a fast pace now, we are seeing this movement towards precision medicine where treatments are more individualised and customised according to a person’s specific needs. And this has so much potential for how we treat all diseases but, in particular, it makes so much sense when it comes to rare diseases.

So, Dr. Thornton, how would you say the genomic research that researchers like Dr. Flanagan are working on and advances in technology, and the ability to be able to sequence the genome – how has that changed the way clinicians are practicing medicine today for conditions like hyperinsulinism and other rare diseases?

Paul Thornton

Well, the recent advances in genetics and diagnosis has really helped the clinician tremendously. Because of all of the different types of hyperinsulinism, some of them respond to certain medications and some don’t, some can be cured by surgery and some can’t and so, if we’re able to get a rapid genetic test with a turnaround time of you know, five to seven days. That can really help us decide which patients are good candidates for 18 F dopa pet scans which helps us localize where the insulin is being made in the pancreas. And if we can remove that abnormal part of the pancreas, we can cure the patient. So, the advent of rapid turnaround genetic testing for children who don’t respond to the typical medicines we use such as diazoxide has really changed the way we treat these babies.

Elaine Quinn

Now Julie just getting back to CHI again which is obviously a fantastic organisation and a huge support for families. How are families connecting with one another? Maybe you can talk to us about some of the programs and initiatives you are running at CHI?

Julie Raskin

Yes, absolutely. So, we work in three areas as, as I said, and in terms of support we have a global support group that has members from over 60 countries. There are 1700 people in it. It’s honestly mostly for the parents and it’s a place that parents go, often, many times a day from many places in the world, so it’s literally active 24 hours a day and parents come with their concerns and they need support. Because it’s a rare disease, there aren’t people in their neighbourhoods, in their towns that necessarily are going through what they’re going through. And so just the very ability to come to this online support group is a great thing. In addition to that we’ve held 20 conferences and meetings where people come together and learn together and share their experiences. And the children come together and have their own very special time. And this has created incredible bonds between families. And even virtually through the Internet, and through different platforms, families have come together. We’ve done this, even through the COVID period and they’ve become really great friends. And the children – we even have songs for the children and they really connect and feel special by being part of – we try and create what is like a something special about being in this community – yes, we have a rare disease, but what is different and special about us? So, we actually affectionately call those born with the condition ‘Sugar Babies’. And the parents and the children – a lot of them really love this and feel special that they’re sweet because they need a lot of sugar. So, we want to celebrate our community, and it also really helps community members to be part of the movement to improve the lives of those born with the condition. I find nothing is more helpful to parents than helping others. And so, we have our own research project – it’s called the HI global registry and we call it a patient powered research project and those who are affected by the condition – they complete surveys about what it’s like to live with the condition, and these are very detailed and together all of these stories then become a natural history for the condition. And this is a good platform for researchers to understand what is happening, moment by moment, day by day, and also to understand what’s happening in terms of quality of life and how is this disease affecting families. We also support research with pilot grants, and we are in the process of putting together a collaborative research network working with great researchers and clinicians like doctors de Leon, Flanagan, and Thornton. And in addition to that, we also work with companies that are developing new treatments, we bring the patient experience to their research and help them with everything from developing their protocols to really getting the word out about the importance of participating in clinical trials.

Elaine Quinn

Wow – amazing firstly that you can keep so many people connected from all over the world especially, at the moment, when staying connected is so important right now with COVID.  And you know ,there is a lot more emphasis on the importance of patient or participants involvement in research and I think clinicians and researchers and industry are really starting to see the value of those unique insights which are so informative! And great to hear you have such support from the clinical and research community too. – Dr. Thornton, did you want to add to that?

Paul Thornton

Yes, from a professional perspective, going to these family meetings is really moving and really inspires us to do better, every day. You know, when we when we sit with our own patients, one on one and we help them that’s one thing, but when you go to a meeting with 70 or 100 families and you hear a diverse range of stories of people from all over the world, it really motivates us to do better, to understand the science better to develop new treatments. So, as a professional we love attending the family meetings and it’s really good for us too.

Elaine Quinn

And Julie, I know you mentioned the research collaborations that you have going on with CHI and one of those is with Exeter University. Dr. Flanagan, would you like to talk a little bit about that project?

Sarah Flanagan

Yeah, I’d love to. So, as we heard from Paul that the genetic testing is absolutely crucial for ensuring that patients with hyperinsulinism receive the best medical care, but unfortunately for many health care providers around the world, there’s not the means to provide genetic testing for patients and for many families, the associated costs of genetic testing is prohibitively expensive. So, to address this issue in 2018 we teamed up with Congenital Hyperinsulinism International to ensure that costs and geography are no longer a barrier for genetic testing for this condition. So, we now provide genetic testing using the charitable money for patients around the world. And since this partnership has begun, we’ve managed to provide testing in our fully accredited genomics laboratory for over 500 families from 50 countries around the world, and this has led to 250 families receiving a genetic diagnosis, for their condition.

Elaine Quinn

That’s incredible and absolutely life changing for those families and so important to have programs like this that can be built upon and hopefully be more widely available and less costly as we move forward. Now Dr. Thornton, how would you see the next 10 years developing then if you’re thinking about how advances in genomics and how it can be applied in the clinical setting are progressing?

Paul Thornton

I think over the next 10 years we’ve got a couple of areas that we really need to work on. Number one is new medical treatments and currently there are many different drugs under investigation for the treatment of hyperinsulinism and that’s very exciting and hopefully in three to five years we’ll have some new treatments and then, I think the second thing we need to do is to be able to take a program like Sarah’s where they’re offering genetic testing for everyone, and somehow be able to get that into the hands of people who need to be able to get those tests done quickly. So, in the United States we’re very blessed, that we have several laboratories around the country who can do rapid turnaround testing, but we need everyone else to understand the importance of that and how it, it affects our daily management. You know, a typical example is I had two children referred to me, both of them turned out to have focal disease. Both of them, the doctors called us and said, you know, we want to send the baby, what should we do next. We said send genetic testing. We told them exactly where to get it done so that there could be rapid turnaround. And, in one case they did that – the baby arrived, had the pet scan; the genetic test was available on the morning of the pet scan. It was clear she had focal disease and she went to surgery and her hospitalisation took 14 days and she was cured. And then another patient didn’t have the rapid turnaround testing. The pet scan wasn’t quite so clear, so we wanted to wait until we got the genetic testing. And it took a total of 21 days for the baby’s test and another eight days for the parent’s test and so that caused a whole delay. So I think, what we need to do is you know what Sarah is doing is great for people around the world who can’t get the testing done, but we also need the places that are near centres where they can get the genetic testing done to be able to do this really quickly, specifically for the two genes ABCCH And KCNJ 11, which are the ones that we could potentially cure and get those families home with their other brothers and sisters and family as fast as possible, so I think to me that’s the two things that we need to focus on right now.

Elaine Quinn

And how do we accelerate that collaboratively? Obviously, having discussions like this and celebrating Rare Disease Day to help raise awareness is absolutely key so that we can really push for policy change but what more can we do?

Paul Thornton

Yeah so part of the things we do is we go out and educate people, so if you talk to Dr de Leon and Dr Flanagan, you will hear us all say that we spend many, many trips every year educating our fellow endocrinologists our fellow neonatologist on the importance of rapid early diagnosis of the hypoglycaemia, rapid early treatment and quick identification of the type of hyperinsulinism. So, you know CHI is helping the families learn about hyperinsulinism. And we, the professionals are out there, teaching our colleagues to try and help them understand that congenital hyperinsulinism is one of those diseases in which the genetic test can make a huge difference in your management and it needs to be done rapidly and efficiently to help affect the right sort of change.

Julie Raskin

And it’s something that we also work with the clinicians and researchers on. We have posters in 21 different languages on the importance of early diagnosis and the signs and symptoms. And we’re blasting on four social media channels every day; Twitter, Facebook, Instagram, and LinkedIn – The Message, which is that brain damage can be prevented if diagnosis is made in a timely manner and Paul, you are absolutely right that there needs to be another campaign. We may not blast it out loud enough specifically about the importance of early genetic testing. And that’s another message that I think we can help with because we have a lot of listeners around the world in the medical community, so we need to join forces on that too.

Elaine Quinn

Absolutely – and I think we can all appreciate the great relationships that you have all developed here and how you are all working together to educate people on how hyperinsulinism can be recognised and how it can be diagnosed more quickly which is so necessary. So, Julie, can you tell us a little bit about Ben? How is he doing these days?

Julie Raskin

Yes, yes, well Ben is great because Ben has a really wonderful as he would say positive mindset. And so, he just frames everything in the most positive light that he can. He’ll be 25 this year. A quarter of a century! He was, unfortunately, not diagnosed right at birth and we talked earlier about the signs and symptoms of hypoglycaemia – and I as a parent who did not have a medical background was aware shortly after birth that something wasn’t right. And that he had symptoms of something I didn’t know what, but I had major concerns. And even though I was at one of the best hospitals in the world, nobody listened to my concerns and after two days we went home. I went home with a feeling in in my heart just filled with sadness and fear that there was something wrong with my baby and no one knew what it was. That led me the next morning to go to a local paediatrician who took one look at my son and said go to the NICU – just race there and we did and upon arrival, we waited and they whisked him away and two hours later, the neonatologist came out and said that Ben’s blood sugar didn’t register. And that he had had five seizures upon arrival. They didn’t know what he had. They knew to hook them up to dextrose and that saved his life and for the next eight days they gave him every kind of test. And nothing showed up. They didn’t know what it was. They brought in, finally, a paediatric endocrinologist. Looked at his labs, talked to us, and figured out what he had – congenital hyperinsulinism. And the reason that this paediatric endocrinologist knew that is that he had trained, and he had worked with endocrinologists at CHOP. He told us to get to CHOP. In that space, though, of those couple of days before we got back to the hospital, Ben suffered neurological damage. It affected his vision, he has nystagmus, he has low vision – he is considered legally blind and that has really had a significant effect on his life. And he also has learning disabilities and very severe fine motor coordination issues – he cannot tie his shoes. But you know we’re so lucky that he was connected to the dextrose when he was. He’s a very good writer, a very good speaker, he’s gotten a bachelor’s degree, and he himself is becoming an advocate. He’s having a full life. He has good friends; he has a girlfriend so he’s part of the force now looking to help others who have disabilities and are trying to create independent paths for themselves.

Elaine Quinn

That’s wonderful and the fact that he’s also now becoming an advocate himself says a lot about the strong person he is. It is great to be hearing voices like his who can help people understand what it’s like to live with a rare condition and how we can do more to support the rare disease community.

Well, we have heard such fantastic perspectives from all of you, and all of your work combined is doing so much to move the needle for congenital hyperinsulinism. We’re just coming to the end now – is there anything anybody would like to add or any final thoughts you want to share before we finish up?

Diva De Leon

I just wanted to say that it’s such an incredible journey for physicians also to have come to this field and to work within this community. It really is a fulfilling experience and very inspiring to learn for our patients to learn from these families. You know I became a paediatric endocrinologist with the idea that I was going to work in diabetes, but when I encountered the first patient with hyperinsulinism during training, you know, I think that was a life changing experience for me.

Sarah Flanagan

I’d just like to agree with Diva, but as a research scientist, it’s very rare that researchers see the direct impact of their work on patient care, and I think I just feel very fortunate to be able to work in this field where the work that you’re doing every day actually impacts on patients and their families.

Elaine Quinn

And Dr. Thornton, we’ll give you the final word.

Paul Thornton

I was just going to add, Elaine, you asked us, you know how do you make the diagnosis of hyperinsulinism. Well in the words of the famous anthem of CHI – when the sugar is low and the insulin is high, you have HI

[Song – “Down and Up” with permission from Congenital Hyperinsulinism International]