Kabuki Syndrome, Part 2 - A Treatable Cause of Intellectual Disability

It has long been thought that the root causes of intellectual disability cannot be treated or cured. However, a growing body of research suggests that a rare genetic condition known as Kabuki syndrome (which we explored in the previous episode) might offer a path forward in being able to treat, and partially reverse the effects of some types of intellectual disability.

On this episode of One Rare Heart we speak with a physician/scientist at the forefront of this research, Dr. Hans Bjornsson, and hear about how his search for answers is also calling into question the medical establishment's long-held dogma surrounding intellectual disability.

As Dr. Bjornsson seeks to provide therapeutic options that could help bolster intellect in the neurodivergent community, the ramifications of his work could be immense, especially for individuals with Kabuki syndrome and related disorders. Take this opportunity to engage with Dr. Bjornnson's exciting research as he shares about his work and as we learn more about the needs of this at-risk and unique community that he seeks to serve.

EPISODE GUEST

Dr. Hans Bjornsson – Dr. Bjornsson is a physician/scientist who runs research laboratories at the University of Iceland and at Johns Hopkins University. Both of his labs focus on identifying the causes of intellectual disability in Kabuki Syndrome, and on the development of therapeutic treatments that could potentially help ameliorate the effects of intellectual disability in individuals with Kabuki, and related disorders. At Johns Hopkins he is Associate Professor of Genetics and Pediatrics, as well as Associate Director of the Epigenetics & Chromatin Clinic. He is also a Full Professor of Translational Medicine and Pediatrics at the University of Iceland, and is Director of Clinical Genetics at the University of Iceland Hospital.

SUPPORT BJORNSSON LABS

Please consider supporting Dr. Bjornsson and his groudbreaking research. You can find more information about his work, his laboratories and how to support this research HERE.

KABUKI SYNDROME - CLINICAL TRIALS

If you or someone you know is interested in taking part in the HOPE clinical trial mentioned in this episode (which is a collaboration between Johns Hopkins University and Oryzon), or other related studies, you can find more information by visiting the research page of the Kabuki Syndrome Foundation.

NEURO-DIVERSITY

Click HERE to learn more about intellectual disability as a form of neuro-diversity, and how you can better support individuals who are neuro-divergent.

Transcript

Derren Raser  0:04 
Almost 6.5 million people in the United States are living with some form of intellectual disability, which might translate more broadly to as many as 200 million people worldwide.

The prevailing dogma around intellectual disability has long presumed that while you can help support and manage its effects on individuals, the root causes cannot be treated or cured.

In the previous episode of One Rare Heart, we explored a rare and unique genetic disorder known as Kabuki syndrome. One characteristic of this condition is that it almost universally causes some degree of intellectual disability in affected individuals. However, researchers are in the process of uncovering something truly remarkable about the relationship between Kabuki syndrome and intellectual disability. Recent studies have shown that certain genetic mechanisms that cause Kabuki syndrome can potentially be reversed. And groundbreaking research by a physician/scientist in Iceland has demonstrated that the intellectual disability caused by Kabuki syndrome might be able to be partially reversed as well. These new revelations have the potential to turn our entire paradigm of intellectual disability on its head.

Is Kabuki syndrome a treatable cause of intellectual disability? In the moments ahead, we will attempt to answer this question and speak with a researcher whose work has helped to drive these remarkable discoveries forward - coming up in just a few heartbeats. Don't go away.

Before we dive into this exciting research, I think it might be helpful to first establish what the term intellectual disability means. According to the American Association of Intellectual and Developmental Disabilities. Intellectual Disability occurs at the intersection of three specific criteria. limitations in intellectual functioning, which often manifests in an IQ below 70 behavioral limitations in adapting to environmental demands, which includes things like conceptual, social or practical self-care skills, and an early age of onset, or during what is known as the developmental period while the brain is still being formed, which is generally understood as being from the time of birth to the age of 22.

There are many causes of intellectual disability, and various risk factors that can exacerbate it. And all of these factors put individuals with intellectual disability at higher risk for many social and health-related vulnerabilities and disparities. This is especially true for people of color who have an intellectual disability. In a troubling recent example, it has been reported that having an intellectual disability was the highest independent risk factor for contracting COVID-19. Similarly, a recent study from a research group at Thomas Jefferson University found that people with intellectual disability are six times more likely to die of COVID-19 than other patients - they were even more at risk than people with congestive heart failure, kidney disease, or lung disease.

Beyond these disparities in health care, other studies have shown that these individuals are also more vulnerable to physical injury as well, and up to six times more likely to die in a fire, from a fall, or by drowning.

Intellectual disability also puts individuals and their families at higher risk of experiencing social and financial disparities like poverty. A 2007 study from the Institute for Health Research at Lancaster University in the UK, suggests that this is caused by a variety of factors. One factor is that exposure to poverty itself can accentuate intellectual disability. This disparity can also be caused by the financial and social impact on families caring for their loved one, and also by the exclusion of people with intellectual disabilities from the workforce.

All of this underscores both the importance of better supporting individuals who experienced intellectual disability and also how incredibly significant it would be if the disability experienced even a small portion of this population could be improved. For those individuals and their families, it would be life changing.

This is what's at stake in the research currently being done by a small, but growing group of researchers who have been hard at work to understand the causes of Kabuki syndrome and the intellectual disability that it causes. And at the forefront of this effort is Dr. Hans Bjornsson.

Dr. Hans Bjornsson  4:35 
How I got to Kabuki was a little bit of a coincidence.

Derren Raser  4:40 
Dr. Bjornsson is a physician/scientist who runs research labs, both in Iceland and at Johns Hopkins University here in the States. At Johns Hopkins he is Associate Professor of genetics and pediatrics, as well as Associate Director of the Epigenetics and Chromatin Clinic. He is also a full professor of translational medicine and pediatrics at the University of Iceland, and is director of clinical genetics there at the University Hospital. From early on in his career, there was something about genetics in particular, the grabbed him.

Dr. Hans Bjornsson  5:11 
I was convinced that I wanted to do nothing but genetics. At that time, genetics was not a very hot topic. It was kind of like this quirky, little, weird field.

Derren Raser  5:26 
He now spends most of his time researching Kabuki syndrome and related disorders. But his connection to Kabuki syndrome happened as the result of one door closing, and another one opening, along with a bit of a stroke of good luck.

When he arrived at his first clinical pediatric genetics fellowship, he was given time to explore research projects. At that time, his primary interest was in a rare genetic disorder called Rubistein Taybi syndrome. Unfortunately, no one else at his institution was connected to the disease, and so pursuing research in this area was not feasible. However, soon after this, by a stroke of good luck, while interacting with patients in the clinical setting, he encountered an individual that had Kabuki syndrome.

Dr. Hans Bjornsson  6:11 
That same week the gene discovery of Kabuki syndrome was announced, and I said, "you know, look, this is another disorder that we might be able to explore, and we could we worked on this." Kabuki is a bit subtle, some of the features. There used to be all these debates at the genetic meetings, whether Kabuki was a real disorder or not. People would say, "well, this is very nonspecific," and so forth. But having a specific gene kind of proved that there was this entity, there was this disorder.

Derren Raser  6:42 
The discovery of this new gene, along with a research connection a mentor at the hospital had to cardiac condition this patient in the clinic presented with, created an opening that Dr. Bjornsen gladly stepped into, and he hasn't looked back since.

Dr. Bjornsson's interest in Kabuki syndrome stemmed from the fact that it's part of a group of conditions known as Mendelian Disorders of the Epigenetic Machinery. Okay, that's certainly a mouthful. But, it's also central to why some aspects of Kabuki syndrome might be treatable. So let's take a minute to talk about what this term means and why it's important.

It might be helpful to start with the word epigenetics.

Dr. Hans Bjornsson  7:27 
Epigenetics kind of just means on the genes. The way I usually describe this for people is like, all the cells in the body have the same genome, but they use them differently. And one of the ways they achieve this is by highlighting the DNA. It kind of, like these little labels to help the DNA behave in the right manner.

Derren Raser  7:48 
Another metaphor that has been used to describe the human genome is that of a book. In this metaphor, our genome comprises the entire contents of a book, chapters and all. And on the other end of that spectrum is our DNA, which can then be thought of as representing every individual letter in that book. The only problem is, there are over 200 different types of cells in the body, and each one reads that DNA a little differently. So, how does the body ensure that though, quote, unquote, "text" is being interpreted in a consistent way? Well, as Dr. Bjornsson mentioned, the body does this by highlighting important areas that cells need to pay attention to. These highlights are known as epigenetic marks.

Dr. Hans Bjornsson  8:31 
It's not the only way that this is regulated, but epigenetics plays one role in kind of setting up which genes are active in which cell type.

Derren Raser  8:41 
As you can imagine, making sure that certain genes are active and being expressed in the right cell type is immensely important to the body developing and operating the way that it should.

Okay, now that we understand a little bit about epigenetics, let's pivot back to Kabuki syndrome and its connection to this process.

Dr. Hans Bjornsson  9:00 
In KMT2D, which is the cause of Kabuki syndrome type one, is kind of like a highlighting enzyme - it puts on these labels to mark DNA at certain sites.

Derren Raser  9:10 
So, you can think of the KMT2D Gene as a giant highlighter, making epigenetic marks on the DNA, helping cells know how to read the information. However, when there is a mutation in the KMT2D gene, which is often the cause of Kabuki syndrome, the gene gets confused, and it starts highlighting areas of the DNA that lead other cells to misinterpret the information and subsequently make mistakes.

Dr. Hans Bjornsson  9:37 
The kids that have Kabuki, or adults that have Kabuki, they have a mutation in a component of the machinery. So, it's a genetic problem that leads to an inability to maintain epigenetic marks.

Derren Raser  9:51 
 One thing that these highlighting marks effect are a mechanism in the cell called chromatin.

Dr. Hans Bjornsson  9:57 
Basically, the DNA is wrapped around histone proteins, there are these tails that stick out, and then you put this mark on locations where chromatin is supposed to be open.

Derren Raser  10:10 
One of the functions of chromatin is to help regulate the transcription process. In transcription, the genetic information stored in DNA is read by proteins, and then transcribed into RNA. Those RNA will later be translated into what's known as functional proteins. These proteins provide a structural framework for the body and help build the body's tissues, which makes these proteins an integral part of constructing a healthy body. So, you can think of chromatin as a kind of cellular gatekeeper, granting access to important DNA information. And they're either open to let proteins read this information, or they're closed, which denies those proteins access. It makes sense then, that having the right balance of open and closed chromatin in a cell is essential.

When a gene like KMT2D marks the wrong part of a strand of DNA, it can lead to these chromatin getting the wrong message, and in turn, changing the delicate balance of which ones are open and which ones are closed. And this imbalance can lead to a multitude of problems.

In Kabuki syndrome, Dr. Bjornson believes there's a connection between this epigenetic dysfunction and the intellectual disability that affected individual's experience.

Dr. Hans Bjornsson  11:29 
Epigenetics has something to do with growth, and it has something to do with normal intellect, and you need the epigenetic system to achieve that. What we don't know is we don't really know exactly when, or which cells. It could be that some of these things only are important during development, you know, early during pregnancy, or it could mean that some of the problems come because you don't have an active epigenetic system after birth. My research has been trying to get at this because the epigenetic machinery is active throughout your life, you keep making cells, you need an active epigenetic system to maintain those cells. And some of our research has been to try to see, is there a window of opportunity after birth that you could manipulate in some beneficial way to decrease the effect of the disorder?

Derren Raser  12:26 
Dr. Bjornsson says that the genes responsible for both types of Kabuki syndrome affect the body's ability to open up chromatin.

Dr. Hans Bjornsson  12:34 
The problem seems to be that you can't open up chromatin well.

Derren Raser  12:39 
His suspicion that this disruption in the epigenetic process in Kabuki syndrome was in some way leading to intellectual disability led him to put his theory to the test.

Dr. Hans Bjornsson  12:49 
We've focused our studies on something called the hippocampus. There's an area there, which is very cool, because you keep making neurons in that area throughout your life. The hippocampus is kind of a memory storage center of the brain.

Derren Raser  13:04 
The hippocampus is thought to play an important role in learning and memory, and is also involved in visual-spatial processing, and navigation. Something unique about the hippocampus is that, as you grow, this area of the brain continues to experience something called neurogenesis, which is the process by which new neurons continue to be formed in the brain. Dr. Bjornsen suspected that something about Kabuki syndrome was affecting this process.

Dr. Hans Bjornsson  13:33 
It was our hypothesis that maybe there was a disruption of this process, that you couldn't make as many neurons or you didn't make them correctly after birth. And that's exactly what we found. We made a mouse model of Kabuki syndrome, and when we looked at this area, the layer of cells seemed to be smaller in the Kabuki mice, compared to the other mice - there seemed to be less neurons being made.

Derren Raser  14:00 
This important discovery seemed to point to the mechanism by which some of the intellectual disability in Kabuki syndrome was being caused. And knowing the specific area of the brain that was being affected, gave Dr. Bjornsson, and his team, a valuable insight into where to focus their energies on trying to affect change. As the connection between an imbalance of chromatin and the reduced number of neurons present in the hippocampi of the Kabuki mice became clear, a question started to arise - was there an agent or a medication that could help the heightened number of closed chromatin present in Kabuki syndrome move back towards an open position?

Dr. Hans Bjornsson  14:38 
We use an agent called AR-42, which is a cancer drug. It's pretty good at opening up chromatin. It pushes the chromatin in general towards an open state. And we asked,  can we rescue this abnormality in the brain that we observe when we put them on this drug that would favor chromatin opening? Could we minimize some of the disease phenotypes with that strategy? And the answer to that is yes.

Derren Raser  15:05 
Let's take a moment to let that sink in.

The way he tested whether or not this treatment was effective was by comparing the brains of the genetically engineered Kabuki mice, both those that were treated in those that weren't with the brains of the untreated typical mice in their study. What they found was in the genetically altered Kabuki mice that have been treated with the medication, the layer of neurons in the hippocampus that originally had been diminished, now looked similar to the brains of the typical mice. This was an incredible breakthrough, but the next important undertaking was to see if this increase in hippocampal neurons translated to any meaningful improvement in the cognitive functioning of these mice.

Dr. Hans Bjornsson  15:47 
We followed that up by doing something called behavioral testing in the mice. So then we train the mice to do a task, and then we put them on a drug, and we see if they can do the task better or worse. And what we found is that the Kabuki's without drug did worse than the regular mice. But when we put them on the drug, they both did a little bit better, but now the Kabuki's we're no worse than the other mice. So, maybe there is some postnatal malleability. We can rescue this histological metric in their brain, and they seem to do better in these behavioral tasks.

Derren Raser  16:22 
This discovery seemed to offer clear evidence that by rescuing the imbalance of chromatin in these Kabuki mice, a more normal level of neurons in the hippocampus could be restored, and that, remarkably, this change could result in meaningful improvements in memory and learning.

As is often the case with animal trials, however, it was unknown if and how these results would translate to human patients. One challenge is a genetic one. Dr. Bjornsen says that the mice that were engineered for his study are all essentially genetically identical.

Dr. Hans Bjornsson  16:57 
They're like twins, they all have exactly the same genetic background. The only difference between them is this one Kabuki gene. So, it's kind of magnified on that background. When we look at patients, people have 20,000 other genes that interact with this change. So, there's more variation in people than there is in mice.

Derren Raser  17:20 
Beyond this genetic variability in human patients, there's another significant challenge specific to treating intellectual disability.

Dr. Hans Bjornsson  17:28 
One of the challenges with intellectual disability is it's harder to test than some other things. We've lacked robust ways to measure whether people are doing better and it's hard to know if something works if you don't have a good way to measure that. And that's why the work of people like Jacqueline Harris at KKI (Kennedy Krieger Institute) Baltimore, is so important because not only is she helping us understand strengths and weaknesses so that we can kind of build around individuals who Kabuki syndrome, but she's also developing outcome measures, things to measure during clinical trials.

Derren Raser  18:04 
The only way to know whether or not this treatment would be equally effective in people with Kabuki syndrome would be to conduct a human clinical trial. And I asked Dr. Bjornsen about that possibility.

Dr. Hans Bjornsson  18:15 
Absolutely. That's been our hope.

Derren Raser  18:17 
However, one clear barrier is that the cancer Dr. The Dr. Bjornsen and his team had used in the trial, AR-42, had side effects that made it less than ideal for use in human Kabuki patients. So, he started searching for another agent that might have similar results, but without some of the negative side effects. Things on this front have actually been moving pretty quickly. And since speaking with Dr. Bjornsen, not only have he and his team identified an FDA-approved drug that could be a candidate, they've also been able to partner with a drug company who is willing to move forward with a human clinical trial, which will soon be underway. This is very exciting news for Dr. Bjornsson's team and for the Kabuki community. But, for many rare disease researchers, finding a drug company that is willing to invest in developing a drug for such a small community is a persistent and significant challenge.

Dr. Hans Bjornsson  19:10 
They want to make some profit over time and if things are very rare, there's not going to be very many patients.

Derren Raser  19:17 
In response to this, one strategy that Dr. Bjornnson has employed is to make the case to drug companies of the broader ways that these breakthroughs might be employed outside of this small Kabuki syndrome community. He notes that there is a larger set of conditions called Mendelian Disorders of the Epigenetic Machinery, which I mentioned earlier, that all stem from similar dysfunctions in epigenetic machinery. There are over 40 of these disorders, and many of them share related phenotypes, or symptoms.

Dr. Hans Bjornsson  19:47 
There are problems with intellectual disability or developmental delay, and there's problems with growth, and those things are unified among all the different machinery disorders.

Derren Raser  19:57 
So, Dr. Bjornsson's argument has been that if you can create an effective treatment for one of these disorders, you might be able to use it as a treatment for many others. This would change the scope of the population that could benefit from a potential treatment from just a handful to potentially many more.

Dr. Hans Bjornsson  20:14 
My argument has been that maybe together all these disorders, they're not that rare. There's a lot of patients that have these. It's just rare for individual causes.

Derren Raser  20:25 
And in a landscape where profit drives research, having a larger pool of patients to use a drug makes research and development more attractive to big drug companies. This approach is becoming more widespread, as many small rare disease communities search for commonalities with each other, in order to increase their leverage in search of viable precision medicine treatments. But, challenges with getting drug companies to invest time and money into developing treatments for rare disorders, unfortunately, still remains a reality for most small rare disease communities.

One thing that sometimes happens in the midst of a study is the inadvertent discovery of an unexpected added benefit of a treatment. And something that is bringing further value to Dr. Bjornsson's research is the fact that he, and others,  have seen some interesting downstream treatment effects and benefits and other parts of the body as well.

Dr. Hans Bjornsson  21:16 
In addition to the therapeutic stuff, we've been able to make some kind of novel discoveries. We have seen that there are some phenotypes that are easy to measure that normalize. One of the things that we often see in the mice says that their spleen is very big. And what we see is that when we put them on treatment, the spleen size seems to get better. So, something is happening for the immune system.

Derren Raser  21:42 
Dr. Bjornsson also hopes that the groundbreaking results of his research, and these other potential treatment benefits, will motivate other scientists to become interested in Kabuki syndrome as a research area as well.

Dr. Hans Bjornsson  21:54 
And I think because of that evidence being available, I'm hoping more people will jump on the bandwagon. When I started, there was not very many people working on Kabuki syndrome. There's many more now. It's moving in the right direction and hopefully people can build upon what we've done. I've kind of been fortunate for the last eight years that I've been able to focus my efforts on Kabuki. I think it allows you to build upon what you've done and push forward.

Derren Raser  22:24 
The exciting discoveries that his research has yielded, also have the potential to start forcing the medical establishment to start rethinking their long held presumptions about intellectual disability.

Dr. Hans Bjornsson  22:35 
It's a dogma issue, I think. When I went to medical school, I was told that intellectual disability was something that happens in the womb, and is not treatable at birth. That was just kind of dogma. And I think because of that dogma, there's not a lot of people that have worked on this. I bet you there's going to be some disorders that are treatable, and others that are not. People often assume that intellectual disability is like a single box, that everyone is going to have the same limitations. But, it's not the case. Our hope is that our insights will lead to a better understanding of intellectual disability in general.

Derren Raser  23:19 
Embedded in Dr. Bjornnson's desire to help individuals with Kabuki syndrome is a realization that he's had through his experience in the clinical setting and with families.

Dr. Hans Bjornsson  23:28 
Kids with Kabuki are just amazingly pleasant and kind. They're very sociable, most of them, and they tend to do well because of that. It's a great strength that individuals with Kabuki have. We have people that are dancers, athletes. Kids with Kabuki and animals with Kabuki have many strengths that helped them throughout their life. And I've often just thought if you could just help them a little bit - it doesn't need a lot, just a little bit - it could just help them have a more fruitful life and take advantage of everything that's out there.

Derren Raser  24:00 
Together with all the discoveries Dr. Bjornsson and his team have made, one thing he's learned from the time he spent investing in this community is that sometimes the best teachers in this process are the people with Kabuki he comes in contact with and their families.

Dr. Hans Bjornsson  24:14 
I always tell people, when I go to these kind of patient organized meetings, I'm there to learn. Sometimes I'll learn things from the families that I can then give back to families that have younger kids or have questions that others have maybe been able to answer.

Derren Raser  24:31 
It's also in these person-to-person interactions that he's realized the importance of raising awareness, so that the breakthroughs he's been making in his lab can continue and hopefully translate to tangible benefits for patients.

Dr. Hans Bjornsson  24:44 
Every community needs to have some advocates, someone that cares about Kabuki syndrome. We need to raise awareness because if funders and companies and others knew about it, I think they're more likely to invest in it.

Derren Raser  25:00 
And while he certainly finds his research meaningful from a scientific perspective, Dr. Bjornsson says that the most rewarding aspects of his work are the relationships that he and his team have formed with the people in this small rare disease community.

Dr. Hans Bjornsson  25:13 
I think both myself and many people in the lab get quite motivated by interacting with the families. You know, I think that's been very meaningful for us. We get a lot of mail from people that have kids with Kabuki and I think that's been quite meaningful for not just myself, but my whole group.

Derren Raser  25:33 
Researchers like Dr. Bjornnson, who are researching rare diseases face an uphill battle in both finding continuing funding for the research, and also in getting drug companies on board for clinical trials and development of viable therapeutic treatments. Dr. Bjornsson also faces the additional and monumental task of trying to persuade the medical establishment to rethink the long-accepted dogma around intellectual disability, and to envision a new path forward - a path that includes treatment, and that can possibly be offered by what was once his small, quirky field of genetics.

Dr. Hans Bjornsson  26:08 
There's a lot of hope in genetics that we will not only be a diagnostic field, but we'll be a therapeutic field too. I think in the next decades, we'll have treatments for rare genetic disorders. There's definitely work that needs to be done there.

Derren Raser  26:24 
This research could offer life-changing therapies to individuals with rare diseases, especially for those with potentially treatable causes of intellectual disability, like Kabuki syndrome. Much of the funding that many of these research teams receive are from families, and from small dollar donors like you. As these therapies pushed forward, it's important that these researchers continue to receive support for their work. Please visit the One Rare Heart website for a link to support Dr. Bjornsson and his lab. Also, if you are an individual's Kabuki syndrome, or you know someone who is, and you are interested in taking part in the current clinical trials testing some of these therapies, you can find links and more information on the One Rare Heart website.

Supporting this research is important, but learning how to support individuals with intellectual disability is also something that we all need to know more about. The goal of this research is not to make people who are neurodivergent more quote, unquote, "typical," but rather to give them the tools to better express their individuality and uniqueness, and to help them better navigate and support themselves within the communities that they live. When we encounter someone who is different, like someone with intellectual disability, I think for many, the tendency is to hesitate or pull back just a little. The next time you encounter someone who is neurodiverse, I want to encourage you to try leaning in instead of pulling back. Try seeing these individuals with different eyes, and consider how you might better support them, affirm their dignity and individuality and value them as an important part of the community that we all share. I am very excited about Dr. Bjornson's research, and the research of those exploring similar paths forward. And the discoveries he's been making have enormous implications for the Kabuki syndrome community, as well as for the entire rare disease community as a whole. Will genetics become a therapeutic field, offering treatments to many rare disorders? Will these breakthroughs create meaningful change for some individuals with intellectual disabilities? And will the medical establishment change its long-held beliefs about intellectual disability and the efficacy and value of investing in this type of research? I certainly hope so. And hopefully, the answers to many of these questions are coming on the nearest horizon. In the meantime, it is my pleasure to be able to continue to share these journeys and experiences. And my hope is that the stories we explore in this space together will inspire and change you, as they've inspired and changed me.

All of the music included in today's episode are my original compositions, with the exception of the song you're listening to now, Heart of Mine, by my friend and amazing artist Erin Bode. Thank you for spending this time with me today. I'm Derren Raser and you've been listening to One Rare Heart.