Podcast: Seeing a Regressive Form of Down Syndrome From All Sides

Mother, scientist address challenges and share hope as collaborative study in research epicenter launches

Written by Chris Casey on November 9, 2022
What You Need To Know

Down Syndrome Regression Disorder is a neurological condition with severe symptoms, such as loss of speech and hallucinations. A new study, being led by researchers at the Linda Crnic Institute for Down Syndrome, will investigate the role of the immune system in DSRD as well as compare current treatments to find the most effective option.

Nine years ago, Miah Yager was an active, life-loving young woman who had made great strides overcoming Down syndrome symptoms when, very suddenly, she crashed. Linda Roan said her daughter changed from her “world-by-the-tail” self to someone completely different. She stopped talking to friends and family, started hallucinating and could no longer sleep, getting maybe an hour each night.

In many significant ways, Roan said, “she was gone.”

Miah and her family have since been riding a roller coaster with her debilitating condition – Down Syndrome Regression Disorder (DSRD) – and the cause of the rare disorder remains a mystery. But hope is emerging, thanks to a collaboration of scientists and physicians from the Linda Crnic Institute for Down Syndrome at the University of Colorado School of Medicine, the Anna and John J. Sie Center for Down Syndrome at Children’s Hospital Colorado, and Children’s Hospital Los Angeles.

The researchers are studying potential causes of DSRD as well as promising therapeutic approaches. The five-year, $5.3 million study, funded by a grant from the Eunice Kennedy Shriver National Institute for Child Health and Human Development, is a first-of-its-kind holistic investigation into DSRD.

“I think the evidence keeps on growing on this idea that the immune system may be involved and is attacking the brain,” said Joaquin Espinosa, PhD, executive director of the Linda Crnic Institute for Down Syndrome, one of the study’s multidisciplinary team leaders. “It may be one of the underlying causes of Down Syndrome Regression Disorder.”

In the episode of CU Anschutz 360 below, Espinosa and Roan talk about the challenges of DSRD – from the perspectives of research and caregiving, respectively – and the promise of this collaborative focus in Colorado, the global epicenter of Down syndrome research.

Thomas Flaig, MD, vice chancellor for research at the CU Anschutz Medical Campus, co-hosts the discussion.

Click below to listen to the full podcast:

 

 

Podcast Episode Transcript

Chris Casey 

My name is Chris Casey and I'm the director of digital storytelling in the Office of Communications here at CU Anschutz. Welcome everybody.

Joaquin Espinosa 

Thank you, Chris.

Linda Roan 

Thanks.

Thomas Flaig 

I'm Thomas Flaig and the vice chancellor for research here at the CU Anschutz Medical Campus.

Joaquin Espinosa 

I'm Joaquin Espinosa, the executive director of the Linda Crnic Institute for Down Syndrome here at the University of Colorado.

Linda Roan 

Hi. I'm Linda Roan and I'm the parent of Miah, who suffers from this condition we're going to be talking about today.

Chris Casey 

Well, again, thank you everybody for arising super early on a Halloween morning to talk about this important topic. Tom, would you like to ask the first question?

Thomas Flaig 

Absolutely. And I just say I'm really looking forward to this conversation today. This is an emerging topic which a lot of people are talking about and there's some great work being done here in Colorado on this. So just to kick things off, just a broad question. So what is Down Syndrome Regression Disorder and how can it affect anyone with Down syndrome?

Joaquin Espinosa 

Thanks, Tom, for the question. Down syndrome regression disorder, or DSRD as we refer to it, is a rare but devastating condition that affects some people with Down syndrome. Well, they basically crash, they lose a lot of their activities that they worked so hard to gain. They may lose speech, they may lose the ability to perform activities of daily living like dressing themselves or feeding themselves. Their sleep may get very dysregulated, they may lose sleep. It may get even worse and they may get hallucinations, de-personalization, something that may look to you like a case of schizophrenia, and so on and so forth. It used to be called other things in the past  – developmental regression, disintegrative disorder. More recently the field has agreed that the better name is Down Syndrome Regression Disorder, and it remains a diagnosis of exclusion. Meaning, you do a workup, Tom, and you realize that it cannot be that, it cannot be this – most likely is Down Syndrome Regression Disorder.

It can affect anyone with Down syndrome, but in order to be able to diagnose it properly, we are talking about the age range between late childhood, say, eight to 10 years old before a potential onset of Alzheimer's, say 30 to 40 years old. So in that range – say 8 years old to 40 years old – we can diagnose it with confidence. Beyond 40 years old, Tom, you know that people with Down syndrome, unfortunately, are highly predisposed to Alzheimer's disease, so we have to make sure that we don't confound those two conditions. Something that is very distinctive of Down Syndrome Regression Disorder is the acute onset. It happens very fast, wheras early onset Alzheimer's disease – it takes longer to take place.

Thomas Flaig 

So it might be true to say that this has been recognized by caregivers, by patients for a long period of time, but maybe in the last little bit of time, researchers, clinicians have defined it more clearly and given it a proper title, and we have a better understanding.

Joaquin Espinosa 

That is correct. Tom, you have to realize this is the first time in history that we have a sizable population of adults with Down syndrome that are receiving proper medical care. So for the first time in history, we are learning about the natural history of Down syndrome and learning about all the co-occurring conditions that are affecting them. Twenty, 30 years ago, we didn't have the opportunity to recognize Down Syndrome Regression Disorder. Now, as you just mentioned, this was out there in the community. Parents like Linda talked about it among themselves, engaged some professionals about it, but only now we have enough critical mass – enough people studying Down syndrome – to be able to recognize that this is a unique clinical entity.

Chris Casey 

Linda, could you explain your experience then with Down Syndrome Regression Disorder and your daughter Miah? When did you first notice her changing? As Joaquin mentioned, there's like a crash almost.

Linda Roan 

Yes, definitely. So Miah was a very happy, young, early 20-something, world by the tail, actually taking some college classes and we noticed that she started talking to herself a lot. Now, that's very common in Down syndrome. She'd talked to herself for years, but this had a different quality to it. It was very internal, and then we noticed the same phrases were being said all the time, and she didn't really want to engage with the family, she didn't want to engage with friends, became more and more internal. And then that talking became hallucinations, and she stopped sleeping. And when I say she stopped sleeping, I literally mean maybe one hour a night she'd get. Her father would stay up at night and rock her – we'd take turns. It was brutal. And we ended up very thankfully and luckily at the (Anna and John J.) Sie Center for Down Syndrome here at Children's Hospital (Colorado), and we started to get some help here. But they didn't know really what it was and it just got worse and worse.

And so for about 18 months, it was bad. I can't really even put the words on what that's like for a family to have your kid just – they're gone, she was gone. But then she came back, and she was really good almost to her old self, I'd say 95% there. And then six months after that, she crashed again. In one day – boom – hallucinations were back. So we've had that cycle. This is nine years. We've had that cycle several times. But because of the work that's being done with the Crnic center, CHLA (Children’s Hospital Los Angeles), her crashes aren't like before at all.

Thomas Flaig

Linda, to build on something Joaquin had commented on, when you first started dealing with this, I suppose the medical field maybe didn't have the sophistication around thinking about this on those initial visits.

Linda Roan 

That's correct. I mean they had seen it, they knew it was a thing. It meant so much to me when Miah’s psychiatrist at Children's Hospital (Colorado) here said, "Linda, this is a thing. We don't understand it completely, but it's a thing." But as time goes on, because at the time – now it's different here – but at (CU) Anschutz at the time, there wasn't a neurologist who actually studied this. So we ended up going to CHLA and met with a Dr. Santoro there who's now part of this research study with Dr. Espinosa, and that got us on a different track with it.

Thomas Flaig 

If you could talk a little bit about what we know about this, maybe on the medical or the developmental side. So what are the causes of this syndrome and disorder?

Joaquin Espinosa

We don't know, Tom, and that is part of this study that we're about to start (which is) funded by the National Institutes of Health. We know it has an acute onset. There's some data that is coming out soon in a publication we are working on suggesting that there are some specific triggers, a stressful event, potentially immune triggers. But we don't know exactly what's going on. However, because of a small amount of evidence about medicines that may be helping here in regression, which we will test very thoroughly in this study, we think there could be a very important component of the immune system in the onset of Down Syndrome Regression Disorder. So the short answer, Tom, is we don't know what causes it. We have some hypotheses that will be tested soon.

Chris Casey 

Joaquin, you mentioned the treatments that'll be looked at. Could you expound on that a bit – what these treatments will target, they'll target different areas?

Joaquin Espinosa

Correct. Historically, Down Syndrome Regression Disorder has been treated with psychiatric medicines trying to affect brain chemistry, brain function, hoping to attenuate or counteract some of the symptoms. But in the last 10 years or so, there's been more and more evidence supporting this idea that there may be an immune component. Something important to note about the clinical trial is that all three medicines that we will be testing have helped some people with Down Syndrome Regression Disorder. But at this point, we don't know who is going to benefit from which medicine. So in the trial, we're going to take the three medicines – a psychiatric medicine – benzodiazepine – and two immune therapies – and compare them side by side with a very rigorous protocol to see who could benefit from which medicine. Hopefully that will lead to better medical care for Down Syndrome Regression Disorder in the future.

Thomas Flaig

So that sounds fantastic, a well-described clinical trial, multiple arms looking at different mechanisms. So maybe I'll ask Linda to just comment. So it sounds like these are some medications that you've seen from your caregiver role, and now they're being enrolled in a clinical trial. I don't know if you've been enrolled in a clinical trial with your child or not, if you want to talk about that experience.

Linda Roan 

Yes, Miah was enrolled in the skin disorder trial that the Crnic center did (in 2020), and she does have a skin disorder, so she was a legitimate candidate. But in the back of my mind, the reason I wanted her in the trial, was to see if it would help her brain, and in fact it did. I mean, she's not had a major regression. As I said before, this is very cyclical. Think rheumatoid arthritis, you know, flares. She hasn't had a major flare since starting (the skin condition clinical trial) and she has had some little blips, but it's not the feed her by hand, put her in Depends – it's none of that. So we're thrilled.

Thomas Flaig 

So, I see a real progression here then from some basic understanding of the mechanism, to trying some drugs in different settings, to now converging in a formal clinical trial to look at these (treatments) better to better understand them.

Joaquin Espinosa 

Absolutely, Tom. This is a great example of a successful story of translating a basic discovery into clinical trials that are helping some of the participants, like Miah in this case. The basic discovery about the aspect of the immune system that is fully dysregulated in Down syndrome – we called it the interferon response – that was published in 2016, not that long ago. In 2020, four years later, we started to recruit participants into the clinical trial for the autoimmune skin conditions, based on that discovery. The first batch of participants in that first clinical trial taught us things, like in the case of Miah, that now lead to a second clinical trial and it's only been what, six years, seven years. So you see how basic science feeds clinical trials. Then if you do those clinical trials in a research-intensive fashion, they give you the data and the ideas to then follow-up with another trial, perhaps comparing medicines or going after a different co-occurring condition.

Thomas Flaig 

And do you want to comment – just to think about the scope and the impact of this disorder? So how many patients have this disorder? What's the percentage of perhaps Down syndrome individuals that experience this?

Joaquin Espinosa 

We don't have good data, Tom. Today, we think it may be in the single digits. But again, we don't have good epidemiology; we need to study more. I always like to say to my trainees that in biology and in medicine, everything is on a spectrum. We like to think of things as dual categories – with or without regression. I'd rather think about the possibility that there are a range of potential regression episodes out there – some of them may be unnoticed, they may not be so obvious, as the case that Linda was describing. So the answer is we don't know, but I remain open-minded that good epidemiology may reveal that this is more common than we are currently appreciating.

Chris Casey 

It seems like you hear occasionally of inflammation of the brain disorders and how severe they are. Is there any chance, Joaquin, that your study here could perhaps inform treatments or just different ways of looking at the problem of when the immune system attacks the brain?

Joaquin Espinosa 

Absolutely, Chris, you're right on target. If we had to place Down Syndrome Regression Disorder somewhere out there in the literature of the conditions affecting the general population, things that come to mind are autoimmune encephalitis, for example. It’s a condition where the immune system starts attacking the brain and is making antibodies that target proteins in the brain. But now that we are, I guess, in the aftermath of the COVID-19 pandemic, we are realizing that there are many neurological aspects of too much immune activity. And in the case of long COVID, many cases of long COVID have a neurological involvement – brain fog or even worse than that. So the answer is, yes, we believe very strongly that if we study Down Syndrome Regression Disorder, we'll be able to understand a lot more about how a hyperactive or dysregulated immune system may attack the brain or impair brain function in the general population, not just in Down syndrome.

Thomas Flaig 

So as you think about the developments are basic understanding of this disorder, this inflammatory overlay, what kind of basic work is being done in this area now to better understand it? And how might that inform future clinical investigations, this sort of thing?

Joaquin Espinosa 

Great. Thank you, Tom. So there is a portfolio of what we could call basic science studies around this phenomenon. All the way from animal models, we have mouse models of Down syndrome and now Dr. Michael Yeager at the Crnic Institute is developing a rat model of Down syndrome. So we can study some of these aspects there. These models, the mouse models, that have Down syndrome display hypersensitivity to immune stimulation. So if you trickle the immune system with viral mimetics or something that looks like a virus, they get very sick, they don't tolerate it. Of course, the models have Down syndrome and have cognitive impairments and other neurological phenotypes.

But we are also doing a lot of basic science studies with bio-specimens that we obtain from people with Down syndrome, with and without regression, and we use those bio-specimens to do a deep, deep study of the immune system and immune dysregulation. This is done through The Human Trisome Project, and a study that you are familiar with that we have here at the University of Colorado – one of the largest, deepest studies of Down syndrome out there. And I can share already with you that when we look at the cerebrospinal fluid of individuals with Down Syndrome Regression Disorder and when we look at the inflammatory markers in that cerebrospinal fluid, they look a lot, Chris, like inflammatory conditions affecting the brain in the general population – things like autoimmune encephalitis, multiple sclerosis, so on, so forth. So I think the evidence keeps on growing on this idea that the immune system may be involved and attacking the brain somehow as one of the underlying causes of Down syndrome regression disorder.

Thomas Flaig 

It's a really good example. This back and forth, this bench to bedside, and back to the bench. So those correlatives – patients on the clinical trials, samples will be collected, then going back in the laboratory for additional investigations be used with the models and so forth. That's a great model.

Joaquin Espinosa

Absolutely. We are great believers of research-intensive clinical trials. Of course, the main intent of the clinical trial is to test the medicine, to monitor the safety and the efficacy. But it is a golden opportunity, Tom, when families, with beloved ones with Down syndrome, when they come forth and they say, "Yes, we want to participate in research," you treat that as the most sacred moment in the enterprise. You make sure that that blood specimen, that electronic health record, that cerebrospinal fluid is treated as the precious entity that it is, and you extract all the information so that their contribution to the research has a big dividend, pays big dividends.

Thomas Flaig 

It's important to say that because I've done work in my career, too, with samples and those are so precious to gather those clinical specimens, how much (significance there is with) patients offering that gift, really, that we can study things. And it's important we say that out loud – that they're a very precious part of our research and we cherish those samples.

Linda Roan 

I might add, that, for me, when I think about my family situation and my daughter nine years ago, and this wasn't going on. Dr. Espinosa just spoke about how much has happened in such a short period of time. And when I think now about families that are beginning the journey with this – this is just starting and what's out there for them, that there are people to go to, there are trials to get in – it just warms my heart. It would've made all the difference for my family nine years ago.

Chris Casey

And I guess it's important to mention that Miah will not be taking part in the current study that is taking place that Dr. Espinosa mentioned.

Linda Roan 

Correct.

Chris Casey 

I'd like to ask you another question, Linda, and Joaquin, you can certainly jump in as well. We're only about two weeks away from a big event that happens every year as a benefit for Down syndrome research here in Denver. It’s called the “Be Beautiful, Be Yourself Fashion Show.” I'm sure you're very familiar with that.

Linda Roan 

Yes.

Chris Casey 

Can you just speak, Linda, as to how important that is as an event to helping just bring awareness to Down syndrome, awareness to research, and also raise money to keep the research robust and going?

Linda Roan 

Well, it is THE event. It's a lot of fun. It's something. But I think what we have here in Denver, I mean, this is the apex of research for Down syndrome goes on here – and Global is the foundation that's behind it all. Global – that’s the first word for a reason, because this is a global thing. So this event helps fund research and medical care for people with Down syndrome around the world, and there's nothing else like it.

Joaquin Espinosa 

I just second that, Chris. We cannot say enough good things about the Global Down Syndrome Foundation, which is a partner with the Crnic Institute for Down Syndrome and the Sie Center. We work together as a network of affiliate organizations, and they fund our work very generously. And we wouldn't be having this conversation today, we wouldn't be having these clinical trials, if it were not only for the philanthropic support of the Global Down Syndrome Foundation here at the Crnic Institute, but also the amazing advocacy working in Washington, D.C., that has led to the creation of the NIH INCLUDE project that has quadrupled the investment of NIH in Down syndrome. And it is the NIH INCLUDE project that is now funding this clinical trial that we're discussing this morning. So big kudos and a lot of gratitude to the Global Down Syndrome Foundation.

Thomas Flaig

I’ll just build those comments. Linda, I'm glad you brought that up because as you look at the research being done around Down syndrome, I would say that the work being done here by the Linda Crnic Institute and the Global Down Syndrome Foundation, there seems to be just this tremendous amount of work being done here. And I would say that the work being done here is recognized globally. Is that the partnership between the academics and the philanthropy with the patient advocacy involvement? What's the special part that’s come together here to make such great success?

Joaquin Espinosa 

You got it, Tom. It's the multiple legs of the stool, the synergy and the collaboration between one of the largest advocacy organizations in this space, the Global Down Syndrome Foundation, and what is now the largest academic center for Down syndrome research in the world, the Crnic Institute, and then the clinic, the Sie Center for Down Syndrome at Children's Hospital Colorado. So when the three parties work together – then we have other affiliates like the Alzheimer's and Cognition Center and the Adult Clinic at Denver Health – when everybody comes to the table and collaborates and works together, the sky is the limit.

And to come back to the example of the research, the Global Down Syndrome Foundation brings us in front of the community where we learn about what's happening in the community. But they also vouch for our studies, if you will, we gain trust from the community in our study. Something that for us in the ivory tower, Tom, would be difficult to do. But the reverse is also true, the Global Down Foundation brings us, the scientists, to Washington, D.C., so that we can explain the science to the members of Congress, so that we can work with our colleagues at NIH on educating the entire enterprise about what we see. So it's not one thing, it's a labor of love, a lot of work. But I would say, collaboration is the key word.

Thomas Flaig 

I mean, I love the word collaboration and why can't we talk about that in the science side, we think about basic scientists, clinical scientists, population scientists working together. And the special part of this and why I think there's such great impact, you've got the research community, the philanthropy community, the patient advocacy community, all coming together – even to make those national changes that you're talking about. I think it's just a really special thing.

Joaquin Espinosa 

I agree. I think what you are naming here is that the Crnic Institute has disrupted potential academic silos. We don't think in dualistic terms or basic science of clinical research. We are here to serve people with Down syndrome, and we do whatever it takes towards that end. And if we need to do a strong basic science, we do it. If we need to partner with strong clinical researchers, we do it. We just don't box ourselves into one silo.

Chris Casey

Well, this has been a fascinating conversation and I appreciate everybody's thoughts on this very important topic. And it's exciting to hear about this very significant clinical trial underway here on our campus being led by Joaquin and his team. And Linda, thank you so much. Do you have any more final thoughts about what you're hopeful for with Miah and where she's at these days? And could you just again tell us where she is?

Linda Roan 

Miah is doing well now. She's had this for nine years, so she's not the person that she was in the beginning, but she's happy, she's healthy, she has a job. Today is Halloween; she's excited about Halloween. She's going to be passing out candy on Pearl Street Mall in Boulder. So it's good, it's good. And my wish is that the progress that's been made in the last 10 years, that same percentage of progress can continue in the next 10 so that in another 10 (years), these questions really won't be questions, they'll be answers. And that is exciting.

Joaquin Espinosa 

Before we go, Chris, I want to make sure that I name some key protagonists in this enterprise. This is a clinical trial that will be funded by the Eunice Kennedy Shriver National Institute for Child Health and Human Development, what we call NICHD. And there are three principal investigators in the trial, I'm the contact principal investigator, but I'm blessed to be working side by side with Dr. Elise Sannar, a psychiatrist here in the Department of Psychiatry, also working at Children's Hospital Colorado, and Dr. Jonathan Santoro at Children's Hospital L.A. And we have a wonderful team of collaborators, Dr. Angela Rachubinski, Lina Patel, Ryan Kammeyer, Jessi Sanders. It takes a village, Tom and Chris, to do one of these projects. So I'm very, very grateful for all the scientists and clinicians that have joined the team.

Linda Roan 

I have a question: If I were a parent and I were listening to this and I was worried about my child or my young adult, what would I do to find out about getting in the trial?

Joaquin Espinosa 

Thank you, Linda, for the question. You can reach out to us here at the Linda Crnic Institute for Down Syndrome. If you go to any web browser and you put crnicinstitute.org, Crnic is C-R-N-I-C, crnicinstitute.org, you will get to our page, you will find our contact information, send us an email, leave a voicemail, and we'll get back to you.

Chris Casey

Great. Thank you for asking that, Linda, that's very important. Well, thanks again everybody for this early Halloween morning discussion. Linda, Joaquin, Tom, thank you very much and everybody have a great week.

Joaquin Espinosa

Thank you, Chris. Thank you, Tom.

Linda Roan 

Thank you.

Thomas Flaig 

Great to be here.

Joaquin Espinosa 

Thank you, Linda.

Linda Roan

Thank you.