Transcription:
Becoming an International Rett Syndrome Foundation Center of Excellence

Dr Hal Altman (Host): Welcome to Pediatric Insights, advances and innovations with Children's Health, where we explore the latest in pediatric care and research. Children's Health provides specialized care for patients diagnosed with Rett Syndrome and was recently designated as a center of excellence by the International Rett Syndrome Foundation.

Today, we'll find out how they achieved this designation and what it means for patients and families. I'm your host, Dr. Hal Altman. Our expert today, Dr. Dallas Armstrong, is a pediatric neurologist and Medical Director of the Rett and Related Disorders Clinic at Children's Health and is an Assistant Professor at UT Southwestern.

In today's discussion, Dr. Armstrong will share the diagnostic nuances of Rett syndrome. We'll review how Children's Health achieved the International Center of Excellence designation. We'll explore the challenges that Rett syndrome patients face, and we'll discuss the latest treatment strategies for Rett syndrome patients.

Dr. Armstrong, it's a pleasure to welcome you to the podcast.

Dr Dallas Armstrong: Thank you so much for having me.

Dr Hal Altman (Host): Rett syndrome is an uncommon but devastating disease that affects patients who are developmentally normal in their first few months of life. Dr. Armstrong, can you start by telling us about Rett syndrome, sharing its demographics, clinical features, and explaining its different classifications.

Dr Dallas Armstrong: Yes, I'd love to comment on that. Rett syndrome is a severe neurodevelopmental disease, as you mentioned, and it affects about one in 10,000 live births in girls. And it has these distinct clinical features. Now, I'm talking about classical Rett syndrome that are beautifully summarized in the 2010 revised diagnostic criteria that came out. Dr. Neul is the first author on that paper, and it's a wonderful resource for people. But there's these very core criteria of a partial or complete loss of acquired purposeful hand skills. Think things children could once do for themselves, suddenly they're totally unable to do those things; a partial or complete loss of the spoken language they once had; gait abnormalities can be loss of gait or an apractic gait, and these very stereotypic hand movements. The ones people are most familiar with are the midline hand ringing or squeezing. But there can certainly be a tapping. There can be tapping behind the back, not just at the midline. But as these hand movements begin is usually around the time of a regression where they start losing the skills that they once acquired.

The interesting thing about classical Rett syndrome is after that period of regression, children often stabilize and actually start to acquire new skills. So, part of what we do with families is usually people come to us after they've gotten this diagnosis. So, we're not doing as much with getting people diagnosed, that's something that's happening in their community. But when they come to us, part of what we're doing is really trying to optimize the development, minimize the regression if they're still in the regression phase and optimize development going forward.

Now, another thing I'd like to comment on, when you think about classical Rett syndrome and their clinical course, is we have these very clearly neurologic criteria of lost hand skills and walking and speaking, and these very clear midline hand stereotypies. But Rett syndrome affects many body systems. Many of the families I meet have taught me so much about how important the GI issues in Rett syndrome are. Many of these young ladies, when I'm thinking about classical Rett, have reflux, they have this air swallowing that really distends their belly and makes them uncomfortable. They have really difficult struggles with constipation. And for some children, the motor skills required to eat and chew will become progressively more difficult, so meals will take more and more time and it becomes very difficult for families to make sure that these young ladies are getting all the calories they need within a reasonable amount of time for each meal.

And another body system that is less troublesome to families in general, but is something we pay very close attention to, is their cardiac system because children with classical Rett syndrome are much more likely to have some cardiac abnormalities that can come and go. So, we screen them with an EKG, electrocardiogram, each year. And we also work very closely with Dr. Hoang Nguyen at Children's Health, who is a cardiologist with particular interest in Rett syndrome and is actually working on some research now, looking at factors that affect this atypical heart rhythm.

Additionally, people with Rett syndrome, especially classical Rett syndrome, have these paroxysms, these sudden episodes of abnormal breathing. For some children, it's very quick breathing. For other children, it's a breath holding that you don't notice until they let that breath out. So, they'll be quiet and still and then you'll hear "swoosh."

And for many of these children, there will also be this very interesting bruxism or tooth grinding that seems to be exacerbated whenever there are constipation flares or they feel very anxious. And to a varying degree, these young ladies will have real struggles with anxiety.

And one of the things we've been learning is that, as we're able to kind of ride the wave of technology advancements, we find that many of these young ladies who aren't able to express communication verbally and aren't able to use, for instance, sign language because of the hand stereotypies that occupy the movements of their hands. Once we use eye gaze devices for augmented communication, we find that there's so much that these young people want to say and communicate, and we find that their anxiety symptoms decrease as we're really aggressive at finding ways that work for them to actually help them express themselves.

And another interesting note about that is for many people with Rett syndrome, there's a subtle contribution of cortical visual impairment, which is hard to assess because they're not talking to us saying, "Oh, no, I can't see that" or "The edge of my vision is blurry," or any of those things. So, we have to design their augmented communication device, assuming that there's a component of cortical visual impairment. So, that we make the images that they're choosing between very rich and compelling and we set them up for success with their device. And all of these are just kind of a smattering of the various body systems affected by classical Rett syndrome and why it's so important to try to go systematically through the body systems for each patient and think about what we need to be screening for and how we can optimize the function of each of those systems.

Dr Hal Altman (Host): That's very interesting. I think we as providers have a tendency to really get into the weeds when it comes to diagnosis and looking at this purely as a neurologic issue. But it's the day to day activities and functions that really affect the kids and the families.

Dr Dallas Armstrong: That's so true.

Dr Hal Altman (Host): You have used the term classical. I assume then that there's a non-classical. Is that correct?

Dr Dallas Armstrong: Yes. And you know what's very interesting is when people were establishing these diagnostic criteria, it's important to remember that the state of genetic testing was very different at that time. So, it was a lot more of that Oliver Sacks in neurology is looking for these constellations of symptoms and really trying to parse out groups. So in that time, the scientific community that was interested in Rett syndrome were able to say this kind of classic quintessential Rett syndrome shares these features. But then, there's this atypical Rett syndrome that shares some main criteria, but not all of them, and that became a more broad umbrella.

And I'll talk about the various diagnoses that we now think of that fall under that atypical Rett designation in just a moment. But what's interesting is as people were doing that on the side, marching to the beat of its own drummer, was advancements in our understanding of the genetics in various neurologic disorders. And throughout those years, certain single gene disorders were discovered that we now realize comprised a large minority of the patients in atypical Rett syndrome. For instance, abnormalities in the FOXG1 gene give a clinical phenotype that shares a lot of characteristics with Rett syndrome and was called atypical Rett syndrome, but not all of them. And similarly, abnormalities in CDKL5 gene are very similar, but usually affect children much earlier. You don't usually have that early normal development time.

And there's some more single gene disorders that we're starting to see that can contribute to that body of patients who fall within atypical Rett syndrome. And then, we also see a subgroup of patients who have very classic abnormalities in the MECP2 gene, which is associated with classic or typical Rett syndrome, but also have something else, a second hit. You know, maybe they had some difficulties with birth and they suffered some brain injury around that in addition to their genetic change or they have a second genetic change. For instance, limb girdle muscular dystrophy, that changed their early development, so they never hit that criteria of early normal development.

And additionally, there are situations where, when you think about classic or typical Rett, you're often thinking of girls because the predominant population are females. But there are these two distinct, very interesting populations of boys, that we often see in our Rett clinics. One is a duplication where instead of not having enough of the MeCP2 protein, which is what we think of in classical Rett syndrome, they have too much. And one of the phrases that you sometimes hear is that MeCP2 is somewhat of a Goldilocks gene. If you don't have enough, it's a problem. If you have too much, it's a problem. And MeCP2 duplication syndrome predominantly affects young men and boys and shares some important features with Rett syndrome, but often has a severe early course, a very long battle with epilepsy.

And similarly, in children who are little boys, the MeCP2 gene resides on the X chromosome, which is an important comment to make. So for some children who are little boys and have only one copy of the MeCP2 gene and have a loss of function, not enough of the MeCP2 protein, just like in classical Rett, there's a much more severe phenotype because they don't have some component of some typical MeCP2 protein. And so, we also take care of little boys with that disorder in our clinic as well. So, it's a wide spectrum of individuals who fall within that umbrella of the Rett and related disorders clinic, and that's why.

Dr Hal Altman (Host): So of the patients that you care for in the clinic, what percentage are typical or classical and what percentage are non-typical?

Dr Dallas Armstrong: It's probably about a 70-30 split. We have a lot of patients who have typical Rett syndrome who have been very well cared for in their community. Many of them by my colleagues here at UT Southwestern, who by the way, taught me as a resident all about Rett syndrome. So, there was excellent care happening here long before we achieved this recent milestone of becoming a center of excellence.

And for those young people, often they come to our Rett clinic just once a year to be part of checking in on what's new in the world of research. And fairly soon, we're going to start having an ongoing registry study where if patients choose to contribute their de-identified data, they can be part of an ongoing repository of clinical information that researchers can then mine to look for important trends on things like the effects of anti-seizure medication on cardiac abnormalities, the effects of anti-seizure medications on one of the other very difficult symptoms of classical Rett syndrome, which are something that used to be called Rett spells. And now, we use the term Rett episodes, which are paroxysmal events that look so much like seizure that often children receive more and more and more seizure medications. And then, it turns out they're actually not seizure phenomenon. They're related to breathing dysrhythmias and anxiety and Rett syndrome. And we're starting to learn that some of our seizure medications also help with that symptom in a kind of a roundabout way. And so, we're really trying to understand that. And some patients will come to our clinic just to be part of that ongoing registry study, even though they're receiving excellent and Rett-informed care from their long-term neurologist.

Dr Hal Altman (Host): Very interesting. An International Center of Excellence designation is indeed a prestigious achievement. Can you guide us through the journey that you and your team traveled in pursuit of that designation?

Dr Dallas Armstrong: Yes. It is something we're very proud of and excited to be part of. The International Rett Syndrome Foundation decided that there needed to be a clear rubric to be a center of excellence in an effort to try to help families navigate their child to a place where they could feel very comfortable that everything that needed to be checked was being checked.

Now, this probably doesn't need saying there are many people providing care to people with Rett syndrome outside of a center of excellence who are doing a wonderful job. So, we don't think we have a monopoly on providing great care, just to be clear. But we did want to be part of jumping through those hoops and really doing the work to receive this certification because we wanted to be a place that families could find, especially when you think of a family who just got a new diagnosis and is going down the rabbit hole, reading online, feeling totally isolated. We wanted them to be able to find us and to come in and to see our clinic where we have so many team members who are very well versed in Rett syndrome.

So, the process honestly started as a dream. What would it take and how can we build it? And we were very lucky to have tons of programmatic support from leadership and some really great mentoring from the International Rett Syndrome Foundation team as well, who wanted us to be successful, which was a great feeling. And so, part of becoming a center of excellence involves having a well established network of specialists who are informed about Rett syndrome and are enthusiastic about taking care of these young ladies. It has to do with the support staff in the clinic, about a commitment to really follow the consensus guidelines for care in children with Rett syndrome.

Dr. Fu out of Vanderbilt was the first author in this beautiful consensus guidelines on managing Rett syndrome across the lifespan paper came out a couple of years ago and it's really well organized into age, so general neurologists, pediatricians can look and see these beautiful tables that tell you here's the health supervision checklist by age for children with Rett and related disorders. And part of becoming a Rett center of excellence was a commitment to make sure that we are doing all those things, we're doing the screening, and we're also taking the very Rett-informed history that lays the foundation for people who want to be part of the registry. But also, just last month, I had a patient who was a new patient to our Rett Center of Excellence. Their child have had Rett for many years was followed elsewhere and we were just doing our history. Does she have this? Does she have this? Does she ever do this? And for several of the questions, her mother would say things like, "I never knew that was a Rett thing." And by the end of the visit, there was this sense of just the questions were meaningful. So much Rett-specific knowledge was given to the family just in our question template, you know, and that just felt so good because Sydney Cooper is our research coordinator for the Rett center, and she and I did a lot of work on parsing out how to ask these and doing a lot of unglamorous type and delete and format, and to see it affect a family was very gratifying.

Dr Hal Altman (Host): Just to let them know that they're not alone.

Dr Dallas Armstrong: Yes. And to just have that lens of so many things where you say, "Oh, that's a Rett thing. I never knew." And your comment about letting families know they're not alone reminds me too that sometimes I think the most important thing that I do for a family in a new visit to the Rett clinic is honestly connecting them to the patient groups if they're not yet connected.

The International Rett Syndrome Foundation had a Rett Strollathon a couple weeks ago. And all these families came together from North Texas, some of them from outside of North Texas. And just seeing all these families together, it was very moving. And to do this walk and see all of the support and the children being celebrated and all these families with their team shirts on, it was very meaningful. And I remember thinking this may be the most important thing I do for families sometimes.

Dr Hal Altman (Host): So, is the center of excellence a regional resource, a national resource? How do you see yourselves?

Dr Dallas Armstrong: Well, the Centers of Excellence is a whole network nationally. But really, our draw is largely Texas and then the surrounding states. Houston has a lovely and well established center of excellence as well, and so families can kind of choose what makes the most sense for them as far as driving because driving with any child, I'm a parent, so driving a long way with any child is a commitment. I understand that. And certainly, driving a long way with a child with particular medical complexity is no small feat. So, we were really proud of that as well. When we think about our families in Oklahoma, who for years maybe had been driving to Houston for a Rett Center of Excellence, opening up our center, really cut those drive times. Took it from an overnight trip to a day trip. And it's not too glamorous, but it sure is meaningful.

Dr Hal Altman (Host): Well, thanks for sharing that. We've already touched on this, but are there specific challenges that Rett syndrome patients and their families encounter that we haven't discussed?

Dr Dallas Armstrong: We've hit on some of the bigger ones. But I would say if you think about typically developing children, all of those predictable challenges, growth spurts, sleep regression, lost skills after you've been sick with the flu, all of those issues, they're just amplified. And people with Rett syndrome and related disorder, all of those things get amplified. And additionally, I think we barely touched on it. But for many people, epilepsy and seizures are a really big part of their struggle. And for some children, those Rett episodes can look so much like seizures, that it becomes this murky water for families. Do we increase this medicine that might make her feel sleepy if we get too high or not, and trying to parse that out and use electroencephalograms, EEGs, effectively to find that out. It can be exhausting for families. And so, it's one of the things that we're very passionate about coming alongside families to wade them through. We really pride ourselves on our responsiveness. Families can send us videos of events and sometimes just the video alone is enough to be very definitive. And so, that can save children an admission and an EEG. So, we really try to work through that with families and check their blood levels of their medications in a way to optimize the seizure medicines while avoiding being overly sedated to try to minimize their pill burden and all that side effect profile to help them live a life that's unencumbered by their epilepsy. And that's something we're really passionate about as well.

Dr Hal Altman (Host): Sure. Can you share some of the latest treatment strategies for Rett syndrome patients and maybe comment on hope for future treatment?

Dr Dallas Armstrong: For a long time, the cutting edge treatments for Rett syndrome involved what not to do. It involved trying to optimize seizure meds and not to overmedicate. And it involved using formulations of seizure meds that could be once daily or one of our medicines comes in like a Listerine breath strip type of formulation, and sometimes that was helpful for young ladies. It was very unglamorous and people had been doing really good work with that.

Recently, there are some advancements, coming in March, which is really coming up. There is a new medication that's going to become prescribable from Acadia Pharmaceuticals called trofinetide. And it's actually a synthetic version of this amino-terminal tripeptide to the insulin-like growth factor-1 that we know is involved in the cascade of how the MeCP2 protein affects the brain. And that is very exciting in the Rett community, because there hasn't been a Rett-specific intervention yet. So, this is very exciting. There's some other things coming that we are hoping to become sites for, but that are not yet, something I can discuss, but it's coming and it's exciting. And there are certainly several labs that are really looking carefully at gene therapy and they're looking at ways to deliver the genetic code for the MeCP2 protein that's missing, and to teach the body how to read that recipe as it were, rather than the abnormal one that the child was born with. And that stuff is so exciting. I mean, I remember being in medical school and hearing people talk about gene therapy and really thinking it was science fiction. And to think that this is something that in my lifetime and in so many of my patients' lifetime is going to become available, it just gives you chills. It's very exciting.

Dr Hal Altman (Host): Absolutely. I couldn't agree with you more. So in closing, Dr. Armstrong, is there anything else that you'd like to share with the audience about the Rett Syndrome and Related Disorders Clinic at Children's Health?

Dr Dallas Armstrong: Yes. I think it's important to share with physicians and families alike that when we created this clinic, we really were thinking of serving kind of three buckets as it were of patients. So, one is what we've already talked about, families who just got a diagnosis, who are reeling, who find their way to the international Rett Syndrome Foundation resources, and find a center of excellence clinic. And they have this moment, I hope, and I dream they have this moment of feeling that weight of responsibility that parents feel, like "I have to find the right thing for my child and they feel it lift." There's a center of excellence. We can get her there. We're going to get him seeing her seen in this clinic. So, that's bucket one.

Bucket two is another set of patients that I've mentioned, children who are just exquisitely well cared for, currently happy and responsibly cared for by their neurologist who just would love to get connected with a Rett center of excellence to hear about any changes in the field as far as research and upcoming research opportunities, and to consider lending their clinical information anonymously to the registry to help future researchers understand more and more about improving the life of children with Rett syndrome.

And then, the third bucket we haven't talked about yet is, in patients who to a point have been doing really well in their current care setting, but have hit one of those stormy moments and they can happen in Rett syndrome, especially when I think about classical Rett syndrome, where seizures just get really hard to manage sometimes. And they really are in a place where the patient and the physician think, "Boy, I wish we had another set of eyes. I wish I had someone else to bounce some ideas off of and try to come up with a good next step for this patient." We really want to be a resource in that way and are happy to talk with physicians and just what we call curbside, just to talk about the case, we're happy to do all of that. We really want to be a resource for all people with Rett that can reach us and all of their physicians. We really want to try to improve the experience of people with Rett syndrome and related disorders, and also be part of through the research efforts moving towards cure, which again, we could see that light, we could see it coming. The question is how and when and how quick. But it's a very exciting time to be in this field and I'm so thankful for the opportunity to talk about it.

Dr Hal Altman (Host): Well, thanks for sharing all that. It's just absolutely wonderful and inspiring when you meet somebody that has the kind of passion that you have and being able to connect it with the expertise that you have as well. So, thanks so much Dr. Armstrong, and to our audience for participating in today's Pediatric Insights, advances in innovations and Rett syndrome with Children's Health.

Providers can gain more information about the Rett Syndrome and Related Disorders Clinic at Children's Health by visiting the website at www.childrens.com/neurology. For updates on the latest on pediatric medical advances, breakthroughs, and research, please follow us on your social channels. You are warmly invited to subscribe, rate, and review this podcast and all other podcasts from Children's Health. Goodbye and thanks again for listening to Pediatric Insights, advances and innovations with Children's Health.