Washington University School of Medicine & St. Louis Children’s Hospital Director of Rett Spectrum Clinic, Dr. Robin Ryther talks about stopping the progression of Rett Syndrome.
Interview conducted by Ivanhoe Broadcast News in 2023.
Tell me what Rett Syndrome is.
Ryther: Rett Syndrome is a genetic disorder that primarily affects girls because it’s on the X chromosome. It’s a whole-body disorder and so it affects everything from the brain to the heart and to their abilities to walk, to speak, to engage in the world in a typical way.
Are you born with it? When are you diagnosed with it? When do the symptoms start to appear?
Ryther: You are born with the changes that lead to Rett Syndrome, but you’re born otherwise looking normal to the rest of the world. Your parents are robbed of a healthy baby. Subtle symptoms typically begin in the four to six-month range and then they become more clearly obvious with low muscle tone and developmental challenges. Then the key marker is regression, which can typically happen from 18 months to about four to five years old. That’s usually what brings the most attention to them to help them get their diagnosis.
It seems like that happens with a lot of other diagnoses, they start to regress. Does it go not diagnosed for a while or a misdiagnose?
Ryther: It can frequently be missed. More and more we’re getting luckier because the approach to genetics has changed and so now they often use broad screening tests called whole-exome sequencing, which sometimes diagnoses them even before regression, which gives us even more opportunity to intervene.
Are these young children? Are they walking and talking and they stop, or do they never get to that point?
Ryther: In many cases, they might have a few words or it may just be babbling and then they tend to lose all of their speech and then in many cases, they’re walking but there are some who haven’t achieved walking yet, and that they’re considered delayed at that point.
What is life like for these kids?
Ryther: It varies dramatically. I think that it depends frequently on your age because there are a number of different phases that you go through. The first that we’ve been talking about is a pre-diagnosis or the pseudo-normal time period. Then there’s a period of developmental delay that is very non-specific. Then after that, when they regress is when they tend to have more substantial challenges that are very alarming and so they have communication difficulties because they can’t speak out loud and they also start to create some extra funny hand movements. Those are a little bit more unique for Rett syndrome, which I feel is seen in other disorders as well.
What are those?
Ryther: They have what’s called a typical ringing, but they might have some other movements, like extra rubbing or tapping but this movement tends to begin as they lose their normal hand function as well.
You said that makes it extremely difficult because they’re not talking?
Ryther: If we don’t do a verbal speech, then usually the next thing we teach someone is we teach sign language. But if you’re not able to use your hands correctly, you can’t learn sign language. If you aren’t even able to reach or have other challenges, then the next thing we would normally have taught you is to use buttons or switches or an iPad and then you can’t use that. But what they do have is this beautiful eye gaze. If you pay attention, they are talking to you with their eyes. They communicate incredibly strongly and it’s really almost a magical moment I think the first time you meet someone because you will have that sense that they’re trying to talk to you and you’re just trying to figure it out and so we take advantage of that eye gaze using different types of technology that exists now and was actually invented for strokes to let them use their eyes to progress across an electronic keyboard or switches and buttons to select what they want to say, and then the machine says it out loud for them.
And mentally these kids are not challenged?
Ryther: It’s a bell curve like it is for many things and there are certain challenges like epilepsy that may impact that answer, but many of them are normal or near normal or frankly ahead. These can be honor roll students, these can be students doing algebra, and these can be students who do have some more challenges. But what is usually missed is that answer and the fact that they are in there. People tend to dismiss them because they compare them to other disorders where they are also non-verbal, but they don’t have the same type of mental capabilities.
And so, to give them this ability to get their voice heard?
Ryther: It’s everything. It’s how their personality blossoms, it’s how they can communicate. It helps of course, with things like behavior, because you can only imagine how frustrating it would be to be underestimated and bored with everything they present to you. If you’re a normal typically developing seventh grader and someone’s trying to teach you colors because they haven’t learned how to listen, that’s not okay and doesn’t help. It’s the foundation of what most of our families are always hoping for, which is to hear their kids talk.
Did you develop this machine that you’re using on your phone?
Ryther: No. Again, it was actually initially developed for stroke patients and so there are brainstem strokes that take, again, a perfectly healthy adult who had a stroke and has left with minimal types of movements and only their face and so they can then use their eyes to move it across a screen to be able to select the same types of things.
Now you said this was a very exciting time for Rett syndrome and the treatment. What did you mean by that?
Ryther: We have now the first FDA-approved treatment for Rett syndrome, a drug called trofinetide or Daybue. We were one of the main sites that were part of the clinical trials that led to that approval. We are thrilled and excited because nobody yet knows what’s going to happen next for people and the natural history of Rett syndrome because we are hopeful that we’re about to change it forever.
How was it treated before?
Ryther: We treated it before by treating the symptoms as best we could. We supported them by providing them with equipment when they needed it to either stabilize their walking or a wheelchair. We help them communicate with augmentative communication technology. If they had seizures, we help them with their seizures. If they had sleep problems, we help them with that. We always focused on just the symptoms but this actually targets Rett syndrome itself. It targets the genetic changes that are being debilitated for these families and these patients and it’s not a cure, but it’s the first step and it’s a huge first step because it’s never happened before. What we know is that a fairly short trial overall. No one knows yet what 10 or 20 years of this drug will bring or what this drug will do to a patient that wasn’t regressed yet, who hasn’t lost that speech, can we preserve it? But I’m excited to find out because it’s a step we’ve never been able to offer before.
Do you know now that and is this a drug that’s taken daily?
Ryther: It’s a drug that is taken twice a day. It’s relatively safe overall though it does have a very significant side effect of diarrhea. That’s a little polar opposite to what we’re used to thinking about in Rett syndrome because most patients have some degree of constipation. It’s the opposite of what we’ve been talking about their whole lives. It can also have some vomiting and some weight loss but for the most part, it’s a relatively safe drug. We expect that they will probably need to be on it for years if not for life, but those are answers that no one has certain yet because this is really within weeks of that approval.
How young can you start them on this drug?
Ryther: The FDA approvals started at age two. We are certainly already in discussions about setting up research trials to think about younger than that both from first to safety standpoint and also well, what happens if you don’t technically have Rett syndrome yet because you haven’t regressed, can we stop that from happening, are we able to, in fact, stop the clock from ever moving forward in this direction, is it safe to do that, and what will happen next.
Is Rett a progressive disease?
Ryther: It is progressive in a sense because the changes that are there lead to a sequence of changes that happen over your lifespan. It’s not progressive in the sense that their brain is getting further poisoned or anything like that, which does happen in other types of disorders.
This drug stops the progression, it doesn’t turn the clock back, but it stops it?
Ryther: We don’t know the answer yet. It has actually turned the clock back for some. In the trials, which is a relatively short time period, there was an improvement in two different scales. One was a family-based scale and one was a physician-based scale. Both of these looked globally overall at the details of the patient. They looked at different elements and that will have significant improvement in both. But there are patients that it didn’t have an obvious impact. There were also patients that didn’t tolerate the diarrhea or the vomiting, that it was simply too much.
What did you see impacted?
Ryther: There are patients that also were what I think of as a super responders. We have one young woman, for example, who has regained verbal speech, and she has over 30 words now and she’s been on drugs for over two years, she’s been on it longer than the trial period itself because she’s been in what we call open-label now for a period of time. We’ve also seen some of our patients start to walk again or walk for the first time. We’ve seen patients who had lost their hand function now regain a pincer grasp and so they are starting to move forward. We also think in general that adding both the medication and intensifying their therapies, where they work with them either at school or in the private sector can amplify that effect because if you think about it, the brain needs to be retrained. If we’re giving the brain added boost to be able to help its function normally still have to learn how to do these things again. Adding extra therapy on top of the actual medication itself, we think actually makes us even more. Every patient is different but we think they’re more awake, more alert, more engaged, faster, and more responding. They tend to have pauses and things like their communication and that communication makes it even more challenging because if you’re also waiting for only their eyes to tell you the answer, but you look away before they answer you, then you’ll never see that answer. On the medication we’ve solved fairly commonly that that pause was short. That it went from 30 seconds to 40 seconds, to almost nothing. Families and teachers and therapists perceive that as being faster, quicker, better able to respond. Again, we saw in unique cases but multiple unique cases, even better results.
What’s that like? From a doctor’s standpoint, when you saw someone maybe lose their ability to do A and then.
Ryther: It’s earth-shattering. It’s why we do what we do. Not every physician ever gets a moment like this in their career where they get to start changing again the actual course of a disorder and we still aren’t done yet. We want a cure. We would like to eliminate Rett syndrome but from that standpoint, to be able to make a truly meaningful specific step forward like this, it’s incredible.
The little girl that we’re going to talk to, was she on this medicine?
Ryther: She’s not.
Is there a reason why they wouldn’t?
Ryther: The family at least didn’t initially try the medication. The medicine is not yet available. April 17th is when the medication will become widely available and the family and I have already had discussions about starting it. I can’t wait to find out what she does next.
Anything I’m missing?
Ryther: I think the other big picture thing to really remember is that with this whole body challenge, it’s really a partnership with not only the physicians and the families that we take care of, but their therapists who are local and are doing the everyday work. Their teachers in school, get them to believe in them, that there is more there to teach, as well as a number of different specialists. It’s an entire team that it really is taking to help take care of these families and their kids so that we can achieve their best outcome and that was before we had something like this to do. Now it’s only going to be even more so.
It’s really fun to see you just light up about this.
Ryther: It’s again, not everyone gets this moment. There are Rett doctors who have worked their entire careers and are retired now and they are watching this from afar.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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